{
 "source": "PubTator",
 "date": "2021-11-30",
 "key": "BioC.key",
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   "id": "10491763",
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    {
     "offset": 0,
     "text": "Hepatocyte nuclear factor-6: associations between genetic variability and type II diabetes and between genetic variability and estimates of insulin secretion.",
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       "infons": {
        "identifier": "3175",
        "type": "GeneOrGeneProduct"
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       "text": "Hepatocyte nuclear factor-6",
       "locations": [
        {
         "offset": 0,
         "length": 27
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       "id": "1",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type II diabetes",
       "locations": [
        {
         "offset": 74,
         "length": 16
        }
       ]
      },
      {
       "id": "2",
       "infons": {
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       "text": "insulin",
       "locations": [
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         "offset": 140,
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     "text": "The transcription factor hepatocyte nuclear factor (HNF)-6 is an upstream regulator of several genes involved in the pathogenesis of maturity-onset diabetes of the young. We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects.   We cloned the coding region as well as the intron-exon boundaries of the HNF-6 gene. We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants. An identified missense variant was examined in association studies and genotype-phenotype studies.   We identified two silent and one missense (Pro75 Ala) variant. In an association study the allelic frequency of the Pro75Ala polymorphism was 3.2% (95% confidence interval, 1.9-4.5) in 330 patients with Type II diabetes mellitus compared with 4.2% (2.4-6.0) in 238 age-matched glucose tolerant control subjects. Moreover, in studies of 238 middle-aged glucose tolerant subjects, of 226 glucose tolerant offspring of Type II diabetic patients and of 367 young healthy subjects, the carriers of the polymorphism did not differ from non-carriers in glucose induced serum insulin or C-peptide responses.   Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined.",
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       "text": "hepatocyte nuclear factor (HNF)-6",
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         "offset": 184,
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       "id": "4",
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       "text": "maturity-onset diabetes",
       "locations": [
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       "id": "5",
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        "identifier": "3175",
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       "text": "HNF-6",
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         "offset": 389,
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       "id": "6",
       "infons": {
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       "text": "Type II (non-insulin-dependent) diabetes mellitus",
       "locations": [
        {
         "offset": 430,
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       "id": "7",
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       "text": "insulin",
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       "text": "glucose",
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       "id": "9",
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        "identifier": "3175",
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       "text": "HNF-6",
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       "text": "MODY",
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       "text": "MODY4",
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       "text": "patients",
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       "id": "15",
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       "text": "Type II diabetes",
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       "id": "16",
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        "identifier": "rs74805019",
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       "text": "Pro75 Ala",
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       "text": "Pro75Ala",
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       "text": "Type II diabetes mellitus",
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       "text": "glucose",
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       "text": "glucose",
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       "text": "glucose",
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       "text": "Type II diabetic",
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       "text": "insulin",
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       "text": "C-peptide",
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       "text": "HNF-6",
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       "infons": {
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       "text": "Type II diabetes",
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       "id": "30",
       "infons": {
        "identifier": "3630",
        "type": "GeneOrGeneProduct"
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       "text": "insulin",
       "locations": [
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         "offset": 1738,
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       ]
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       "id": "31",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "glucose",
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      "novel": "No"
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  {
   "id": "10661407",
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    {
     "offset": 0,
     "text": "Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules.",
     "annotations": [
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       "infons": {
        "identifier": "50489",
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       "text": "Langerin",
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       "id": "1",
       "infons": {
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       "text": "C-type lectin",
       "locations": [
        {
         "offset": 18,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 135,
     "text": "We have identified a type II Ca2+-dependent lectin displaying mannose-binding specificity, exclusively expressed by Langerhans cells (LC), and named Langerin. LC are uniquely characterized by Birbeck granules (BG), which are organelles consisting of superimposed and zippered membranes. Here, we have shown that Langerin is constitutively associated with BG and that antibody to Langerin is internalized into these structures. Remarkably, transfection of Langerin cDNA into fibroblasts created a compact network of membrane structures with typical features of BG. Langerin is thus a potent inducer of membrane superimposition and zippering leading to BG formation. Our data suggest that induction of BG is a consequence of the antigen-capture function of Langerin, allowing routing into these organelles and providing access to a nonclassical antigen-processing pathway.",
     "annotations": [
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       "id": "2",
       "infons": {
        "identifier": "50489",
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       "text": "type II Ca2+-dependent lectin",
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       "id": "3",
       "infons": {
        "identifier": "D008358",
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       "text": "mannose",
       "locations": [
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         "length": 7
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       "infons": {
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       "text": "Langerin",
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       "text": "Langerin",
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       "text": "Langerin",
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       "text": "Langerin",
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       "text": "Langerin",
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       "id": "9",
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        "identifier": "50489",
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       "text": "Langerin",
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   ]
  },
  {
   "id": "10788334",
   "passages": [
    {
     "offset": 0,
     "text": "Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
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       "text": "BRCA1",
       "locations": [
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       "id": "1",
       "infons": {
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       "text": "breast-ovarian cancer",
       "locations": [
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    {
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     "text": "We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population. The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age < 50 years. A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only. Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family. The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants. Mutations were found in 35 (53%) of the 66 families studied. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; five of these occurred in two or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Three BRCA1 abnormalities - 5382insC, C61G, and 4153delA - accounted for 51%, 20%, and 11% of the identified mutations, respectively.. ",
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       "text": "BRCA1",
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       "text": "cancer",
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       "text": "breast or ovarian cancer",
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       "text": "cancer",
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       "id": "7",
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        "identifier": "D001943,D010051",
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       "text": "breast and ovarian cancers",
       "locations": [
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         "offset": 474,
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       ]
      },
      {
       "id": "8",
       "infons": {
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       "text": "ovarian cancers",
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       "text": "breast cancers",
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       "text": "woman",
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       "text": "BRCA1",
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       "text": "BRCA2",
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       "id": "13",
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        "identifier": "672",
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       "text": "BRCA1",
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       "id": "14",
       "infons": {
        "identifier": "OMIM:604370",
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       "text": "BRCA1 abnormalities",
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       "id": "15",
       "infons": {
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       "text": "ovarian cancer",
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        "identifier": "D001943,D010051",
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       "text": "breast and ovarian cancer",
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       "text": "breast cancer",
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        "identifier": "675",
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       "text": "BRCA2",
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       "text": "breast-ovarian cancer syndrome",
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       "infons": {
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       "text": "BRCA1 abnormalities",
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       "id": "21",
       "infons": {
        "identifier": "c|INS|5382|C",
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       "text": "5382insC",
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         "length": 8
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       "infons": {
        "identifier": "rs28897672",
        "type": "SequenceVariant"
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       "text": "C61G",
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         "offset": 1480,
         "length": 4
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       "id": "23",
       "infons": {
        "identifier": "c|DEL|4153|A",
        "type": "SequenceVariant"
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       "text": "4153delA",
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         "offset": 1490,
         "length": 8
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     "text": "BACKGROUND: The calcineurin inhibitors cyclosporine and tacrolimus are both known to be nephrotoxic. Their use in orthotopic liver transplantation (OLTX) has dramatically improved success rates. Recently, however, we have had an increase of patients who are presenting after OLTX with end-stage renal disease (ESRD). This retrospective study examines the incidence and treatment of ESRD and chronic renal failure (CRF) in OLTX patients. METHODS: Patients receiving an OLTX only from June 1985 through December of 1994 who survived 6 months postoperatively were studied (n=834). Our prospectively collected database was the source of information. Patients were divided into three groups: Controls, no CRF or ESRD, n=748; CRF, sustained serum creatinine >2.5 mg/dl, n=41; and ESRD, n=45. Groups were compared for preoperative laboratory variables, diagnosis, postoperative variables, survival, type of ESRD therapy, and survival from onset of ESRD. RESULTS: At 13 years after OLTX, the incidence of severe renal dysfunction was 18.1% (CRF 8.6% and ESRD 9.5%). Compared with control patients, CRF and ESRD patients had higher preoperative serum creatinine levels, a greater percentage of patients with hepatorenal syndrome, higher percentage requirement for dialysis in the first 3 months postoperatively, and a higher 1-year serum creatinine. Multivariate stepwise logistic regression analysis using preoperative and postoperative variables identified that an increase of serum creatinine compared with average at 1 year, 3 months, and 4 weeks postoperatively were independent risk factors for the development of CRF or ESRD with odds ratios of 2.6, 2.2, and 1.6, respectively. Overall survival from the time of OLTX was not significantly different among groups, but by year 13, the survival of the patients who had ESRD was only 28.2% compared with 54.6% in the control group. Patients developing ESRD had a 6-year survival after onset of ESRD of 27% for the patients receiving hemodialysis versus 71.4% for the patients developing ESRD who subsequently received kidney transplants. CONCLUSIONS: Patients who are more than 10 years post-OLTX have CRF and ESRD at a high rate. The development of ESRD decreases survival, particularly in those patients treated with dialysis only. Patients who develop ESRD have a higher preoperative and 1-year serum creatinine and are more likely to have hepatorenal syndrome. However, an increase of serum creatinine at various times postoperatively is more predictive of the development of CRF or ESRD. New strategies for long-term immunosuppression may be needed to decrease this complication.",
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       "text": "calcineurin",
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       "text": "cyclosporine",
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       "text": "nephrotoxic",
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       "text": "end-stage renal disease",
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       "text": "renal dysfunction",
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  {
   "id": "12442272",
   "passages": [
    {
     "offset": 0,
     "text": "D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs80265967",
        "type": "SequenceVariant"
       },
       "text": "D90A",
       "locations": [
        {
         "offset": 0,
         "length": 4
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       ]
      },
      {
       "id": "1",
       "infons": {
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       "text": "SOD1",
       "locations": [
        {
         "offset": 5,
         "length": 4
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       ]
      },
      {
       "id": "2",
       "infons": {
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       "text": "amyotrophic lateral sclerosis",
       "locations": [
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         "length": 29
        }
       ]
      }
     ]
    },
    {
     "offset": 157,
     "text": "More than 100 different heterozygous mutations in copper/zinc superoxide dismutase (SOD1) have been found in patients with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Uniquely, D90A-SOD1 has been identified in recessive, dominant and apparently sporadic pedigrees. The phenotype of homozygotes is stereotyped with an extended survival, whereas that of affected heterozygotes varies. The frequency of D90A-SOD1 is 50 times higher in Scandinavia (2.5%) than elsewhere, though ALS prevalence is not raised there. Our earlier study indicated separate founders for recessive and dominant/sporadic ALS and we proposed a disease-modifying factor linked to the recessive mutation. Here we have doubled our sample set and employed novel markers to characterise the mutation's origin and localise any modifying factor. Linkage disequilibrium analysis indicates that D90A homozygotes and heterozygotes share a rare haplotype and are all descended from a single ancient founder (alpha 0.974) c.895 generations ago. Homozygotes arose subsequently only c.63 generations ago (alpha 0.878). Recombination has reduced the region shared by recessive kindreds to 97-265 kb around SOD1, excluding all neighbouring genes. We propose that a cis-acting regulatory polymorphism has arisen close to D90A-SOD1 in the recessive founder, which decreases ALS susceptibility in heterozygotes and slows disease progression.",
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       "text": "copper/zinc superoxide dismutase",
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       "text": "amyotrophic lateral sclerosis",
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       "text": "ALS",
       "locations": [
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         "offset": 311,
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       ]
      },
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       "id": "8",
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       "text": "neurodegenerative disease",
       "locations": [
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         "length": 25
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs80265967",
        "type": "SequenceVariant"
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       "text": "D90A",
       "locations": [
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         "offset": 362,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "6647",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD1",
       "locations": [
        {
         "offset": 367,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs80265967",
        "type": "SequenceVariant"
       },
       "text": "D90A",
       "locations": [
        {
         "offset": 585,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "6647",
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       },
       "text": "SOD1",
       "locations": [
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         "offset": 590,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D000690",
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       },
       "text": "ALS",
       "locations": [
        {
         "offset": 659,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000690",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALS",
       "locations": [
        {
         "offset": 777,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs80265967",
        "type": "SequenceVariant"
       },
       "text": "D90A",
       "locations": [
        {
         "offset": 1041,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "6647",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD1",
       "locations": [
        {
         "offset": 1346,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs80265967",
        "type": "SequenceVariant"
       },
       "text": "D90A",
       "locations": [
        {
         "offset": 1459,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "6647",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD1",
       "locations": [
        {
         "offset": 1464,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D000690",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALS",
       "locations": [
        {
         "offset": 1511,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "6647",
      "entity2": "D000690",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs80265967",
      "entity2": "D000690",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "1353340",
   "passages": [
    {
     "offset": 0,
     "text": "Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D007966",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "metachromatic leukodystrophy",
       "locations": [
        {
         "offset": 11,
         "length": 28
        }
       ]
      }
     ]
    },
    {
     "offset": 78,
     "text": "We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD.. ",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "410",
        "type": "GeneOrGeneProduct"
       },
       "text": "arylsulfatase A",
       "locations": [
        {
         "offset": 111,
         "length": 15
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "410",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARSA",
       "locations": [
        {
         "offset": 128,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D007966",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "metachromatic leukodystrophy",
       "locations": [
        {
         "offset": 159,
         "length": 28
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D007966",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MLD",
       "locations": [
        {
         "offset": 189,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "rs74315458",
        "type": "SequenceVariant"
       },
       "text": "arginine84",
       "locations": [
        {
         "offset": 210,
         "length": 10
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "410",
        "type": "GeneOrGeneProduct"
       },
       "text": "arylsulfatase",
       "locations": [
        {
         "offset": 264,
         "length": 13
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007966",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MLD",
       "locations": [
        {
         "offset": 363,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs74315458",
        "type": "SequenceVariant"
       },
       "text": "arginine84 to glutamine",
       "locations": [
        {
         "offset": 372,
         "length": 23
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "410",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARSA",
       "locations": [
        {
         "offset": 442,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "410",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARSA",
       "locations": [
        {
         "offset": 484,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 562,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D007966",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MLD",
       "locations": [
        {
         "offset": 576,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "410",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARSA",
       "locations": [
        {
         "offset": 655,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D007966",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MLD",
       "locations": [
        {
         "offset": 712,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "410",
      "entity2": "D007966",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs74315458",
      "entity2": "D007966",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "14722929",
   "passages": [
    {
     "offset": 0,
     "text": "Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 17,
         "length": 8
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 37,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 80,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 95,
     "text": "A large proportion of non-syndromic autosomal recessive deafness (NSARD) in many populations is caused by variants of the GJB2 gene. Here, the frequency of GJB2 variants was studied in 406 and 183 apparently unrelated children from Kenya and Sudan, respectively, with mostly severe to profound non-syndromic deafness. Nine (2.2 %) Kenyan and 12 (6.6 %) of the Sudanese children only were carriers of variants within the coding sequence of the GJB2 gene. Variants in the 5'-adjacent region were detected in further 115 individuals. A total of 10 novel variants was recognized, among them four variants in the adjacent 5'-region of the GJB2 coding exon 2 (g.3318-6T>A, g.3318-15C>T, g.3318-34C>T, g.3318-35T>G), a 6 base-pair deletion (g.3455_3460del [p.Asp46_Gln48delinsGlu]), a variant leading to a stop codon (g.3512C>A [p.Tyr65X]), synonymous variants (g.3395C>T [p.Thr26], g.3503C>T [p.Asn62], g.3627A>C [p.Arg104]), and one non-synonymous variant (g.3816C>A [p.Val167Met]). In addition, the previously described variants g.3352delG (commonly designated 30delG or 35 delG), g.3426G>A [p.Val37Ile], g.3697G>A [p.Arg127His], g.3774G>A [p.Val153Ile], and g.3795G>A [p.Gly160Ser] were identified. With the exception of g.3318-34C>T and g.3352delG, all variants occurred heterozygously. For most of the variants identified in the Kenyan and Sudanese study population, a causative association with NSARD appears to be unlikely. Compared to many other ethnic groups, deafness-associated variants of the coding region of GJB2 are rare in Sudan and Kenya, suggesting a role of other genetic, or epigenetic factors as a cause for deafness in these countries.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "C567134",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "non-syndromic autosomal recessive deafness",
       "locations": [
        {
         "offset": 117,
         "length": 42
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C567134",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NSARD",
       "locations": [
        {
         "offset": 161,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 217,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 251,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "non-syndromic deafness",
       "locations": [
        {
         "offset": 389,
         "length": 22
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 538,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 729,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "g|SUB|T|3318-6|A",
        "type": "SequenceVariant"
       },
       "text": "g.3318-6T>A",
       "locations": [
        {
         "offset": 749,
         "length": 11
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "g|SUB|C|3318-15|T",
        "type": "SequenceVariant"
       },
       "text": "g.3318-15C>T",
       "locations": [
        {
         "offset": 762,
         "length": 12
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "g|SUB|C|3318-34|T",
        "type": "SequenceVariant"
       },
       "text": "g.3318-34C>T",
       "locations": [
        {
         "offset": 776,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "g|SUB|T|3318-35|G",
        "type": "SequenceVariant"
       },
       "text": "g.3318-35T>G",
       "locations": [
        {
         "offset": 790,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "g|DEL|3455_3460|",
        "type": "SequenceVariant"
       },
       "text": "g.3455_3460del",
       "locations": [
        {
         "offset": 829,
         "length": 14
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "p|INDEL|46_48|Glu",
        "type": "SequenceVariant"
       },
       "text": "p.Asp46_Gln48delinsGlu",
       "locations": [
        {
         "offset": 845,
         "length": 22
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs763572195",
        "type": "SequenceVariant"
       },
       "text": "g.3512C>A",
       "locations": [
        {
         "offset": 906,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs763572195",
        "type": "SequenceVariant"
       },
       "text": "p.Tyr65X",
       "locations": [
        {
         "offset": 917,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "g|SUB|C|3395|T",
        "type": "SequenceVariant"
       },
       "text": "g.3395C>T",
       "locations": [
        {
         "offset": 950,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "p|Allele|T|26",
        "type": "SequenceVariant"
       },
       "text": "p.Thr26",
       "locations": [
        {
         "offset": 961,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "g|SUB|C|3503|T",
        "type": "SequenceVariant"
       },
       "text": "g.3503C>T",
       "locations": [
        {
         "offset": 971,
         "length": 9
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "p|Allele|N|62",
        "type": "SequenceVariant"
       },
       "text": "p.Asn62",
       "locations": [
        {
         "offset": 982,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "g|SUB|A|3627|C",
        "type": "SequenceVariant"
       },
       "text": "g.3627A>C",
       "locations": [
        {
         "offset": 992,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "p|Allele|R|104",
        "type": "SequenceVariant"
       },
       "text": "p.Arg104",
       "locations": [
        {
         "offset": 1003,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs111033360",
        "type": "SequenceVariant"
       },
       "text": "g.3816C>A",
       "locations": [
        {
         "offset": 1047,
         "length": 9
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs111033360",
        "type": "SequenceVariant"
       },
       "text": "p.Val167Met",
       "locations": [
        {
         "offset": 1058,
         "length": 11
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "g|DEL|3352|G",
        "type": "SequenceVariant"
       },
       "text": "g.3352delG",
       "locations": [
        {
         "offset": 1120,
         "length": 10
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "c|DEL|30|G",
        "type": "SequenceVariant"
       },
       "text": "30delG",
       "locations": [
        {
         "offset": 1152,
         "length": 6
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "c|DEL|35|G",
        "type": "SequenceVariant"
       },
       "text": "35 delG",
       "locations": [
        {
         "offset": 1162,
         "length": 7
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "rs72474224",
        "type": "SequenceVariant"
       },
       "text": "g.3426G>A",
       "locations": [
        {
         "offset": 1172,
         "length": 9
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "rs72474224",
        "type": "SequenceVariant"
       },
       "text": "p.Val37Ile",
       "locations": [
        {
         "offset": 1183,
         "length": 10
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "rs111033196",
        "type": "SequenceVariant"
       },
       "text": "g.3697G>A",
       "locations": [
        {
         "offset": 1196,
         "length": 9
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "rs111033196",
        "type": "SequenceVariant"
       },
       "text": "p.Arg127His",
       "locations": [
        {
         "offset": 1207,
         "length": 11
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "rs111033186",
        "type": "SequenceVariant"
       },
       "text": "g.3774G>A",
       "locations": [
        {
         "offset": 1221,
         "length": 9
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "rs111033186",
        "type": "SequenceVariant"
       },
       "text": "p.Val153Ile",
       "locations": [
        {
         "offset": 1232,
         "length": 11
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "rs34988750",
        "type": "SequenceVariant"
       },
       "text": "g.3795G>A",
       "locations": [
        {
         "offset": 1250,
         "length": 9
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "rs34988750",
        "type": "SequenceVariant"
       },
       "text": "p.Gly160Ser",
       "locations": [
        {
         "offset": 1261,
         "length": 11
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "g|SUB|C|3318-34|T",
        "type": "SequenceVariant"
       },
       "text": "g.3318-34C>T",
       "locations": [
        {
         "offset": 1313,
         "length": 12
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "g|DEL|3352|G",
        "type": "SequenceVariant"
       },
       "text": "g.3352delG",
       "locations": [
        {
         "offset": 1330,
         "length": 10
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "C567134",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NSARD",
       "locations": [
        {
         "offset": 1490,
         "length": 5
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 1558,
         "length": 8
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 1611,
         "length": 4
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 1718,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "2706",
      "entity2": "C567134",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "15099351",
   "passages": [
    {
     "offset": 0,
     "text": "Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "255738",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCSK9",
       "locations": [
        {
         "offset": 17,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D006938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant hypercholesterolemia",
       "locations": [
        {
         "offset": 55,
         "length": 39
        }
       ]
      }
     ]
    },
    {
     "offset": 96,
     "text": "Proprotein convertase subtilisin/kexin type 9 (PCSK9) is at a locus for autosomal dominant hypercholesterolemia, and recent data indicate that the PCSK9 gene is involved in cholesterol biosynthesis. Mutations within this gene have previously been found to segregate with hypercholesterolemia. In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded. Two novel missense mutations were detected in the catalytic subdomain of the PCSK9 gene. Two patients were heterozygotes for D374Y, and one patient was a double heterozygote for D374Y and N157K. D374Y segregated with hypercholesterolemia in the two former families where family members were available for study. Our findings support the notion that mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "255738",
        "type": "GeneOrGeneProduct"
       },
       "text": "Proprotein convertase subtilisin/kexin type 9",
       "locations": [
        {
         "offset": 96,
         "length": 45
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "255738",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCSK9",
       "locations": [
        {
         "offset": 143,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D006938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant hypercholesterolemia",
       "locations": [
        {
         "offset": 168,
         "length": 39
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "255738",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCSK9",
       "locations": [
        {
         "offset": 243,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002784",
        "type": "ChemicalEntity"
       },
       "text": "cholesterol",
       "locations": [
        {
         "offset": 269,
         "length": 11
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D006937",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypercholesterolemia",
       "locations": [
        {
         "offset": 367,
         "length": 20
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "255738",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCSK9",
       "locations": [
        {
         "offset": 442,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D006937",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "familial hypercholesterolemia",
       "locations": [
        {
         "offset": 526,
         "length": 29
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3949",
        "type": "GeneOrGeneProduct"
       },
       "text": "low-density lipoprotein receptor",
       "locations": [
        {
         "offset": 579,
         "length": 32
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs5742904",
        "type": "SequenceVariant"
       },
       "text": "R3500Q",
       "locations": [
        {
         "offset": 630,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "338",
        "type": "GeneOrGeneProduct"
       },
       "text": "apolipoprotein B-100",
       "locations": [
        {
         "offset": 644,
         "length": 20
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "255738",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCSK9",
       "locations": [
        {
         "offset": 766,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 782,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs137852912",
        "type": "SequenceVariant"
       },
       "text": "D374Y",
       "locations": [
        {
         "offset": 814,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 829,
         "length": 7
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs137852912",
        "type": "SequenceVariant"
       },
       "text": "D374Y",
       "locations": [
        {
         "offset": 867,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs143117125",
        "type": "SequenceVariant"
       },
       "text": "N157K",
       "locations": [
        {
         "offset": 877,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs137852912",
        "type": "SequenceVariant"
       },
       "text": "D374Y",
       "locations": [
        {
         "offset": 884,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D006937",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypercholesterolemia",
       "locations": [
        {
         "offset": 906,
         "length": 20
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "255738",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCSK9",
       "locations": [
        {
         "offset": 1055,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D006938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant hypercholesterolemia",
       "locations": [
        {
         "offset": 1072,
         "length": 39
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs143117125",
      "entity2": "D006938",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D006938",
      "entity2": "255738",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "255738",
      "entity2": "D002784",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "255738",
      "entity2": "D006937",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "rs137852912",
      "entity2": "D006938",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D006937",
      "entity2": "rs137852912",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15122708",
   "passages": [
    {
     "offset": 0,
     "text": "Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Desmin-related myopathy",
       "locations": [
        {
         "offset": 0,
         "length": 23
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "57190",
        "type": "GeneOrGeneProduct"
       },
       "text": "selenoprotein N",
       "locations": [
        {
         "offset": 88,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 110,
     "text": "Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Desmin-related myopathies",
       "locations": [
        {
         "offset": 110,
         "length": 25
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRMs",
       "locations": [
        {
         "offset": 137,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "muscle disorders",
       "locations": [
        {
         "offset": 172,
         "length": 16
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1674",
        "type": "GeneOrGeneProduct"
       },
       "text": "desmin",
       "locations": [
        {
         "offset": 249,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1674",
        "type": "GeneOrGeneProduct"
       },
       "text": "desmin",
       "locations": [
        {
         "offset": 274,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1410",
        "type": "GeneOrGeneProduct"
       },
       "text": "alpha-B crystallin",
       "locations": [
        {
         "offset": 289,
         "length": 18
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRM",
       "locations": [
        {
         "offset": 357,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRMs",
       "locations": [
        {
         "offset": 501,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 547,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "57190",
        "type": "GeneOrGeneProduct"
       },
       "text": "selenoprotein N",
       "locations": [
        {
         "offset": 585,
         "length": 15
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "57190",
        "type": "GeneOrGeneProduct"
       },
       "text": "SEPN1",
       "locations": [
        {
         "offset": 607,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SEPN-related myopathy",
       "locations": [
        {
         "offset": 633,
         "length": 21
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SEPN-RM",
       "locations": [
        {
         "offset": 656,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myopathy",
       "locations": [
        {
         "offset": 687,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "C535683",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "rigid spine muscular dystrophy",
       "locations": [
        {
         "offset": 754,
         "length": 30
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C564969",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "multiminicore disease",
       "locations": [
        {
         "offset": 818,
         "length": 21
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SEPN-RM",
       "locations": [
        {
         "offset": 924,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRM",
       "locations": [
        {
         "offset": 976,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "57190",
        "type": "GeneOrGeneProduct"
       },
       "text": "SEPN1",
       "locations": [
        {
         "offset": 984,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRM",
       "locations": [
        {
         "offset": 1010,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "57190",
        "type": "GeneOrGeneProduct"
       },
       "text": "SEPN1",
       "locations": [
        {
         "offset": 1077,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "57190",
        "type": "GeneOrGeneProduct"
       },
       "text": "SEPN1",
       "locations": [
        {
         "offset": 1127,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "c|DEL|-19_+73|92",
        "type": "SequenceVariant"
       },
       "text": "del 92 nucleotide -19/+73",
       "locations": [
        {
         "offset": 1143,
         "length": 25
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1186,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRM",
       "locations": [
        {
         "offset": 1238,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SEPN-RM",
       "locations": [
        {
         "offset": 1246,
         "length": 7
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRM",
       "locations": [
        {
         "offset": 1319,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SEPN-RM",
       "locations": [
        {
         "offset": 1348,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DRM",
       "locations": [
        {
         "offset": 1416,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SEPN-RM",
       "locations": [
        {
         "offset": 1458,
         "length": 7
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myopathies",
       "locations": [
        {
         "offset": 1551,
         "length": 10
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1410",
      "entity2": "C563319",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "1674",
      "entity2": "C563319",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "57190",
      "entity2": "C564969",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "57190",
      "entity2": "C535683",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "57190",
      "entity2": "D009135",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "C563319",
      "entity2": "c|DEL|-19_+73|92",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "C563319",
      "entity2": "57190",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15177686",
   "passages": [
    {
     "offset": 0,
     "text": "Altered replication timing of the HIRA/Tuple1 locus in the DiGeorge and Velocardiofacial syndromes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7290",
        "type": "GeneOrGeneProduct"
       },
       "text": "HIRA",
       "locations": [
        {
         "offset": 34,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "7290",
        "type": "GeneOrGeneProduct"
       },
       "text": "Tuple1",
       "locations": [
        {
         "offset": 39,
         "length": 6
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DiGeorge and Velocardiofacial syndromes",
       "locations": [
        {
         "offset": 59,
         "length": 39
        }
       ]
      }
     ]
    },
    {
     "offset": 100,
     "text": "DiGeorge and Velocardiofacial syndromes (DGS/VCFS) are endowed by a similar complex phenotype including cardiovascular, craniofacial, and thymic malformations, and are associated with heterozygous deletions of 22q11 chromosomal band. The Typically Deleted Region in the 22q11.21 subband (here called TDR22) is very gene-dense, and the extent of the deletion has been defined precisely in several studies. However, to date there is no evidence for a mechanism of haploinsufficiency that can fully explain the DGS/VCFS phenotype. In this study, we show that the candidate gene HIRA/Tuple1 mapping on the non-deleted TDR22, in DGS/VCFS subjects presents a delayed replication timing. Moreover, we observed an increase in the cell ratio showing the HIRA/Tuple1 locus localised toward the nuclear periphery. It is known that replication timing and nuclear location are generally correlated to the transcription activity of the relative DNA region. We propose that the alteration in the replication/nuclear location pattern of the non-deleted TDR22 indicates an altered gene regulation hence an altered transcritpion in DGS/VCFS.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DiGeorge and Velocardiofacial syndromes",
       "locations": [
        {
         "offset": 100,
         "length": 39
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DGS",
       "locations": [
        {
         "offset": 141,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VCFS",
       "locations": [
        {
         "offset": 145,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D018376,D019465",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiovascular, craniofacial, and thymic malformations",
       "locations": [
        {
         "offset": 204,
         "length": 54
        }
       ]
      },
      {
       "id": "7",
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     "text": "Catecholamine-induced cardiomyopathy due to chronic excess of endogenous catecholamines has been recognized for decades as a clinical phenomenon. In contrast, reports of myocardial dysfunction due to acute iatrogenic overdose are rare. A 35-year-old woman whose cervix uteri was inadvertently injected with 8 mg of epinephrine developed myocardial stunning that was characterized by severe hemodynamic compromise, profound, albeit transient, left ventricular systolic and diastolic dysfunction, and only modestly elevated biochemical markers of myocardial necrosis. Our case illustrates the serious consequences of medical errors that can be avoided through improved medication labeling and staff supervision.",
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     "text": "Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis.",
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     "text": "There have been concerns that the risk of cardiovascular thrombotic events may be higher with cyclooxygenase (COX)-2-specific inhibitors than nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We evaluated cardiovascular event data for valdecoxib, a new COX-2-specific inhibitor in approximately 8000 patients with osteoarthritis and rheumatoid arthritis treated with this agent in randomized clinical trials. The incidence of cardiovascular thrombotic events (cardiac, cerebrovascular and peripheral vascular, or arterial thrombotic) was determined by analyzing pooled valdecoxib (10-80 mg daily), nonselective NSAID (diclofenac 75 mg bid, ibuprofen 800 mg tid, or naproxen 500 mg bid) and placebo data from 10 randomized osteoarthritis and rheumatoid arthritis trials that were 6-52 weeks in duration. The incidence rates of events were determined in all patients (n = 7934) and in users of low-dose (< or =325 mg daily) aspirin (n = 1051) and nonusers of aspirin (n = 6883). Crude and exposure-adjusted incidences of thrombotic events were similar for valdecoxib, NSAIDs, and placebo. The risk of serious thrombotic events was also similar for each valdecoxib dose. Thrombotic risk was consistently higher for users of aspirin users than nonusers of aspirin (placebo, 1.4% vs. 0%; valdecoxib, 1.7% vs. 0.2%; NSAIDs, 1.9% vs. 0.5%). The rates of events in users of aspirin were similar for all 3 treatment groups and across valdecoxib doses. Short- and intermediate-term treatment with therapeutic (10 or 20 mg daily) and supratherapeutic (40 or 80 mg daily) valdecoxib doses was not associated with an increased incidence of thrombotic events relative to nonselective NSAIDs or placebo in osteoarthritis and rheumatoid arthritis patients in controlled clinical trials.",
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       "text": "osteoarthritis",
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  },
  {
   "id": "16005363",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7466",
        "type": "GeneOrGeneProduct"
       },
       "text": "WFS1",
       "locations": [
        {
         "offset": 26,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "p|INS|344_345|AFF",
        "type": "SequenceVariant"
       },
       "text": "AFF344-345ins",
       "locations": [
        {
         "offset": 41,
         "length": 13
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 68,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D014929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Wolfram syndrome",
       "locations": [
        {
         "offset": 82,
         "length": 16
        }
       ]
      }
     ]
    },
    {
     "offset": 100,
     "text": "Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D014929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Wolfram syndrome",
       "locations": [
        {
         "offset": 100,
         "length": 16
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D014929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "WFS",
       "locations": [
        {
         "offset": 118,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal recessive disorder",
       "locations": [
        {
         "offset": 129,
         "length": 28
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes mellitus",
       "locations": [
        {
         "offset": 187,
         "length": 17
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009896",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "optic atrophy",
       "locations": [
        {
         "offset": 218,
         "length": 13
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D006319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sensorineural deafness",
       "locations": [
        {
         "offset": 233,
         "length": 22
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003919",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes insipidus",
       "locations": [
        {
         "offset": 260,
         "length": 18
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "renal tract abnormalities",
       "locations": [
        {
         "offset": 315,
         "length": 25
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D001523",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psychiatric syndromes",
       "locations": [
        {
         "offset": 367,
         "length": 21
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "7466",
        "type": "GeneOrGeneProduct"
       },
       "text": "WFS1",
       "locations": [
        {
         "offset": 390,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D014929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "WFS",
       "locations": [
        {
         "offset": 471,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "7466",
        "type": "GeneOrGeneProduct"
       },
       "text": "WFS1",
       "locations": [
        {
         "offset": 559,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 578,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|INS||9",
        "type": "SequenceVariant"
       },
       "text": "nine nucleotide insertion",
       "locations": [
        {
         "offset": 622,
         "length": 25
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|INS|344_345|AFF",
        "type": "SequenceVariant"
       },
       "text": "AFF344-345ins",
       "locations": [
        {
         "offset": 649,
         "length": 13
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 691,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D007018",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypopituitarism",
       "locations": [
        {
         "offset": 716,
         "length": 15
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D014929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "WFS",
       "locations": [
        {
         "offset": 764,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D014929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "WFS",
       "locations": [
        {
         "offset": 835,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D014929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "WFS",
       "locations": [
        {
         "offset": 905,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|INS||9",
      "entity2": "D014929",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "7466",
      "entity2": "D014929",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "p|INS|344_345|AFF",
      "entity2": "D014929",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16200390",
   "passages": [
    {
     "offset": 0,
     "text": "A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 73,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 112,
     "text": "Migraine is a common debilitating primary headache disorder with significant mental, physical and social health implications. The brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is involved in nociceptive pathways and has been implicated in the pathophysiology of migraine. With few genetic studies investigating biosynthetic and metabolic enzymes governing the rate of 5-HT activity and their relationship to migraine, it was the objective of this study to assess genetic variants within the human tryptophan hydroxylase (TPH), amino acid decarboxylase (AADC) and monoamine oxidase A (MAOA) genes in migraine susceptibility. This objective was undertaken using a high-throughput DNA pooling experimental design, which proved to be a very accurate, sensitive and specific method of estimating allele frequencies for single nucleotide polymorphism, insertion deletion and variable number tandem repeat loci. Application of DNA pooling to a wide array of genetic loci provides greater scope in the assessment of population-based genetic association study designs. Despite the application of this high-throughput genotyping method, negative results from the two-stage DNA pooling design used to screen loci within the TPH, AADC and MAOA genes did not support their role in migraine susceptibility.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Migraine",
       "locations": [
        {
         "offset": 112,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D020773",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "headache disorder",
       "locations": [
        {
         "offset": 154,
         "length": 17
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D018377",
        "type": "ChemicalEntity"
       },
       "text": "neurotransmitter",
       "locations": [
        {
         "offset": 248,
         "length": 16
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D012701",
        "type": "ChemicalEntity"
       },
       "text": "5-hydroxytryptamine",
       "locations": [
        {
         "offset": 265,
         "length": 19
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D012701",
        "type": "ChemicalEntity"
       },
       "text": "5-HT",
       "locations": [
        {
         "offset": 286,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D012701",
        "type": "ChemicalEntity"
       },
       "text": "serotonin",
       "locations": [
        {
         "offset": 292,
         "length": 9
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 389,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012701",
        "type": "ChemicalEntity"
       },
       "text": "5-HT",
       "locations": [
        {
         "offset": 495,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 535,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 618,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "7166",
        "type": "GeneOrGeneProduct"
       },
       "text": "tryptophan hydroxylase",
       "locations": [
        {
         "offset": 624,
         "length": 22
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "7166",
        "type": "GeneOrGeneProduct"
       },
       "text": "TPH",
       "locations": [
        {
         "offset": 648,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "1644",
        "type": "GeneOrGeneProduct"
       },
       "text": "amino acid decarboxylase",
       "locations": [
        {
         "offset": 654,
         "length": 24
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "1644",
        "type": "GeneOrGeneProduct"
       },
       "text": "AADC",
       "locations": [
        {
         "offset": 680,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "4128",
        "type": "GeneOrGeneProduct"
       },
       "text": "monoamine oxidase A",
       "locations": [
        {
         "offset": 690,
         "length": 19
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "4128",
        "type": "GeneOrGeneProduct"
       },
       "text": "MAOA",
       "locations": [
        {
         "offset": 711,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 726,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "7166",
        "type": "GeneOrGeneProduct"
       },
       "text": "TPH",
       "locations": [
        {
         "offset": 1340,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "1644",
        "type": "GeneOrGeneProduct"
       },
       "text": "AADC",
       "locations": [
        {
         "offset": 1345,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "4128",
        "type": "GeneOrGeneProduct"
       },
       "text": "MAOA",
       "locations": [
        {
         "offset": 1354,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 1395,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D012701",
      "entity2": "D008881",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "16369751",
   "passages": [
    {
     "offset": 0,
     "text": "5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D005472",
        "type": "ChemicalEntity"
       },
       "text": "5-Fluorouracil",
       "locations": [
        {
         "offset": 0,
         "length": 14
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D066126",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiotoxicity",
       "locations": [
        {
         "offset": 15,
         "length": 14
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C032348",
        "type": "ChemicalEntity"
       },
       "text": "alpha-fluoro-beta-alanine",
       "locations": [
        {
         "offset": 41,
         "length": 25
        }
       ]
      }
     ]
    },
    {
     "offset": 68,
     "text": "Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D066126",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Cardiotoxicity",
       "locations": [
        {
         "offset": 68,
         "length": 14
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D005472",
        "type": "ChemicalEntity"
       },
       "text": "5-fluorouracil",
       "locations": [
        {
         "offset": 123,
         "length": 14
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D005472",
        "type": "ChemicalEntity"
       },
       "text": "5-FU",
       "locations": [
        {
         "offset": 139,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "malignancies",
       "locations": [
        {
         "offset": 159,
         "length": 12
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "man",
       "locations": [
        {
         "offset": 216,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D005472",
        "type": "ChemicalEntity"
       },
       "text": "5-FU",
       "locations": [
        {
         "offset": 225,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D066126",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiotoxicity",
       "locations": [
        {
         "offset": 238,
         "length": 14
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "C032348",
        "type": "ChemicalEntity"
       },
       "text": "alpha-fluoro-beta-alanine",
       "locations": [
        {
         "offset": 284,
         "length": 25
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C032348",
        "type": "ChemicalEntity"
       },
       "text": "FBAL",
       "locations": [
        {
         "offset": 311,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 335,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003110",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colon cancer",
       "locations": [
        {
         "offset": 365,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D009362",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "metastases",
       "locations": [
        {
         "offset": 378,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 525,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D005472",
        "type": "ChemicalEntity"
       },
       "text": "5-FU",
       "locations": [
        {
         "offset": 579,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D002637",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "precordial pain",
       "locations": [
        {
         "offset": 612,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D002037",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "right bundle branch block",
       "locations": [
        {
         "offset": 633,
         "length": 25
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C032348",
        "type": "ChemicalEntity"
       },
       "text": "FBAL",
       "locations": [
        {
         "offset": 700,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D002637",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "precordial pain",
       "locations": [
        {
         "offset": 743,
         "length": 15
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D005472",
        "type": "ChemicalEntity"
       },
       "text": "5-FU",
       "locations": [
        {
         "offset": 851,
         "length": 4
        }
       ]
      },
      {
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  {
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     "offset": 0,
     "text": "Pilocarpine seizures cause age-dependent impairment in auditory location discrimination.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D010862",
        "type": "ChemicalEntity"
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       "text": "Pilocarpine",
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       "infons": {
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       "text": "impairment in auditory location discrimination",
       "locations": [
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    {
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     "text": "Children who have status epilepticus have continuous or rapidly repeating seizures that may be life-threatening and may cause life-long changes in brain and behavior. The extent to which status epilepticus causes deficits in auditory discrimination is unknown. A naturalistic auditory location discrimination method was used to evaluate this question using an animal model of status epilepticus. Male Sprague-Dawley rats were injected with saline on postnatal day (P) 20, or a convulsant dose of pilocarpine on P20 or P45. Pilocarpine on either day induced status epilepticus; status epilepticus at P45 resulted in CA3 cell loss and spontaneous seizures, whereas P20 rats had no cell loss or spontaneous seizures. Mature rats were trained with sound-source location and sound-silence discriminations. Control (saline P20) rats acquired both discriminations immediately. In status epilepticus (P20) rats, acquisition of the sound-source location discrimination was moderately impaired. Status epilepticus (P45) rats failed to acquire either sound-source location or sound-silence discriminations. Status epilepticus in rat causes an age-dependent, long-term impairment in auditory discrimination. This impairment may explain one cause of impaired auditory location discrimination in humans.",
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        "identifier": "D013226",
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       "text": "status epilepticus",
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       "text": "deficits in auditory discrimination",
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       "text": "status epilepticus",
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       "id": "8",
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       "text": "rats",
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       "text": "Pilocarpine",
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       "id": "11",
       "infons": {
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       "text": "status epilepticus",
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       ]
      },
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       "id": "12",
       "infons": {
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       "text": "status epilepticus",
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       ]
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       "id": "13",
       "infons": {
        "identifier": "CVCL_JW73",
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       "text": "CA3",
       "locations": [
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         "offset": 704,
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       "id": "14",
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       "text": "seizures",
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       "text": "rats",
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       "id": "21",
       "infons": {
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       "text": "Status epilepticus",
       "locations": [
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       "id": "22",
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        "type": "OrganismTaxon"
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       "text": "rats",
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       "infons": {
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       "text": "Status epilepticus",
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       "id": "24",
       "infons": {
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       "text": "rat",
       "locations": [
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         "offset": 1207,
         "length": 3
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       ]
      },
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       "id": "25",
       "infons": {
        "identifier": "D001308",
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       "text": "impairment in auditory discrimination",
       "locations": [
        {
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         "length": 37
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D001308",
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       },
       "text": "impaired auditory location discrimination",
       "locations": [
        {
         "offset": 1326,
         "length": 41
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "humans",
       "locations": [
        {
         "offset": 1371,
         "length": 6
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       ]
      }
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    }
   ],
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     "infons": {
      "entity1": "D010862",
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      "novel": "Novel"
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010862",
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D010862",
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      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17000021",
   "passages": [
    {
     "offset": 0,
     "text": "No independent role of the -1123 G>C and+2740 A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs2488457",
        "type": "SequenceVariant"
       },
       "text": "-1123 G>C",
       "locations": [
        {
         "offset": 27,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs1217412",
        "type": "SequenceVariant"
       },
       "text": "+2740 A>G",
       "locations": [
        {
         "offset": 40,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 81,
         "length": 6
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 93,
         "length": 15
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D001171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "juvenile idiopathic arthritis",
       "locations": [
        {
         "offset": 113,
         "length": 29
        }
       ]
      }
     ]
    },
    {
     "offset": 173,
     "text": "INTRODUCTION: The PTPN22 is a negative regulator of the T cell response. Its +1858C>T (R620W) polymorphism has been shown to associate with a risk for multiple autoimmune diseases, including type 1 diabetes (T1D) and juvenile idiopathic arthritis (JIA). The minor (susceptibility) allele is absent in Asian populations, but a recent study suggested an independent involvement of another polymorphism located within the promoter -1123 nucleotides relative to the translational start site. AIMS: We aimed to analyse the association of three PTPN22 polymorphisms in two distinct Caucasian populations, the Czechs (with T1D and with JIA) and Azeri (with T1D). METHODS: The single nucleotide polymorphisms (SNP) at positions -1123 (rs2488457), +1858 (rs2476601, the R620W substitution), and +2740 (rs1217412) were genotyped using TaqMan assays in 372 subjects with childhood-onset T1D, 130 subjects with JIA, and 400 control subjects of Czech origin, and in 160 subjects with T1D and 271 healthy controls of Azeri origin. RESULTS: In the Czechs, all three SNPs were in a tight linkage disequlibrium, while in the Azeri, the linkage disequlibrium was limited to between the promoter and 3'-UTR polymorphism, D'(-1123, +2740)=0.99, r(2)=0.72. Haplotype reconstruction via the expectation-maximization algorithm showed in both populations that only the haplotype containing the minor (W) allele at codon 620 was associated with T1D (OR=2.26, 95% CI 1.68-3.02 in Czechs, OR=14.8, 95% CI 2.0-651 in Azeri) or JIA (OR=2.43, 95% CI 1.66-3.56 in Czechs). The haplotypes having the wild-type (R) allele at codon 620 and minor alleles at -1123 and/or +2740 were neutral as to the risk of autoimmune conditions in both populations. CONCLUSIONS: In two different Caucasian populations, the Czechs and the Azeri, no independent contribution can be detected either of the -1123 promoter SNP or the +2740 3'-UTR SNP, and only the minor allele at PTPN22 codon 620 contributes to the risk of autoimmunity.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 191,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "rs2476601",
        "type": "SequenceVariant"
       },
       "text": "+1858C>T",
       "locations": [
        {
         "offset": 250,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs2476601",
        "type": "SequenceVariant"
       },
       "text": "R620W",
       "locations": [
        {
         "offset": 260,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D001327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autoimmune diseases",
       "locations": [
        {
         "offset": 333,
         "length": 19
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D003922",
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     "offset": 0,
     "text": "A polymorphism of C-to-T substitution at -31 IL1B is associated with the risk of advanced gastric adenocarcinoma in a Japanese population.",
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       "infons": {
        "identifier": "rs1143627",
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       "text": "C-to-T substitution at -31",
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     "text": "Proinflammatory cytokine gene polymorphisms have been demonstrated to associate with gastric cancer risk, of which IL1B-31T/C and -511C/T changes have been well investigated due to the possibility that they may alter the IL1B transcription. The signal transduction target upon interleukin 1 beta (IL1beta) stimulation, the nuclear factor of kappa B (NFkappaB) activation, supports cancer development, signal transduction in which is mediated by FS-7 cell-associated cell surface antigen (FAS) signaling. Based on recent papers describing the prognostic roles of the polymorphisms and the NFkappaB functions on cancer development, we sought to determine if Japanese gastric cancer patients were affected by the IL1B -31/-511 and FAS-670 polymorphisms. A case-control study was conducted on incident gastric adenocarcinoma patients (n=271) and age-gender frequency-matched control subjects (n=271). We observed strong linkage disequilibrium between the T allele at -511 and the C allele at -31 and between the C allele at -511 and the T allele at -31 in IL1B in both the cases and controls (R (2)=0.94). Neither IL1B-31, -511 nor FAS-670 polymorphisms showed significantly different risks of gastric adenocarcinoma. Though FAS-670 polymorphisms did not show any significant difference, the proportion of subjects with IL1B-31TT (or IL1B-511CC) increased according to stage (trend P=0.019). In particular, subjects with stage IV had a two times higher probability of having either IL1B-31TT (or IL1B-511CC) genotype compared with stage I subjects. These observations suggest that IL1B-31TT and IL1B-511CC are associated with disease progression.",
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       "text": "Proinflammatory cytokine",
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       "id": "11",
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       "text": "nuclear factor of kappa B",
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       "text": "cancer",
       "locations": [
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         "offset": 520,
         "length": 6
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       ]
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       "id": "14",
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        "identifier": "355",
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       "text": "FS-7 cell-associated cell surface antigen",
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         "offset": 584,
         "length": 41
        }
       ]
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       "id": "15",
       "infons": {
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       "id": "16",
       "infons": {
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       "text": "T allele at -31",
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       "id": "28",
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       "text": "IL1B",
       "locations": [
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         "offset": 1191,
         "length": 4
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       ]
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      {
       "id": "29",
       "infons": {
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       "text": "IL1B",
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         "offset": 1249,
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       "id": "30",
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        "identifier": "355",
        "type": "GeneOrGeneProduct"
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       "text": "FAS",
       "locations": [
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         "offset": 1267,
         "length": 3
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      },
      {
       "id": "31",
       "infons": {
        "identifier": "D013274",
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       "text": "gastric adenocarcinoma",
       "locations": [
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         "offset": 1329,
         "length": 22
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       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "355",
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       "text": "FAS",
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        "type": "SequenceVariant"
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       "id": "39",
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       "text": "IL1B",
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       "id": "1",
       "infons": {
        "identifier": "D013439",
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       "text": "sulfhydryl reagent",
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       "id": "2",
       "infons": {
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       "text": "thiol",
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         "offset": 65,
         "length": 5
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       "id": "3",
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       "text": "ifosfamide",
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       "id": "4",
       "infons": {
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     "offset": 105,
     "text": "Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients.",
     "annotations": [
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       "id": "5",
       "infons": {
        "identifier": "C004656",
        "type": "ChemicalEntity"
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       "text": "Chloroacetaldehyde",
       "locations": [
        {
         "offset": 105,
         "length": 18
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       "id": "6",
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       "text": "CAA",
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         "offset": 125,
         "length": 3
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       "text": "alkylating agent",
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       "id": "8",
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       "text": "ifosfamide",
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         "length": 3
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       "id": "10",
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       "text": "renal damage",
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       "text": "sulfhydryl",
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       "infons": {
        "identifier": "CVCL_K278",
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       "text": "hRPTEC",
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       "id": "22",
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       "id": "23",
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         "length": 6
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       "id": "30",
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       "text": "cysteine proteases",
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       "text": "caspase-3",
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       "text": "caspase-8",
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       "id": "33",
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       "text": "cathepsin B",
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       "text": "Caspase",
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       "text": "cisplatin",
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       "id": "39",
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       "text": "cysteine protease",
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       "id": "46",
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       "text": "cysteine protease",
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    {
     "offset": 0,
     "text": "Delayed institution of hypertension during focal cerebral ischemia: effect on brain edema.",
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       "infons": {
        "identifier": "D006973",
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     "text": "The effect of induced hypertension instituted after a 2-h delay following middle cerebral artery occlusion (MCAO) on brain edema formation and histochemical injury was studied. Under isoflurane anesthesia, the MCA of 14 spontaneously hypertensive rats was occluded. In the control group (n = 7), the mean arterial pressure (MAP) was not manipulated. In the hypertensive group (n = 7), the MAP was elevated by 25-30 mm Hg beginning 2 h after MCAO. Four hours after MCAO, the rats were killed and the brains harvested. The brains were sectioned along coronal planes spanning the distribution of ischemia produced by MCAO. Specific gravity (SG) was determined in the subcortex and in two sites in the cortex (core and periphery of the ischemic territory). The extent of neuronal injury was determined by 2,3,5-triphenyltetrazolium staining. In the ischemic core, there was no difference in SG in the subcortex and cortex in the two groups. In the periphery of the ischemic territory, SG in the cortex was greater (less edema accumulation) in the hypertensive group (1.041 +/- 0.001 vs 1.039 +/- 0.001, P less than 0.05). The area of histochemical injury (as a percent of the cross-sectional area of the hemisphere) was less in the hypertensive group (33 +/- 3% vs 21 +/- 2%, P less than 0.05). The data indicate that phenylephrine-induced hypertension instituted 2 h after MCAO does not aggravate edema in the ischemic core, that it improves edema in the periphery of the ischemic territory, and that it reduces the area of histochemical neuronal dysfunction.",
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       "infons": {
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       },
       "text": "rats",
       "locations": [
        {
         "offset": 565,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemia",
       "locations": [
        {
         "offset": 684,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D020244",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MCAO",
       "locations": [
        {
         "offset": 705,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic",
       "locations": [
        {
         "offset": 823,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D009410",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neuronal injury",
       "locations": [
        {
         "offset": 858,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "C009591",
        "type": "ChemicalEntity"
       },
       "text": "2,3,5-triphenyltetrazolium",
       "locations": [
        {
         "offset": 892,
         "length": 26
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic",
       "locations": [
        {
         "offset": 936,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic",
       "locations": [
        {
         "offset": 1052,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D004487",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "edema",
       "locations": [
        {
         "offset": 1107,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertensive",
       "locations": [
        {
         "offset": 1134,
         "length": 12
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertensive",
       "locations": [
        {
         "offset": 1319,
         "length": 12
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D010656",
        "type": "ChemicalEntity"
       },
       "text": "phenylephrine",
       "locations": [
        {
         "offset": 1405,
         "length": 13
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1427,
         "length": 12
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D020244",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MCAO",
       "locations": [
        {
         "offset": 1461,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D004487",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "edema",
       "locations": [
        {
         "offset": 1485,
         "length": 5
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic",
       "locations": [
        {
         "offset": 1498,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D004487",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "edema",
       "locations": [
        {
         "offset": 1530,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic",
       "locations": [
        {
         "offset": 1560,
         "length": 8
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D009410",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neuronal dysfunction",
       "locations": [
        {
         "offset": 1626,
         "length": 20
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D010656",
      "entity2": "D006973",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17391797",
   "passages": [
    {
     "offset": 0,
     "text": "The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "phosphatidylethanolamine N-methyltransferase",
       "locations": [
        {
         "offset": 4,
         "length": 44
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "V175M",
       "locations": [
        {
         "offset": 54,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 121,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 150,
     "text": "BACKGROUND/AIMS: The genetic predisposition on the development of nonalcoholic steatohepatitis (NASH) has been poorly understood. A functional polymorphism Val175Met was reported in phosphatidylethanolamine N-methyltransferase (PEMT) that catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine. The aim of this study was to investigate whether the carriers of Val175Met variant impaired in PEMT activity are more susceptible to NASH. METHODS: Blood samples of 107 patients with biopsy-proven NASH and of 150 healthy volunteers were analyzed by the polymerase chain reaction (PCR) and restriction fragment length polymorphism. RESULTS: Val175Met variant allele of the PEMT gene was significantly more frequent in NASH patients than in healthy volunteers (p<0.001), and carriers of Val175Met variant were significantly more frequent in NASH patients than in healthy volunteers (p<0.01). Among NASH patients, body mass index was significantly lower (p<0.05), and non-obese patients were significantly more frequent (p<0.001) in carriers of Val175Met variant than in homozygotes of wild type PEMT. CONCLUSIONS: Val175Met variant of PEMT could be a candidate molecule that determines the susceptibility to NASH, because it is more frequently observed in NASH patients and non-obese persons with Val175Met variant of PEMT are facilitated to develop NASH.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nonalcoholic steatohepatitis",
       "locations": [
        {
         "offset": 216,
         "length": 28
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 246,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "Val175Met",
       "locations": [
        {
         "offset": 306,
         "length": 9
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "phosphatidylethanolamine N-methyltransferase",
       "locations": [
        {
         "offset": 332,
         "length": 44
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "PEMT",
       "locations": [
        {
         "offset": 378,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D010714",
        "type": "ChemicalEntity"
       },
       "text": "phosphatidylethanolamine",
       "locations": [
        {
         "offset": 417,
         "length": 24
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D010713",
        "type": "ChemicalEntity"
       },
       "text": "phosphatidylcholine",
       "locations": [
        {
         "offset": 445,
         "length": 19
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "Val175Met",
       "locations": [
        {
         "offset": 531,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "PEMT",
       "locations": [
        {
         "offset": 561,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 599,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 635,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 663,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "Val175Met",
       "locations": [
        {
         "offset": 806,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "PEMT",
       "locations": [
        {
         "offset": 838,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 883,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 888,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "Val175Met",
       "locations": [
        {
         "offset": 951,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 1005,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1010,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 1062,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1067,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "obese",
       "locations": [
        {
         "offset": 1135,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1141,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "Val175Met",
       "locations": [
        {
         "offset": 1208,
         "length": 9
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "PEMT",
       "locations": [
        {
         "offset": 1259,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "Val175Met",
       "locations": [
        {
         "offset": 1278,
         "length": 9
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "PEMT",
       "locations": [
        {
         "offset": 1299,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 1372,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 1420,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1425,
         "length": 8
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "obese",
       "locations": [
        {
         "offset": 1442,
         "length": 5
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "Val175Met",
       "locations": [
        {
         "offset": 1461,
         "length": 9
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
       },
       "text": "PEMT",
       "locations": [
        {
         "offset": 1482,
         "length": 4
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NASH",
       "locations": [
        {
         "offset": 1514,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "10400",
      "entity2": "D065626",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010714",
      "entity2": "D010713",
      "type": "Conversion",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs7946",
      "entity2": "D010713",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs7946",
      "entity2": "D010714",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "rs7946",
      "entity2": "D065626",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17495183",
   "passages": [
    {
     "offset": 0,
     "text": "Tenomodulin is associated with obesity and diabetes risk: the Finnish diabetes prevention study.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "64102",
        "type": "GeneOrGeneProduct"
       },
       "text": "Tenomodulin",
       "locations": [
        {
         "offset": 0,
         "length": 11
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "obesity",
       "locations": [
        {
         "offset": 31,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes",
       "locations": [
        {
         "offset": 43,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes",
       "locations": [
        {
         "offset": 70,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 97,
     "text": "We recently showed that long-term weight reduction changes the gene expression profile of adipose tissue in overweight individuals with impaired glucose tolerance (IGT). One of the responding genes was X-chromosomal tenomodulin (TNMD), a putative angiogenesis inhibitor. Our aim was to study the associations of individual single nucleotide polymorphisms and haplotypes with adiposity, glucose metabolism, and the risk of type 2 diabetes (T2D). Seven single nucleotide polymorphisms from two different haploblocks were genotyped from 507 participants of the Finnish Diabetes Prevention Study (DPS). Sex-specific genotype effects were observed. Three markers of haploblock 1 were associated with features of adiposity in women (rs5966709, rs4828037) and men (rs11798018). Markers rs2073163 and rs1155794 from haploblock 2 were associated with 2-hour plasma glucose levels in men during the 3-year follow-up. The same two markers together with rs2073162 associated with the conversion of IGT to T2D in men. The risk of developing T2D was approximately 2-fold in individuals with genotypes associated with higher 2-hour plasma glucose levels; the hazard ratios were 2.192 (p = 0.025) for rs2073162-A, 2.191 (p = 0.027) for rs2073163-C, and 1.998 (p = 0.054) for rs1155974-T. These results suggest that TNMD polymorphisms are associated with adiposity and also with glucose metabolism and conversion from IGT to T2D in men.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D050177",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "overweight",
       "locations": [
        {
         "offset": 205,
         "length": 10
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D018149",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "impaired glucose tolerance",
       "locations": [
        {
         "offset": 233,
         "length": 26
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D018149",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IGT",
       "locations": [
        {
         "offset": 261,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "64102",
        "type": "GeneOrGeneProduct"
       },
       "text": "tenomodulin",
       "locations": [
        {
         "offset": 313,
         "length": 11
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "64102",
        "type": "GeneOrGeneProduct"
       },
       "text": "TNMD",
       "locations": [
        {
         "offset": 326,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "adiposity",
       "locations": [
        {
         "offset": 472,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D005947",
        "type": "ChemicalEntity"
       },
       "text": "glucose",
       "locations": [
        {
         "offset": 483,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 519,
         "length": 15
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "T2D",
       "locations": [
        {
         "offset": 536,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003920",
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  {
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     "offset": 0,
     "text": "Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease.",
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       "infons": {
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     "text": "BACKGROUND AND AIMS: A number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD). Materials and METHODS: A cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6. RESULTS: When compared with Crohn's disease patients without CARD15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively. CONCLUSION: Variants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD.",
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       "text": "innate immune receptor",
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     "offset": 0,
     "text": "An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia.",
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      {
       "id": "0",
       "infons": {
        "identifier": "2261",
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       "text": "FGFR3",
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         "offset": 63,
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       "id": "1",
       "infons": {
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       "text": "G380R",
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         "offset": 69,
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       "id": "2",
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       "text": "achondroplasia",
       "locations": [
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     "text": "Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7500. In more than 98% of cases, the disease is associated with a G to A or G to C substitution at nucleotide position 1138 (p.G380R) of the fibroblast growth factor receptor 3 (FGFR3) gene. We have developed a sensitive single tube tetra-primer PCR assay to detect both the c.1138G>A and c.1138G>C mutations and can successfully distinguish DNA samples that are homozygous and heterozygous for the c.1138G>A mutation. Titration studies showed that the assay could reliably detect one copy of the mutant allele in a mix of 100 wild-type alleles. The assay has been tested in 50 healthy controls, 3 known patients with achondroplasia, and 5 amniotic fluids suspected of having achondroplasia and for whom we had previously determined the genotypes for the c.1138G>A mutation by PCR-RFLP. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for FGFR3 p.G380R genotyping, which could be used even in \"low-tech\" laboratories.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D000130",
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       "text": "Achondroplasia",
       "locations": [
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         "offset": 116,
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       "id": "4",
       "infons": {
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       "text": "dwarfism",
       "locations": [
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         "offset": 158,
         "length": 8
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       ]
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       "id": "5",
       "infons": {
        "identifier": "rs28931614",
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       "text": "G to A or G to C substitution at nucleotide position 1138",
       "locations": [
        {
         "offset": 273,
         "length": 57
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "rs28931614",
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       "text": "p.G380R",
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        {
         "offset": 332,
         "length": 7
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       ]
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       "id": "7",
       "infons": {
        "identifier": "2261",
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       "text": "fibroblast growth factor receptor 3",
       "locations": [
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         "offset": 348,
         "length": 35
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       ]
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       "id": "8",
       "infons": {
        "identifier": "2261",
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       "text": "FGFR3",
       "locations": [
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         "offset": 385,
         "length": 5
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       ]
      },
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       "id": "9",
       "infons": {
        "identifier": "rs28931614",
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       "text": "c.1138G>A",
       "locations": [
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         "offset": 482,
         "length": 9
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs28931614",
        "type": "SequenceVariant"
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       "text": "c.1138G>C",
       "locations": [
        {
         "offset": 496,
         "length": 9
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs28931614",
        "type": "SequenceVariant"
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       "text": "c.1138G>A",
       "locations": [
        {
         "offset": 606,
         "length": 9
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       ]
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       "id": "12",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patients",
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         "offset": 811,
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D000130",
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       "text": "achondroplasia",
       "locations": [
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         "offset": 825,
         "length": 14
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000130",
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       "text": "achondroplasia",
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         "offset": 883,
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       "id": "15",
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        "identifier": "rs28931614",
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       "text": "c.1138G>A",
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         "offset": 962,
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       ]
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       "id": "16",
       "infons": {
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       "text": "FGFR3",
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         "offset": 1127,
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       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "rs28931614",
        "type": "SequenceVariant"
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       "text": "p.G380R",
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        {
         "offset": 1133,
         "length": 7
        }
       ]
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     ]
    }
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      "novel": "No"
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     "id": "R1",
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  {
   "id": "18166824",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic investigation of four meiotic genes in women with premature ovarian failure.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "women",
       "locations": [
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         "offset": 47,
         "length": 5
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D016649",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "premature ovarian failure",
       "locations": [
        {
         "offset": 58,
         "length": 25
        }
       ]
      }
     ]
    },
    {
     "offset": 85,
     "text": "OBJECTIVE: The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF). DESIGN: Case-control study. METHODS: Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls). RESULTS: A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V). CONCLUSIONS: The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of the MSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon.",
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       "id": "2",
       "infons": {
        "identifier": "11144",
        "type": "GeneOrGeneProduct"
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       "text": "DMC1",
       "locations": [
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         "offset": 204,
         "length": 4
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      },
      {
       "id": "3",
       "infons": {
        "identifier": "850545",
        "type": "GeneOrGeneProduct"
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       "text": "MutS",
       "locations": [
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         "offset": 211,
         "length": 4
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       ]
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      {
       "id": "4",
       "infons": {
        "identifier": "4438",
        "type": "GeneOrGeneProduct"
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       "text": "MSH4",
       "locations": [
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         "offset": 225,
         "length": 4
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       ]
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       "id": "5",
       "infons": {
        "identifier": "4439",
        "type": "GeneOrGeneProduct"
       },
       "text": "MSH5",
       "locations": [
        {
         "offset": 232,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4932",
        "type": "OrganismTaxon"
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       "text": "S. cerevisiae",
       "locations": [
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         "offset": 242,
         "length": 13
        }
       ]
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       "id": "7",
       "infons": {
        "identifier": "856364",
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       "text": "SPO11",
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         "offset": 265,
         "length": 5
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       ]
      },
      {
       "id": "8",
       "infons": {
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       "text": "premature ovarian failure",
       "locations": [
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         "offset": 294,
         "length": 25
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       "id": "9",
       "infons": {
        "identifier": "D016649",
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       "text": "POF",
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         "offset": 321,
         "length": 3
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       ]
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       "id": "10",
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       "text": "patients",
       "locations": [
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         "offset": 464,
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       "id": "11",
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       "text": "women",
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         "offset": 578,
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       "id": "12",
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       "text": "POF",
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         "offset": 589,
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       ]
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       "id": "13",
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       "text": "women",
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         "length": 5
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       "id": "14",
       "infons": {
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       "text": "cytosine residue with thymidine",
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         "length": 31
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       ]
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       "id": "15",
       "infons": {
        "identifier": "4439",
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       "text": "MSH5",
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         "offset": 739,
         "length": 4
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       "id": "16",
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       "text": "women",
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         "offset": 772,
         "length": 5
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       ]
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       "id": "17",
       "infons": {
        "identifier": "D016649",
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       "text": "POF",
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         "offset": 786,
         "length": 3
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       ]
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       "id": "18",
       "infons": {
        "identifier": "rs2075789",
        "type": "SequenceVariant"
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       "text": "(proline) with a polar amino acid (serine) at position 29",
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         "offset": 891,
         "length": 57
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       "id": "19",
       "infons": {
        "identifier": "rs2075789",
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       "text": "P29S",
       "locations": [
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         "offset": 950,
         "length": 4
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       "id": "20",
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        "type": "OrganismTaxon"
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       "text": "women",
       "locations": [
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         "offset": 976,
         "length": 5
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       ]
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       "id": "21",
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        "type": "OrganismTaxon"
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       "text": "patients",
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         "offset": 995,
         "length": 8
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       ]
      },
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       "id": "22",
       "infons": {
        "identifier": "D016649",
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       "text": "POF",
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         "offset": 1009,
         "length": 3
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       ]
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       "id": "23",
       "infons": {
        "identifier": "D016649",
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       "text": "POF",
       "locations": [
        {
         "offset": 1058,
         "length": 3
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       ]
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       "id": "24",
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        "type": "OrganismTaxon"
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       "text": "patient",
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         "offset": 1062,
         "length": 7
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       ]
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       "id": "25",
       "infons": {
        "identifier": "11144",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMC1",
       "locations": [
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         "offset": 1142,
         "length": 4
        }
       ]
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       "id": "26",
       "infons": {
        "identifier": "rs2227914",
        "type": "SequenceVariant"
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       "text": "M200V",
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         "offset": 1224,
         "length": 5
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       ]
      },
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       "id": "27",
       "infons": {
        "identifier": "D007247",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "infertility",
       "locations": [
        {
         "offset": 1261,
         "length": 11
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "11144",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMC1",
       "locations": [
        {
         "offset": 1289,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1334,
         "length": 8
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "4439",
        "type": "GeneOrGeneProduct"
       },
       "text": "MSH5",
       "locations": [
        {
         "offset": 1393,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "4439",
        "type": "GeneOrGeneProduct"
       },
       "text": "MSH5",
       "locations": [
        {
         "offset": 1523,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "11144",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMC1",
       "locations": [
        {
         "offset": 1532,
         "length": 4
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D016649",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "POF",
       "locations": [
        {
         "offset": 1574,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "11144",
      "entity2": "D007247",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "11144",
      "entity2": "D016649",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "4439",
      "entity2": "D016649",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D007247",
      "entity2": "4439",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D007247",
      "entity2": "rs2227914",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D007247",
      "entity2": "rs2075789",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "rs2227914",
      "entity2": "D016649",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "D016649",
      "entity2": "rs2075789",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18408250",
   "passages": [
    {
     "offset": 0,
     "text": "A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 40,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "rheumatoid arthritis",
       "locations": [
        {
         "offset": 98,
         "length": 20
        }
       ]
      }
     ]
    },
    {
     "offset": 147,
     "text": "OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects. METHODS: We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion-deletion polymorphism in the IRF5 gene. We performed 2 sets of case-control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays. RESULTS: A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated. CONCLUSIONS: These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "Interferon regulatory factor 5",
       "locations": [
        {
         "offset": 159,
         "length": 30
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 191,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF",
       "locations": [
        {
         "offset": 216,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "3553",
        "type": "GeneOrGeneProduct"
       },
       "text": "proinflammatory cytokines",
       "locations": [
        {
         "offset": 286,
         "length": 25
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 334,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythaematosus",
       "locations": [
        {
         "offset": 388,
         "length": 29
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 419,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D001327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autoimmune diseases",
       "locations": [
        {
         "offset": 491,
         "length": 19
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 569,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "rheumatoid arthritis",
       "locations": [
        {
         "offset": 595,
         "length": 20
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 617,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 757,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 856,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 870,
         "length": 2
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 908,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 922,
         "length": 2
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 991,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "3123",
        "type": "GeneOrGeneProduct"
       },
       "text": "leukocyte antigen (HLA)-DRB1",
       "locations": [
        {
         "offset": 997,
         "length": 28
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs729302",
        "type": "SequenceVariant"
       },
       "text": "rs729302",
       "locations": [
        {
         "offset": 1139,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 1162,
         "length": 2
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1291,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs729302",
        "type": "SequenceVariant"
       },
       "text": "rs729302",
       "locations": [
        {
         "offset": 1331,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 1387,
         "length": 2
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1393,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1483,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 1626,
         "length": 2
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs729302",
        "type": "SequenceVariant"
       },
       "text": "rs729302",
       "locations": [
        {
         "offset": 1649,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 1759,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 1813,
         "length": 2
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1881,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "3663",
      "entity2": "D008180",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "3663",
      "entity2": "D001172",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs729302",
      "entity2": "D001172",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18439317",
   "passages": [
    {
     "offset": 0,
     "text": "Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4312",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMP1",
       "locations": [
        {
         "offset": 51,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C535531",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lumbar disc disease",
       "locations": [
        {
         "offset": 60,
         "length": 19
        }
       ]
      }
     ]
    },
    {
     "offset": 101,
     "text": "BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD. METHODS: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test. RESULTS: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele. CONCLUSION: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "4312",
        "type": "GeneOrGeneProduct"
       },
       "text": "Matrix metalloproteinases",
       "locations": [
        {
         "offset": 113,
         "length": 25
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "4312",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMPs",
       "locations": [
        {
         "offset": 140,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "c|DEL|-1607|G",
        "type": "SequenceVariant"
       },
       "text": "guanine insertion/deletion (G/D), the -1607 promoter polymorphism",
       "locations": [
        {
         "offset": 244,
         "length": 65
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4312",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMP1",
       "locations": [
        {
         "offset": 318,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D055959",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DDD",
       "locations": [
        {
         "offset": 471,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D055959",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DDD",
       "locations": [
        {
         "offset": 573,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "4312",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMP1",
       "locations": [
        {
         "offset": 969,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D055959",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DDD",
       "locations": [
        {
         "offset": 978,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D055959",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DDD",
       "locations": [
        {
         "offset": 1060,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D055959",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DDD",
       "locations": [
        {
         "offset": 1220,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|Allele|D|-1607",
        "type": "SequenceVariant"
       },
       "text": "D allele for the -1607",
       "locations": [
        {
         "offset": 1706,
         "length": 22
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "4312",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMP1",
       "locations": [
        {
         "offset": 1754,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D055959",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DDD",
       "locations": [
        {
         "offset": 1807,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|DEL|-1607|G",
      "entity2": "C535531",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D055959",
      "entity2": "c|DEL|-1607|G",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|Allele|D|-1607",
      "entity2": "D055959",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "4312",
      "entity2": "D055959",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "C535531",
      "entity2": "4312",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18657397",
   "passages": [
    {
     "offset": 0,
     "text": "Detailed spectral profile analysis of penicillin-induced epileptiform activity in anesthetized rats.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D010406",
        "type": "ChemicalEntity"
       },
       "text": "penicillin",
       "locations": [
        {
         "offset": 38,
         "length": 10
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epileptiform activity",
       "locations": [
        {
         "offset": 57,
         "length": 21
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 95,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 101,
     "text": "Penicillin model is a widely used experimental model for epilepsy research. In the present study we aimed to portray a detailed spectral analysis of penicillin-induced epileptiform activity in comparison with basal brain activity in anesthetized Wistar rats. Male Wistar rats were anesthetized with i.p. urethane and connected to an electrocorticogram setup. After a short period of basal activity recording, epileptic focus was induced by injecting 400IU/2 microl penicillin-G potassium into the left lateral ventricle while the cortical activity was continuously recorded. Basal activity, latent period and the penicillin-induced epileptiform activity periods were then analyzed using both conventional methods and spectral analysis. Spectral analyses were conducted by dividing the whole spectrum into different frequency bands including delta, theta (slow and fast), alpha-sigma, beta (1 and 2) and gamma (1 and 2) bands. Our results show that the most affected frequency bands were delta, theta, beta-2 and gamma-2 bands during the epileptiform activity and there were marked differences in terms of spectral densities between three investigated episodes (basal activity, latent period and epileptiform activity). Our results may help to analyze novel data obtained using similar experimental models and the simple analysis method described here can be used in similar studies to investigate the basic neuronal mechanism of this or other types of experimental epilepsies.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D010406",
        "type": "ChemicalEntity"
       },
       "text": "Penicillin",
       "locations": [
        {
         "offset": 101,
         "length": 10
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epilepsy",
       "locations": [
        {
         "offset": 158,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D010406",
        "type": "ChemicalEntity"
       },
       "text": "penicillin",
       "locations": [
        {
         "offset": 250,
         "length": 10
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epileptiform activity",
       "locations": [
        {
         "offset": 269,
         "length": 21
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 354,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 372,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D014520",
        "type": "ChemicalEntity"
       },
       "text": "urethane",
       "locations": [
        {
         "offset": 405,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epileptic",
       "locations": [
        {
         "offset": 510,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D010400",
        "type": "ChemicalEntity"
       },
       "text": "penicillin-G potassium",
       "locations": [
        {
         "offset": 566,
         "length": 22
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D010406",
        "type": "ChemicalEntity"
       },
       "text": "penicillin",
       "locations": [
        {
         "offset": 714,
         "length": 10
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epileptiform activity",
       "locations": [
        {
         "offset": 733,
         "length": 21
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epileptiform activity",
       "locations": [
        {
         "offset": 1138,
         "length": 21
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epileptiform activity",
       "locations": [
        {
         "offset": 1296,
         "length": 21
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epilepsies",
       "locations": [
        {
         "offset": 1566,
         "length": 10
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D004827",
      "entity2": "D010400",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010406",
      "entity2": "D004827",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "18681856",
   "passages": [
    {
     "offset": 0,
     "text": "Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C563786",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "non-autoimmune hyperthyroidism",
       "locations": [
        {
         "offset": 31,
         "length": 30
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs121908864",
        "type": "SequenceVariant"
       },
       "text": "p.M453T",
       "locations": [
        {
         "offset": 102,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "7253",
        "type": "GeneOrGeneProduct"
       },
       "text": "thyrotropin receptor",
       "locations": [
        {
         "offset": 118,
         "length": 20
        }
       ]
      }
     ]
    },
    {
     "offset": 145,
     "text": "OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "C563786",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "non-autoimmune hyperthyroidism",
       "locations": [
        {
         "offset": 220,
         "length": 30
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C563786",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NAH",
       "locations": [
        {
         "offset": 252,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "7253",
        "type": "GeneOrGeneProduct"
       },
       "text": "thyrotropin receptor",
       "locations": [
        {
         "offset": 306,
         "length": 20
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "7253",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSHR",
       "locations": [
        {
         "offset": 328,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "PATIENTS",
       "locations": [
        {
         "offset": 340,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "7253",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSHR",
       "locations": [
        {
         "offset": 638,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs121908864",
        "type": "SequenceVariant"
       },
       "text": "T to C",
       "locations": [
        {
         "offset": 756,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "7253",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSHR",
       "locations": [
        {
         "offset": 792,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs121908864",
        "type": "SequenceVariant"
       },
       "text": "c.1358T-->C",
       "locations": [
        {
         "offset": 803,
         "length": 11
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs121908864",
        "type": "SequenceVariant"
       },
       "text": "methionine (ATG) by threonine (ACG) at codon 453",
       "locations": [
        {
         "offset": 849,
         "length": 48
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs121908864",
        "type": "SequenceVariant"
       },
       "text": "p.M453T",
       "locations": [
        {
         "offset": 899,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D006980",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperthyroidism",
       "locations": [
        {
         "offset": 1049,
         "length": 15
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D006849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ventriculomegaly",
       "locations": [
        {
         "offset": 1066,
         "length": 16
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D006849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Ventriculomegaly",
       "locations": [
        {
         "offset": 1250,
         "length": 16
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C563786",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NAH",
       "locations": [
        {
         "offset": 1404,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "7253",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSHR",
       "locations": [
        {
         "offset": 1433,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "D006849",
      "entity2": "rs121908864",
      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D006980",
      "entity2": "rs121908864",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "7253",
      "entity2": "D006849",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "7253",
      "entity2": "D006980",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "C563786",
      "entity2": "7253",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "C563786",
      "entity2": "rs121908864",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19067809",
   "passages": [
    {
     "offset": 0,
     "text": "Hemodynamic parameters and heart rate variability during a tilt test in relation to gene polymorphism of renin-angiotensin and serotonin system.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5972",
        "type": "GeneOrGeneProduct"
       },
       "text": "renin",
       "locations": [
        {
         "offset": 105,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensin",
       "locations": [
        {
         "offset": 111,
         "length": 11
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D012701",
        "type": "ChemicalEntity"
       },
       "text": "serotonin",
       "locations": [
        {
         "offset": 127,
         "length": 9
        }
       ]
      }
     ]
    },
    {
     "offset": 145,
     "text": "PURPOSE: The aim of the study was to evaluate the renin-angiotensin system and serotonin transporter gene polymorphisms in relation to hemodynamic parameters and heart rate variability during a head-up tilt test (HUT) in patients with vasovagal syncope. METHODS: DNA was collected from 191 patients (mean age 44+/-18 years, 61 men, 130 women). The following gene polymorphisms were determined in genomic DNA: angiotensin-converting enzyme insertion/deletion polymorphism (I/D ACE), angiotensinogen gene polymorphism (M 235), angiotensin II receptor type 1 (ATR1) polymorphism (A 11666C), and polymorphism of serotonin transporter gene (5HTTLPR).Heart rate variability during HUT was assessed in 5-minute intervals by low frequency, high frequency, standard deviation of the normal-to-normal (SDNN), and root mean square successive difference parameters. RESULTS: AA genotype of A 1166C polymorphism was associated with lower minimal systolic blood pressure (SBP) and diastolic blood pressure (DBP) during HUT compared with other genotypes (minimal SBP: AA 59.6+/-21,8, AC 79.9+/-22.7, CC 65.4+/-22.7 mmHg, P=0.007), (minimal DBP: AA 36.4+/-22.7, AC 52.3+/-22.9, CC 45.4+/-19.5 mmHg, P=0.007).AA genotype was also associated with higher SDNN compared to other genotypes in the early phase of HUT (SDNN in 5 minutes of tilt: AA 59.7+/-24.6, AC 50.6+/-20.6, CC 46.0+/-13.2, P=0.01) and at syncope occurrence (SDNN: AA 71.0+/-20.9, AC 58.2+/-17.9, CC 58+/-10, P=0.04) CONCLUSION: AA genotype of A 1166C polymorphism in the ATR1 gene may be associated with hypotension and decline in sympathetic tone during HUT. Its role in genetic predisposition to vasovagal syncope cannot be excluded.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "5972",
        "type": "GeneOrGeneProduct"
       },
       "text": "renin",
       "locations": [
        {
         "offset": 195,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensin",
       "locations": [
        {
         "offset": 201,
         "length": 11
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "serotonin transporter",
       "locations": [
        {
         "offset": 224,
         "length": 21
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 366,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D019462",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "vasovagal syncope",
       "locations": [
        {
         "offset": 380,
         "length": 17
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 435,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 472,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 481,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1636",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensin-converting enzyme",
       "locations": [
        {
         "offset": 554,
         "length": 29
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "1636",
        "type": "GeneOrGeneProduct"
       },
       "text": "ACE",
       "locations": [
        {
         "offset": 621,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensinogen",
       "locations": [
        {
         "offset": 627,
         "length": 15
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|Allele|M|235",
        "type": "SequenceVariant"
       },
       "text": "M 235",
       "locations": [
        {
         "offset": 662,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "185",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensin II receptor type 1",
       "locations": [
        {
         "offset": 670,
         "length": 30
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "185",
        "type": "GeneOrGeneProduct"
       },
       "text": "ATR1",
       "locations": [
        {
         "offset": 702,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs5186",
        "type": "SequenceVariant"
       },
       "text": "A 11666C",
       "locations": [
        {
         "offset": 722,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "serotonin transporter",
       "locations": [
        {
         "offset": 753,
         "length": 21
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "5HTTLPR",
       "locations": [
        {
         "offset": 781,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs5186",
        "type": "SequenceVariant"
       },
       "text": "A 1166C",
       "locations": [
        {
         "offset": 1023,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D013575",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "syncope",
       "locations": [
        {
         "offset": 1531,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs5186",
        "type": "SequenceVariant"
       },
       "text": "A 1166C",
       "locations": [
        {
         "offset": 1636,
         "length": 7
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "185",
        "type": "GeneOrGeneProduct"
       },
       "text": "ATR1",
       "locations": [
        {
         "offset": 1664,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D007022",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypotension",
       "locations": [
        {
         "offset": 1697,
         "length": 11
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D019462",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "vasovagal syncope",
       "locations": [
        {
         "offset": 1791,
         "length": 17
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "185",
      "entity2": "D019462",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "185",
      "entity2": "D007022",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D013575",
      "entity2": "185",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D013575",
      "entity2": "rs5186",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "rs5186",
      "entity2": "D019462",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
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   "id": "19508969",
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     "offset": 0,
     "text": "Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "91147",
        "type": "GeneOrGeneProduct"
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       "text": "meckelin",
       "locations": [
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         "offset": 25,
         "length": 8
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "91147",
        "type": "GeneOrGeneProduct"
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       "text": "MKS3",
       "locations": [
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         "offset": 35,
         "length": 4
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       ]
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      {
       "id": "2",
       "infons": {
        "identifier": "91147",
        "type": "GeneOrGeneProduct"
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       "text": "TMEM67",
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         "offset": 40,
         "length": 6
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       "id": "3",
       "infons": {
        "identifier": "OMIM:613550",
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       },
       "text": "nephronophthisis with liver fibrosis",
       "locations": [
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         "offset": 54,
         "length": 36
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "OMIM:613550",
        "type": "DiseaseOrPhenotypicFeature"
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         "offset": 92,
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     "offset": 101,
     "text": "BACKGROUND: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in nine genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Loken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis. METHODS: To identify a causative gene for the subset of patients with associated liver fibrosis, the authors performed a genome wide linkage search in a consanguineous family with three affected patients using 50K SNP microarrays and homozygosity mapping. RESULTS: The authors obtained a significant maximum parametric LOD (logarithm of odds) score of Z(max) = 3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a worldwide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether four novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in five of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6, are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded seven different (four novel) mutations in five patients, four of whom also presented with congenital liver fibrosis. CONCLUSIONS: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.",
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       "text": "Nephronophthisis",
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         "length": 16
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         "offset": 131,
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       "text": "cerebellar anomalies",
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    {
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     "text": "Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson's disease in Italy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "Serotonin transporter",
       "locations": [
        {
         "offset": 0,
         "length": 21
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HTTLPR",
       "locations": [
        {
         "offset": 47,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Parkinson's disease",
       "locations": [
        {
         "offset": 87,
         "length": 19
        }
       ]
      }
     ]
    },
    {
     "offset": 117,
     "text": "Parkinson's disease (PD) is a neurodegenerative disorder causing muscular rigidity, resting tremor and bradykinesia. We conducted an association study assessing how PD risk in Italy was influenced by the serotonin transporter gene (SLC6A4) polymorphic region 5-HTTLPR, consisting of an insertion/deletion (long allele-L/short allele-S) of 43 bp in the SLC6A4 promoter region. The SLC6A4 promoter single nucleotide polymorphism rs25531(A-->G) was evaluated too. We collected 837 independent subjects (393 PD, 444 controls). An association between the 5-HTTLPR polymorphism and risk of PD (S/S genotype OR [95% CI]: 1.7[1.2-2.5], p = 0.002) was found. The rs25531 and the haplotype 5-HTTLPR/rs25531 did not associate with risk of PD. Our data indicate that the 5-HTTLPR polymorphic element within the SLC6A4 promoter may govern the genetic risk of PD in Italians.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Parkinson's disease",
       "locations": [
        {
         "offset": 117,
         "length": 19
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 138,
         "length": 2
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D019636",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurodegenerative disorder",
       "locations": [
        {
         "offset": 147,
         "length": 26
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009127",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "muscular rigidity",
       "locations": [
        {
         "offset": 182,
         "length": 17
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D014202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "resting tremor",
       "locations": [
        {
         "offset": 201,
         "length": 14
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D018476",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bradykinesia",
       "locations": [
        {
         "offset": 220,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 282,
         "length": 2
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "serotonin transporter",
       "locations": [
        {
         "offset": 321,
         "length": 21
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLC6A4",
       "locations": [
        {
         "offset": 349,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HTTLPR",
       "locations": [
        {
         "offset": 376,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|INDEL||43",
        "type": "SequenceVariant"
       },
       "text": "insertion/deletion (long allele-L/short allele-S) of 43 bp",
       "locations": [
        {
         "offset": 403,
         "length": 58
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLC6A4",
       "locations": [
        {
         "offset": 469,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLC6A4",
       "locations": [
        {
         "offset": 497,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs25531",
        "type": "SequenceVariant"
       },
       "text": "rs25531",
       "locations": [
        {
         "offset": 544,
         "length": 7
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs25531",
        "type": "SequenceVariant"
       },
       "text": "A-->G",
       "locations": [
        {
         "offset": 552,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 621,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HTTLPR",
       "locations": [
        {
         "offset": 667,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 701,
         "length": 2
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs25531",
        "type": "SequenceVariant"
       },
       "text": "rs25531",
       "locations": [
        {
         "offset": 771,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HTTLPR",
       "locations": [
        {
         "offset": 797,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs25531",
        "type": "SequenceVariant"
       },
       "text": "rs25531",
       "locations": [
        {
         "offset": 806,
         "length": 7
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 845,
         "length": 2
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HTTLPR",
       "locations": [
        {
         "offset": 876,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "6532",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLC6A4",
       "locations": [
        {
         "offset": 916,
         "length": 6
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 963,
         "length": 2
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D010300",
      "entity2": "c|INDEL||43",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "6532",
      "entity2": "D010300",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19728177",
   "passages": [
    {
     "offset": 0,
     "text": "Prolonged hypothermia as a bridge to recovery for cerebral edema and intracranial hypertension associated with fulminant hepatic failure.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D007036",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypothermia",
       "locations": [
        {
         "offset": 10,
         "length": 11
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D001929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebral edema",
       "locations": [
        {
         "offset": 50,
         "length": 14
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D019586",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intracranial hypertension",
       "locations": [
        {
         "offset": 69,
         "length": 25
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D017114",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fulminant hepatic failure",
       "locations": [
        {
         "offset": 111,
         "length": 25
        }
       ]
      }
     ]
    },
    {
     "offset": 138,
     "text": "BACKGROUND: To review evidence-based treatment options in patients with cerebral edema complicating fulminant hepatic failure (FHF) and discuss the potential applications of hypothermia. METHOD: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with FHF from acetaminophen and resultant cerebral edema. RESULTS: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from acetaminophen which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed FHF from acetaminophen and cerebral edema. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her cerebral edema and intracranial hypertension. At discharge, she had complete recovery of neurological and hepatic functions. CONCLUSION: In patients with FHF and cerebral edema from acetaminophen overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 196,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D001929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebral edema",
       "locations": [
        {
         "offset": 210,
         "length": 14
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D017114",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fulminant hepatic failure",
       "locations": [
        {
         "offset": 238,
         "length": 25
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D017114",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FHF",
       "locations": [
        {
         "offset": 265,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D007036",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypothermia",
       "locations": [
        {
         "offset": 312,
         "length": 11
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D017114",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FHF",
       "locations": [
        {
         "offset": 456,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000082",
        "type": "ChemicalEntity"
       },
       "text": "acetaminophen",
       "locations": [
        {
         "offset": 465,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebral edema",
       "locations": [
        {
         "offset": 493,
         "length": 14
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 522,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "toxicity",
       "locations": [
        {
         "offset": 600,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000082",
        "type": "ChemicalEntity"
       },
       "text": "acetaminophen",
       "locations": [
        {
         "offset": 614,
         "length": 13
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 672,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D003866",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "depressed",
       "locations": [
        {
         "offset": 684,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D017114",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FHF",
       "locations": [
        {
         "offset": 782,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D000082",
        "type": "ChemicalEntity"
       },
       "text": "acetaminophen",
       "locations": [
        {
         "offset": 791,
         "length": 13
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D001929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebral edema",
       "locations": [
        {
         "offset": 809,
         "length": 14
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 829,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D006985",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperventilation",
       "locations": [
        {
         "offset": 876,
         "length": 16
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D010243",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "paralysis",
       "locations": [
        {
         "offset": 917,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D007036",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypothermia",
       "locations": [
        {
         "offset": 1035,
         "length": 11
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1094,
         "length": 7
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D001929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebral edema",
       "locations": [
        {
         "offset": 1124,
         "length": 14
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D019586",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intracranial hypertension",
       "locations": [
        {
         "offset": 1143,
         "length": 25
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1264,
         "length": 8
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D017114",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FHF",
       "locations": [
        {
         "offset": 1278,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D001929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebral edema",
       "locations": [
        {
         "offset": 1286,
         "length": 14
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D000082",
        "type": "ChemicalEntity"
       },
       "text": "acetaminophen",
       "locations": [
        {
         "offset": 1306,
         "length": 13
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D007036",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypothermia",
       "locations": [
        {
         "offset": 1352,
         "length": 11
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D007036",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypothermia",
       "locations": [
        {
         "offset": 1486,
         "length": 11
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1501,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D000082",
      "entity2": "D003866",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D000082",
      "entity2": "D017114",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D000082",
      "entity2": "D001929",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "19881468",
   "passages": [
    {
     "offset": 0,
     "text": "hOGG1 Ser326Cys polymorphism and risk of lung cancer by histological type.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4968",
        "type": "GeneOrGeneProduct"
       },
       "text": "hOGG1",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs1052133",
        "type": "SequenceVariant"
       },
       "text": "Ser326Cys",
       "locations": [
        {
         "offset": 6,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 41,
         "length": 11
        }
       ]
      }
     ]
    },
    {
     "offset": 75,
     "text": "Human 8-oxoguanine DNA glycosylase 1 (hOGG1) has a major role in the repair of 8-hydroxyguanine, a major promutagenic DNA lesion. The genetic polymorphism rs1052133, which leads to substitution of the amino acid at codon 326 from Ser to Cys, shows functional differences, namely a decrease in enzyme activity in hOGG1-Cys326. Although several studies have investigated the association between rs1052133 and lung cancer susceptibility, the effect of this locus on lung cancer according to histology remains unclear. We therefore conducted a case-control study with 515 incident lung cancer cases and 1030 age- and sex-matched controls without cancer, and further conducted a meta-analysis. In overall analysis, the homozygous Cys/Cys genotype showed a significant association with lung cancer compared to Ser allele carrier status (odds ratio (OR)=1.31, 95% confidence interval (CI)=1.02-1.69). By histology-based analysis, the Cys/Cys genotype showed a significantly positive association with small-cell carcinoma (OR=2.40, 95% CI=1.32-4.49) and marginally significant association with adenocarcinoma (OR=1.32, 95% CI=0.98-1.77). A meta-analysis of previous and our present study revealed that this polymorphism is positively associated with adenocarcinoma, although suggestive associations were also found for squamous- and small-cell lung cancers. These results indicate that rs1052133 contributes to the risk of adenocarcinoma of lung.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Human",
       "locations": [
        {
         "offset": 75,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "4968",
        "type": "GeneOrGeneProduct"
       },
       "text": "8-oxoguanine DNA glycosylase 1",
       "locations": [
        {
         "offset": 81,
         "length": 30
        }
       ]
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       "text": "lung cancer",
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       "text": "lung cancer",
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       "text": "lung cancer",
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       "text": "cancer",
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       "id": "16",
       "infons": {
        "identifier": "D008175",
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       "text": "lung cancer",
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         "offset": 855,
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       "text": "small-cell carcinoma",
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         "offset": 1068,
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       "id": "18",
       "infons": {
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       "id": "19",
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       "infons": {
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       "text": "squamous- and small-cell lung cancers",
       "locations": [
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       "text": "adenocarcinoma of lung",
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         "length": 22
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  {
   "id": "20005218",
   "passages": [
    {
     "offset": 0,
     "text": "A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9365",
        "type": "GeneOrGeneProduct"
       },
       "text": "Klotho",
       "locations": [
        {
         "offset": 77,
         "length": 6
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "D000075222",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "essential hypertension",
       "locations": [
        {
         "offset": 112,
         "length": 22
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       ]
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     ]
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    {
     "offset": 166,
     "text": "BACKGROUND: Mice with defects in the Klotho gene exhibit multiple aging phenotypes including arteriosclerosis. We hypothesised that the G-395A polymorphism in the promoter region of the human Klotho gene may contribute to the prevalence of Essential Hypertension (EH). METHODS: We investigate whether the G-395A polymorphism of Klotho is associated with EH in a population consisting of 215 patients with EH and 220 non-hypertensive subjects. We also tested whether a G/A substitution at the G-395A site affected the transcription level in vitro through the dual-luciferase reporter assay. RESULTS: Differences in the genotype distributions of the G-395A polymorphism between the EH and non-hypertension groups are statistically significant (P=0.032). There are differential effects of age, gender and smoking status on the association of the G-395A polymorphism with EH; the G-395A polymorphism is significantly associated with EH in subjects over 60years old, in females and in nonsmokers. A multiple logistic regression analysis indicated that the odds ratio for EH in the -395A allele carriers as compared with the control group was 0.593 (P=0.024) after adjusting for current traditional risk factors. The dual-luciferase reporter assay revealed that the -395A carrier of a 498-bp DNA fragment (containing the G-395A site) upstream of the Klotho gene has higher relative luciferase activity than the -395G carrier. CONCLUSIONS: The G-395A polymorphism of the human Klotho gene is associated with EH and may be a potential regulatory site.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "Mice",
       "locations": [
        {
         "offset": 178,
         "length": 4
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "16591",
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       "text": "Klotho",
       "locations": [
        {
         "offset": 203,
         "length": 6
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       ]
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       "id": "4",
       "infons": {
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       "text": "arteriosclerosis",
       "locations": [
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         "offset": 259,
         "length": 16
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       "id": "5",
       "infons": {
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       "text": "G-395A",
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        {
         "offset": 302,
         "length": 6
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       ]
      },
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       "id": "6",
       "infons": {
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       "text": "human",
       "locations": [
        {
         "offset": 352,
         "length": 5
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       ]
      },
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       "id": "7",
       "infons": {
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       "text": "Klotho",
       "locations": [
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         "offset": 358,
         "length": 6
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       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "D000075222",
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       "text": "Essential Hypertension",
       "locations": [
        {
         "offset": 406,
         "length": 22
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000075222",
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       "text": "EH",
       "locations": [
        {
         "offset": 430,
         "length": 2
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs1207568",
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       "text": "G-395A",
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        {
         "offset": 471,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
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       "text": "Klotho",
       "locations": [
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         "offset": 494,
         "length": 6
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       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "D000075222",
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       "text": "EH",
       "locations": [
        {
         "offset": 520,
         "length": 2
        }
       ]
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       "id": "13",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 557,
         "length": 8
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       "id": "14",
       "infons": {
        "identifier": "D000075222",
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       "text": "EH",
       "locations": [
        {
         "offset": 571,
         "length": 2
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D006973",
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       "text": "hypertensive",
       "locations": [
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         "offset": 586,
         "length": 12
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       "id": "16",
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       "text": "G/A",
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         "offset": 634,
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       "id": "17",
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         "offset": 658,
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        "identifier": "rs1207568",
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         "offset": 814,
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       "id": "19",
       "infons": {
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       "text": "EH",
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        {
         "offset": 846,
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       "id": "20",
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       "text": "hypertension",
       "locations": [
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         "offset": 857,
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       "id": "21",
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         "offset": 1009,
         "length": 6
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       "text": "EH",
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         "offset": 1034,
         "length": 2
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       "id": "23",
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         "offset": 1042,
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       "id": "24",
       "infons": {
        "identifier": "D000075222",
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       "text": "EH",
       "locations": [
        {
         "offset": 1095,
         "length": 2
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       ]
      },
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       "id": "25",
       "infons": {
        "identifier": "D000075222",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "EH",
       "locations": [
        {
         "offset": 1232,
         "length": 2
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs1207568",
        "type": "SequenceVariant"
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       "text": "-395A",
       "locations": [
        {
         "offset": 1242,
         "length": 5
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "rs1207568",
        "type": "SequenceVariant"
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       "text": "-395A",
       "locations": [
        {
         "offset": 1426,
         "length": 5
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs1207568",
        "type": "SequenceVariant"
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       "text": "G-395A",
       "locations": [
        {
         "offset": 1481,
         "length": 6
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "9365",
        "type": "GeneOrGeneProduct"
       },
       "text": "Klotho",
       "locations": [
        {
         "offset": 1510,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "rs1207568",
        "type": "SequenceVariant"
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       "text": "-395G",
       "locations": [
        {
         "offset": 1571,
         "length": 5
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       ]
      },
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       "id": "31",
       "infons": {
        "identifier": "rs1207568",
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       "text": "G-395A",
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        {
         "offset": 1603,
         "length": 6
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       "id": "32",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
        {
         "offset": 1630,
         "length": 5
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       ]
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       "id": "33",
       "infons": {
        "identifier": "9365",
        "type": "GeneOrGeneProduct"
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       "text": "Klotho",
       "locations": [
        {
         "offset": 1636,
         "length": 6
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D000075222",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "EH",
       "locations": [
        {
         "offset": 1667,
         "length": 2
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     "id": "R1",
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   ]
  },
  {
   "id": "20034406",
   "passages": [
    {
     "offset": 0,
     "text": "Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "24770",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL2",
       "locations": [
        {
         "offset": 10,
         "length": 4
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "60463",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR2",
       "locations": [
        {
         "offset": 32,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D010862",
        "type": "ChemicalEntity"
       },
       "text": "pilocarpine",
       "locations": [
        {
         "offset": 80,
         "length": 11
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D013226",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "status epilepticus",
       "locations": [
        {
         "offset": 100,
         "length": 18
        }
       ]
      }
     ]
    },
    {
     "offset": 120,
     "text": "BACKGROUND: Neuroinflammation occurs after seizures and is implicated in epileptogenesis. CCR2 is a chemokine receptor for CCL2 and their interaction mediates monocyte infiltration in the neuroinflammatory cascade triggered in different brain pathologies. In this work CCR2 and CCL2 expression were examined following status epilepticus (SE) induced by pilocarpine injection. METHODS: SE was induced by pilocarpine injection. Control rats were injected with saline instead of pilocarpine. Five days after SE, CCR2 staining in neurons and glial cells was examined using imunohistochemical analyses. The number of CCR2 positive cells was determined using stereology probes in the hippocampus. CCL2 expression in the hippocampus was examined by molecular assay. RESULTS: Increased CCR2 was observed in the hippocampus after SE. Seizures also resulted in alterations to the cell types expressing CCR2. Increased numbers of neurons that expressed CCR2 was observed following SE. Microglial cells were more closely apposed to the CCR2-labeled cells in SE rats. In addition, rats that experienced SE exhibited CCR2-labeling in populations of hypertrophied astrocytes, especially in CA1 and dentate gyrus. These CCR2+ astroctytes were not observed in control rats. Examination of CCL2 expression showed that it was elevated in the hippocampus following SE. CONCLUSION: The data show that CCR2 and CCL2 are up-regulated in the hippocampus after pilocarpine-induced SE. Seizures also result in changes to CCR2 receptor expression in neurons and astrocytes. These changes might be involved in detrimental neuroplasticity and neuroinflammatory changes that occur following seizures.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Neuroinflammation",
       "locations": [
        {
         "offset": 132,
         "length": 17
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D012640",
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       "text": "seizures",
       "locations": [
        {
         "offset": 163,
         "length": 8
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       ]
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       "id": "6",
       "infons": {
        "identifier": "60463",
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       "text": "CCR2",
       "locations": [
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         "offset": 210,
         "length": 4
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       ]
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       "id": "7",
       "infons": {
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     "offset": 0,
     "text": "Association of adipocyte genes with ASP expression: a microarray analysis of subcutaneous and omental adipose tissue in morbidly obese subjects.",
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      {
       "id": "0",
       "infons": {
        "identifier": "718",
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     "text": "BACKGROUND: Prevalence of obesity is increasing to pandemic proportions. However, obese subjects differ in insulin resistance, adipokine production and co-morbidities. Based on fasting plasma analysis, obese subjects were grouped as Low Acylation Stimulating protein (ASP) and Triglyceride (TG) (LAT) vs High ASP and TG (HAT). Subcutaneous (SC) and omental (OM) adipose tissues (n = 21) were analysed by microarray, and biologic pathways in lipid metabolism and inflammation were specifically examined. METHODS: LAT and HAT groups were matched in age, obesity, insulin, and glucose, and had similar expression of insulin-related genes (InsR, IRS-1). ASP related genes tended to be increased in the HAT group and were correlated (factor B, adipsin, complement C3, p < 0.01 each). Differences between LAT and HAT group were almost exclusively in SC tissue, with little difference in OM tissue. Increased C5L2 (p < 0.01), an ASP receptor, in HAT suggests a compensatory ASP pathway, associated with increased TG storage. RESULTS: HAT adipose tissue demonstrated increased lipid related genes for storage (CD36, DGAT1, DGAT2, SCD1, FASN, and LPL), lipolysis (HSL, CES1, perilipin), fatty acid binding proteins (FABP1, FABP3) and adipocyte differentiation markers (CEBPalpha, CEBPbeta, PPARgamma). By contrast, oxidation related genes were decreased (AMPK, UCP1, CPT1, FABP7). HAT subjects had increased anti-inflammatory genes TGFB1, TIMP1, TIMP3, and TIMP4 while proinflammatory PIG7 and MMP2 were also significantly increased; all genes, p < 0.025. CONCLUSION: Taken together, the profile of C5L2 receptor, ASP gene expression and metabolic factors in adipose tissue from morbidly obese HAT subjects suggests a compensatory response associated with the increased plasma ASP and TG.",
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      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D046150",
      "entity2": "p|SUB|R|211|H",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D046150",
      "entity2": "2690",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "C563867",
      "entity2": "c|DUP|899|C|",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "C563867",
      "entity2": "p|SUB|R|211|H",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "C563867",
      "entity2": "2690",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "20708777",
   "passages": [
    {
     "offset": 0,
     "text": "Association of DNA polymorphisms within the CYP11B2/CYP11B1 locus and postoperative hypertension risk in the patients with aldosterone-producing adenomas.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1585",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B2",
       "locations": [
        {
         "offset": 44,
         "length": 7
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "1584",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B1",
       "locations": [
        {
         "offset": 52,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 84,
         "length": 12
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 109,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000236",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aldosterone-producing adenomas",
       "locations": [
        {
         "offset": 123,
         "length": 30
        }
       ]
      }
     ]
    },
    {
     "offset": 155,
     "text": "OBJECTIVES: Hypertension often persists after adrenalectomy for primary aldosteronism. Traditional factors associated with postoperative hypertension were evaluated, but whether genetic determinants were involved remains poorly understood. The aim of this study was to investigate the association of DNA polymorphisms within steroid synthesis genes (CYP11B2, CYP11B1) and the postoperative resolution of hypertension in Chinese patients undergoing adrenalectomy for aldosterone-producing adenomas (APA). METHODS: Ninety-three patients with APA were assessed for postoperative resolution of hypertension. All patients were genotyped for rs1799998 (C-344 T), intron 2 conversion, rs4539 (A2718G) within CYP11B2 and rs6410 (G22 5A), rs6387 (A2803G) within CYP11B1. The associations between CYPB11B2/CYP11B1 polymorphisms and persistent postoperative hypertension were assessed by multivariate analysis. RESULTS: CYP11B2-CYP11B1 haplotype was associated with persistent postoperative hypertension in Chinese patients undergoing adrenalectomy with APA (P = .006). Specifically, the rs4539 (AA) polymorphism was associated with persistent postoperative hypertension (P = .002). Multivariate logistic regression revealed the common haplotypes H1 (AGACT), H2 (AGAWT), and H3 (AGAWC) were associated with the persistent postoperative hypertension (P = .01, 0.03, 0.005 after Bonferroni correction). Additional predictors of persistent postoperative hypertension included duration of hypertension (P <.0005), family history of hypertension (P = .001), and elevated systolic blood pressure (P = .015). CONCLUSIONS: The rs4539 (AA), H1, H2, and H3 are genetic predictors for postoperative persistence of hypertension for Chinese patients treated by adrenalectomy with APA. DNA polymorphisms at CYP11B2/B1 locus may confer susceptibility to postoperative hypertension of patients with APA.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hypertension",
       "locations": [
        {
         "offset": 167,
         "length": 12
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 292,
         "length": 12
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1584,1585",
        "type": "GeneOrGeneProduct"
       },
       "text": "steroid synthesis genes",
       "locations": [
        {
         "offset": 480,
         "length": 23
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "1585",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B2",
       "locations": [
        {
         "offset": 505,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1584",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B1",
       "locations": [
        {
         "offset": 514,
         "length": 7
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 559,
         "length": 12
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 583,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D000236",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aldosterone-producing adenomas",
       "locations": [
        {
         "offset": 621,
         "length": 30
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D000236",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "APA",
       "locations": [
        {
         "offset": 653,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 681,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000236",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "APA",
       "locations": [
        {
         "offset": 695,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 745,
         "length": 12
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 763,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs1799998",
        "type": "SequenceVariant"
       },
       "text": "rs1799998",
       "locations": [
        {
         "offset": 791,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs1799998",
        "type": "SequenceVariant"
       },
       "text": "C-344 T",
       "locations": [
        {
         "offset": 802,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs4539",
        "type": "SequenceVariant"
       },
       "text": "rs4539",
       "locations": [
        {
         "offset": 833,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs4539",
        "type": "SequenceVariant"
       },
       "text": "A2718G",
       "locations": [
        {
         "offset": 841,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "1585",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B2",
       "locations": [
        {
         "offset": 856,
         "length": 7
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs6410",
        "type": "SequenceVariant"
       },
       "text": "rs6410",
       "locations": [
        {
         "offset": 868,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs6410",
        "type": "SequenceVariant"
       },
       "text": "G22 5A",
       "locations": [
        {
         "offset": 876,
         "length": 6
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs6387",
        "type": "SequenceVariant"
       },
       "text": "rs6387",
       "locations": [
        {
         "offset": 885,
         "length": 6
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs6387",
        "type": "SequenceVariant"
       },
       "text": "A2803G",
       "locations": [
        {
         "offset": 893,
         "length": 6
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "1584",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B1",
       "locations": [
        {
         "offset": 908,
         "length": 7
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "1585",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYPB11B2",
       "locations": [
        {
         "offset": 942,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "1584",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B1",
       "locations": [
        {
         "offset": 951,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1002,
         "length": 12
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "1585",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B2",
       "locations": [
        {
         "offset": 1064,
         "length": 7
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "1584",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B1",
       "locations": [
        {
         "offset": 1072,
         "length": 7
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1135,
         "length": 12
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1159,
         "length": 8
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D000236",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "APA",
       "locations": [
        {
         "offset": 1198,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "rs4539",
        "type": "SequenceVariant"
       },
       "text": "rs4539",
       "locations": [
        {
         "offset": 1232,
         "length": 6
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1302,
         "length": 12
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1480,
         "length": 12
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1595,
         "length": 12
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1629,
         "length": 12
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1672,
         "length": 12
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "rs4539",
        "type": "SequenceVariant"
       },
       "text": "rs4539",
       "locations": [
        {
         "offset": 1763,
         "length": 6
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1847,
         "length": 12
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1872,
         "length": 8
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "D000236",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "APA",
       "locations": [
        {
         "offset": 1911,
         "length": 3
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "1584,1585",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP11B2/B1",
       "locations": [
        {
         "offset": 1937,
         "length": 10
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1997,
         "length": 12
        }
       ]
      },
      {
       "id": "48",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 2013,
         "length": 8
        }
       ]
      },
      {
       "id": "49",
       "infons": {
        "identifier": "D000236",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "APA",
       "locations": [
        {
         "offset": 2027,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1584",
      "entity2": "D006973",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D006973",
      "entity2": "1585",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D006973",
      "entity2": "rs6387",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D006973",
      "entity2": "rs6410",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D006973",
      "entity2": "rs4539",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D006973",
      "entity2": "rs1799998",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D000236",
      "entity2": "1584",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "D000236",
      "entity2": "1585",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "D000236",
      "entity2": "rs6387",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "D000236",
      "entity2": "rs6410",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "D000236",
      "entity2": "rs4539",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "D000236",
      "entity2": "rs1799998",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "20806042",
   "passages": [
    {
     "offset": 0,
     "text": "A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "2703",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJA8",
       "locations": [
        {
         "offset": 20,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C538287",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cataract-microcornea syndrome",
       "locations": [
        {
         "offset": 44,
         "length": 29
        }
       ]
      }
     ]
    },
    {
     "offset": 97,
     "text": "PURPOSE: To identify the underlying genetic defect in a four-generation family of Chinese origin with autosomal dominant congenital cataract-microcornea syndrome (CCMC). METHODS: All individuals in the study underwent a full clinical examination and the details of history were collected . Genomic DNA extracted from peripheral blood was amplified by polymerase chain reaction (PCR) method and the exons of all candidate genes were sequenced. RESULTS: Direct sequencing of the encoding regions of the candidate genes revealed a heterozygous mutation c.592C-->T in exon 2 of the gap junction protein, alpha 8 (GJA8) gene. This mutation was responsible for the familial disorder through the substitution of a highly conserved arginine to tryptophan at codon 198 (p.R198W). This change co-segregated with all affected members of the family, but was not detected either in the non-carrier relatives or in the 100 normal controls. CONCLUSIONS: This report is the first to relate p.R198W mutation in GJA8 with CCMC. The result expands the mutation spectrum of GJA8 in associated with congenital cataract and microcornea, and implies that this gene has direct involvement with the development of the lens as well as the other anterior segment of the eye.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "genetic defect",
       "locations": [
        {
         "offset": 133,
         "length": 14
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C538287",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cataract-microcornea syndrome",
       "locations": [
        {
         "offset": 229,
         "length": 29
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C538287",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CCMC",
       "locations": [
        {
         "offset": 260,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "c|SUB|C|592|T",
        "type": "SequenceVariant"
       },
       "text": "c.592C-->T",
       "locations": [
        {
         "offset": 647,
         "length": 10
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2703",
        "type": "GeneOrGeneProduct"
       },
       "text": "gap junction protein, alpha 8",
       "locations": [
        {
         "offset": 675,
         "length": 29
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2703",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJA8",
       "locations": [
        {
         "offset": 706,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "p|SUB|R|198|W",
        "type": "SequenceVariant"
       },
       "text": "arginine to tryptophan at codon 198",
       "locations": [
        {
         "offset": 821,
         "length": 35
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "p|SUB|R|198|W",
        "type": "SequenceVariant"
       },
       "text": "p.R198W",
       "locations": [
        {
         "offset": 858,
         "length": 7
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "p|SUB|R|198|W",
        "type": "SequenceVariant"
       },
       "text": "p.R198W",
       "locations": [
        {
         "offset": 1071,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "2703",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJA8",
       "locations": [
        {
         "offset": 1091,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C538287",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CCMC",
       "locations": [
        {
         "offset": 1101,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "2703",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJA8",
       "locations": [
        {
         "offset": 1151,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D002386",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cataract",
       "locations": [
        {
         "offset": 1186,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D005124",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microcornea",
       "locations": [
        {
         "offset": 1199,
         "length": 11
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|C|592|T",
      "entity2": "D005124",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|SUB|C|592|T",
      "entity2": "C538287",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D002386",
      "entity2": "c|SUB|C|592|T",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "p|SUB|R|198|W",
      "entity2": "D005124",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "p|SUB|R|198|W",
      "entity2": "D002386",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "p|SUB|R|198|W",
      "entity2": "C538287",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "2703",
      "entity2": "D005124",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "2703",
      "entity2": "D002386",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "C538287",
      "entity2": "2703",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "21163864",
   "passages": [
    {
     "offset": 0,
     "text": "The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs699",
        "type": "SequenceVariant"
       },
       "text": "M235T",
       "locations": [
        {
         "offset": 4,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensinogen",
       "locations": [
        {
         "offset": 30,
         "length": 15
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 67,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertrophic cardiomyopathy",
       "locations": [
        {
         "offset": 79,
         "length": 27
        }
       ]
      }
     ]
    },
    {
     "offset": 108,
     "text": "INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI. RESULTS: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM. CONCLUSION: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hypertrophic cardiomyopathy",
       "locations": [
        {
         "offset": 122,
         "length": 27
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCM",
       "locations": [
        {
         "offset": 151,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D006331",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiac disease",
       "locations": [
        {
         "offset": 206,
         "length": 15
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs699",
        "type": "SequenceVariant"
       },
       "text": "T704C",
       "locations": [
        {
         "offset": 327,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensinogen",
       "locations": [
        {
         "offset": 363,
         "length": 15
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "AGT",
       "locations": [
        {
         "offset": 380,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCM",
       "locations": [
        {
         "offset": 395,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCM",
       "locations": [
        {
         "offset": 493,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sporadic hypertrophic cardiomyopathy",
       "locations": [
        {
         "offset": 501,
         "length": 36
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SHCM",
       "locations": [
        {
         "offset": 539,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D024741",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "familial hypertrophic cardiomyopathy",
       "locations": [
        {
         "offset": 552,
         "length": 36
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D024741",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FHCM",
       "locations": [
        {
         "offset": 590,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 597,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 673,
         "length": 12
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D017379",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "left ventricular hypertrophy",
       "locations": [
        {
         "offset": 690,
         "length": 28
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "AGT",
       "locations": [
        {
         "offset": 825,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs699",
        "type": "SequenceVariant"
       },
       "text": "methionine to threonine substitution at codon 235",
       "locations": [
        {
         "offset": 862,
         "length": 49
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs699",
        "type": "SequenceVariant"
       },
       "text": "M235T",
       "locations": [
        {
         "offset": 913,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "-",
        "type": "ChemicalEntity"
       },
       "text": "SfaNI",
       "locations": [
        {
         "offset": 1054,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SHCM",
       "locations": [
        {
         "offset": 1202,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1207,
         "length": 8
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D024741",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FHCM",
       "locations": [
        {
         "offset": 1281,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "183",
        "type": "GeneOrGeneProduct"
       },
       "text": "AGT",
       "locations": [
        {
         "offset": 1344,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D002312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SHCM",
       "locations": [
        {
         "offset": 1386,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D024741",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FHCM",
       "locations": [
        {
         "offset": 1516,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "183",
      "entity2": "D002312",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D002312",
      "entity2": "rs699",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "21615796",
   "passages": [
    {
     "offset": 0,
     "text": "Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "Interleukin-17F",
       "locations": [
        {
         "offset": 0,
         "length": 15
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 37,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D016553",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic immune thrombocytopenia",
       "locations": [
        {
         "offset": 51,
         "length": 31
        }
       ]
      }
     ]
    },
    {
     "offset": 84,
     "text": "INTRODUCTION: IL-17F is a novel inflammatory cytokine and plays an important role in some autoimmune diseases. We investigated the association between chronic ITP and the frequency of the single-nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161. PATIENTS AND METHODS: We examined 102 patients (men/women, 40/62; median age, 42) diagnosed with chronic ITP and 188 healthy controls (men/women, 78/110; median age, 38). Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Compared with the control group, patients with chronic ITP had a significantly lower frequency of the IL-17F 7488CC genotype (0% vs. 4.8%, P<0.05). The number of IL-17F 7488C alleles among the patients with chronic ITP was also significantly lower than in the control group (8.7% vs. 15.2% OR=0.48, 95%CI=0.27-0.84, P=0.016). Furthermore, patients with the IL-17F 7488TT genotype showed a severe thrombocytopenic state (platelet count<10 10(9) /L) at diagnosis than those with the IL-17F 7488TC genotype (20.9% vs. 0%, P=0.04). CONCLUSION: These findings suggest that the IL-17F 7488 T allele is significantly associated with the development of chronic ITP, suggesting a role for IL-17F in the pathogenesis of chronic ITP.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17F",
       "locations": [
        {
         "offset": 98,
         "length": 6
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "inflammatory cytokine",
       "locations": [
        {
         "offset": 116,
         "length": 21
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D001327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autoimmune diseases",
       "locations": [
        {
         "offset": 174,
         "length": 19
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D016553",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic ITP",
       "locations": [
        {
         "offset": 235,
         "length": 11
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "rs763780",
       "locations": [
        {
         "offset": 303,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "7488T/C",
       "locations": [
        {
         "offset": 313,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "His-to-Arg substitution at amino acid 161",
       "locations": [
        {
         "offset": 338,
         "length": 41
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "PATIENTS",
       "locations": [
        {
         "offset": 381,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 419,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 429,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 433,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D016553",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic ITP",
       "locations": [
        {
         "offset": 478,
         "length": 11
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 516,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 520,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 716,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D016553",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic ITP",
       "locations": [
        {
         "offset": 730,
         "length": 11
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17F",
       "locations": [
        {
         "offset": 785,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "7488CC",
       "locations": [
        {
         "offset": 792,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17F",
       "locations": [
        {
         "offset": 845,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "7488C",
       "locations": [
        {
         "offset": 852,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 876,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D016553",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic ITP",
       "locations": [
        {
         "offset": 890,
         "length": 11
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1022,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17F",
       "locations": [
        {
         "offset": 1040,
         "length": 6
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "7488TT",
       "locations": [
        {
         "offset": 1047,
         "length": 6
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D011696",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "thrombocytopenic",
       "locations": [
        {
         "offset": 1079,
         "length": 16
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17F",
       "locations": [
        {
         "offset": 1164,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "7488TC",
       "locations": [
        {
         "offset": 1171,
         "length": 6
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17F",
       "locations": [
        {
         "offset": 1255,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "rs763780",
        "type": "SequenceVariant"
       },
       "text": "7488 T",
       "locations": [
        {
         "offset": 1262,
         "length": 6
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D016553",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic ITP",
       "locations": [
        {
         "offset": 1328,
         "length": 11
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "112744",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17F",
       "locations": [
        {
         "offset": 1363,
         "length": 6
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D016553",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic ITP",
       "locations": [
        {
         "offset": 1393,
         "length": 11
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "112744",
      "entity2": "D011696",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "112744",
      "entity2": "D016553",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D001327",
      "entity2": "112744",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs763780",
      "entity2": "D011696",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D016553",
      "entity2": "rs763780",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "21682595",
   "passages": [
    {
     "offset": 0,
     "text": "XRCC1 Arg399Gln gene polymorphism and the risk of systemic lupus erythematosus in the Polish population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7515",
        "type": "GeneOrGeneProduct"
       },
       "text": "XRCC1",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs25487",
        "type": "SequenceVariant"
       },
       "text": "Arg399Gln",
       "locations": [
        {
         "offset": 6,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 50,
         "length": 28
        }
       ]
      }
     ]
    },
    {
     "offset": 105,
     "text": "It has been shown that DNA repair is reduced in patients with systemic lupus erythematosus (SLE) and that the X-ray repair cross-complementing (XRCC1) Arg399Gln (rs25487) polymorphism may contribute to DNA repair. We evaluated the frequency of the XRCC1 Arg399Gln substitution in patients with SLE (n=265) and controls (n=360) in a sample of the Polish population. The odds ratio (OR) for SLE patients with the Gln/Gln versus Gln/Arg or Arg/Arg genotypes was 1.553 (95% confidence interval [CI]=0.9573-2.520; p=0.0729). OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.551 (95% CI=1.122-2.144, p=0.0077). The OR for the 399 Gln allele in patients with SLE was 1.406 (95% CI=1.111-1.779, p=0.0045). There was also a statistically significant p-value of the (2) test for the trend observed in the XRCC1 Arg399Gln polymorphism (ptrend=0.0048). We also found a significant contribution of the Gln/Gln or Arg/Gln versus Arg/Arg genotype to the presence of either the malar rash or photosensitivity manifestations of SLE OR=2.241 (1.328-3.781, p=0.0023, pcorr=0.0414). Moreover, the meta-analysis of Taiwanese Han Chinese, Brazilian, and Polish populations showed that the Gln/Gln or Gln/Arg genotype and Gln allele were associated with SLE incidence. OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.440 (95% CI=1.15-1.80, p=0.0019) and OR for the Gln allele was 1.27 (95% CI=1.08-1.51, p=0.0051). Our studies may confirm that the XRCC1 Arg399Gln polymorphism may increase the risk of incidence of SLE and the occurrence of some SLE manifestations.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 153,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 167,
         "length": 28
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 197,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "7515",
        "type": "GeneOrGeneProduct"
       },
       "text": "X-ray repair cross-complementing",
       "locations": [
        {
         "offset": 215,
         "length": 32
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "7515",
        "type": "GeneOrGeneProduct"
       },
       "text": "XRCC1",
       "locations": [
        {
         "offset": 249,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs25487",
        "type": "SequenceVariant"
       },
       "text": "Arg399Gln",
       "locations": [
        {
         "offset": 256,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs25487",
        "type": "SequenceVariant"
       },
       "text": "rs25487",
       "locations": [
        {
         "offset": 267,
         "length": 7
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "7515",
        "type": "GeneOrGeneProduct"
       },
       "text": "XRCC1",
       "locations": [
        {
         "offset": 353,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs25487",
        "type": "SequenceVariant"
       },
       "text": "Arg399Gln",
       "locations": [
        {
         "offset": 359,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 385,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 399,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 494,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 498,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs25487",
        "type": "SequenceVariant"
       },
       "text": "399 Gln",
       "locations": [
        {
         "offset": 736,
         "length": 7
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 754,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 768,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "7515",
        "type": "GeneOrGeneProduct"
       },
       "text": "XRCC1",
       "locations": [
        {
         "offset": 911,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs25487",
        "type": "SequenceVariant"
       },
       "text": "Arg399Gln",
       "locations": [
        {
         "offset": 917,
         "length": 9
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D005076",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "malar rash",
       "locations": [
        {
         "offset": 1078,
         "length": 10
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 1127,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 1347,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "7515",
        "type": "GeneOrGeneProduct"
       },
       "text": "XRCC1",
       "locations": [
        {
         "offset": 1553,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs25487",
        "type": "SequenceVariant"
       },
       "text": "Arg399Gln",
       "locations": [
        {
         "offset": 1559,
         "length": 9
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 1620,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 1651,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "7515",
      "entity2": "D008180",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "7515",
      "entity2": "D005076",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs25487",
      "entity2": "D008180",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D005076",
      "entity2": "rs25487",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "22808010",
   "passages": [
    {
     "offset": 0,
     "text": "Defining an EPOR- regulated transcriptome for primary progenitors, including Tnfr-sf13c as a novel mediator of EPO- dependent erythroblast formation.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "13857",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPOR",
       "locations": [
        {
         "offset": 12,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "72049",
        "type": "GeneOrGeneProduct"
       },
       "text": "Tnfr-sf13c",
       "locations": [
        {
         "offset": 77,
         "length": 10
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "13856",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPO",
       "locations": [
        {
         "offset": 111,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 150,
     "text": "Certain concepts concerning EPO/EPOR action modes have been challenged by in vivo studies: Bcl-x levels are elevated in maturing erythroblasts, but not in their progenitors; truncated EPOR alleles that lack a major p85/PI3K recruitment site nonetheless promote polycythemia; and Erk1 disruption unexpectedly bolsters erythropoiesis. To discover novel EPO/EPOR action routes, global transcriptome analyses presently are applied to interrogate EPO/EPOR effects on primary bone marrow-derived CFUe-like progenitors. Overall, 160 EPO/EPOR target transcripts were significantly modulated 2-to 21.8-fold. A unique set of EPO-regulated survival factors included Lyl1, Gas5, Pim3, Pim1, Bim, Trib3 and Serpina 3g. EPO/EPOR-modulated cell cycle mediators included Cdc25a, Btg3, Cyclin-d2, p27-kip1, Cyclin-g2 and CyclinB1-IP-1. EPO regulation of signal transduction factors was also interestingly complex. For example, not only Socs3 plus Socs2 but also Spred2, Spred1 and Eaf1 were EPO-induced as negative-feedback components. Socs2, plus five additional targets, further proved to comprise new EPOR/Jak2/Stat5 response genes (which are important for erythropoiesis during anemia). Among receptors, an atypical TNF-receptor Tnfr-sf13c was up-modulated    >5-fold by EPO. Functionally, Tnfr-sf13c ligation proved to both promote proerythroblast survival, and substantially enhance erythroblast formation. The EPOR therefore engages a sophisticated set of transcriptome response circuits, with Tnfr-sf13c deployed as one novel positive regulator of proerythroblast formation.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "13856",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPO",
       "locations": [
        {
         "offset": 178,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "13857",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPOR",
       "locations": [
        {
         "offset": 182,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "12048",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bcl-x",
       "locations": [
        {
         "offset": 241,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "13857",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPOR",
       "locations": [
        {
         "offset": 334,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "18708",
        "type": "GeneOrGeneProduct"
       },
       "text": "p85/PI3K",
       "locations": [
        {
         "offset": 365,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D011086",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "polycythemia",
       "locations": [
        {
         "offset": 411,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "26417",
        "type": "GeneOrGeneProduct"
       },
       "text": "Erk1",
       "locations": [
        {
         "offset": 429,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "13856",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPO",
       "locations": [
        {
         "offset": 501,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "13857",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPOR",
       "locations": [
        {
         "offset": 505,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "13856",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPO",
       "locations": [
        {
         "offset": 592,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "13857",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPOR",
       "locations": [
        {
         "offset": 596,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "13856",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPO",
       "locations": [
        {
         "offset": 676,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "13857",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPOR",
       "locations": [
        {
         "offset": 680,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "13856",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPO",
       "locations": [
        {
         "offset": 765,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "17095",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lyl1",
       "locations": [
        {
         "offset": 805,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "14455",
        "type": "GeneOrGeneProduct"
       },
       "text": "Gas5",
       "locations": [
        {
         "offset": 811,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "223775",
        "type": "GeneOrGeneProduct"
       },
       "text": "Pim3",
       "locations": [
        {
         "offset": 817,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "18712",
        "type": "GeneOrGeneProduct"
       },
       "text": "Pim1",
       "locations": [
        {
         "offset": 823,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "12125",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bim",
       "locations": [
        {
         "offset": 829,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "228775",
        "type": "GeneOrGeneProduct"
       },
       "text": "Trib3",
       "locations": [
        {
         "offset": 834,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "20715",
        "type": "GeneOrGeneProduct"
       },
       "text": "Serpina 3g",
       "locations": [
        {
         "offset": 844,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "13856",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPO",
       "locations": [
        {
         "offset": 856,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "13857",
        "type": "GeneOrGeneProduct"
       },
       "text": "EPOR",
       "locations": [
        {
         "offset": 860,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "12530",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cdc25a",
       "locations": [
        {
         "offset": 905,
         "length": 6
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "12228",
        "type": "GeneOrGeneProduct"
       },
       "text": "Btg3",
       "locations": [
        {
         "offset": 913,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "12444",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cyclin-d2",
       "locations": [
        {
         "offset": 919,
         "length": 9
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "12576",
        "type": "GeneOrGeneProduct"
       },
       "text": "p27-kip1",
       "locations": [
        {
         "offset": 930,
         "length": 8
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "12452",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cyclin-g2",
       "locations": [
        {
         "offset": 940,
         "length": 9
        }
       ]
      },
      {
       "id": "31",
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     "offset": 0,
     "text": "Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients.",
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       "id": "0",
       "infons": {
        "identifier": "9456",
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     "text": "Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.",
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   "passages": [
    {
     "offset": 0,
     "text": "Midline B3 serotonin nerves in rat medulla are involved in hypotensive effect of methyldopa.",
     "annotations": [
      {
       "id": "0",
       "infons": {
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     "text": "Previous experiments in this laboratory have shown that microinjection of methyldopa onto the ventrolateral cells of the B3 serotonin neurons in the medulla elicits a hypotensive response mediated by a projection descending into the spinal cord. The present experiments were designed to investigate the role of the midline cells of the B3 serotonin neurons in the medulla, coinciding with the raphe magnus. In spontaneously hypertensive, stroke-prone rats, microinjection of methyldopa into the area of the midline B3 serotonin cell group in the ventral medulla caused a potent hypotension of 30-40 mm Hg, which was maximal 2-3 h after administration and was abolished by the serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) injected intracerebroventricularly. However, intraspinal injection of 5,7-DHT to produce a more selective lesion of only descending serotonin projections in the spinal cord did not affect this hypotension. Further, 5,7-DHT lesion of serotonin nerves travelling in the median forebrain bundle, one of the main ascending pathways from the B3 serotonin cells, did not affect the fall in blood pressure associated with a midline B3 serotonin methyldopa injection. It is concluded therefore that, unlike the ventrolateral B3 cells which mediate a methyldopa-induced hypotension via descending projections, the midline serotonin B3 cells in the medulla contribute to the hypotensive action of methyldopa, either by way of an ascending projection which does not pass through the median forebrain bundle, or through a projection restricted to the caudal brainstem.",
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     "text": "Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity.",
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     "text": "PURPOSE: NADPH oxidase-generated reactive oxygen species (ROS) are implicated in angiogenesis. Isoforms of NADPH oxidase NOX1, NOX2, and NOX4 are reported to be expressed in endothelial cells (ECs). Of these, NOX1 and NOX2 have been reported to contribute to intravitreal neovascularization (IVNV) in oxygen-induced retinopathy (OIR) models. In this study, we tested the hypothesis that the isoform NOX4 in ECs contributed to vascular endothelial growth factor (VEGF)-induced angiogenesis and IVNV. METHODS: Isoforms of NADPH oxidase MRNA were measured in several types of cultured vascular ecs: human retinal microvascular ECs (hRMVECs), choroidal ECs (CECs), and human umbilical vascular ECs (HUVECs) using real-time PCR. Newborn rat pups and dams were placed into an OIR model that cycled oxygen concentration between 50% and 10% every 24 h for 14 days, and then were placed in room air (RA) for an additional 4 days (rat OIR model). NOX4 expression in retinal lysates from the RA-raised pups at postnatal day 0 (P0), P14, and P18 was determined with western blots. STAT3 activation was determined as the ratio of phosphorylated STAT3 to total STAT3 with western blot analysis of retinal lysates from pups raised in RA or from the rat OIR model at P18. Semiquantitative assessment of the density of NOX4 colabeling with lectin-stained retinal ECs was determined by immunolabeling of retinal cryosections from P18 pups in OIR or in RA. In hRMVECs transfected with NOX4 siRNA and treated with VEGF or control, 1) ROS generation was measured using the 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester fluorescence assay and 2) phosphorylated VEGF receptor 2 and STAT3, and total VEGFR2 and STAT3 were measured in western blot analyses. VEGF-stimulated hRMVEC proliferation was measured following transfection with NOX4 siRNA or STAT3 siRNA, or respective controls. RESULTS: NOX4 was the most prevalent isoform of NADPH oxidase in vascular ECs. NOX4 expression in retinal lysates was significantly decreased during development in RA. Compared to RA, the expression of retinal NOX4 increased at P18. At p18 OIR, semiquantitative assessment of the density of lectin and NOX4 colabeling in retinal vascular ECs was greater in retinal cryosections and activated STAT3 was greater in retinal lysates when compared to the RA-raised pups. In cultured hRMVECs, knockdown of NOX4 by siRNA transfection inhibited VEGF-induced ROS generation. VEGF induced a physical interaction of phosphorylated-VEGFR2 and NOX4. Knockdown of NOX4: 1) reduced VEGFR2 activation but did not abolish it and 2) abolished STAT3 activation in response to VEGF. Knockdown of either NOX4 or STAT3 inhibited VEGF-induced EC proliferation. CONCLUSIONS: Our data suggest that in a model representative of human retinopathy of prematurity, NOX4 was increased at a time point when IVNV developed. VEGF-activated NOX4 led to an interaction between VEGF-activated VEGFR2 and NOX4 that mediated EC proliferation via activation of STAT3. Altogether, our results suggest that NOX4 may regulate VEGFR2-mediated IVNV through activated STAT3.",
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     "text": "Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures.",
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     "id": "R12",
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      "entity1": "C573355",
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    },
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  {
   "id": "24971338",
   "passages": [
    {
     "offset": 0,
     "text": "Conversion to sirolimus ameliorates cyclosporine-induced nephropathy in the rat: focus on serum, urine, gene, and protein renal expression biomarkers.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D020123",
        "type": "ChemicalEntity"
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       "text": "sirolimus",
       "locations": [
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       "id": "1",
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       "text": "cyclosporine",
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         "length": 12
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       "infons": {
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       "text": "nephropathy",
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         "length": 11
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       ]
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       "text": "rat",
       "locations": [
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         "offset": 76,
         "length": 3
        }
       ]
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     ]
    },
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     "offset": 151,
     "text": "Protocols of conversion from cyclosporin A (CsA) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-b, NF- kb, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF- b and IL-7, TBARs clearance, and kidney TGF-b and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to SRL.",
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       "id": "4",
       "infons": {
        "identifier": "D016572",
        "type": "ChemicalEntity"
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       "text": "cyclosporin A",
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         "length": 3
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       "text": "sirolimus",
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       "text": "SRL",
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         "length": 3
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        "identifier": "D016572",
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       ]
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       "text": "nephropathy",
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         "length": 11
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        "identifier": "D020123",
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       "text": "SRL",
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         "length": 3
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       ]
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       "id": "12",
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       "text": "rat",
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        {
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         "length": 3
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       "text": "SRL",
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       "id": "15",
       "infons": {
        "identifier": "D016572",
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       "text": "CsA",
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       ]
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        "identifier": "D020123",
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       "text": "SRL",
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       "text": "Renal lesions",
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       "text": "renal damage",
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       "id": "38",
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       "id": "39",
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  {
   "id": "25054547",
   "passages": [
    {
     "offset": 0,
     "text": "Characterization of a novel BCHE \"silent\" allele: point mutation (p.Val204Asp) causes loss of activity and prolonged apnea with suxamethonium.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "590",
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       "text": "BCHE",
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       "id": "1",
       "infons": {
        "identifier": "p|SUB|V|204|D",
        "type": "SequenceVariant"
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       "text": "p.Val204Asp",
       "locations": [
        {
         "offset": 66,
         "length": 11
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      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001049",
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       "text": "apnea",
       "locations": [
        {
         "offset": 117,
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      {
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       "text": "suxamethonium",
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    {
     "offset": 143,
     "text": "Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a \"silent\" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 uM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels.",
     "annotations": [
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       "id": "4",
       "infons": {
        "identifier": "C537417",
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       "text": "Butyrylcholinesterase deficiency",
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     "id": "R5",
     "infons": {
      "entity1": "3939",
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  {
   "id": "27640183",
   "passages": [
    {
     "offset": 0,
     "text": "Erythropoietin does not activate erythropoietin receptor signaling or lipolytic pathways in human subcutaneous white adipose tissue in vivo.",
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       "id": "0",
       "infons": {
        "identifier": "2056",
        "type": "GeneOrGeneProduct"
       },
       "text": "Erythropoietin",
       "locations": [
        {
         "offset": 0,
         "length": 14
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       "id": "1",
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       "text": "erythropoietin receptor",
       "locations": [
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         "offset": 33,
         "length": 23
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       "id": "2",
       "infons": {
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       "text": "human",
       "locations": [
        {
         "offset": 92,
         "length": 5
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     ]
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     "offset": 141,
     "text": "BACKGROUND: Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo. METHOD: Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA). RESULTS: No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA. CONCLUSION: Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.",
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       "text": "Erythropoietin",
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       "text": "mice",
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       "text": "humans",
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         "offset": 284,
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         "offset": 291,
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         "offset": 349,
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       "text": "human",
       "locations": [
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         "offset": 392,
         "length": 5
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       "id": "11",
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         "offset": 489,
         "length": 3
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       "text": "human",
       "locations": [
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         "offset": 505,
         "length": 5
        }
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       "id": "13",
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        "identifier": "2056",
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       "text": "Epo",
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         "offset": 586,
         "length": 3
        }
       ]
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       "id": "14",
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       "text": "erythropoiesis-stimulating agent",
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         "length": 32
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       "id": "15",
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         "offset": 723,
         "length": 3
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       "id": "16",
       "infons": {
        "identifier": "-",
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       "text": "Perilipin",
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  {
   "id": "27999109",
   "passages": [
    {
     "offset": 0,
     "text": "A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "288264,686326",
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       "text": "Type I Interferon Receptor",
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     "offset": 97,
     "text": "The pathogenesis of human type 1 diabetes, characterized by immune-mediated damage of insulin-producing b-cells of pancreatic islets, may involve viral infection. Essential components of the innate immune antiviral response, including type I interferon (IFN) and IFN receptor-mediated signaling pathways, are candidates for determining susceptibility to human type 1 diabetes. Numerous aspects of human type 1 diabetes pathogenesis are recapitulated in the LEW.1WR1 rat model. Diabetes can be induced in LEW.1WR1 weanling rats challenged with virus or with the viral mimetic polyinosinic:polycytidylic acid (poly I:C). We hypothesized that disrupting the cognate type I IFN receptor (type I IFN a/b receptor [IFNAR]) to interrupt IFN signaling would prevent or delay the development of virus-induced diabetes. We generated IFNAR1 subunit-deficient LEW.1WR1 rats using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9) genome editing and confirmed functional disruption of the Ifnar1 gene. IFNAR1 deficiency significantly delayed the onset and frequency of diabetes and greatly reduced the intensity of insulitis after poly I:C treatment. The occurrence of Kilham rat virus-induced diabetes was also diminished in IFNAR1-deficient animals. These findings firmly establish that alterations in innate immunity influence the course of autoimmune diabetes and support the use of targeted strategies to limit or prevent the development of type 1 diabetes.",
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       "text": "human",
       "locations": [
        {
         "offset": 451,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D003922",
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       "text": "type 1 diabetes",
       "locations": [
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       ]
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       "id": "12",
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       "text": "human",
       "locations": [
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         "offset": 494,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003922",
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       "text": "type 1 diabetes",
       "locations": [
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         "length": 15
        }
       ]
      },
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       "id": "14",
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       "text": "rat",
       "locations": [
        {
         "offset": 563,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D003920",
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       "text": "Diabetes",
       "locations": [
        {
         "offset": 574,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
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       "text": "rats",
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        }
       ]
      },
      {
       "id": "17",
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       "text": "polyinosinic:polycytidylic acid",
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        }
       ]
      },
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       "id": "18",
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       "text": "poly I:C",
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       "text": "type I IFN a/b receptor",
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      },
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       "id": "21",
       "infons": {
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     "text": "Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease.",
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     "text": "Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacological therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120,286 participants in the UK Biobank and summary association results from four large-scale genome-wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes, and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (odds ratio [OR] 0.93; 95% CI 0.91, 0.95; P = 1.2 x 10(-11)). The variant was associated with increased BMI (+0.062 kg/m(2); 95% CI 0.037, 0.086; P = 8.1 x 10(-7)) but lower waist-to-hip ratio adjusted for BMI, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98; 95% CI 0.96, 0.99; P = 5.9 x 10(-4)). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease.",
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     "text": "Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor.",
     "annotations": [
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       "id": "0",
       "infons": {
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       "text": "inflammatory",
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     "text": "The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected against barrier dysfunction caused by vasoactive peptide thrombin and proinflammatory bacterial wall lipopolysaccharide (LPS). Receptor screening using pharmacological and molecular inhibitory approaches identified EP4 as a novel PGA2 receptor. EP4 mediated barrier-protective effects of PGA2 by activating Rap1/Rac1 GTPase and protein kinase A targets at cell adhesions and cytoskeleton: VE-cadherin, p120-catenin, ZO-1, cortactin, and VASP. PGA2 also suppressed LPS-induced inflammatory signaling by inhibiting the NFkB pathway and expression of EC adhesion molecules ICAM1 and VCAM1. These effects were abolished by pharmacological or molecular inhibition of EP4. In vivo, PGA2 was protective in two distinct models of acute lung injury (ALI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and injection of thrombin receptor-activating peptide. These protective effects were abolished in mice with endothelial-specific EP4 knockout. The results suggest a novel role for the PGA2-EP4 axis in vascular EC protection that is critical for improvement of pathological states associated with increased vascular leakage and inflammation.",
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       "text": "thrombin",
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     "text": "Hypoglycemic Effect of Combined Ghrelin and Glucagon Receptor Blockade.",
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     "text": "Glucagon receptor (GcgR) blockade has been proposed as an alternative to insulin monotherapy for treating type 1 diabetes since deletion or inhibition of GcgRs corrects hyperglycemia in models of diabetes. The factors regulating glycemia in a setting devoid of insulin and glucagon function remain unclear but may include the hormone ghrelin. Not only is ghrelin release controlled by glucose but also ghrelin has many actions that can raise or reduce falls in blood glucose level. Here, we tested the hypothesis that ghrelin rises to prevent hypoglycemia in the absence of glucagon function. Both GcgR knockout (Gcgr(-/-)) mice and db/db mice that were administered GcgR monoclonal antibody displayed lower blood glucose levels accompanied by elevated plasma ghrelin levels. Although treatment with the pancreatic b-cell toxin streptozotocin induced hyperglycemia and raised plasma ghrelin levels in wild-type mice, hyperglycemia was averted in similarly treated Gcgr(-/-) mice and the plasma ghrelin level was further increased. Notably, administration of a ghrelin receptor antagonist further reduced blood glucose levels into the markedly hypoglycemic range in overnight-fasted, streptozotocin-treated Gcgr(-/-) mice. A lowered blood glucose level also was observed in overnight-fasted, streptozotocin-treated ghrelin receptor-null mice that were administered GcgR monoclonal antibody. These data suggest that when glucagon activity is blocked in the setting of type 1 diabetes, the plasma ghrelin level rises, preventing hypoglycemia.",
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     "offset": 0,
     "text": "Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma.",
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       "id": "0",
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       "text": "LH-releasing hormone",
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       "text": "LH-RH",
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       "text": "NaCl",
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       "text": "hyperprolactinemia",
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     "text": "Cardiovascular complications associated with terbutaline treatment for preterm labor.",
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       "id": "0",
       "infons": {
        "identifier": "D002318",
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     "text": "Severe cardiovascular complications occurred in eight of 160 patients treated with terbutaline for preterm labor. Associated corticosteroid therapy and twin gestations appear to be predisposing factors. Potential mechanisms of the pathophysiology are briefly discussed.",
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       "id": "3",
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     "text": "Cloning of human very-long-chain acyl-coenzyme A dehydrogenase and molecular characterization of its deficiency in two patients.",
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     "text": "Two overlapping cDNA clones (1, 991 bp and 736 bp, respectively) encoding the precursor of human mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) were cloned and sequenced. The cDNA inserts of these clones together encompass a region of 2, 177 bases, encoding the entire protein of 655 amino acids, including a 40-amino acid leader peptide and a 615-amino acid mature polypeptide. PCR-amplified VLCAD cDNAs were sequenced in cultured fibroblasts from two VLCAD-deficient patients. In both patients, a 105-bp deletion encompassing bases 1078-1182 in VLCAD cDNA was identified. The deletion seems to occur due to exon skipping during processing of VLCAD pre-mRNA. This is the first demonstration of a mutation causing VLCAD deficiency. Quantitative cDNA expression of normal human VLCAD was performed in the patients fibroblasts, using vaccinia viral system, which demonstrated that the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients fibroblasts. In patient fibroblasts, raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts, which may offer important information for the rational design of future somatic gene therapy for VLCAD deficiency.. ",
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       "text": "deficiency of the normal VLCAD protein",
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       "text": "long-chain fatty acid",
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     "offset": 0,
     "text": "Human mu opiate receptor. cDNA and genomic clones, pharmacologic characterization and chromosomal assignment.",
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       "text": "Human",
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     "text": "A human mu opiate receptor cDNA has been identified from a cerebral cortical cDNA library using sequences from the rat mu opiate receptor cDNA. The human mu opiate receptor (h mu OR1) shares 95% amino acid identity with the rat sequence. The expressed mu OR1 recognized tested opiate drugs and opioid peptides in a sodium- and GTP-sensitive fashion with affinities virtually identical to those displayed by the rat mu opiate receptor. Effects on cyclic AMP are similar to those noted for the rat mu opiate receptor. An 18 kb genomic clone hybridizing with the h mu OR1 cDNA contains 63 and 489 bp exonic sequences flanked by splice donor/acceptor sequences. Analysis of hybridization to DNA prepared from human rodent hybrid cell lines and chromosomal in situ hybridization studies indicate localization to 6q24-25. An MspI polymorphism, producing a 3.7 kb band, may prove useful in assessing this gene's involvement in neuropsychiatric disorders involving opiatergic systems.",
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       "text": "h mu OR1",
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       "text": "mu OR1",
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       "text": "opiate",
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         "offset": 387,
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       "infons": {
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       "text": "opioid peptides",
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       "text": "sodium",
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       "text": "h mu OR1",
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       "text": "human",
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      },
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       "text": "neuropsychiatric disorders",
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D006160",
      "entity2": "25601",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "25601",
      "entity2": "D018847",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "25601",
      "entity2": "D053610",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D012964",
      "entity2": "25601",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "8002973",
   "passages": [
    {
     "offset": 0,
     "text": "Adrenoleukodystrophy gene encodes an 80 kDa membrane protein.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "215",
        "type": "GeneOrGeneProduct"
       },
       "text": "Adrenoleukodystrophy gene",
       "locations": [
        {
         "offset": 0,
         "length": 25
        }
       ]
      }
     ]
    },
    {
     "offset": 62,
     "text": "An antibody against the synthetic C-terminal peptides deduced from the cDNA of the gene responsible for X-linked adrenoleukodystrophy (ALD) was produced to characterize the product of the ALD gene. The antibody reacted with the 80 kDa band protein in control fibroblasts, while no bands were detected in the fibroblasts from a patient with ALD (# 163), in which mRNA of the ALD gene was undetectable based on Northern blot analysis. The 293T cells transfected with the full-coding cDNA inserted in the expression vector produced a new 80 kDa protein, as detected by Western blot. In an immunocytological study, the staining was in a punctate pattern, in the normal fibroblasts. However, there was no punctate staining in the # 163 cells. These data thus indicate that the ALD gene encodes an 80 kDa membrane protein.. ",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked adrenoleukodystrophy",
       "locations": [
        {
         "offset": 166,
         "length": 29
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 197,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "215",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 250,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 389,
         "length": 7
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 402,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "215",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 436,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "CVCL_0063",
        "type": "CellLine"
       },
       "text": "293T",
       "locations": [
        {
         "offset": 499,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "215",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 834,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D000326",
      "entity2": "215",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "8755918",
   "passages": [
    {
     "offset": 0,
     "text": "Mutations associated with variant phenotypes in ataxia-telangiectasia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D001260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ataxia-telangiectasia",
       "locations": [
        {
         "offset": 48,
         "length": 21
        }
       ]
      }
     ]
    },
    {
     "offset": 71,
     "text": "We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10% -15% of A-T families identified in the United Kingdom). In 10 of these families, all the homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice-donor site. The second A-T allele has a different mutation in each patient. We show that the less severe phenotype in these patients is caused by some degree of normal splicing, which occurs as an alternative product from the insertion-containing allele. The level of the 137-bp PCR product containing the insertion was lowest in two patients who showed a later onset of cerebellar ataxia. A further four families who do not have this insertion have been identified. Mutations detected in two of four of these are missense mutations, normally rare in A-T patients. The demonstration of mutations giving rise to a slightly milder phenotype in A-T raises the interesting question of what range of phenotypes might occur in individuals in whom both mutations are milder. One possibility might be that individuals who are compound heterozygotes for ATM mutations are more common than we realize.. ",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D001260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ataxia-telangiectasia",
       "locations": [
        {
         "offset": 107,
         "length": 21
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "A-T",
       "locations": [
        {
         "offset": 130,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "472",
        "type": "GeneOrGeneProduct"
       },
       "text": "ATM",
       "locations": [
        {
         "offset": 160,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D001260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "A-T",
       "locations": [
        {
         "offset": 261,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "c|INS||137",
        "type": "SequenceVariant"
       },
       "text": "137-bp insertion",
       "locations": [
        {
         "offset": 361,
         "length": 16
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "A-T",
       "locations": [
        {
         "offset": 476,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 520,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 577,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 787,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D002524",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebellar ataxia",
       "locations": [
        {
         "offset": 824,
         "length": 17
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "A-T",
       "locations": [
        {
         "offset": 1004,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1008,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D001260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "A-T",
       "locations": [
        {
         "offset": 1095,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "472",
        "type": "GeneOrGeneProduct"
       },
       "text": "ATM",
       "locations": [
        {
         "offset": 1298,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "472",
      "entity2": "D002524",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D001260",
      "entity2": "472",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|INS||137",
      "entity2": "D002524",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|INS||137",
      "entity2": "D001260",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "9294109",
   "passages": [
    {
     "offset": 0,
     "text": "Myotonic dystrophy protein kinase is involved in the modulation of the Ca2+ homeostasis in skeletal muscle cells.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "Myotonic dystrophy protein kinase",
       "locations": [
        {
         "offset": 0,
         "length": 33
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2+",
       "locations": [
        {
         "offset": 71,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 114,
     "text": "Myotonic dystrophy (DM), the most prevalent muscular disorder in adults, is caused by (CTG) n-repeat expansion in a gene encoding a protein kinase (DM protein kinase; DMPK) and involves changes in cytoarchitecture and ion homeostasis. To obtain clues to the normal biological role of DMPK in cellular ion homeostasis, we have compared the resting [Ca2 +] i, the amplitude and shape of depolarization-induced Ca2 + transients, and the content of ATP-driven ion pumps in cultured skeletal muscle cells of wild-type and DMPK [-/-] knockout mice. In vitro-differentiated DMPK [-/-] myotubes exhibit a higher resting [Ca2 +] i than do wild-type myotubes because of an altered open probability of voltage-dependent l-type Ca2 + and Na + channels. The mutant myotubes exhibit smaller and slower Ca2 + responses upon triggering by acetylcholine or high external K +. In addition, we observed that these Ca2 + transients partially result from an influx of extracellular Ca2 + through the l-type Ca2 + channel. Neither the content nor the activity of Na +/K + ATPase and sarcoplasmic reticulum Ca2 + -ATPase are affected by DMPK absence. In conclusion, our data suggest that DMPK is involved in modulating the initial events of excitation-contraction coupling in skeletal muscle.. ",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D009223",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Myotonic dystrophy",
       "locations": [
        {
         "offset": 114,
         "length": 18
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009223",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DM",
       "locations": [
        {
         "offset": 134,
         "length": 2
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "muscular disorder",
       "locations": [
        {
         "offset": 158,
         "length": 17
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "DM protein kinase",
       "locations": [
        {
         "offset": 262,
         "length": 17
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMPK",
       "locations": [
        {
         "offset": 281,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMPK",
       "locations": [
        {
         "offset": 398,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 462,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 522,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000255",
        "type": "ChemicalEntity"
       },
       "text": "ATP",
       "locations": [
        {
         "offset": 559,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMPK",
       "locations": [
        {
         "offset": 631,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 651,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMPK",
       "locations": [
        {
         "offset": 681,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 727,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 830,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D012964",
        "type": "ChemicalEntity"
       },
       "text": "Na +",
       "locations": [
        {
         "offset": 840,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 902,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D000109",
        "type": "ChemicalEntity"
       },
       "text": "acetylcholine",
       "locations": [
        {
         "offset": 937,
         "length": 13
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D011188",
        "type": "ChemicalEntity"
       },
       "text": "K +",
       "locations": [
        {
         "offset": 968,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 1009,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 1075,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca2 +",
       "locations": [
        {
         "offset": 1100,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "-",
        "type": "ChemicalEntity"
       },
       "text": "Na +/K + ATPase",
       "locations": [
        {
         "offset": 1155,
         "length": 15
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D053498",
        "type": "ChemicalEntity"
       },
       "text": "sarcoplasmic reticulum Ca2 + -ATPase",
       "locations": [
        {
         "offset": 1175,
         "length": 36
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMPK",
       "locations": [
        {
         "offset": 1228,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "13400",
        "type": "GeneOrGeneProduct"
       },
       "text": "DMPK",
       "locations": [
        {
         "offset": 1279,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D009223",
      "entity2": "13400",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D002118",
      "entity2": "13400",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "9647766",
   "passages": [
    {
     "offset": 0,
     "text": "cDNA sequence and chromosomal localization of the remaining three human nuclear encoded iron sulphur protein (IP) subunits of complex I: the human IP fraction is completed.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 66,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4720,4722,4726",
        "type": "GeneOrGeneProduct"
       },
       "text": "nuclear encoded iron sulphur protein (IP) subunits of complex I",
       "locations": [
        {
         "offset": 72,
         "length": 63
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 141,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "4720,4722,4726",
        "type": "GeneOrGeneProduct"
       },
       "text": "IP",
       "locations": [
        {
         "offset": 147,
         "length": 2
        }
       ]
      }
     ]
    },
    {
     "offset": 173,
     "text": "NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain can be fragmented in a flavoprotein (FP), iron-sulfur protein (IP), and hydrophobic protein (HP) subfraction. The IP subfraction is hypothesized to be significant, since it contains important prosthetic groups highly conserved among species. We cloned the cDNA of three remaining human NADH:ubiquinone oxidoreductase subunits of this IP fraction: the NDUFS2 (49 kDa), NDUFS3 (30 kDa), and NDUFS6 (13 kDa) subunits. All presented cDNAs include the complete open reading frame (ORF), which consist of 1392, 795, and 375 base pairs, coding for 463, 264, and 124 amino acids, respectively. The latter show 96, 90, and 83% homology with the corresponding bovine translation products. The 3' untranslated regions (UTR) are complete in all three cDNAs. Polymerase chain reaction performed with DNA isolated from somatic human-rodent cell hybrids containing defined human chromosomes as template gave a human-specific signal which mapped the NDUFS2 and NDUFS3 subunits to chromosomes 1 and 11, respectively. In the case of the NDUFS6 subunit a pseudogene may be present since signals were seen in the lanes containing chromosomes 5 and 6. The NDUFS2 contains a highly conserved protein kinase C phosphorylation site and the NDUFS3 subunit contains a highly conserved casein kinase II phosphorylation site which make them strong candidates for future mutation detection studies in enzymatic complex I-deficient patients.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "4720,4722,4726",
        "type": "GeneOrGeneProduct"
       },
       "text": "NADH:ubiquinone oxidoreductase (complex I)",
       "locations": [
        {
         "offset": 173,
         "length": 42
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "-",
        "type": "GeneOrGeneProduct"
       },
       "text": "flavoprotein",
       "locations": [
        {
         "offset": 278,
         "length": 12
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "-",
        "type": "GeneOrGeneProduct"
       },
       "text": "FP",
       "locations": [
        {
         "offset": 292,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "4720,4722,4726",
        "type": "GeneOrGeneProduct"
       },
       "text": "iron-sulfur protein",
       "locations": [
        {
         "offset": 297,
         "length": 19
        }
       ]
      },
      {
       "id": "8",
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     "text": "Inappropriate use of carbamazepine and vigabatrin in typical absence seizures.",
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     "text": "Carbamazepine and vigabatrin are contraindicated in typical absence seizures. Of 18 consecutive referrals of children with resistant typical absences only, eight were erroneously treated with carbamazepine either as monotherapy or as an add-on. Vigabatrin was also used in the treatment of two children. Frequency of absences increased in four children treated with carbamazepine and two of these developed myoclonic jerks, which resolved on withdrawal of carbamazepine. Absences were aggravated in both cases where vigabatrin was added on to concurrent treatment. Optimal control of the absences was achieved with sodium valproate, lamotrigine, or ethosuximide alone or in combination.",
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   "passages": [
    {
     "offset": 0,
     "text": "CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "971",
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       "text": "CD72",
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       "locations": [
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       "text": "systemic lupus erythematosus",
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     "text": "We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P=0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of AS/common isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P=0.000038) or *1/*2 (P=0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72(c) allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72.",
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       "text": "systemic lupus erythematosus",
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       "text": "murine",
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       "text": "human",
       "locations": [
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         "length": 5
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       ]
      },
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       "id": "12",
       "infons": {
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       "text": "CD72",
       "locations": [
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         "offset": 404,
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       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "D008180",
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       "text": "SLE",
       "locations": [
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       ]
      },
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       "id": "14",
       "infons": {
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       "text": "FCGR2B",
       "locations": [
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      },
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       "id": "15",
       "infons": {
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       "text": "SLE",
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      },
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       "id": "16",
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       "text": "SLE",
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       ]
      },
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       "id": "17",
       "infons": {
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       "text": "SLE",
       "locations": [
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         "offset": 612,
         "length": 3
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SLE",
       "locations": [
        {
         "offset": 877,
         "length": 3
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       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D009393",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nephritis",
       "locations": [
        {
         "offset": 947,
         "length": 9
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       ]
      },
      {
       "id": "20",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 976,
         "length": 8
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "CVCL_0224",
        "type": "CellLine"
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       "text": "COS-7",
       "locations": [
        {
         "offset": 1103,
         "length": 5
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       ]
      },
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       "id": "22",
       "infons": {
        "identifier": "2213",
        "type": "GeneOrGeneProduct"
       },
       "text": "FCGR2B",
       "locations": [
        {
         "offset": 1341,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs1050501",
        "type": "SequenceVariant"
       },
       "text": "232Thr",
       "locations": [
        {
         "offset": 1348,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 1364,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "971",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD72",
       "locations": [
        {
         "offset": 1405,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "2213",
        "type": "GeneOrGeneProduct"
       },
       "text": "FCGR2B",
       "locations": [
        {
         "offset": 1468,
         "length": 6
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "rs1050501",
        "type": "SequenceVariant"
       },
       "text": "232Ile",
       "locations": [
        {
         "offset": 1475,
         "length": 6
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "971",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD72",
       "locations": [
        {
         "offset": 1491,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "12517",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD72",
       "locations": [
        {
         "offset": 1844,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "murine",
       "locations": [
        {
         "offset": 1875,
         "length": 6
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 1882,
         "length": 3
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "971",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD72",
       "locations": [
        {
         "offset": 1932,
         "length": 4
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1966,
         "length": 5
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 1972,
         "length": 3
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "2213",
        "type": "GeneOrGeneProduct"
       },
       "text": "FCGR2B",
       "locations": [
        {
         "offset": 1989,
         "length": 6
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "rs1050501",
        "type": "SequenceVariant"
       },
       "text": "232Thr",
       "locations": [
        {
         "offset": 1996,
         "length": 6
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "971",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD72",
       "locations": [
        {
         "offset": 2045,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs1050501",
      "entity2": "D008180",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D009393",
      "entity2": "971",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "2213",
      "entity2": "D008180",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "971",
      "entity2": "2213",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D008180",
      "entity2": "971",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "12517",
      "entity2": "D008180",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "15599941",
   "passages": [
    {
     "offset": 0,
     "text": "Polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "prostate specific antigen",
       "locations": [
        {
         "offset": 21,
         "length": 25
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "androgen receptor",
       "locations": [
        {
         "offset": 74,
         "length": 17
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 117,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 134,
     "text": "BACKGROUND: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS: One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS: We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006). CONCLUSIONS: Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "prostate specific antigen",
       "locations": [
        {
         "offset": 198,
         "length": 25
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "PSA",
       "locations": [
        {
         "offset": 225,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 243,
         "length": 15
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 260,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "PSA",
       "locations": [
        {
         "offset": 274,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|G||A",
        "type": "SequenceVariant"
       },
       "text": "G/A",
       "locations": [
        {
         "offset": 294,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000728",
        "type": "ChemicalEntity"
       },
       "text": "androgen",
       "locations": [
        {
         "offset": 318,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "androgen receptor",
       "locations": [
        {
         "offset": 364,
         "length": 17
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 383,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 518,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 541,
         "length": 2
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "PSA",
       "locations": [
        {
         "offset": 555,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 608,
         "length": 2
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 666,
         "length": 2
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 669,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "benign prostate hyperplasia",
       "locations": [
        {
         "offset": 710,
         "length": 27
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "PSA",
       "locations": [
        {
         "offset": 826,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "6548",
        "type": "GeneOrGeneProduct"
       },
       "text": "Nhe 1",
       "locations": [
        {
         "offset": 895,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|SUB|G||A",
        "type": "SequenceVariant"
       },
       "text": "G/A",
       "locations": [
        {
         "offset": 935,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 948,
         "length": 2
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|DUP||CAG_GGC|",
        "type": "SequenceVariant"
       },
       "text": "CAG and GGC repeat",
       "locations": [
        {
         "offset": 951,
         "length": 18
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "PSA",
       "locations": [
        {
         "offset": 1076,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 1099,
         "length": 2
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "benign prostatic hyperplasia",
       "locations": [
        {
         "offset": 1120,
         "length": 28
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BPH",
       "locations": [
        {
         "offset": 1150,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 1276,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "PSA",
       "locations": [
        {
         "offset": 1329,
         "length": 3
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "c|DUP||CAG|",
        "type": "SequenceVariant"
       },
       "text": "CAG repeat",
       "locations": [
        {
         "offset": 1368,
         "length": 10
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BPH",
       "locations": [
        {
         "offset": 1415,
         "length": 3
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "354",
        "type": "GeneOrGeneProduct"
       },
       "text": "PSA",
       "locations": [
        {
         "offset": 1552,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 1601,
         "length": 2
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 1629,
         "length": 3
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "c|DUP||G|",
        "type": "SequenceVariant"
       },
       "text": "glutamine repeat",
       "locations": [
        {
         "offset": 1685,
         "length": 16
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "malignant disease",
       "locations": [
        {
         "offset": 1770,
         "length": 17
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|G||A",
      "entity2": "D011471",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|DUP||G|",
      "entity2": "D009369",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D009369",
      "entity2": "367",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "354",
      "entity2": "367",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "c|DUP||CAG_GGC|",
      "entity2": "D011471",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D011471",
      "entity2": "354",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "367",
      "entity2": "D011471",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "15609295",
   "passages": [
    {
     "offset": 0,
     "text": "Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs5030764",
        "type": "SequenceVariant"
       },
       "text": "Asn45Ser",
       "locations": [
        {
         "offset": 69,
         "length": 8
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "2815",
        "type": "GeneOrGeneProduct"
       },
       "text": "glycoprotein IX",
       "locations": [
        {
         "offset": 103,
         "length": 15
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 129,
         "length": 7
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Bernard-Soulier syndrome",
       "locations": [
        {
         "offset": 142,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 168,
     "text": "Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Bernard-Soulier syndrome",
       "locations": [
        {
         "offset": 168,
         "length": 24
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BSS",
       "locations": [
        {
         "offset": 194,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D025861",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inherited bleeding disorder",
       "locations": [
        {
         "offset": 209,
         "length": 27
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2811,2814,2815",
        "type": "GeneOrGeneProduct"
       },
       "text": "glycoprotein (GP) Ib/IX/V",
       "locations": [
        {
         "offset": 302,
         "length": 25
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "von Willebrand factor",
       "locations": [
        {
         "offset": 347,
         "length": 21
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2814",
        "type": "GeneOrGeneProduct"
       },
       "text": "GPV",
       "locations": [
        {
         "offset": 524,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BSS",
       "locations": [
        {
         "offset": 543,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BSS",
       "locations": [
        {
         "offset": 615,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 652,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "2811,2814,2815",
        "type": "GeneOrGeneProduct"
       },
       "text": "glycoproteins",
       "locations": [
        {
         "offset": 730,
         "length": 13
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "2811,2814,2815",
        "type": "GeneOrGeneProduct"
       },
       "text": "GPIb/IX/V",
       "locations": [
        {
         "offset": 751,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 805,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "2815",
        "type": "GeneOrGeneProduct"
       },
       "text": "GPIX",
       "locations": [
        {
         "offset": 868,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|DEL|1952|9",
        "type": "SequenceVariant"
       },
       "text": "nine-nucleotide deletion starting at position 1952",
       "locations": [
        {
         "offset": 887,
         "length": 50
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|SUB|NRTP|86_89|A",
        "type": "SequenceVariant"
       },
       "text": "changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline)",
       "locations": [
        {
         "offset": 955,
         "length": 110
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs5030764",
        "type": "SequenceVariant"
       },
       "text": "asparagine (AAC) for serine (AGC) at residue 45",
       "locations": [
        {
         "offset": 1130,
         "length": 47
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs5030764",
        "type": "SequenceVariant"
       },
       "text": "Asn45Ser",
       "locations": [
        {
         "offset": 1215,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "2815",
        "type": "GeneOrGeneProduct"
       },
       "text": "GPIX",
       "locations": [
        {
         "offset": 1356,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BSS",
       "locations": [
        {
         "offset": 1390,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1411,
         "length": 7
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "2814",
      "entity2": "7450",
      "type": "Bind",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "2814",
      "entity2": "D001606",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "2811",
      "entity2": "7450",
      "type": "Bind",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "2811",
      "entity2": "D001606",
      "type": "Association",
      "novel": "No"
     }
    },
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     "id": "R4",
     "infons": {
      "entity1": "7450",
      "entity2": "D001606",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "2815",
      "entity2": "7450",
      "type": "Bind",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "2815",
      "entity2": "D001606",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "rs5030764",
      "entity2": "D001606",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "p|SUB|NRTP|86_89|A",
      "entity2": "D001606",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "c|DEL|1952|9",
      "entity2": "D001606",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16288197",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital microcoria",
       "locations": [
        {
         "offset": 34,
         "length": 21
        }
       ]
      }
     ]
    },
    {
     "offset": 90,
     "text": "PURPOSE: Congenital microcoria is a rare autosomal dominant developmental disorder of the iris associated with myopia and juvenile open angle glaucoma. Linkage to the chromosomal locus 13q31-q32 has previously been reported in a large French family. In the current study, a three generation Asian Indian family with 15 congenital microcoria (pupils with a diameter <2 mm) affected members was studied for linkage to candidate microsatellite markers at the 13q31-q32 locus. METHODS: Twenty-four members of the family were clinically examined and genomic DNA was extracted. Microsatellite markers at 13q31-q32 were PCR amplified and run on an ABI Prism 310 genetic analyzer and genotyped with the GeneScan analysis. Two point and multipoint linkage analyses were performed using the MLINK and SUPERLINK programs. RESULTS: Peak two point LOD scores of 3.5, 4.7, and 5.3 were found co-incident with consecutive markers D13S154, DCT, and D13S1280. Multipoint analysis revealed a 4 cM region encompassing D13S1300 to D13S1280 where the LOD remains just over 6.0 Thus we confirm localization of the congenital microcoria locus to chromosomal locus 13q31-q32. In addition, eight individuals who had both microcoria and glaucoma were screened for glaucoma genes: myocilin (MYOC), optineurin (OPTN) and CYP1B1. Using direct sequencing a point mutation (144 G>A) resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five of the eight glaucoma patients, but not in unaffected family members and 100 unrelated controls. CONCLUSIONS: We have confirmed the localization of the congenital microcoria locus (MCOR) to 13q31-q32 in a large Asian Indian family and conclude that current information suggests this is a single locus disorder and genetically homogeneous. When combined with the initial linkage paper our haplotype and linkage data map the MCOR locus to a 6-7 cM region between D13S265 and D13S1280. The DCT locus, a member of the tyrosinase family involved in pigmentation, maps within this region. Data presented here supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma, although this observation is complicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), a mutation known to be associated with glaucoma in India. Fine mapping and candidate gene analysis continues with the hope that characterizing the micocoria gene will lead to a better understanding of microcoria and glaucoma causation. The relationship between microcoria, glaucoma, and the MYOC Q48H mutation in this family is discussed.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Congenital microcoria",
       "locations": [
        {
         "offset": 99,
         "length": 21
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D007499",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant developmental disorder of the iris",
       "locations": [
        {
         "offset": 131,
         "length": 53
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009216",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myopia",
       "locations": [
        {
         "offset": 201,
         "length": 6
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D005902",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "juvenile open angle glaucoma",
       "locations": [
        {
         "offset": 212,
         "length": 28
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital microcoria",
       "locations": [
        {
         "offset": 409,
         "length": 21
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DCT",
       "locations": [
        {
         "offset": 1014,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital microcoria",
       "locations": [
        {
         "offset": 1182,
         "length": 21
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microcoria",
       "locations": [
        {
         "offset": 1286,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 1301,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 1328,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "4653",
        "type": "GeneOrGeneProduct"
       },
       "text": "myocilin",
       "locations": [
        {
         "offset": 1344,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "4653",
        "type": "GeneOrGeneProduct"
       },
       "text": "MYOC",
       "locations": [
        {
         "offset": 1354,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "10133",
        "type": "GeneOrGeneProduct"
       },
       "text": "optineurin",
       "locations": [
        {
         "offset": 1361,
         "length": 10
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "10133",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPTN",
       "locations": [
        {
         "offset": 1373,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1545",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP1B1",
       "locations": [
        {
         "offset": 1383,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs74315339",
        "type": "SequenceVariant"
       },
       "text": "144 G>A",
       "locations": [
        {
         "offset": 1433,
         "length": 7
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs74315339",
        "type": "SequenceVariant"
       },
       "text": "Q48H",
       "locations": [
        {
         "offset": 1457,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "4653",
        "type": "GeneOrGeneProduct"
       },
       "text": "MYOC",
       "locations": [
        {
         "offset": 1492,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 1536,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1545,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital microcoria",
       "locations": [
        {
         "offset": 1675,
         "length": 21
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "8104",
        "type": "GeneOrGeneProduct"
       },
       "text": "MCOR",
       "locations": [
        {
         "offset": 1704,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "8104",
        "type": "GeneOrGeneProduct"
       },
       "text": "MCOR",
       "locations": [
        {
         "offset": 1946,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "1638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DCT",
       "locations": [
        {
         "offset": 2010,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "7299",
        "type": "GeneOrGeneProduct"
       },
       "text": "tyrosinase",
       "locations": [
        {
         "offset": 2037,
         "length": 10
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D010859",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pigmentation",
       "locations": [
        {
         "offset": 2067,
         "length": 12
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital microcoria",
       "locations": [
        {
         "offset": 2155,
         "length": 21
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 2208,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "4653",
        "type": "GeneOrGeneProduct"
       },
       "text": "MYOC",
       "locations": [
        {
         "offset": 2289,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "rs74315339",
        "type": "SequenceVariant"
       },
       "text": "Q48H",
       "locations": [
        {
         "offset": 2294,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 2354,
         "length": 8
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "8104",
        "type": "GeneOrGeneProduct"
       },
       "text": "micocoria",
       "locations": [
        {
         "offset": 2462,
         "length": 9
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microcoria",
       "locations": [
        {
         "offset": 2516,
         "length": 10
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 2531,
         "length": 8
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "C537550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microcoria",
       "locations": [
        {
         "offset": 2576,
         "length": 10
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 2588,
         "length": 8
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "4653",
        "type": "GeneOrGeneProduct"
       },
       "text": "MYOC",
       "locations": [
        {
         "offset": 2606,
         "length": 4
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "rs74315339",
        "type": "SequenceVariant"
       },
       "text": "Q48H",
       "locations": [
        {
         "offset": 2611,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1638",
      "entity2": "D010859",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs74315339",
      "entity2": "D005901",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "1545",
      "entity2": "D005901",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "10133",
      "entity2": "D005901",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "C537550",
      "entity2": "8104",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "C537550",
      "entity2": "rs74315339",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "C537550",
      "entity2": "1545",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "C537550",
      "entity2": "10133",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "C537550",
      "entity2": "4653",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R9",
     "infons": {
      "entity1": "4653",
      "entity2": "D005901",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17177139",
   "passages": [
    {
     "offset": 0,
     "text": "A novel mutation (E333D) in the thyroid hormone beta receptor causing resistance to thyroid hormone syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "p|SUB|E|333|D",
        "type": "SequenceVariant"
       },
       "text": "E333D",
       "locations": [
        {
         "offset": 18,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6955",
        "type": "GeneOrGeneProduct"
       },
       "text": "thyroid hormone beta receptor",
       "locations": [
        {
         "offset": 32,
         "length": 29
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D018382",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "resistance to thyroid hormone syndrome",
       "locations": [
        {
         "offset": 70,
         "length": 38
        }
       ]
      }
     ]
    },
    {
     "offset": 110,
     "text": "Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.",
     "annotations": [
      {
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     "offset": 0,
     "text": "Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer.",
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        "type": "DiseaseOrPhenotypicFeature"
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     "text": "PURPOSE: The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer. PATIENTS AND METHODS: We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer. RESULTS: Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes. CONCLUSION: These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.",
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       "text": "breast cancer",
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  {
   "id": "18699851",
   "passages": [
    {
     "offset": 0,
     "text": "Integrated genomic and expression profiling in mantle cell lymphoma: identification of gene-dosage regulated candidate genes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D020522",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "mantle cell lymphoma",
       "locations": [
        {
         "offset": 47,
         "length": 20
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       ]
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     ]
    },
    {
     "offset": 126,
     "text": "Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation and several other cytogenetic aberrations, including heterozygous loss of chromosomal arms 1p, 6q, 11q and 13q and/or gains of 3q and 8q. The common intervals of chromosomal imbalance have been narrowed down using array-comparative genomic hybridization (CGH). However, the chromosomal intervals still contain many genes potentially involved in MCL pathogeny. Combined analysis of tiling-resolution array-CGH with gene expression profiling on 11 MCL tumours enabled the identification of genomic alterations and their corresponding gene expression profiles. Only subsets of genes located within given cytogenetic anomaly-intervals showed a concomitant change in mRNA expression level. The genes that showed consistent correlation between DNA copy number and RNA expression levels are likely to be important in MCL pathology. Besides several 'anonymous genes', we also identified various fully annotated genes, whose gene products are involved in cyclic adenosine monophosphate-regulated pathways (PRKACB), DNA damage repair, maintenance of chromosome stability and prevention of rereplication (ATM, ERCC5, FBXO5), energy metabolism (such as genes that are involved in the synthesis of proteins encoded by the mitochondrial genome) and signal transduction (ARHGAP29). Deregulation of these gene products may interfere with the signalling pathways that are involved in MCL tumour development and maintenance.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D020522",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Mantle cell lymphoma",
       "locations": [
        {
         "offset": 126,
         "length": 20
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       ]
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       "id": "2",
       "infons": {
        "identifier": "D020522",
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       "text": "MCL",
       "locations": [
        {
         "offset": 148,
         "length": 3
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D020522",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "MCL",
       "locations": [
        {
         "offset": 554,
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D020522",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MCL tumours",
       "locations": [
        {
         "offset": 655,
         "length": 11
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D020522",
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       },
       "text": "MCL",
       "locations": [
        {
         "offset": 1019,
         "length": 3
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       ]
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      {
       "id": "6",
       "infons": {
        "identifier": "D000242",
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       "text": "cyclic adenosine monophosphate",
       "locations": [
        {
         "offset": 1155,
         "length": 30
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       "id": "7",
       "infons": {
        "identifier": "5567",
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       "text": "PRKACB",
       "locations": [
        {
         "offset": 1206,
         "length": 6
        }
       ]
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      {
       "id": "8",
       "infons": {
        "identifier": "472",
        "type": "GeneOrGeneProduct"
       },
       "text": "ATM",
       "locations": [
        {
         "offset": 1303,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2073",
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       "text": "ERCC5",
       "locations": [
        {
         "offset": 1308,
         "length": 5
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       ]
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      {
       "id": "10",
       "infons": {
        "identifier": "26271",
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       },
       "text": "FBXO5",
       "locations": [
        {
         "offset": 1315,
         "length": 5
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9411",
        "type": "GeneOrGeneProduct"
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       "text": "ARHGAP29",
       "locations": [
        {
         "offset": 1465,
         "length": 8
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D020522",
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       "text": "MCL tumour",
       "locations": [
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         "offset": 1576,
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      "entity1": "D020522",
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     "infons": {
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    }
   ]
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  {
   "id": "20086182",
   "passages": [
    {
     "offset": 0,
     "text": "The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "841",
        "type": "GeneOrGeneProduct"
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       "text": "CASP8",
       "locations": [
        {
         "offset": 53,
         "length": 5
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D000077195",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "squamous cell carcinoma of the head and neck",
       "locations": [
        {
         "offset": 112,
         "length": 44
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       ]
      }
     ]
    },
    {
     "offset": 158,
     "text": "Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion (-652 6N ins/del) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted.",
     "annotations": [
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       "id": "2",
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       "text": "Caspase 8",
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       "id": "3",
       "infons": {
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       "text": "CASP8",
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         "offset": 169,
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       "id": "4",
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        "identifier": "841",
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       "text": "CASP8",
       "locations": [
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         "offset": 301,
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       ]
      },
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       "id": "5",
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       "text": "-652 6N ins/del",
       "locations": [
        {
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         "length": 15
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       ]
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       "id": "6",
       "infons": {
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       "text": "D302H",
       "locations": [
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         "offset": 403,
         "length": 5
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D009369",
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       "text": "cancer",
       "locations": [
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         "offset": 450,
         "length": 6
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D006258",
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       "text": "head and neck cancer",
       "locations": [
        {
         "offset": 563,
         "length": 20
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "841",
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       "text": "CASP8",
       "locations": [
        {
         "offset": 648,
         "length": 5
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "c|DEL|-652|6",
        "type": "SequenceVariant"
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       "text": "-652 6N del",
       "locations": [
        {
         "offset": 654,
         "length": 11
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       ]
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       "id": "11",
       "infons": {
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       "text": "302H",
       "locations": [
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         "offset": 670,
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       "id": "12",
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       "text": "patients",
       "locations": [
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         "offset": 693,
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       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "D000077195",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "squamous cell carcinoma of the head and neck",
       "locations": [
        {
         "offset": 707,
         "length": 44
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000077195",
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       "text": "SCCHN",
       "locations": [
        {
         "offset": 753,
         "length": 5
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "841",
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       "text": "CASP8",
       "locations": [
        {
         "offset": 929,
         "length": 5
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       ]
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       "id": "16",
       "infons": {
        "identifier": "c|DEL|-652|6",
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       "text": "-652 6N del",
       "locations": [
        {
         "offset": 935,
         "length": 11
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       ]
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      {
       "id": "17",
       "infons": {
        "identifier": "D000077195",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SCCHN",
       "locations": [
        {
         "offset": 1010,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "841",
        "type": "GeneOrGeneProduct"
       },
       "text": "CASP8",
       "locations": [
        {
         "offset": 1259,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|DEL|-652|6",
        "type": "SequenceVariant"
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       "text": "-652 6N del",
       "locations": [
        {
         "offset": 1265,
         "length": 11
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      {
       "id": "20",
       "infons": {
        "identifier": "rs1045485",
        "type": "SequenceVariant"
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       "text": "302H",
       "locations": [
        {
         "offset": 1286,
         "length": 4
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      {
       "id": "21",
       "infons": {
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       "text": "camptothecin",
       "locations": [
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         "offset": 1352,
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       "id": "22",
       "infons": {
        "identifier": "7157",
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       "text": "p53",
       "locations": [
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         "offset": 1373,
         "length": 3
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       ]
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       "id": "23",
       "infons": {
        "identifier": "841",
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       "text": "CASP8",
       "locations": [
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         "offset": 1466,
         "length": 5
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       "id": "24",
       "infons": {
        "identifier": "c|DEL|-652|6",
        "type": "SequenceVariant"
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       "text": "-652 6N del",
       "locations": [
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         "offset": 1472,
         "length": 11
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      {
       "id": "25",
       "infons": {
        "identifier": "D000077195",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SCCHN",
       "locations": [
        {
         "offset": 1540,
         "length": 5
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      "novel": "No"
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    {
     "id": "R1",
     "infons": {
      "entity1": "D009369",
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      "novel": "No"
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     "infons": {
      "entity1": "D002166",
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      "novel": "No"
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     "infons": {
      "entity1": "c|DEL|-652|6",
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      "type": "Positive_Correlation",
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     "id": "R4",
     "infons": {
      "entity1": "c|DEL|-652|6",
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     "id": "R5",
     "infons": {
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      "type": "Association",
      "novel": "No"
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     "id": "R6",
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     "id": "R7",
     "infons": {
      "entity1": "841",
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      "type": "Association",
      "novel": "Novel"
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    {
     "id": "R8",
     "infons": {
      "entity1": "841",
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      "novel": "Novel"
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    }
   ]
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  {
   "id": "24914936",
   "passages": [
    {
     "offset": 0,
     "text": "Thyroid hormone receptor a mutation causes a severe and thyroxine-resistant skeletal dysplasia in female mice.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "21833",
        "type": "GeneOrGeneProduct"
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       "text": "Thyroid hormone receptor a",
       "locations": [
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       "id": "1",
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       "text": "thyroxine",
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       "id": "2",
       "infons": {
        "identifier": "D001848",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "skeletal dysplasia",
       "locations": [
        {
         "offset": 76,
         "length": 18
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      {
       "id": "3",
       "infons": {
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       "text": "mice",
       "locations": [
        {
         "offset": 105,
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    {
     "offset": 111,
     "text": "A new genetic disorder has been identified that results from mutation of THRA, encoding thyroid hormone receptor a1 (TRa1). Affected children have a high serum T3:T4 ratio and variable degrees of intellectual deficit and constipation but exhibit a consistently severe skeletal dysplasia. In an attempt to improve developmental delay and alleviate symptoms of hypothyroidism, patients are receiving varying doses and durations of T4 treatment, but responses have been inconsistent so far. Thra1(PV/+) mice express a similar potent dominant-negative mutant TRa1 to affected individuals, and thus represent an excellent disease model. We hypothesized that Thra1(PV/+) mice could be used to predict the skeletal outcome of human THRA mutations and determine whether prolonged treatment with a supraphysiological dose of T4 ameliorates the skeletal abnormalities. Adult female Thra1(PV/+) mice had short stature, grossly abnormal bone morphology but normal bone strength despite high bone mass. Although T4 treatment suppressed TSH secretion, it had no effect on skeletal maturation, linear growth, or bone mineralization, thus demonstrating profound tissue resistance to thyroid hormone. Despite this, prolonged T4 treatment abnormally increased bone stiffness and strength, suggesting the potential for detrimental consequences in the long term. Our studies establish that TRa1 has an essential role in the developing and adult skeleton and predict that patients with different THRA mutations will display variable responses to T4 treatment, which depend on the severity of the causative mutation.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "7067",
        "type": "GeneOrGeneProduct"
       },
       "text": "THRA",
       "locations": [
        {
         "offset": 184,
         "length": 4
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "7067",
        "type": "GeneOrGeneProduct"
       },
       "text": "thyroid hormone receptor a1",
       "locations": [
        {
         "offset": 199,
         "length": 27
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "7067",
        "type": "GeneOrGeneProduct"
       },
       "text": "TRa1",
       "locations": [
        {
         "offset": 228,
         "length": 4
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D014284",
        "type": "ChemicalEntity"
       },
       "text": "T3",
       "locations": [
        {
         "offset": 271,
         "length": 2
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D013974",
        "type": "ChemicalEntity"
       },
       "text": "T4",
       "locations": [
        {
         "offset": 274,
         "length": 2
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intellectual deficit",
       "locations": [
        {
         "offset": 307,
         "length": 20
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003248",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "constipation",
       "locations": [
        {
         "offset": 332,
         "length": 12
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "skeletal dysplasia",
       "locations": [
        {
         "offset": 379,
         "length": 18
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D002658",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "developmental delay",
       "locations": [
        {
         "offset": 424,
         "length": 19
        }
       ]
      },
      {
       "id": "13",
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      "entity1": "12013",
      "entity2": "14775",
      "type": "Negative_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R5",
     "infons": {
      "entity1": "12013",
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      "type": "Negative_Correlation",
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    {
     "id": "R6",
     "infons": {
      "entity1": "12013",
      "entity2": "D011658",
      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R7",
     "infons": {
      "entity1": "12013",
      "entity2": "D001761",
      "type": "Positive_Correlation",
      "novel": "No"
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    }
   ]
  },
  {
   "id": "28368537",
   "passages": [
    {
     "offset": 0,
     "text": "Tissue-Specific Ablation of the LIF Receptor in the Murine Uterine Epithelium Results in Implantation Failure.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIF Receptor",
       "locations": [
        {
         "offset": 32,
         "length": 12
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
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       "text": "Murine",
       "locations": [
        {
         "offset": 52,
         "length": 6
        }
       ]
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     ]
    },
    {
     "offset": 111,
     "text": "The cytokine leukemia inhibitory factor (LIF) is essential for rendering the uterus receptive for blastocyst implantation. In mice, LIF receptor expression (LIFR) is largely restricted to the uterine luminal epithelium (LE). LIF, secreted from the endometrial glands (GEs), binds to the LIFR, activating the Janus kinase-signal transducer and activation of transcription (STAT) 3 (Jak-Stat3) signaling pathway in the LE. JAK-STAT activation converts the LE to a receptive state so that juxtaposed blastocysts begin to implant. To specifically delete the LIFR in the LE, we derived a line of mice in which Cre recombinase was inserted into the endogenous lactoferrin gene (Ltf-Cre). Lactoferrin expression in the LE is induced by E2, and we demonstrate that Cre recombinase activity is restricted to the LE and GE. To determine the requirement of the LIFR in implantation, we derived an additional mouse line carrying a conditional (floxed) Lifr flx/flx gene. Crossing Ltf-Cre mice with Lifr flx/flx mice generated Lifr flx/D:Ltf Cre/+ females that were overtly normal but infertile. Many of these females, despite repeated matings, did not become pregnant. Unimplanted blastocysts were recovered from the Lifr flx/D:Ltf Cre/+ uteri and, when transferred to wild-type recipients, implanted normally, indicating that uterine receptivity rather than the embryo's competency is compromised. The loss of Lifr results in both the failure for STAT3 to translocate to the LE nuclei and a reduction in the expression of the LIF regulated gene Msx1 that regulates uterine receptivity. These results reveal that uterine expression of the LIFR is essential for embryo implantation and further define the components of the LIF signaling pathway necessary for effective implantation.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
       },
       "text": "leukemia inhibitory factor",
       "locations": [
        {
         "offset": 124,
         "length": 26
        }
       ]
      },
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       "id": "3",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
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       "text": "LIF",
       "locations": [
        {
         "offset": 152,
         "length": 3
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       ]
      },
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       "id": "4",
       "infons": {
        "identifier": "10090",
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       },
       "text": "mice",
       "locations": [
        {
         "offset": 237,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIF receptor",
       "locations": [
        {
         "offset": 243,
         "length": 12
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIFR",
       "locations": [
        {
         "offset": 268,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIF",
       "locations": [
        {
         "offset": 336,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIFR",
       "locations": [
        {
         "offset": 398,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "16452",
        "type": "GeneOrGeneProduct"
       },
       "text": "Janus kinase",
       "locations": [
        {
         "offset": 419,
         "length": 12
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "20848",
        "type": "GeneOrGeneProduct"
       },
       "text": "signal transducer and activation of transcription (STAT) 3",
       "locations": [
        {
         "offset": 432,
         "length": 58
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "16452",
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       "text": "Jak",
       "locations": [
        {
         "offset": 492,
         "length": 3
        }
       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "20848",
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       },
       "text": "Stat3",
       "locations": [
        {
         "offset": 496,
         "length": 5
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "16452",
        "type": "GeneOrGeneProduct"
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       "text": "JAK",
       "locations": [
        {
         "offset": 532,
         "length": 3
        }
       ]
      },
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       "id": "14",
       "infons": {
        "identifier": "20848",
        "type": "GeneOrGeneProduct"
       },
       "text": "STAT",
       "locations": [
        {
         "offset": 536,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIFR",
       "locations": [
        {
         "offset": 665,
         "length": 4
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       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 702,
         "length": 4
        }
       ]
      },
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       "id": "17",
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       },
       "text": "lactoferrin",
       "locations": [
        {
         "offset": 765,
         "length": 11
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
       },
       "text": "Ltf",
       "locations": [
        {
         "offset": 783,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "17002",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lactoferrin",
       "locations": [
        {
         "offset": 793,
         "length": 11
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIFR",
       "locations": [
        {
         "offset": 961,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "10090",
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       "text": "mouse",
       "locations": [
        {
         "offset": 1008,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lifr",
       "locations": [
        {
         "offset": 1051,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
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       "text": "Ltf",
       "locations": [
        {
         "offset": 1079,
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        }
       ]
      },
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       "id": "24",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
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       "text": "mice",
       "locations": [
        {
         "offset": 1087,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lifr",
       "locations": [
        {
         "offset": 1097,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 1110,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lifr",
       "locations": [
        {
         "offset": 1125,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
       },
       "text": "Ltf",
       "locations": [
        {
         "offset": 1136,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lifr",
       "locations": [
        {
         "offset": 1316,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
       },
       "text": "Ltf",
       "locations": [
        {
         "offset": 1327,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lifr",
       "locations": [
        {
         "offset": 1510,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "20848",
        "type": "GeneOrGeneProduct"
       },
       "text": "STAT3",
       "locations": [
        {
         "offset": 1547,
         "length": 5
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       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIF",
       "locations": [
        {
         "offset": 1626,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "17701",
        "type": "GeneOrGeneProduct"
       },
       "text": "Msx1",
       "locations": [
        {
         "offset": 1645,
         "length": 4
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "16880",
        "type": "GeneOrGeneProduct"
       },
       "text": "LIFR",
       "locations": [
        {
         "offset": 1738,
         "length": 4
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "16878",
        "type": "GeneOrGeneProduct"
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       "text": "LIF",
       "locations": [
        {
         "offset": 1821,
         "length": 3
        }
       ]
      }
     ]
    }
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      "novel": "No"
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      "type": "Association",
      "novel": "No"
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     "infons": {
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      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R6",
     "infons": {
      "entity1": "16452",
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "16452",
      "entity2": "20848",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "28650467",
   "passages": [
    {
     "offset": 0,
     "text": "Genome-wide loss-of-function genetic screening identifies opioid receptor u1 as a key regulator of L-asparaginase resistance in pediatric acute lymphoblastic leukemia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "opioid receptor u1",
       "locations": [
        {
         "offset": 58,
         "length": 18
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D001215",
        "type": "ChemicalEntity"
       },
       "text": "L-asparaginase",
       "locations": [
        {
         "offset": 99,
         "length": 14
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D054198",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "acute lymphoblastic leukemia",
       "locations": [
        {
         "offset": 138,
         "length": 28
        }
       ]
      }
     ]
    },
    {
     "offset": 168,
     "text": "L-asparaginase is a critical chemotherapeutic agent for acute lymphoblastic leukemia (ALL). It hydrolyzes plasma asparagine into aspartate and NH3, causing asparagine deficit and inhibition of protein synthesis and eventually, leukemic cell death. However, patient relapse often occurs due to development of resistance. The molecular mechanism by which ALL cells acquire resistance to L-asparaginase is unknown. Therefore, we sought to identify genes that are involved in L-asparaginase resistance in primary leukemic cells. By unbiased genome-wide RNAi screening, we found that among 10 resistant ALL clones, six hits were for opioid receptor mu 1 (oprm1), two hits were for carbonic anhydrase 1 (ca1) and another two hits were for ubiquitin-conjugating enzyme E2C (ube2c). We also found that OPRM1 is expressed in all leukemic cells tested. Specific knockdown of OPRM1 confers L-asparaginase resistance, validating our genome-wide retroviral shRNA library screening data. Methadone, an agonist of OPRM1, enhances the sensitivity of parental leukemic cells, but not OPRM1-depleted cells, to L-asparaginase treatment, indicating that OPRM1 is required for the synergistic action of L-asparaginase and methadone, and that OPRM1 loss promotes leukemic cell survival likely through downregulation of the OPRM1-mediated apoptotic pathway. Consistent with this premise, patient leukemic cells with relatively high levels of OPRM1 are more sensitive to L-asparaginase treatment compared to OPRM1-depleted leukemic cells, further indicating that OPRM1 loss has a crucial role in L-asparaginase resistance in leukemic patients. Thus, our study demonstrates for the first time, a novel OPRM1-mediated mechanism for L-asparaginase resistance in ALL, and identifies OPRM1 as a functional biomarker for defining high-risk subpopulations and for the detection of evolving resistant clones. Oprm1 may also be utilized for effective treatment of L-asparaginase-resistant ALL.Oncogene advance online publication, 26 June 2017; doi:10.1038/onc.2017.211.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D001215",
        "type": "ChemicalEntity"
       },
       "text": "L-asparaginase",
       "locations": [
        {
         "offset": 168,
         "length": 14
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D054198",
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       },
       "text": "acute lymphoblastic leukemia",
       "locations": [
        {
         "offset": 224,
         "length": 28
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D054198",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALL",
       "locations": [
        {
         "offset": 254,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001216",
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       },
       "text": "asparagine",
       "locations": [
        {
         "offset": 281,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001224",
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       },
       "text": "aspartate",
       "locations": [
        {
         "offset": 297,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000641",
        "type": "ChemicalEntity"
       },
       "text": "NH3",
       "locations": [
        {
         "offset": 311,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "OMIM:615574",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "asparagine deficit",
       "locations": [
        {
         "offset": 324,
         "length": 18
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D007938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "leukemic",
       "locations": [
        {
         "offset": 395,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 425,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D054198",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALL",
       "locations": [
        {
         "offset": 521,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D001215",
        "type": "ChemicalEntity"
       },
       "text": "L-asparaginase",
       "locations": [
        {
         "offset": 553,
         "length": 14
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D001215",
        "type": "ChemicalEntity"
       },
       "text": "L-asparaginase",
       "locations": [
        {
         "offset": 640,
         "length": 14
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D007938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "leukemic",
       "locations": [
        {
         "offset": 677,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D054198",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALL",
       "locations": [
        {
         "offset": 766,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "opioid receptor mu 1",
       "locations": [
        {
         "offset": 796,
         "length": 20
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "oprm1",
       "locations": [
        {
         "offset": 818,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "759",
        "type": "GeneOrGeneProduct"
       },
       "text": "carbonic anhydrase 1",
       "locations": [
        {
         "offset": 844,
         "length": 20
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "759",
        "type": "GeneOrGeneProduct"
       },
       "text": "ca1",
       "locations": [
        {
         "offset": 866,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "11065",
        "type": "GeneOrGeneProduct"
       },
       "text": "ubiquitin-conjugating enzyme E2C",
       "locations": [
        {
         "offset": 901,
         "length": 32
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "11065",
        "type": "GeneOrGeneProduct"
       },
       "text": "ube2c",
       "locations": [
        {
         "offset": 935,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 962,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D007938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "leukemic",
       "locations": [
        {
         "offset": 988,
         "length": 8
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 1033,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D001215",
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       "text": "L-asparaginase",
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       "text": "L-asparaginase",
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       "text": "L-asparaginase",
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       "text": "L-asparaginase",
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       "text": "Oprm1",
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       "text": "L-asparaginase",
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  {
   "id": "15748645",
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    {
     "offset": 0,
     "text": "Photochemoprevention of ultraviolet B signaling and photocarcinogenesis.",
     "annotations": []
    },
    {
     "offset": 73,
     "text": "Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.",
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       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
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         "offset": 185,
         "length": 5
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       "id": "1",
       "infons": {
        "identifier": "D002294,D018295",
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       "text": "basal and squamous cell cancers",
       "locations": [
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       "id": "2",
       "infons": {
        "identifier": "D008545",
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       "text": "melanoma",
       "locations": [
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         "offset": 286,
         "length": 8
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       ]
      },
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       "id": "3",
       "infons": {
        "identifier": "D002386",
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       "text": "cataracts",
       "locations": [
        {
         "offset": 296,
         "length": 9
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D012878",
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       "text": "skin cancer",
       "locations": [
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         "offset": 410,
         "length": 11
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D012878",
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       "text": "skin cancer",
       "locations": [
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         "offset": 633,
         "length": 11
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D012878",
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       "text": "skin cancer",
       "locations": [
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         "offset": 665,
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D009369",
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       "text": "carcinogenesis",
       "locations": [
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         "offset": 945,
         "length": 14
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009369",
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       "text": "Tumor",
       "locations": [
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         "offset": 1116,
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D009369",
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       "text": "cancer",
       "locations": [
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         "offset": 1160,
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       ]
      },
      {
       "id": "10",
       "infons": {
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       "text": "Tumor",
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      },
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       "id": "11",
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       "text": "tumor",
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         "offset": 1480,
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      },
      {
       "id": "12",
       "infons": {
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       "text": "skin cancer",
       "locations": [
        {
         "offset": 1511,
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D007249",
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       "text": "inflammation",
       "locations": [
        {
         "offset": 1603,
         "length": 12
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D006965",
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       "text": "epidermal hyperplasia",
       "locations": [
        {
         "offset": 1636,
         "length": 21
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       ]
      },
      {
       "id": "15",
       "infons": {
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       "text": "antioxidant",
       "locations": [
        {
         "offset": 1698,
         "length": 11
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       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "5742",
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       "text": "cyclooxygenase",
       "locations": [
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         "offset": 1777,
         "length": 14
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       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "D011453",
        "type": "ChemicalEntity"
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       "text": "prostaglandin",
       "locations": [
        {
         "offset": 1805,
         "length": 13
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "4953",
        "type": "GeneOrGeneProduct"
       },
       "text": "ornithine decarboxylase",
       "locations": [
        {
         "offset": 1847,
         "length": 23
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       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D012878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "skin cancer",
       "locations": [
        {
         "offset": 1963,
         "length": 11
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D000975",
        "type": "ChemicalEntity"
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       "text": "antioxidants",
       "locations": [
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         "offset": 2036,
         "length": 12
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
        {
         "offset": 2103,
         "length": 5
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       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
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         "offset": 2190,
         "length": 5
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       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D012878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "skin cancer",
       "locations": [
        {
         "offset": 2784,
         "length": 11
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       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "humans",
       "locations": [
        {
         "offset": 2799,
         "length": 6
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       ]
      }
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   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "D012878",
      "entity2": "D000975",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D012878",
      "entity2": "4953",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D012878",
      "entity2": "D011453",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "16543197",
   "passages": [
    {
     "offset": 0,
     "text": "A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs62636275",
        "type": "SequenceVariant"
       },
       "text": "G1103R",
       "locations": [
        {
         "offset": 2,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "23418",
        "type": "GeneOrGeneProduct"
       },
       "text": "CRB1",
       "locations": [
        {
         "offset": 21,
         "length": 4
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D006956",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperopia",
       "locations": [
        {
         "offset": 52,
         "length": 9
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D057130",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Leber congenital amaurosis",
       "locations": [
        {
         "offset": 66,
         "length": 26
        }
       ]
      }
     ]
    },
    {
     "offset": 94,
     "text": "PURPOSE: To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. MATERIALS AND METHODS: The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. RESULTS: All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. CONCLUSION: Although hyperopia has been associated with LCA, it is typically moderate and variable between patients with the same mutation. In addition, some CRB1 mutations can be associated with either RP or LCA. We have shown that hyperopia and LCA are linked to the mutant CRB1 gene itself and are not dependent on unlinked modifiers.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "C565497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "high hyperopia",
       "locations": [
        {
         "offset": 161,
         "length": 14
        }
       ]
      },
      {
       "id": "5",
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       "text": "Drosophila",
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       "infons": {
        "identifier": "D012174",
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       "text": "retinitis pigmentosa",
       "locations": [
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         "offset": 1001,
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       ]
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       "infons": {
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       "id": "18",
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       "text": "LCA",
       "locations": [
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       "id": "19",
       "infons": {
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       "text": "LCA",
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       ]
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       ]
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       "id": "25",
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        {
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         "length": 2
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       "id": "26",
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       ]
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       "id": "27",
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       "text": "hyperopia",
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       "id": "28",
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   "id": "16574712",
   "passages": [
    {
     "offset": 0,
     "text": "MDMA polydrug users show process-specific central executive impairments coupled with impaired social and emotional judgement processes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D018817",
        "type": "ChemicalEntity"
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       "text": "MDMA",
       "locations": [
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       "infons": {
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       "text": "impaired social and emotional judgement processes",
       "locations": [
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     "text": "In recent years working memory deficits have been reported in users of MDMA (3,4-methylenedioxymethamphetamine, ecstasy). The current study aimed to assess the impact of MDMA use on three separate central executive processes (set shifting, inhibition and memory updating) and also on \"prefrontal\" mediated social and emotional judgement processes. Fifteen polydrug ecstasy users and 15 polydrug non-ecstasy user controls completed a general drug use questionnaire, the Brixton Spatial Anticipation task (set shifting), Backward Digit Span procedure (memory updating), Inhibition of Return (inhibition), an emotional intelligence scale, the Tromso Social Intelligence Scale and the Dysexecutive Questionnaire (DEX). Compared with MDMA-free polydrug controls, MDMA polydrug users showed impairments in set shifting and memory updating, and also in social and emotional judgement processes. The latter two deficits remained significant after controlling for other drug use. These data lend further support to the proposal that cognitive processes mediated by the prefrontal cortex may be impaired by recreational ecstasy use.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D008569",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "memory deficits",
       "locations": [
        {
         "offset": 160,
         "length": 15
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       "id": "3",
       "infons": {
        "identifier": "D018817",
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       "text": "MDMA",
       "locations": [
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         "offset": 207,
         "length": 4
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       ]
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      {
       "id": "4",
       "infons": {
        "identifier": "D018817",
        "type": "ChemicalEntity"
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       "text": "3,4-methylenedioxymethamphetamine",
       "locations": [
        {
         "offset": 213,
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      },
      {
       "id": "5",
       "infons": {
        "identifier": "D018817",
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       "text": "ecstasy",
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         "offset": 248,
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       "id": "6",
       "infons": {
        "identifier": "D018817",
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       "text": "MDMA",
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       "id": "7",
       "infons": {
        "identifier": "D018817",
        "type": "ChemicalEntity"
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       "text": "ecstasy",
       "locations": [
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         "offset": 501,
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       "id": "8",
       "infons": {
        "identifier": "D018817",
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       "text": "ecstasy",
       "locations": [
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         "offset": 535,
         "length": 7
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       ]
      },
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       "id": "9",
       "infons": {
        "identifier": "D018817",
        "type": "ChemicalEntity"
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       "text": "MDMA",
       "locations": [
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         "offset": 865,
         "length": 4
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       ]
      },
      {
       "id": "10",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "MDMA",
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         "offset": 894,
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D018817",
        "type": "ChemicalEntity"
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       "text": "ecstasy",
       "locations": [
        {
         "offset": 1246,
         "length": 7
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   ],
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      "novel": "No"
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    {
     "id": "R1",
     "infons": {
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      "type": "Positive_Correlation",
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    }
   ]
  },
  {
   "id": "16575011",
   "passages": [
    {
     "offset": 0,
     "text": "Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Tumor",
       "locations": [
        {
         "offset": 0,
         "length": 5
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "7298",
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       "text": "thymidylate synthase",
       "locations": [
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         "offset": 6,
         "length": 20
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "c|DEL|1494|6",
        "type": "SequenceVariant"
       },
       "text": "1494del6",
       "locations": [
        {
         "offset": 27,
         "length": 8
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "colorectal cancer",
       "locations": [
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         "offset": 71,
         "length": 17
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 89,
         "length": 8
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       ]
      },
      {
       "id": "5",
       "infons": {
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       "locations": [
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         "offset": 108,
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     ]
    },
    {
     "offset": 147,
     "text": "PURPOSE: The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. PATIENTS AND METHODS: One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. RESULTS: Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/-6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. CONCLUSION: Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.",
     "annotations": [
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       "id": "6",
       "infons": {
        "identifier": "D009369",
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       "text": "tumor",
       "locations": [
        {
         "offset": 223,
         "length": 5
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       ]
      },
      {
       "id": "7",
       "infons": {
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       "text": "thymidylate synthase",
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "7298",
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       "text": "TS",
       "locations": [
        {
         "offset": 251,
         "length": 2
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colorectal cancer",
       "locations": [
        {
         "offset": 304,
         "length": 17
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 322,
         "length": 8
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D005472",
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       "text": "fluorouracil",
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         "offset": 350,
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       ]
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       "id": "12",
       "infons": {
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       "text": "FU",
       "locations": [
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         "offset": 364,
         "length": 2
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "PATIENTS",
       "locations": [
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         "offset": 386,
         "length": 8
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       ]
      },
      {
       "id": "14",
       "infons": {
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       "text": "colorectal cancer",
       "locations": [
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         "offset": 432,
         "length": 17
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       ]
      },
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       "id": "15",
       "infons": {
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       "text": "patients",
       "locations": [
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         "offset": 450,
         "length": 8
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       ]
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       "id": "16",
       "infons": {
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       "text": "FU",
       "locations": [
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         "offset": 486,
         "length": 2
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       ]
      },
      {
       "id": "17",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "levamisole",
       "locations": [
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         "offset": 494,
         "length": 10
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       ]
      },
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       "id": "18",
       "infons": {
        "identifier": "D002955",
        "type": "ChemicalEntity"
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       "text": "leucovorin",
       "locations": [
        {
         "offset": 508,
         "length": 10
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       ]
      },
      {
       "id": "19",
       "infons": {
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       "text": "TS",
       "locations": [
        {
         "offset": 558,
         "length": 2
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       ]
      },
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       "id": "20",
       "infons": {
        "identifier": "c|SUB|G||C",
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       "text": "G > C",
       "locations": [
        {
         "offset": 581,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "7298",
        "type": "GeneOrGeneProduct"
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       "text": "TS",
       "locations": [
        {
         "offset": 629,
         "length": 2
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       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "c|DEL|1494|6",
        "type": "SequenceVariant"
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       "text": "1494del6",
       "locations": [
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         "offset": 632,
         "length": 8
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       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumor",
       "locations": [
        {
         "offset": 708,
         "length": 5
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       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "7298",
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       "text": "TS",
       "locations": [
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         "offset": 738,
         "length": 2
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       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D009369",
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       "text": "tumors",
       "locations": [
        {
         "offset": 792,
         "length": 6
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D009362",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "metastases",
       "locations": [
        {
         "offset": 832,
         "length": 10
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "7298",
        "type": "GeneOrGeneProduct"
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       "text": "TS",
       "locations": [
        {
         "offset": 844,
         "length": 2
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D009369",
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       "text": "tumors",
       "locations": [
        {
         "offset": 912,
         "length": 6
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       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D009369",
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       "text": "Tumor",
       "locations": [
        {
         "offset": 1009,
         "length": 5
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       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "c|SUB|G||C",
        "type": "SequenceVariant"
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       "text": "G > C",
       "locations": [
        {
         "offset": 1214,
         "length": 5
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       "text": "colorectal cancer",
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    {
     "offset": 0,
     "text": "Valproate-induced chorea and encephalopathy in atypical nonketotic hyperglycinemia.",
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       "id": "0",
       "infons": {
        "identifier": "D014635",
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     "text": "Nonketotic hyperglycinemia is a disorder of amino acid metabolism in which a defect in the glycine cleavage system leads to an accumulation of glycine in the brain and other body compartments. In the classical form it presents as neonatal apnea, intractable seizures, and hypotonia, followed by significant psychomotor retardation. An important subset of children with nonketotic hyperglycinemia are atypical variants who present in a heterogeneous manner. This report describes a patient with mild language delay and mental retardation, who was found to have nonketotic hyperglycinemia following her presentation with acute encephalopathy and chorea shortly after initiation of valproate therapy.",
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       "text": "seizures",
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       "text": "nonketotic hyperglycinemia",
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       "text": "patient",
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       "text": "language delay",
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       "text": "mental retardation",
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       "text": "nonketotic hyperglycinemia",
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         "length": 26
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       ]
      },
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       "text": "encephalopathy",
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       ]
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       "text": "chorea",
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       ]
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   "id": "18310445",
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     "offset": 0,
     "text": "Bone morphogenetic protein-4 interacts with activin and GnRH to modulate gonadotrophin secretion in LbetaT2 gonadotrophs.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "652",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bone morphogenetic protein-4",
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       "text": "gonadotrophin",
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       "infons": {
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    {
     "offset": 122,
     "text": "We have shown previously that, in sheep primary pituitary cells, bone morphogenetic proteins (BMP)-4 inhibits FSHbeta mRNA expression and FSH release. In contrast, in mouse LbetaT2 gonadotrophs, others have shown a stimulatory effect of BMPs on basal or activin-stimulated FSHbeta promoter-driven transcription. As a species comparison with our previous results, we used LbetaT2 cells to investigate the effects of BMP-4 on gonadotrophin mRNA and secretion modulated by activin and GnRH. BMP-4 alone had no effect on FSH production, but enhanced the activin+GnRH-induced stimulation of FSHbeta mRNA and FSH secretion, without any effect on follistatin mRNA. BMP-4 reduced LHbeta mRNA up-regulation in response to GnRH (+/-activin) and decreased GnRH receptor expression, which would favour FSH, rather than LH, synthesis and secretion. In contrast to sheep pituitary gonadotrophs, which express only BMP receptor types IA (BMPRIA) and II (BMPRII), LbetaT2 cells also express BMPRIB. Smad1/5 phosphorylation induced by BMP-4, indicating activation of BMP signalling, was the same whether BMP-4 was used alone or combined with activin+/-GnRH. We hypothesized that activin and/or GnRH pathways may be modulated by BMP-4, but neither the activin-stimulated phosphorylation of Smad2/3 nor the GnRH-induced ERK1/2 or cAMP response element-binding phosphorylation were modified. However, the GnRH-induced activation of p38 MAPK was decreased by BMP-4. This was associated with increased FSHbeta mRNA levels and FSH secretion, but decreased LHbeta mRNA levels. These results confirm 1. BMPs as important modulators of activin and/or GnRH-stimulated gonadotrophin synthesis and release and 2. important species differences in these effects, which could relate to differences in BMP receptor expression in gonadotrophs.",
     "annotations": [
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       "id": "5",
       "infons": {
        "identifier": "9940",
        "type": "OrganismTaxon"
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       "text": "sheep",
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         "offset": 156,
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       "text": "bone morphogenetic proteins (BMP)-4",
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       "text": "BMPs",
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       "text": "BMP-4",
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         "length": 5
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       ]
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       "id": "30",
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       "text": "GnRH receptor",
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         "length": 13
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       ]
      },
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       "id": "31",
       "infons": {
        "identifier": "443387,443538",
        "type": "GeneOrGeneProduct"
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       "text": "FSH",
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         "offset": 912,
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     "offset": 0,
     "text": "Combination of polymorphisms within 5' and 3' untranslated regions of thymidylate synthase gene modulates survival in 5 fluorouracil-treated colorectal cancer patients.",
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       "text": "thymidylate synthase",
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     "text": "In the present study we explored the effect of three polymorphisms of the TS gene on overall and progression- free survival of colorectal cancer (CRC) patients subjected to 5FU chemotherapy. A 28 bp variable number of tandem repeats (VNTR), a G/C single nucleotide polymorphism (SNP), and a deletion of 6 bp at position 1494 were studied. The possible combined effect of these DNA polymorphisms on the clinical outcome of patients was also evaluated. A retrospective study was carried out on paraffin-embedded sections from 113 patients diagnosed of advanced CRC. TS genotyping methods were polymerase chain reaction (PCR) for VNTR and PCR, followed by restriction length fragment polymorphism (PCR-RFLP) for SNP and ins/del 6 bp. To study the combined effect of TS polymorphisms, four categories were defined accordingly to the level of expression attributed to SNP and ins/del 6 bp genotypes: C_allele 6-, C_6+/6+, G_allele6- and G_6+/6+. VNTR and ins/del 6 bp genotypes varied with tumour anatomical site: 2R/2R genotype was rare in left-sided tumours (7.0% vs. 26.3% of right-sided and 24.1% of rectal cancers; P<0.01), where the variant allele 6- was very frequent (69.0%). Instead, most patients with right-sided tumours were wild-type homozygous 6+/6+ (63.9%) (P<0.01). Heterozygous 6+/6- genotype was more frequent among tumours classified as C (50.0%) and D (76.5%) Dukes stages (P=0.05). None of the studied polymorphisms alone affected overall or progression-free survival (PFS). C_6+/6+ and G_6+/6+ combined genotypes were respectively associated to the best and worst PFS (P=0.03 when compared with each other), while combinations carrying the allele 6- determined an intermediate evolution that might be indicative of a variable response to chemotherapy. The rate of Dukes B stage tumours was unexpectedly high (59.1%) among patients with the unfavourable G_6+/6+ combination. In our study the combination of high TS expression genotypes G_6+/6+ identifies a group of high risk within CRC patients treated with 5FU.",
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     "text": "Phosphatidylinositol 3-kinase p85alpha regulatory subunit gene Met326Ile polymorphism in women with polycystic ovary syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5295",
        "type": "GeneOrGeneProduct"
       },
       "text": "Phosphatidylinositol 3-kinase",
       "locations": [
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         "offset": 0,
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "5295",
        "type": "GeneOrGeneProduct"
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       "text": "p85alpha",
       "locations": [
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         "length": 8
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       ]
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       "id": "2",
       "infons": {
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       "text": "Met326Ile",
       "locations": [
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         "offset": 63,
         "length": 9
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       ]
      },
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       "id": "3",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "women",
       "locations": [
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         "offset": 89,
         "length": 5
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D011085",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "polycystic ovary syndrome",
       "locations": [
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         "length": 25
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     "text": "BACKGROUND: Insulin resistance is a core feature of polycystic ovary syndrome (PCOS). Phosphatidylinositol (PI) 3-kinase is an important enzyme in the early insulin signaling cascade and plays a key role in insulin-mediated glucose transport. In its regulatory subunit, p85alpha, there is a common amino acid substitution (the Met326Ile polymorphism), and this amino acid may be crucial for the function of the p85alpha regulatory subunit and PI3-kinase. METHODS: Analysis of the Met326Ile polymorphism was carried out on DNA samples from 256 PCOS patients and 283 controls. Clinical and biochemical profiles of participants were also compared. RESULTS: The genotype distribution of the Met326Ile polymorphism in the PCOS group was not different from that of the controls (Met326Met/Met326Ile/Ile326Ile rates were 73.4%/23.4%/3.2% and 70.3%/26.1%/3.6% for the PCOS and control groups, respectively, P = 0.72). The PCOS group was divided into two subgroups according to the presence of the variant 326Ile allele. Compared with those carrying at least one variant 326Ile allele, carriers with the Met326Met genotype had higher serum 17-hydroxyprogesterone (17-OHP) {1.1 [95% confidence interval (CI) 1.1-1.3] ng/ml in those with the Met326Met genotype versus 0.8 (95% CI 0.7-1.0) ng/ml in those with Ile326Ile and Met326Ile genotypes, P = 0.0073} and free testosterone levels [1.2 (95% CI 1.1-1.4) pg/ml for Met326Met genotype versus 0.9 (95% CI 0.6-1.3) pg/ml for Ile326Ile and Met326Ile genotypes, P = 0.038]. CONCLUSIONS: Our results suggest that the PI3-kinase gene Met326Ile polymorphism may not be a major determinant for the development of PCOS, but it may modulate the concentrations of serum 17-OHP or free testosterone in PCOS patients.",
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       "text": "Insulin resistance",
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       "text": "PCOS",
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       "id": "8",
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       "text": "p85alpha",
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       "id": "14",
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       "text": "p85alpha",
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       "id": "15",
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       "id": "20",
       "infons": {
        "identifier": "D011085",
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       "text": "PCOS",
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       "id": "21",
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       "id": "24",
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       "id": "25",
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       "text": "326Ile",
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       "id": "27",
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       "text": "326Ile",
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         "offset": 1189,
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       "id": "28",
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       "text": "Met326Met",
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         "offset": 1222,
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       "id": "29",
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       "id": "30",
       "infons": {
        "identifier": "D019326",
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       "text": "17-OHP",
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         "offset": 1282,
         "length": 6
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       "id": "31",
       "infons": {
        "identifier": "rs3730089",
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       "text": "Met326Met",
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         "offset": 1358,
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       "id": "32",
       "infons": {
        "identifier": "rs3730089",
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       "text": "Ile326Ile",
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       "id": "33",
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       "id": "34",
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       "text": "testosterone",
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       "id": "39",
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       "id": "40",
       "infons": {
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       "id": "41",
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       "text": "testosterone",
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       "text": "PCOS",
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         "offset": 1857,
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       "id": "44",
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       "locations": [
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         "length": 15
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       "id": "1",
       "infons": {
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       "text": "seizures",
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     "text": "BACKGROUND: In 2 separate centers, we observed a notable increase in the incidence of postoperative convulsive seizures from 1.3% to 3.8% in patients having undergone major cardiac surgical procedures. These events were temporally coincident with the initial use of high-dose tranexamic acid (TXA) therapy after withdrawal of aprotinin from general clinical usage. The purpose of this review was to perform a retrospective analysis to examine whether there was a relation between TXA usage and seizures after cardiac surgery. METHODS: An in-depth chart review was undertaken in all 24 patients who developed perioperative seizures. Electroencephalographic activity was recorded in 11 of these patients, and all patients had a formal neurological evaluation and brain imaging studies. RESULTS: Twenty-one of the 24 patients did not have evidence of new cerebral ischemic injury, but seizures were likely due to ischemic brain injury in 3 patients. All patients with seizures did not have permanent neurological abnormalities. All 24 patients with seizures received high doses of TXA intraoperatively ranging from 61 to 259 mg/kg, had a mean age of 69.9 years, and 21 of 24 had undergone open chamber rather than coronary bypass procedures. All but one patient were managed using cardiopulmonary bypass. No evidence of brain ischemic, metabolic, or hyperthermia-induced causes for their seizures was apparent. CONCLUSION: Our results suggest that use of high-dose TXA in older patients in conjunction with cardiopulmonary bypass and open-chamber cardiac surgery is associated with clinical seizures in susceptible patients.",
     "annotations": [
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     "text": "Cocaine causes memory and learning impairments in rats: involvement of nuclear factor kappa B and oxidative stress, and prevention by topiramate.",
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     "text": "Different mechanisms have been suggested for cocaine toxicity including an increase in oxidative stress but the association between oxidative status in the brain and cocaine induced-behaviour is poorly understood. Nuclear factor kappa B (NFkappaB) is a sensor of oxidative stress and participates in memory formation that could be involved in drug toxicity and addiction mechanisms. Therefore NFkappaB activity, oxidative stress, neuronal nitric oxide synthase (nNOS) activity, spatial learning and memory as well as the effect of topiramate, a previously proposed therapy for cocaine addiction, were evaluated in an experimental model of cocaine administration in rats. NFkappaB activity was decreased in the frontal cortex of cocaine treated rats, as well as GSH concentration and glutathione peroxidase activity in the hippocampus, whereas nNOS activity in the hippocampus was increased. Memory retrieval of experiences acquired prior to cocaine administration was impaired and negatively correlated with NFkappaB activity in the frontal cortex. In contrast, learning of new tasks was enhanced and correlated with the increase of nNOS activity and the decrease of glutathione peroxidase. These results provide evidence for a possible mechanistic role of oxidative and nitrosative stress and NFkappaB in the alterations induced by cocaine. Topiramate prevented all the alterations observed, showing novel neuroprotective properties.",
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     "text": "Dexamethasone- (Dex-) induced hypertension is associated with enhanced oxidative stress. Lactoferrin (LF) is an iron-binding glycoprotein with antihypertensive properties. In this study, we investigated the effect of chronic administration of LF on oxidative stress and hypertension upon Dex administration. Male Wistar rats were treated by Dex (30  u g/kg/day subcutaneously) or saline for 14 days. Oral bovine LF (30, 100, 300 mg/kg) was given from day 8 to 14 in a reversal study. In a prevention study, rats received 4 days of LF treatment followed by Dex and continued during the test period. Systolic blood pressure (SBP) was measured using tail-cuff method. Thymus weight was used as a marker of glucocorticoid activity. Plasma hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) value were determined. Dexamethasone significantly increased SBP and plasma H2O2 level and decreased thymus and body weights. LF lowered (P < 0.01) and dose dependently prevented (P < 0.001) Dex-induced hypertension. LF prevented body weight loss and significantly reduced the elevated plasma H2O2 and increased FRAP values. Chronic administration of LF strongly reduced the blood pressure and production of ROS and improved antioxidant capacity in Dex-induced hypertension, suggesting the role of inhibition of oxidative stress as another mechanism of antihypertensive action of LF.",
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     "offset": 0,
     "text": "IL-3 and CSF-1 interact to promote generation of CD11c+ IL-10-producing macrophages.",
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     "text": "Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia.",
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     "text": "Dystonia is a neurological movement disorder that forces the body into twisting, repetitive movements or sometimes painful abnormal postures. With the advent of next-generation sequencing technologies, the homozygous mutations T71N and A190T in the neuronal calcium sensor (NCS) hippocalcin were identified as the genetic cause of primary isolated dystonia (DYT2 dystonia). However, the effect of these mutations on the physiological role of hippocalcin has not yet been elucidated. Using a multidisciplinary approach, we demonstrated that hippocalcin oligomerises in a calcium-dependent manner and binds to voltage-gated calcium channels. Mutations T71N and A190T in hippocalcin did not affect stability, calcium-binding affinity or translocation to cellular membranes (Ca2+/myristoyl switch). We obtained the first crystal structure of hippocalcin and alignment with other NCS proteins showed significant variability in the orientation of the C-terminal part of the molecule, the region expected to be important for target binding. We demonstrated that the disease-causing mutations did not affect the structure of the protein, however both mutants showed a defect in oligomerisation. In addition, we observed an increased calcium influx in KCl-depolarised cells expressing mutated hippocalcin, mostly driven by N-type voltage-gated calcium channels. Our data demonstrate that the dystonia-causing mutations strongly affect hippocalcin cellular functions which suggest a central role for perturbed calcium signalling in DYT2 dystonia.",
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     "offset": 0,
     "text": "Ca2+-dependent endoplasmic reticulum stress correlation with astrogliosis involves upregulation of KCa3.1 and inhibition of AKT/mTOR signaling.",
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     "text": "BACKGROUND: The intermediate-conductance Ca2+-activated K+ channel KCa3.1 was recently shown to control the phenotype switch of reactive astrogliosis (RA) in Alzheimer's disease (AD). METHODS: KCa3.1 channels expression and cell localization in the brains of AD patients and APP/PS1 mice model were measured by immunoblotting and immunostaining. APP/PS1 mice and KCa3.1-/-/APP/PS1 mice were subjected to Morris water maze test to evaluate the spatial memory deficits. Glia activation and neuron loss was measured by immunostaining. Fluo-4AM was used to measure cytosolic Ca2+ level in beta-amyloid (Abeta) induced reactive astrocytes in vitro. RESULTS: KCa3.1 expression was markedly associated with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in both Abeta-stimulated primary astrocytes and brain lysates of AD patients and APP/PS1 AD mice. The KCa3.1 channel was shown to regulate store-operated Ca2+ entry (SOCE) through an interaction with the Ca2+ channel Orai1 in primary astrocytes. Gene deletion or pharmacological blockade of KCa3.1 protected against SOCE-induced Ca2+ overload and ER stress via the protein kinase B (AKT) signaling pathway in astrocytes. Importantly, gene deletion or blockade of KCa3.1 restored AKT/mechanistic target of rapamycin signaling both in vivo and in vitro. Consistent with these in vitro data, expression levels of the ER stress markers 78-kDa glucose-regulated protein and CCAAT/enhancer-binding protein homologous protein, as well as that of the RA marker glial fibrillary acidic protein were increased in APP/PS1 AD mouse model. Elimination of KCa3.1 in KCa3.1-/-/APP/PS1 mice corrected these abnormal responses. Moreover, glial activation and neuroinflammation were attenuated in the hippocampi of KCa3.1-/-/APP/PS1 mice, as compared with APP/PS1 mice. In addition, memory deficits and neuronal loss in APP/PS1 mice were reversed in KCa3.1-/-/APP/PS1 mice. CONCLUSIONS: Overall, these results suggest that KCa3.1 is involved in the regulation of Ca2+ homeostasis in astrocytes and attenuation of the UPR and ER stress, thus contributing to memory deficits and neuronal loss.",
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      "novel": "No"
     }
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     "id": "R22",
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      "entity1": "16534",
      "entity2": "14580",
      "type": "Negative_Correlation",
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    },
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    },
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    },
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     }
    },
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     }
    },
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     "infons": {
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      "novel": "No"
     }
    },
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    },
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     "infons": {
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      "novel": "Novel"
     }
    },
    {
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     "infons": {
      "entity1": "D002118",
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      "novel": "Novel"
     }
    },
    {
     "id": "R37",
     "infons": {
      "entity1": "D002118",
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      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15461822",
   "passages": [
    {
     "offset": 0,
     "text": "Vaccine candidates derived from a novel infectious cDNA clone of an American genotype dengue virus type 2.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "dengue virus type 2",
       "locations": [
        {
         "offset": 86,
         "length": 19
        }
       ]
      }
     ]
    },
    {
     "offset": 107,
     "text": "BACKGROUND: A dengue virus type 2 (DEN-2 Tonga/74) isolated from a 1974 epidemic was characterized by mild illness and belongs to the American genotype of DEN-2 viruses. To prepare a vaccine candidate, a previously described 30 nucleotide deletion (Delta30) in the 3' untranslated region of DEN-4 has been engineered into the DEN-2 isolate. METHODS: A full-length cDNA clone was generated from the DEN-2 virus and used to produce recombinant DEN-2 (rDEN-2) and rDEN2Delta30. Viruses were evaluated for replication in SCID mice transplanted with human hepatoma cells (SCID-HuH-7 mice), in mosquitoes, and in rhesus monkeys. Neutralizing antibody induction and protective efficacy were also assessed in rhesus monkeys. RESULTS: The rDEN2Delta30 virus was ten-fold reduced in replication in SCID-HuH-7 mice when compared to the parent virus. The rDEN-2 viruses were not infectious for Aedes mosquitoes, but both readily infected Toxorynchites mosquitoes. In rhesus monkeys, rDEN2Delta30 appeared to be slightly attenuated when compared to the parent virus as measured by duration and peak of viremia and neutralizing antibody induction. A derivative of rDEN2Delta30, designated rDEN2Delta30-4995, was generated by incorporation of a point mutation previously identified in the NS3 gene of DEN-4 and was found to be more attenuated than rDEN2Delta30 in SCID-HuH-7 mice. CONCLUSIONS: The rDEN2Delta30 and rDEN2Delta30-4995 viruses can be considered for evaluation in humans and for inclusion in a tetravalent dengue vaccine.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "dengue virus type 2",
       "locations": [
        {
         "offset": 121,
         "length": 19
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "DEN-2",
       "locations": [
        {
         "offset": 142,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "DEN-2",
       "locations": [
        {
         "offset": 262,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "30 nucleotide deletion",
       "locations": [
        {
         "offset": 332,
         "length": 22
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "Delta30",
       "locations": [
        {
         "offset": 356,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "11070",
        "type": "OrganismTaxon"
       },
       "text": "DEN-4",
       "locations": [
        {
         "offset": 398,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "DEN-2",
       "locations": [
        {
         "offset": 433,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "DEN-2",
       "locations": [
        {
         "offset": 505,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "DEN-2",
       "locations": [
        {
         "offset": 549,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN-2",
       "locations": [
        {
         "offset": 556,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 568,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "Delta30",
       "locations": [
        {
         "offset": 573,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 629,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 652,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hepatoma",
       "locations": [
        {
         "offset": 658,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "CVCL_0336",
        "type": "CellLine"
       },
       "text": "SCID-HuH-7",
       "locations": [
        {
         "offset": 674,
         "length": 10
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 685,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9544",
        "type": "OrganismTaxon"
       },
       "text": "rhesus monkeys",
       "locations": [
        {
         "offset": 714,
         "length": 14
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9544",
        "type": "OrganismTaxon"
       },
       "text": "rhesus monkeys",
       "locations": [
        {
         "offset": 808,
         "length": 14
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 837,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "Delta30",
       "locations": [
        {
         "offset": 842,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "CVCL_0336",
        "type": "CellLine"
       },
       "text": "SCID-HuH-7",
       "locations": [
        {
         "offset": 895,
         "length": 10
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 906,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN-2",
       "locations": [
        {
         "offset": 950,
         "length": 6
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "1245352",
        "type": "OrganismTaxon"
       },
       "text": "Aedes mosquitoes",
       "locations": [
        {
         "offset": 989,
         "length": 16
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "2498889",
        "type": "OrganismTaxon"
       },
       "text": "Toxorynchites mosquitoes",
       "locations": [
        {
         "offset": 1033,
         "length": 24
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9544",
        "type": "OrganismTaxon"
       },
       "text": "rhesus monkeys",
       "locations": [
        {
         "offset": 1062,
         "length": 14
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 1078,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "Delta30",
       "locations": [
        {
         "offset": 1083,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D014766",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "viremia",
       "locations": [
        {
         "offset": 1196,
         "length": 7
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 1257,
         "length": 5
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "Delta30",
       "locations": [
        {
         "offset": 1262,
         "length": 7
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 1282,
         "length": 5
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "c|DEL|4995|30",
        "type": "SequenceVariant"
       },
       "text": "Delta30-4995",
       "locations": [
        {
         "offset": 1287,
         "length": 12
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "5130010",
        "type": "GeneOrGeneProduct"
       },
       "text": "NS3",
       "locations": [
        {
         "offset": 1381,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "11070",
        "type": "OrganismTaxon"
       },
       "text": "DEN-4",
       "locations": [
        {
         "offset": 1393,
         "length": 5
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 1440,
         "length": 5
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "Delta30",
       "locations": [
        {
         "offset": 1445,
         "length": 7
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "CVCL_0336",
        "type": "CellLine"
       },
       "text": "SCID-HuH-7",
       "locations": [
        {
         "offset": 1456,
         "length": 10
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 1467,
         "length": 4
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 1490,
         "length": 5
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "c|DEL||30",
        "type": "SequenceVariant"
       },
       "text": "Delta30",
       "locations": [
        {
         "offset": 1495,
         "length": 7
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "11060",
        "type": "OrganismTaxon"
       },
       "text": "rDEN2",
       "locations": [
        {
         "offset": 1507,
         "length": 5
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "c|DEL|4995|30",
        "type": "SequenceVariant"
       },
       "text": "Delta30-4995",
       "locations": [
        {
         "offset": 1512,
         "length": 12
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "humans",
       "locations": [
        {
         "offset": 1569,
         "length": 6
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "D003715",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dengue",
       "locations": [
        {
         "offset": 1611,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "c|DEL|4995|30",
      "entity2": "D003715",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|DEL||30",
      "entity2": "D003715",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|DEL||30",
      "entity2": "D014766",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16418600",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic investigation of the TSPYL1 gene in sudden infant death syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7259",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSPYL1",
       "locations": [
        {
         "offset": 29,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D013398",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sudden infant death syndrome",
       "locations": [
        {
         "offset": 44,
         "length": 28
        }
       ]
      }
     ]
    },
    {
     "offset": 74,
     "text": "BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D013398",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Sudden infant death syndrome",
       "locations": [
        {
         "offset": 86,
         "length": 28
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D013398",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SIDS",
       "locations": [
        {
         "offset": 116,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D003643",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "death",
       "locations": [
        {
         "offset": 161,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C563856",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sudden infant death with dysgenesis of the testes syndrome",
       "locations": [
        {
         "offset": 253,
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     "text": "A 74-year-old man with depressive symptoms was admitted to a psychiatric hospital due to insomnia, loss of appetite, exhaustion, and agitation. Medical treatment was initiated at a daily dose of 20 mg paroxetine and 1.2 mg alprazolam. On the 10th day of paroxetine and alprazolam treatment, the patient exhibited marked psychomotor retardation, disorientation, and severe muscle rigidity with tremors. The patient had a fever (38.2 degrees C), fluctuating blood pressure (between 165/90 and 130/70 mg mm Hg), and severe extrapyramidal symptoms. Laboratory tests showed an elevation of creatine phosphokinase (2218 IU/L), aspartate aminotransferase (134 IU/L), alanine aminotransferase (78 IU/L), and BUN (27.9 mg/ml) levels. The patient received bromocriptine and diazepam to treat his symptoms. 7 days later, the fever disappeared and the patient's serum CPK levels were normalized (175 IU/L). This patient presented with symptoms of neuroleptic malignant syndrome (NMS), thus demonstrating that NMS-like symptoms can occur after combined paroxetine and alprazolam treatment. The adverse drug reaction score obtained by the Naranjo algorithm was 6 in our case, indicating a probable relationship between the patient's NMS-like adverse symptoms and the combined treatment used in this case. The involvement of physiologic and environmental aspects specific to this patient was suspected. Several risk factors for NMS should be noted in elderly depressive patients whose symptoms often include dehydration, agitation, malnutrition, and exhaustion. Careful therapeutic intervention is necessary in cases involving elderly patients who suffer from depression.",
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  {
   "id": "16904497",
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    {
     "offset": 0,
     "text": "Cauda equina syndrome after epidural steroid injection: a case report.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D011128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Cauda equina syndrome",
       "locations": [
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         "length": 21
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       ]
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       "id": "1",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "steroid",
       "locations": [
        {
         "offset": 37,
         "length": 7
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       ]
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     ]
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     "offset": 71,
     "text": "OBJECTIVE: Conventional treatment methods of lumbusacral radiculopathy are physical therapy, epidural steroid injections, oral medications, and spinal manipulative therapy. Cauda equina syndrome is a rare complication of epidural anesthesia. The following case is a report of cauda equina syndrome possibly caused by epidural injection of triamcinolone and bupivacaine. CLINICAL FEATURES: A 50-year-old woman with low back and right leg pain was scheduled for epidural steroid injection. INTERVENTION AND OUTCOME: An 18-gauge Touhy needle was inserted until loss of resistance occurred at the L4-5 level. Spread of the contrast medium within the epidural space was determined by radiographic imaging. After verifying the epidural space, bupivacaine and triamcinolone diacetate were injected. After the injection, there was a reduction in radicular symptoms. Three hours later, she complained of perineal numbness and lower extremity weakness. The neurologic evaluation revealed loss of sensation in the saddle area and medial aspect of her right leg. There was a decrease in the perception of pinprick test. Deep-tendon reflexes were decreased especially in the right leg. She was unable to urinate. The patient's symptoms improved slightly over the next few hours. She had a gradual return of motor function and ability of feeling Foley catheter. All of the symptoms were completely resolved over the next 8 hours. CONCLUSION: Complications associated with epidural steroid injections are rare. Clinical examination and continued vigilance for neurologic deterioration after epidural steroid injections is important.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D011843",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "radiculopathy",
       "locations": [
        {
         "offset": 128,
         "length": 13
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D013256",
        "type": "ChemicalEntity"
       },
       "text": "steroid",
       "locations": [
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         "offset": 173,
         "length": 7
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       ]
      },
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       "id": "4",
       "infons": {
        "identifier": "D011128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Cauda equina syndrome",
       "locations": [
        {
         "offset": 244,
         "length": 21
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D011128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cauda equina syndrome",
       "locations": [
        {
         "offset": 347,
         "length": 21
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       ]
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       "id": "6",
       "infons": {
        "identifier": "D014221",
        "type": "ChemicalEntity"
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       "text": "triamcinolone",
       "locations": [
        {
         "offset": 410,
         "length": 13
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       ]
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       "id": "7",
       "infons": {
        "identifier": "D002045",
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       "text": "bupivacaine",
       "locations": [
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         "offset": 428,
         "length": 11
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       ]
      },
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       "id": "8",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "woman",
       "locations": [
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         "offset": 474,
         "length": 5
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D010146,D017116",
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       "text": "low back and right leg pain",
       "locations": [
        {
         "offset": 485,
         "length": 27
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D013256",
        "type": "ChemicalEntity"
       },
       "text": "steroid",
       "locations": [
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         "offset": 540,
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       ]
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       "id": "11",
       "infons": {
        "identifier": "D002045",
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       "text": "bupivacaine",
       "locations": [
        {
         "offset": 808,
         "length": 11
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       ]
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       "id": "12",
       "infons": {
        "identifier": "C030262",
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       "text": "triamcinolone diacetate",
       "locations": [
        {
         "offset": 824,
         "length": 23
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D006987",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "numbness",
       "locations": [
        {
         "offset": 975,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D020335",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lower extremity weakness",
       "locations": [
        {
         "offset": 988,
         "length": 24
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D006987",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "loss of sensation",
       "locations": [
        {
         "offset": 1049,
         "length": 17
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       ]
      },
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       "id": "16",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patient",
       "locations": [
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         "offset": 1275,
         "length": 7
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       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "D013256",
        "type": "ChemicalEntity"
       },
       "text": "steroid",
       "locations": [
        {
         "offset": 1538,
         "length": 7
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009422",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurologic deterioration",
       "locations": [
        {
         "offset": 1616,
         "length": 24
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D013256",
        "type": "ChemicalEntity"
       },
       "text": "steroid",
       "locations": [
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         "offset": 1656,
         "length": 7
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      "novel": "No"
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     "id": "R1",
     "infons": {
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      "novel": "No"
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      "novel": "No"
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      "type": "Positive_Correlation",
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     "infons": {
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      "type": "Positive_Correlation",
      "novel": "Novel"
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    {
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     "infons": {
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      "type": "Positive_Correlation",
      "novel": "Novel"
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    {
     "id": "R8",
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      "novel": "Novel"
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     "infons": {
      "entity1": "D011128",
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      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R10",
     "infons": {
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      "type": "Positive_Correlation",
      "novel": "Novel"
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  },
  {
   "id": "17083016",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "729238",
        "type": "GeneOrGeneProduct"
       },
       "text": "surfactant protein-A2",
       "locations": [
        {
         "offset": 46,
         "length": 21
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008589",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "meningococcal disease",
       "locations": [
        {
         "offset": 96,
         "length": 21
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       ]
      }
     ]
    },
    {
     "offset": 119,
     "text": "BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D008589",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Meningococcal disease",
       "locations": [
        {
         "offset": 131,
         "length": 21
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D006069",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Neisseria meningitidis",
       "locations": [
        {
         "offset": 203,
         "length": 22
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "653509,729238",
        "type": "GeneOrGeneProduct"
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       "text": "Surfactant protein (SP)-A",
       "locations": [
        {
         "offset": 227,
         "length": 25
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "6441",
        "type": "GeneOrGeneProduct"
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       "text": "SP-D",
       "locations": [
        {
         "offset": 257,
         "length": 4
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "inflammatory",
       "locations": [
        {
         "offset": 335,
         "length": 12
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D000073893",
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       "text": "sugars",
       "locations": [
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         "offset": 399,
         "length": 6
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "653509",
        "type": "GeneOrGeneProduct"
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       "text": "SP-A1",
       "locations": [
        {
         "offset": 544,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "729238",
        "type": "GeneOrGeneProduct"
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       "text": "SP-A2",
       "locations": [
        {
         "offset": 551,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "6441",
        "type": "GeneOrGeneProduct"
       },
       "text": "SP-D",
       "locations": [
        {
         "offset": 562,
         "length": 4
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       ]
      },
      {
       "id": "11",
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       },
       "text": "patients",
       "locations": [
        {
         "offset": 619,
         "length": 8
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008589",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "meningococcal disease",
       "locations": [
        {
         "offset": 658,
         "length": 21
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 694,
         "length": 8
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D003643",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "died",
       "locations": [
        {
         "offset": 707,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "729238",
        "type": "GeneOrGeneProduct"
       },
       "text": "SP-A2",
       "locations": [
        {
         "offset": 786,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D008589",
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       },
       "text": "meningococcal disease",
       "locations": [
        {
         "offset": 814,
         "length": 21
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "653509,729238",
        "type": "GeneOrGeneProduct"
       },
       "text": "SP-A",
       "locations": [
        {
         "offset": 1025,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|SUB|Q|223|K",
        "type": "SequenceVariant"
       },
       "text": "lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223",
       "locations": [
        {
         "offset": 1082,
         "length": 64
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D002241",
        "type": "ChemicalEntity"
       },
       "text": "carbohydrate",
       "locations": [
        {
         "offset": 1154,
         "length": 12
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D008589",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "meningococcal disease",
       "locations": [
        {
         "offset": 1227,
         "length": 21
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|Allele|K|223",
        "type": "SequenceVariant"
       },
       "text": "lysine at residue 223",
       "locations": [
        {
         "offset": 1307,
         "length": 21
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1349,
         "length": 8
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       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D003643",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "died",
       "locations": [
        {
         "offset": 1362,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "653509",
        "type": "GeneOrGeneProduct"
       },
       "text": "SP-A1",
       "locations": [
        {
         "offset": 1474,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "6441",
        "type": "GeneOrGeneProduct"
       },
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     "text": "A novel missense mutation in the paired domain of human PAX9 causes oligodontia.",
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       "id": "0",
       "infons": {
        "identifier": "9606",
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       "text": "human",
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     "text": "PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype.",
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       "text": "humans",
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       "text": "nonsyndromic and syndromic oligodontia",
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       "text": "nonsyndromic oligodontia",
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       "text": "PAX9",
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       "text": "MSX1",
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       ]
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       "id": "10",
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       "text": "C139T",
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       "id": "11",
       "infons": {
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       "text": "PAX9",
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       ]
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       "id": "12",
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       "text": "MSX1",
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       "id": "13",
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       ]
      },
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       "id": "14",
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       "text": "arginine by a tryptophan",
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   "id": "18366737",
   "passages": [
    {
     "offset": 0,
     "text": "The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency.",
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       "id": "0",
       "infons": {
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       "text": "FH",
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       "text": "fumarate hydratase",
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       "text": "MCUL",
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       "id": "3",
       "infons": {
        "identifier": "C535516",
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       "text": "HLRCC",
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      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009369",
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       "text": "tumor syndrome",
       "locations": [
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         "offset": 106,
         "length": 14
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C538191",
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       "text": "fumarase deficiency",
       "locations": [
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         "length": 19
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       ]
      }
     ]
    },
    {
     "offset": 157,
     "text": "BACKGROUND: Fumarate hydratase (HGNC approved gene symbol - FH), also known as fumarase, is an enzyme of the tricarboxylic acid (TCA) cycle, involved in fundamental cellular energy production. First described by Zinn et al in 1986, deficiency of FH results in early onset, severe encephalopathy. In 2002, the Multiple Leiomyoma Consortium identified heterozygous germline mutations of FH in patients with multiple cutaneous and uterine leiomyomas, (MCUL: OMIM 150800). In some families renal cell cancer also forms a component of the complex and as such has been described as hereditary leiomyomatosis and renal cell cancer (HLRCC: OMIM 605839). The identification of FH as a tumor suppressor was an unexpected finding and following the identification of subunits of succinate dehydrogenase in 2000 and 2001, was only the second description of the involvement of an enzyme of intermediary metabolism in tumorigenesis. DESCRIPTION: The FH mutation database is a part of the TCA cycle gene mutation database (formerly the succinate dehydrogenase gene mutation database) and is based on the Leiden Open (source) Variation Database (LOVD) system. The variants included in the database were derived from the published literature and annotated to conform to current mutation nomenclature. The FH database applies HGVS nomenclature guidelines, and will assist researchers in applying these guidelines when directly submitting new sequence variants online. Since the first molecular characterization of an FH mutation by Bourgeron et al in 1994, a series of reports of both FH deficiency patients and patients with MCUL/HLRRC have described 107 variants, of which 93 are thought to be pathogenic. The most common type of mutation is missense (57%), followed by frameshifts & nonsense (27%), and diverse deletions, insertions and duplications. Here we introduce an online database detailing all reported FH sequence variants. CONCLUSION: The FH mutation database strives to systematically unify all current genetic knowledge of FH variants. We believe that this knowledge will assist clinical geneticists and treating physicians when advising patients and their families, will provide a rapid and convenient resource for research scientists, and may eventually assist in gaining novel insights into FH and its related clinical syndromes.",
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       "text": "Fumarate hydratase",
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       "text": "tricarboxylic acid",
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       "id": "11",
       "infons": {
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       "text": "deficiency of FH",
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       "text": "encephalopathy",
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       "id": "28",
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       "id": "29",
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      },
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       "id": "30",
       "infons": {
        "identifier": "C538191",
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       "text": "FH deficiency",
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       ]
      },
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       "id": "31",
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       "text": "patients",
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       ]
      },
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       "id": "32",
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       "text": "patients",
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       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "C535516",
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       },
       "text": "MCUL",
       "locations": [
        {
         "offset": 1764,
         "length": 4
        }
       ]
      },
      {
       "id": "34",
       "infons": {
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       "text": "HLRRC",
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         "offset": 1769,
         "length": 5
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       ]
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       "id": "35",
       "infons": {
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         "length": 2
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       "text": "patients",
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       "id": "39",
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         "offset": 2447,
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     "infons": {
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   "id": "18827003",
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    {
     "offset": 0,
     "text": "A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 59,
         "length": 5
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "2908",
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       "text": "glucocorticoid receptor",
       "locations": [
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         "offset": 65,
         "length": 23
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       "id": "2",
       "infons": {
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         "offset": 90,
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       "id": "3",
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        "identifier": "2908",
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       "locations": [
        {
         "offset": 110,
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    {
     "offset": 140,
     "text": "CONTEXT: Interindividual variations in glucocorticoid sensitivity have been associated with manifestations of cortisol excess or deficiency and may be partly explained by polymorphisms in the human glucocorticoid receptor (hGR) gene. We studied a 43-yr-old female, who presented with manifestations consistent with tissue-selective glucocorticoid hypersensitivity. We detected a novel, single, heterozygous nucleotide (G --> C) substitution at position 1201 (exon 2) of the hGR gene, which resulted in aspartic acid to histidine substitution at amino acid position 401 in the amino-terminal domain of the hGRalpha. We investigated the molecular mechanisms of action of the natural mutant receptor hGRalphaD401H. METHODS-RESULTS: Compared with the wild-type hGRalpha, the mutant receptor hGRalphaD401H demonstrated a 2.4-fold increase in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone but had similar affinity for the ligand (dissociation constant = 6.2 +/- 0.6 vs. 6.1 +/- 0.6 nm) and time to nuclear translocation (14.75 +/- 0.25 vs. 14.25 +/- 1.13 min). The mutant receptor hGRalphaD401H did not exert a dominant positive or negative effect upon the wild-type receptor, it preserved its ability to bind to glucocorticoid response elements, and displayed a normal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. CONCLUSIONS: The mutant receptor hGRalphaD401H enhances the transcriptional activity of glucocorticoid-responsive genes. The presence of the D401H mutation may predispose subjects to obesity, hypertension, and other manifestations of the metabolic syndrome.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D005938",
        "type": "ChemicalEntity"
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       "text": "glucocorticoid",
       "locations": [
        {
         "offset": 179,
         "length": 14
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       ]
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       "id": "5",
       "infons": {
        "identifier": "D006854",
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       "text": "cortisol",
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        {
         "offset": 250,
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       "id": "6",
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       "text": "human",
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         "offset": 332,
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         "offset": 363,
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       "text": "glucocorticoid",
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       "id": "10",
       "infons": {
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       "text": "hypersensitivity",
       "locations": [
        {
         "offset": 487,
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      },
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       "id": "11",
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       "text": "(G --> C) substitution at position 1201",
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         "offset": 558,
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       ]
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       "id": "12",
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       "id": "13",
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        "identifier": "p|SUB|D|401|H",
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       "text": "aspartic acid to histidine substitution at amino acid position 401",
       "locations": [
        {
         "offset": 642,
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        }
       ]
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       "id": "14",
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         "offset": 1010,
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       "id": "21",
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       "text": "mouse mammary tumor virus",
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         "offset": 1035,
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       "id": "26",
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       "text": "glucocorticoid receptor-interacting protein 1",
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         "offset": 1501,
         "length": 45
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       "id": "27",
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       "text": "hGRalpha",
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       "text": "D401H",
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       "id": "29",
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       "text": "glucocorticoid-responsive genes",
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         "length": 31
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       "id": "30",
       "infons": {
        "identifier": "p|SUB|D|401|H",
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         "offset": 1701,
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       "id": "31",
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       "text": "obesity",
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         "offset": 1743,
         "length": 7
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       "id": "32",
       "infons": {
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       "text": "hypertension",
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        {
         "offset": 1752,
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       "id": "33",
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       "text": "metabolic syndrome",
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        {
         "offset": 1798,
         "length": 18
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      "novel": "No"
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   ]
  },
  {
   "id": "20105280",
   "passages": [
    {
     "offset": 0,
     "text": "Activated Ras alters lens and corneal development through induction of distinct downstream targets.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3265",
        "type": "GeneOrGeneProduct"
       },
       "text": "Ras",
       "locations": [
        {
         "offset": 10,
         "length": 3
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    {
     "offset": 100,
     "text": "BACKGROUND: Mammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. Activation of the fibroblast growth factor (FGF) signaling pathway induces the corneal epithelial cells to proliferate and the lens epithelial cells to exit the cell cycle. The molecular mechanisms that regulate the differential responses of these two related tissues have not been defined. We have generated transgenic mice that express a constitutively active version of human H-Ras in their lenses and corneas. RESULTS: Ras transgenic lenses and corneal epithelial cells showed increased proliferation with concomitant increases in cyclin D1 and D2 expression. This initial increase in proliferation is sustained in the cornea but not in the lens epithelial cells. Coincidentally, cdk inhibitors p27Kip1 and p57Kip2 were upregulated in the Ras transgenic lenses but not in the corneas. Phospho-Erk1 and Erk2 levels were elevated in the lens but not in the cornea and Spry 1 and Spry 2, negative regulators of Ras-Raf-Erk signaling, were upregulated more in the corneal than in the lens epithelial cells. Both lens and corneal differentiation programs were sensitive to Ras activation. Ras transgenic embryos showed a distinctive alteration in the architecture of the lens pit. Ras activation, though sufficient for upregulation of Prox1, a transcription factor critical for cell cycle exit and initiation of fiber differentiation, is not sufficient for induction of terminal fiber differentiation. Expression of Keratin 12, a marker of corneal epithelial differentiation, was reduced in the Ras transgenic corneas. CONCLUSIONS: Collectively, these results suggest that Ras activation a) induces distinct sets of downstream targets in the lens and cornea resulting in distinct cellular responses and b) is sufficient for initiation but not completion of lens fiber differentiation.",
     "annotations": [
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       "id": "1",
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       "text": "Ras",
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       "text": "human",
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       "text": "cancers",
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       "text": "Tumor",
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         "offset": 257,
         "length": 5
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       ]
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       "id": "5",
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       "text": "murine",
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       "id": "7",
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       "text": "fibroblast growth factor",
       "locations": [
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       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "64654",
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       "text": "FGF",
       "locations": [
        {
         "offset": 565,
         "length": 3
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
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         "offset": 841,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
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       "text": "human",
       "locations": [
        {
         "offset": 894,
         "length": 5
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "3265",
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       "text": "H-Ras",
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        {
         "offset": 900,
         "length": 5
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       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "3265",
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       "text": "Ras",
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         "offset": 944,
         "length": 3
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      },
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       "id": "13",
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       "text": "cyclin D1 and D2",
       "locations": [
        {
         "offset": 1056,
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       ]
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       "id": "14",
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        "identifier": "12575",
        "type": "GeneOrGeneProduct"
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       "text": "cdk",
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         "offset": 1205,
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "12576",
        "type": "GeneOrGeneProduct"
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     "text": "A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome.",
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     "text": "BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. AIM: To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. RESULTS: The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). CONCLUSIONS: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome.",
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     "text": "Our recent study showed that SAG/RBX2 E3 ubiquitin ligase regulates apoptosis and vasculogenesis by promoting degradation of NOXA and NF1, and co-operates with Kras to promote lung tumorigenesis by activating NFkappaB and mTOR pathways via targeted degradation of tumor suppressive substrates including IkappaB, DEPTOR, p21 and p27. Here we investigated the role of Sag/Rbx2 E3 ligase in cellular senescence and immortalization of mouse embryonic fibroblasts (MEFs) and report that Sag is required for proper cell proliferation and Kras(G12D)-induced immortalization. Sag inactivation by genetic deletion remarkably suppresses cell proliferation by inducing senescence, which is associated with accumulation of p16, but not p53. Mechanistically, Sag deletion caused accumulation of Jun-B, a substrate of Sag-Fbxw7 E3 ligase and a transcription factor that drives p16 transcription. Importantly, senescence triggered by Sag deletion can be largely rescued by simultaneous deletion of Cdkn2a, the p16 encoding gene, indicating its causal role. Furthermore, Kras(G12D)-induced immortalization can also be abrogated by Sag deletion via senescence induction, which is again rescued by simultaneous deletion of Cdkn2a. Finally, we found that Sag deletion inactivates Kras(G12D) activity and block the MAPK signaling pathway, together with accumulated p16, to induce senescence. Taken together, our results demonstrated that Sag is a Kras(G12D)-cooperating oncogene required for Kras(G12D)-induced immortalization and transformation, and targeting SAG-SCF E3 ligase may, therefore, have therapeutic value for senescence-based cancer treatment.",
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  {
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   "passages": [
    {
     "offset": 0,
     "text": "Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps.",
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       "id": "0",
       "infons": {
        "identifier": "D001151",
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     "text": "BACKGROUND: Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer. OBJECTIVES: This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure. DISCUSSION: Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects. CONCLUSIONS: Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes.",
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     "text": "Brain-derived neurotrophic factor attenuates doxorubicin-induced cardiac dysfunction through activating Akt signalling in rats.",
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       "id": "8",
       "infons": {
        "identifier": "D001281",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atrial fibrillation",
       "locations": [
        {
         "offset": 325,
         "length": 19
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D004317",
        "type": "ChemicalEntity"
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       "text": "doxorubicin",
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         "offset": 368,
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       ]
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       "text": "patient",
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001281",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Atrial fibrillation",
       "locations": [
        {
         "offset": 420,
         "length": 19
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D001145",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "cardiac arrhythmias",
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         "offset": 449,
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       "text": "patients",
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       ]
      },
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       "id": "14",
       "infons": {
        "identifier": "D066126",
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       "text": "cardiac toxicity",
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         "offset": 538,
         "length": 16
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       ]
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       "id": "15",
       "infons": {
        "identifier": "D001145",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "arrhythmia",
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         "offset": 668,
         "length": 10
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       "text": "patient",
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   "id": "15184369",
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    {
     "offset": 0,
     "text": "Ca2+ dependence of the Ca2+-selective TRPV6 channel.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
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       "text": "Ca2+",
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       "id": "1",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "TRPV6",
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         "offset": 38,
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    },
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     "offset": 53,
     "text": "Microfluorimetry and patch-clamp experiments were performed on TRPV6-expressing HEK cells to determine whether this Ca(2+)-sensing Ca(2+) channel is constitutively active. Intact cells loaded with fura-2 had an elevated intracellular free Ca(2+) concentration ((i)), which decreased to the same level such as in non-transfected cells if external Ca(2+) was chelated by EGTA. Whole cell recordings from non-transfected HEK cells and cells expressing human TRPV6 revealed the presence of a basal inward current in both types of cells when the internal solution contained 0.1 mm EGTA and 100 nm (i) or if the cytosolic Ca(2+) buffering remained undisturbed in perforated patch-clamp experiments. If recombinantly expressed TRPV6 forms open channels, one would expect Ca(2+)-induced current inhibition, because TRPV6 is negatively regulated by internal Ca(2+). However, dialyzing solutions with high  such as 1 microm into TRPV6-expressing cells did not block the basal inward current, which was not different from the recordings from non-transfected cells. In contrast, dialyzing 0.5 mm EGTA into TRPV6-expressing cells readily activated Ca(2+) inward currents, which were undetectable in non-transfected cells. Interestingly, monovalent cations permeated the TRPV6 channels under conditions where no Ca(2+) permeation was detectable, indicating that divalent cations block TRPV6 channels from the extracellular side. Like human TRPV6, the truncated human TRPV6(Delta695-725), which lacks the C-terminal domain required for Ca(2+)-calmodulin binding, does not form constitutive active channels, whereas the human TRPV6(D542A), carrying a point mutation in the presumed pore region, does not function as a channel. In summary, no constitutive open TRPV6 channels were detected in patch-clamp experiments from transfected HEK cells. However, channel activity is highly regulated by intracellular and extracellular divalent cations.",
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       "id": "3",
       "infons": {
        "identifier": "55503",
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       "text": "TRPV6",
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       "infons": {
        "identifier": "CVCL_M624",
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         "offset": 133,
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       "text": "Ca(2+)",
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        "identifier": "D016257",
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       "text": "fura-2",
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         "offset": 250,
         "length": 6
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       "id": "8",
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       "text": "Ca(2+)",
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         "offset": 422,
         "length": 4
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       "id": "11",
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        "identifier": "CVCL_M624",
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       "text": "HEK",
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         "offset": 471,
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       "text": "human",
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       "id": "13",
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        "identifier": "55503",
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       "text": "TRPV6",
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       "text": "TRPV6",
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       "text": "TRPV6",
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       "text": "TRPV6",
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       "text": "TRPV6",
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       ]
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       "id": "27",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "human",
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         "offset": 1473,
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       ]
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       "id": "28",
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        "identifier": "55503",
        "type": "GeneOrGeneProduct"
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       "text": "TRPV6",
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         "offset": 1479,
         "length": 5
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       ]
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       "id": "29",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
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         "offset": 1500,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "55503",
        "type": "GeneOrGeneProduct"
       },
       "text": "TRPV6",
       "locations": [
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         "offset": 1506,
         "length": 5
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       ]
      },
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       "id": "31",
       "infons": {
        "identifier": "p|DEL|695-725|",
        "type": "SequenceVariant"
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       "text": "Delta695-725",
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         "offset": 1512,
         "length": 12
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       ]
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       "id": "32",
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       "text": "Ca(2+)",
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       "infons": {
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       "text": "human",
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       "id": "34",
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       "text": "TRPV6",
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         "offset": 1663,
         "length": 5
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       "id": "35",
       "infons": {
        "identifier": "p|SUB|D|542|A",
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       "text": "D542A",
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         "offset": 1669,
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       "id": "36",
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       "text": "TRPV6",
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         "offset": 1797,
         "length": 5
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       "id": "37",
       "infons": {
        "identifier": "CVCL_M624",
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       "locations": [
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         "offset": 1870,
         "length": 3
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   ]
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  {
   "id": "15807692",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of novel type VII collagen gene mutations resulting in severe recessive dystrophic epidermolysis bullosa.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1294",
        "type": "GeneOrGeneProduct"
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       "text": "VII collagen",
       "locations": [
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         "offset": 29,
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D016108",
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       "text": "recessive dystrophic epidermolysis bullosa",
       "locations": [
        {
         "offset": 77,
         "length": 42
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    },
    {
     "offset": 121,
     "text": "In this work, we studied the proband in a small nuclear family of Chinese and Dutch/German descent and identified two novel mutations in the type VII collagen gene leading to recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens variant (HS-RDEB). The maternal mutation is a single base pair deletion of a cytosine nucleotide in exon 26, designated 3472delC, resulting in a frameshift and a premature termination codon (PTC) within the same exon, 7 bp downstream of the site of the mutation. The paternal mutation is a G-->A transition located at the 5' donor splice site within intron 51, designated IVS51 + 1G-->A. This mutation leads to the activation of a cryptic splice site, 32 bp downstream of the mutation site and to subsequent aberrant out-of-frame splicing, resulting in two alternative mRNA transcripts and a downstream PTC. To our knowledge, these two mutations have not been previously reported. These findings extend the body of evidence for compound heterozygous mutations leading to HS-RDEB and provide the basis for prenatal diagnosis in this family.",
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       "id": "2",
       "infons": {
        "identifier": "1294",
        "type": "GeneOrGeneProduct"
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       "text": "VII collagen",
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         "offset": 267,
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       ]
      },
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       "id": "3",
       "infons": {
        "identifier": "D016108",
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       "text": "recessive dystrophic epidermolysis bullosa",
       "locations": [
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       "id": "4",
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       "text": "Hallopeau-Siemens",
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       "text": "HS-RDEB",
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        }
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       "text": "single base pair deletion of a cytosine nucleotide",
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       "id": "7",
       "infons": {
        "identifier": "c|DEL|3472|C",
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       "text": "3472delC",
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         "length": 8
        }
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      },
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       "id": "8",
       "infons": {
        "identifier": "c|SUB|G||A",
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       "text": "G-->A",
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         "offset": 648,
         "length": 5
        }
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      },
      {
       "id": "9",
       "infons": {
        "identifier": "c|SUB|G|IVS51+1|A",
        "type": "SequenceVariant"
       },
       "text": "IVS51 + 1G-->A",
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         "offset": 730,
         "length": 14
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D016108",
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       },
       "text": "HS-RDEB",
       "locations": [
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         "offset": 1129,
         "length": 7
        }
       ]
      }
     ]
    }
   ],
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    },
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    },
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     "id": "R4",
     "infons": {
      "entity1": "D016108",
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      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16157158",
   "passages": [
    {
     "offset": 0,
     "text": "A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23-Ser 23",
       "locations": [
        {
         "offset": 2,
         "length": 13
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "3358",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HT(2C) receptor",
       "locations": [
        {
         "offset": 36,
         "length": 17
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D016574",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "seasonal affective disorder",
       "locations": [
        {
         "offset": 109,
         "length": 27
        }
       ]
      }
     ]
    },
    {
     "offset": 180,
     "text": "Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D016574",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "seasonal affective disorder",
       "locations": [
        {
         "offset": 198,
         "length": 27
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D016574",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SAD",
       "locations": [
        {
         "offset": 227,
         "length": 3
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D015430",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "weight gain when depressed",
       "locations": [
        {
         "offset": 293,
         "length": 26
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3358",
        "type": "GeneOrGeneProduct"
       },
       "text": "serotonin 2C receptor",
       "locations": [
        {
         "offset": 325,
         "length": 21
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "3358",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HT(2C)",
       "locations": [
        {
         "offset": 348,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "3358",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HT(2C)",
       "locations": [
        {
         "offset": 413,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 422,
         "length": 10
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 494,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "3358",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HT(2C)",
       "locations": [
        {
         "offset": 517,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "3358",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-HT(2C)",
       "locations": [
        {
         "offset": 560,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 600,
         "length": 10
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D016574",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SAD",
       "locations": [
        {
         "offset": 656,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D016574",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SAD",
       "locations": [
        {
         "offset": 716,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D016574",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SAD",
       "locations": [
        {
         "offset": 764,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 801,
         "length": 10
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 864,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 950,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 986,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1212,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 1222,
         "length": 10
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 1356,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D016574",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SAD",
       "locations": [
        {
         "offset": 1435,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs6318",
        "type": "SequenceVariant"
       },
       "text": "Cys 23 Ser",
       "locations": [
        {
         "offset": 1518,
         "length": 10
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "infons": {
      "entity1": "rs6318",
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "3358",
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      "type": "Association",
      "novel": "No"
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    }
   ]
  },
  {
   "id": "17192049",
   "passages": [
    {
     "offset": 0,
     "text": "Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1543",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cytochrome p4501A1",
       "locations": [
        {
         "offset": 0,
         "length": 18
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 62,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 79,
     "text": "CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "1543",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP1A1",
       "locations": [
        {
         "offset": 79,
         "length": 6
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 232,
         "length": 15
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "rs1048943",
        "type": "SequenceVariant"
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       "text": "A to G",
       "locations": [
        {
         "offset": 339,
         "length": 6
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "rs1048943",
        "type": "SequenceVariant"
       },
       "text": "Ile462Val",
       "locations": [
        {
         "offset": 401,
         "length": 9
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "g|SUB|T|3801|C",
        "type": "SequenceVariant"
       },
       "text": "T3801C",
       "locations": [
        {
         "offset": 415,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1543",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP1A1",
       "locations": [
        {
         "offset": 435,
         "length": 6
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 450,
         "length": 15
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1543",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP1A1",
       "locations": [
        {
         "offset": 650,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "1543",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP1A1",
       "locations": [
        {
         "offset": 714,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs1048943",
        "type": "SequenceVariant"
       },
       "text": "Ile/Val",
       "locations": [
        {
         "offset": 721,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 809,
         "length": 15
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 924,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1033,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1280,
         "length": 15
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D011471",
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      "novel": "Novel"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D011471",
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      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18356633",
   "passages": [
    {
     "offset": 0,
     "text": "An evaluation of amikacin nephrotoxicity in the hematology/oncology population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000583",
        "type": "ChemicalEntity"
       },
       "text": "amikacin",
       "locations": [
        {
         "offset": 17,
         "length": 8
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D007674",
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       "text": "nephrotoxicity",
       "locations": [
        {
         "offset": 26,
         "length": 14
        }
       ]
      }
     ]
    },
    {
     "offset": 80,
     "text": "Amikacin is an aminoglycoside commonly used to provide empirical double gram-negative treatment for febrile neutropenia and other suspected infections. Strategies of extended-interval and conventional dosing have been utilized extensively in the general medical population; however, data are lacking to support a dosing strategy in the hematology/oncology population. To evaluate amikacin-associated nephrotoxicity in an adult hematology/oncology population, a prospective, randomized, open-label trial was conducted at a university-affiliated medical center. Forty patients with a diagnosis consistent with a hematologic/oncologic disorder that required treatment with an aminoglycoside were randomized to either conventional or extended-interval amikacin. The occurrence of nephrotoxicity by means of an increase in serum creatinine and evaluation of efficacy via amikacin serum concentrations with respective pathogens were assessed. The occurrence of nephrotoxicity was similar between the conventional and extended-interval groups, at 10% and 5%, respectively (P = 1.00). Six patients in the conventional group had a positive culture, compared with none in the extended-interval group (P = 0.002). The occurrence of nephrotoxicity was similar between the two dosing regimens, but the distribution of risk factors was variable between the two groups. Efficacy could not be assessed.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D000583",
        "type": "ChemicalEntity"
       },
       "text": "Amikacin",
       "locations": [
        {
         "offset": 80,
         "length": 8
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D000617",
        "type": "ChemicalEntity"
       },
       "text": "aminoglycoside",
       "locations": [
        {
         "offset": 95,
         "length": 14
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009503",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "febrile neutropenia",
       "locations": [
        {
         "offset": 180,
         "length": 19
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D007239",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "infections",
       "locations": [
        {
         "offset": 220,
         "length": 10
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D000583",
        "type": "ChemicalEntity"
       },
       "text": "amikacin",
       "locations": [
        {
         "offset": 460,
         "length": 8
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007674",
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       },
       "text": "nephrotoxicity",
       "locations": [
        {
         "offset": 480,
         "length": 14
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
        {
         "offset": 646,
         "length": 8
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D006402,D009369",
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       },
       "text": "hematologic/oncologic disorder",
       "locations": [
        {
         "offset": 690,
         "length": 30
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000617",
        "type": "ChemicalEntity"
       },
       "text": "aminoglycoside",
       "locations": [
        {
         "offset": 753,
         "length": 14
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D000583",
        "type": "ChemicalEntity"
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       "text": "amikacin",
       "locations": [
        {
         "offset": 828,
         "length": 8
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nephrotoxicity",
       "locations": [
        {
         "offset": 856,
         "length": 14
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003404",
        "type": "ChemicalEntity"
       },
       "text": "creatinine",
       "locations": [
        {
         "offset": 904,
         "length": 10
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000583",
        "type": "ChemicalEntity"
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       "text": "amikacin",
       "locations": [
        {
         "offset": 946,
         "length": 8
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nephrotoxicity",
       "locations": [
        {
         "offset": 1035,
         "length": 14
        }
       ]
      },
      {
       "id": "16",
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       "text": "patients",
       "locations": [
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      },
      {
       "id": "17",
       "infons": {
        "identifier": "D007674",
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       "text": "nephrotoxicity",
       "locations": [
        {
         "offset": 1301,
         "length": 14
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      "novel": "Novel"
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      "novel": "Novel"
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    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D007674",
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      "type": "Positive_Correlation",
      "novel": "No"
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    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D000583",
      "entity2": "D007239",
      "type": "Negative_Correlation",
      "novel": "No"
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    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D000583",
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      "type": "Negative_Correlation",
      "novel": "No"
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    },
    {
     "id": "R7",
     "infons": {
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      "entity2": "D007674",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19696792",
   "passages": [
    {
     "offset": 0,
     "text": "Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9429",
        "type": "GeneOrGeneProduct"
       },
       "text": "ABCG2",
       "locations": [
        {
         "offset": 34,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D000077146",
        "type": "ChemicalEntity"
       },
       "text": "irinotecan",
       "locations": [
        {
         "offset": 59,
         "length": 10
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001855",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myelosuppression",
       "locations": [
        {
         "offset": 85,
         "length": 16
        }
       ]
      }
     ]
    },
    {
     "offset": 103,
     "text": "Irinotecan is an anti-neoplastic agent that is widely used for treating colorectal and lung cancers, but often causes toxicities such as severe myelosuppression and diarrhea. In this study, we performed a two-stage case-control association study for irinotecan-induced severe myelosuppression (grades 3 and 4). In the first stage, 23 patients who developed severe myelosuppression and 58 patients who did not develop any toxicity were examined for 170 single nucleotide polymorphisms (SNPs) in 14 genes involved in the metabolism and transport of irinotecan. A total of five SNPs were identified to show the possible association with severe myelosuppression (P(Fisher)<0.01) and were further examined in 7 cases and 20 controls in the second stage of the study. An intronic SNP, rs2622604, in ABCG2 showed P(Fisher)=0.0419 in the second stage and indicated a significant association with severe myelosuppression in the combined study (P(Fisher)=0.000237; P(Corrected)=0.036). Although only limited subjects were investigated, our results suggested that a genetic polymorphism in ABCG2 might alter the transport activity for the drug and elevate the systemic circulation level of irinotecan, leading to severe myelosuppression.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D000077146",
        "type": "ChemicalEntity"
       },
       "text": "Irinotecan",
       "locations": [
        {
         "offset": 103,
         "length": 10
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008175,D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colorectal and lung cancers",
       "locations": [
        {
         "offset": 175,
         "length": 27
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "toxicities",
       "locations": [
        {
         "offset": 221,
         "length": 10
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001855",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myelosuppression",
       "locations": [
        {
         "offset": 247,
         "length": 16
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D003967",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diarrhea",
       "locations": [
        {
         "offset": 268,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000077146",
        "type": "ChemicalEntity"
       },
       "text": "irinotecan",
       "locations": [
        {
         "offset": 353,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D001855",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myelosuppression",
       "locations": [
        {
         "offset": 379,
         "length": 16
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 437,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001855",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myelosuppression",
       "locations": [
        {
         "offset": 467,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 491,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "toxicity",
       "locations": [
        {
         "offset": 524,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000077146",
        "type": "ChemicalEntity"
       },
       "text": "irinotecan",
       "locations": [
        {
         "offset": 650,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D001855",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myelosuppression",
       "locations": [
        {
         "offset": 744,
         "length": 16
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs2622604",
        "type": "SequenceVariant"
       },
       "text": "rs2622604",
       "locations": [
        {
         "offset": 882,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9429",
        "type": "GeneOrGeneProduct"
       },
       "text": "ABCG2",
       "locations": [
        {
         "offset": 896,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D001855",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myelosuppression",
       "locations": [
        {
         "offset": 998,
         "length": 16
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9429",
        "type": "GeneOrGeneProduct"
       },
       "text": "ABCG2",
       "locations": [
        {
         "offset": 1182,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D000077146",
        "type": "ChemicalEntity"
       },
       "text": "irinotecan",
       "locations": [
        {
         "offset": 1282,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D001855",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myelosuppression",
       "locations": [
        {
         "offset": 1312,
         "length": 16
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs2622604",
      "entity2": "D001855",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs2622604",
      "entity2": "D000077146",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D001855",
      "entity2": "9429",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D000077146",
      "entity2": "D003967",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D000077146",
      "entity2": "D015179",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D000077146",
      "entity2": "D008175",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D000077146",
      "entity2": "D001855",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "D000077146",
      "entity2": "9429",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "20226780",
   "passages": [
    {
     "offset": 0,
     "text": "Zebrafish chordin-like and chordin are functionally redundant in regulating patterning of the dorsoventral axis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7955",
        "type": "OrganismTaxon"
       },
       "text": "Zebrafish",
       "locations": [
        {
         "offset": 0,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "chordin-like",
       "locations": [
        {
         "offset": 10,
         "length": 12
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "30161",
        "type": "GeneOrGeneProduct"
       },
       "text": "chordin",
       "locations": [
        {
         "offset": 27,
         "length": 7
        }
       ]
      }
     ]
    },
    {
     "offset": 113,
     "text": "Chordin is the prototype of a group of cysteine-rich domain-containing proteins that bind and modulate signaling of various TGFbeta-like ligands. Chordin-like 1 and 2 (CHL1 and 2) are two members of this group that have been described in human, mouse, and chick. However, in vivo roles for CHL1 and 2 in early development are unknown due to lack of loss-of-function analysis. Here we identify and characterize zebrafish, Danio rerio, CHL (Chl). The chl gene is on a region of chromosome 21 syntenic with the area of murine chromosome 7 bearing the CHL2 gene. Inability to identify a separate zebrafish gene corresponding to the mammalian CHL1 gene suggests that Chl may serve roles in zebrafish distributed between CHL1 and CHL2 in other species. Chl is a maternal factor that is also zygotically expressed later in development and has spatiotemporal expression patterns that differ from but overlap those of zebrafish chordin (Chd), suggesting differences but also possible overlap in developmental roles of the two proteins. Chl, like Chd, dorsalizes embryos upon overexpression and is cleaved by BMP1, which antagonizes this activity. Loss-of-function experiments demonstrate that Chl serves as a BMP antagonist with functions that overlap and are redundant with those of Chd in forming the dorsoventral axis.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "30161",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chordin",
       "locations": [
        {
         "offset": 113,
         "length": 7
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "25884,30161,373985,419054,563085,69121,83453,91851",
        "type": "GeneOrGeneProduct"
       },
       "text": "cysteine-rich domain-containing proteins",
       "locations": [
        {
         "offset": 152,
         "length": 40
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "359834",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFbeta",
       "locations": [
        {
         "offset": 237,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "373985,83453,91851,25884,419054,69121",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chordin-like 1 and 2",
       "locations": [
        {
         "offset": 259,
         "length": 20
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "373985,83453,91851,25884,419054,69121",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHL1 and 2",
       "locations": [
        {
         "offset": 281,
         "length": 10
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 351,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 358,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9031",
        "type": "OrganismTaxon"
       },
       "text": "chick",
       "locations": [
        {
         "offset": 369,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "373985,83453,91851,25884,419054,69121",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHL1 and 2",
       "locations": [
        {
         "offset": 403,
         "length": 10
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "7955",
        "type": "OrganismTaxon"
       },
       "text": "zebrafish",
       "locations": [
        {
         "offset": 523,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "7955",
        "type": "OrganismTaxon"
       },
       "text": "Danio rerio",
       "locations": [
        {
         "offset": 534,
         "length": 11
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHL",
       "locations": [
        {
         "offset": 547,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chl",
       "locations": [
        {
         "offset": 552,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "chl",
       "locations": [
        {
         "offset": 562,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "murine",
       "locations": [
        {
         "offset": 629,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "69121",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHL2",
       "locations": [
        {
         "offset": 661,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "7955",
        "type": "OrganismTaxon"
       },
       "text": "zebrafish",
       "locations": [
        {
         "offset": 705,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "91851",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHL1",
       "locations": [
        {
         "offset": 751,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chl",
       "locations": [
        {
         "offset": 775,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "7955",
        "type": "OrganismTaxon"
       },
       "text": "zebrafish",
       "locations": [
        {
         "offset": 798,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "91851",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHL1",
       "locations": [
        {
         "offset": 828,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "25884",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHL2",
       "locations": [
        {
         "offset": 837,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chl",
       "locations": [
        {
         "offset": 860,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "7955",
        "type": "OrganismTaxon"
       },
       "text": "zebrafish",
       "locations": [
        {
         "offset": 1022,
         "length": 9
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "30161",
        "type": "GeneOrGeneProduct"
       },
       "text": "chordin",
       "locations": [
        {
         "offset": 1032,
         "length": 7
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "30161",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chd",
       "locations": [
        {
         "offset": 1041,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chl",
       "locations": [
        {
         "offset": 1140,
         "length": 3
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "30161",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chd",
       "locations": [
        {
         "offset": 1150,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "30204",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP1",
       "locations": [
        {
         "offset": 1212,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "563085",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chl",
       "locations": [
        {
         "offset": 1297,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "30204",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP",
       "locations": [
        {
         "offset": 1313,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "30161",
        "type": "GeneOrGeneProduct"
       },
       "text": "Chd",
       "locations": [
        {
         "offset": 1388,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "30161",
      "entity2": "30204",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "30161",
      "entity2": "359834",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "563085",
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      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "563085",
      "entity2": "25884",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "563085",
      "entity2": "91851",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "563085",
      "entity2": "69121",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "20579626",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "121340",
        "type": "GeneOrGeneProduct"
       },
       "text": "Osterix",
       "locations": [
        {
         "offset": 43,
         "length": 7
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 56,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "recessive osteogenesis imperfecta",
       "locations": [
        {
         "offset": 69,
         "length": 33
        }
       ]
      }
     ]
    },
    {
     "offset": 104,
     "text": "Osteogenesis imperfecta, or \"brittle bone disease,\" is a type I collagen-related condition associated with osteoporosis and increased risk of bone fractures. Using a combination of homozygosity mapping and candidate gene approach, we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta. The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera. OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation. The frameshift caused by the c.1052delA deletion removes the last 81 amino acids of the protein, including the third zinc-finger motif. This finding adds another locus to the spectrum of genes associated with osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in human bone development.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Osteogenesis imperfecta",
       "locations": [
        {
         "offset": 104,
         "length": 23
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "brittle bone disease",
       "locations": [
        {
         "offset": 133,
         "length": 20
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1278",
        "type": "GeneOrGeneProduct"
       },
       "text": "type I collagen",
       "locations": [
        {
         "offset": 161,
         "length": 15
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D010024",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "osteoporosis",
       "locations": [
        {
         "offset": 211,
         "length": 12
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D050723",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bone fractures",
       "locations": [
        {
         "offset": 246,
         "length": 14
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs137853893",
        "type": "SequenceVariant"
       },
       "text": "single base pair deletion",
       "locations": [
        {
         "offset": 367,
         "length": 25
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs137853893",
        "type": "SequenceVariant"
       },
       "text": "c.1052delA",
       "locations": [
        {
         "offset": 394,
         "length": 10
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "121340",
        "type": "GeneOrGeneProduct"
       },
       "text": "SP7",
       "locations": [
        {
         "offset": 409,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "121340",
        "type": "GeneOrGeneProduct"
       },
       "text": "Osterix",
       "locations": [
        {
         "offset": 413,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "121340",
        "type": "GeneOrGeneProduct"
       },
       "text": "OSX",
       "locations": [
        {
         "offset": 422,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "recessive osteogenesis imperfecta",
       "locations": [
        {
         "offset": 453,
         "length": 33
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 520,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D050723",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fractures",
       "locations": [
        {
         "offset": 546,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D001847",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bone deformities",
       "locations": [
        {
         "offset": 562,
         "length": 16
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D014079",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tooth eruption",
       "locations": [
        {
         "offset": 588,
         "length": 14
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "121340",
        "type": "GeneOrGeneProduct"
       },
       "text": "OSX",
       "locations": [
        {
         "offset": 638,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 761,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs137853893",
        "type": "SequenceVariant"
       },
       "text": "c.1052delA",
       "locations": [
        {
         "offset": 847,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "osteogenesis imperfecta",
       "locations": [
        {
         "offset": 1027,
         "length": 23
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "121340",
        "type": "GeneOrGeneProduct"
       },
       "text": "SP7",
       "locations": [
        {
         "offset": 1068,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "121340",
        "type": "GeneOrGeneProduct"
       },
       "text": "OSX",
       "locations": [
        {
         "offset": 1072,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1101,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1278",
      "entity2": "D050723",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "1278",
      "entity2": "D010024",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs137853893",
      "entity2": "D010013",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D010013",
      "entity2": "1278",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D010013",
      "entity2": "121340",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "22051099",
   "passages": [
    {
     "offset": 0,
     "text": "Variation in the CXCR1 gene (IL8RA) is not associated with susceptibility to chronic periodontitis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3577",
        "type": "GeneOrGeneProduct"
       },
       "text": "CXCR1",
       "locations": [
        {
         "offset": 17,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "3577",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL8RA",
       "locations": [
        {
         "offset": 29,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D055113",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic periodontitis",
       "locations": [
        {
         "offset": 77,
         "length": 21
        }
       ]
      }
     ]
    },
    {
     "offset": 100,
     "text": "BACKGROUND: The chemokine receptor 1 CXCR-1 (or IL8R-alpha) is a specific receptor for the interleukin 8 (IL-8), which is chemoattractant for neutrophils and has an important role in the inflammatory response. The polymorphism rs2234671 at position Ex2+860G>C of the CXCR1 gene causes a conservative amino acid substitution (S276T). This single nucleotide polymorphism (SNP) seemed to be functional as it was associated with decreased lung cancer risk. Previous studies of our group found association of haplotypes in the IL8 and in the CXCR2 genes with the multifactorial disease chronic periodontitis. In this study we investigated the polymorphism rs2234671 in 395 Brazilian subjects with and without chronic periodontitis. FINDINGS: Similar distribution of the allelic and genotypic frequencies were observed between the groups (p>0.05). CONCLUSIONS: The polymorphism rs2234671 in the CXCR1 gene was not associated with the susceptibility to chronic periodontitis in the studied Brazilian population.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "3577",
        "type": "GeneOrGeneProduct"
       },
       "text": "chemokine receptor 1 CXCR-1",
       "locations": [
        {
         "offset": 116,
         "length": 27
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "3577",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL8R-alpha",
       "locations": [
        {
         "offset": 148,
         "length": 10
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "3576",
        "type": "GeneOrGeneProduct"
       },
       "text": "interleukin 8",
       "locations": [
        {
         "offset": 191,
         "length": 13
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3576",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-8",
       "locations": [
        {
         "offset": 206,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 287,
         "length": 12
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs2234671",
        "type": "SequenceVariant"
       },
       "text": "rs2234671",
       "locations": [
        {
         "offset": 327,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs2234671",
        "type": "SequenceVariant"
       },
       "text": "Ex2+860G>C",
       "locations": [
        {
         "offset": 349,
         "length": 10
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3577",
        "type": "GeneOrGeneProduct"
       },
       "text": "CXCR1",
       "locations": [
        {
         "offset": 367,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs2234671",
        "type": "SequenceVariant"
       },
       "text": "S276T",
       "locations": [
        {
         "offset": 425,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 535,
         "length": 11
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "3576",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL8",
       "locations": [
        {
         "offset": 622,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "3579",
        "type": "GeneOrGeneProduct"
       },
       "text": "CXCR2",
       "locations": [
        {
         "offset": 637,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D055113",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic periodontitis",
       "locations": [
        {
         "offset": 681,
         "length": 21
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs2234671",
        "type": "SequenceVariant"
       },
       "text": "rs2234671",
       "locations": [
        {
         "offset": 751,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D055113",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic periodontitis",
       "locations": [
        {
         "offset": 804,
         "length": 21
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs2234671",
        "type": "SequenceVariant"
       },
       "text": "rs2234671",
       "locations": [
        {
         "offset": 972,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "3577",
        "type": "GeneOrGeneProduct"
       },
       "text": "CXCR1",
       "locations": [
        {
         "offset": 989,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D055113",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic periodontitis",
       "locations": [
        {
         "offset": 1046,
         "length": 21
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "3579",
      "entity2": "D055113",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "3576",
      "entity2": "D007249",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "3576",
      "entity2": "D055113",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "3577",
      "entity2": "D007249",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "3577",
      "entity2": "3576",
      "type": "Bind",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "3577",
      "entity2": "D008175",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "rs2234671",
      "entity2": "D008175",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "22303482",
   "passages": [
    {
     "offset": 0,
     "text": "TBX21 and HLX1 polymorphisms influence cytokine secretion at birth.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "30009",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX21",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "3142",
        "type": "GeneOrGeneProduct"
       },
       "text": "HLX1",
       "locations": [
        {
         "offset": 10,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 68,
     "text": "BACKGROUND: TBX21 (T cell specific T-box transcription factor) and HLX1 (H.20-like homeobox 1) are crucial transcription factors of T(H)1-cells, inducing their differentiation and suppressing T(H)2 commitment, particularly important for early life immune development. This study investigated the influence of TBX21 and HLX1 single nucleotide polymorphisms (SNPs), which have previously been shown to be associated with asthma, on T(H)1/T(H)2 lineage cytokines at birth. METHODS AND FINDINGS: Cord blood mononuclear cells (CBMCs) of 200 neonates were genotyped for two TBX21 and three HLX1 SNPs. CBMCs were stimulated with innate (Lipid A, LpA; Peptidoglycan, Ppg), adaptive stimuli (house dust mite Dermatophagoides pteronyssinus 1, Derp1) or mitogen (phytohemagglutinin, PHA). Cytokines, T-cells and mRNA expression of T(H)1/T(H)2-related genes were assessed. Atopic diseases during the first 3 years of life were assessed by questionnaire answered by the parents. Carriers of TBX21 promoter SNP rs17250932 and HLX1 promoter SNP rs2738751 showed reduced or trendwise reduced (p<0.07) IL-5, IL-13 and TNF-a secretion after LpA-stimulation. Carriers of HLX1 SNP rs2738751 had lower IL-13 levels following Ppg-stimulation (p = 0.08). Carriers of HLX1 exon 1 SNP rs12141189 showed increased IL-5 (LpA, p = 0.007; Ppg, p = 0.10), trendwise increased IL-13 (LpA), higher GM-CSF (LpA/Ppg, p<0.05) and trendwise decreased IFN-g secretion (Derp1+LpA-stimulation, p = 0.1). Homozygous carriers of HLX1 promoter SNP rs3806325 showed increased IL-13 and IL-6 (unstimulated, p<0.03). In carriers of TBX21 intron 3 SNP rs11079788 no differences in cytokine secretion were observed. mRNA expression of T(H)1/T(H)2-related genes partly correlated with cytokines at protein level. TBX21 SNP rs11079788 carriers developed less symptoms of atopic dermatitis at 3 years of age (p = 0.03). CONCLUSIONS: Polymorphisms in TBX21 and HLX1 influenced primarily IL-5 and IL-13 secretion after LpA-stimulation in cord blood suggesting that genetic variations in the transcription factors essential for the T(H)1-pathway may contribute to modified T(H)2-immune responses already early in life. Further follow-up of the cohort is required to study the polymorphisms' relevance for immune-mediated diseases such as childhood asthma.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "30009",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX21",
       "locations": [
        {
         "offset": 80,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "30009",
        "type": "GeneOrGeneProduct"
       },
       "text": "T cell specific T-box transcription factor",
       "locations": [
        {
         "offset": 87,
         "length": 42
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "3142",
        "type": "GeneOrGeneProduct"
       },
       "text": "HLX1",
       "locations": [
        {
         "offset": 135,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "3142",
        "type": "GeneOrGeneProduct"
       },
       "text": "H.20-like homeobox 1",
       "locations": [
        {
         "offset": 141,
         "length": 20
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "30009",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX21",
       "locations": [
        {
         "offset": 377,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "3142",
        "type": "GeneOrGeneProduct"
       },
       "text": "HLX1",
       "locations": [
        {
         "offset": 387,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D001249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "asthma",
       "locations": [
        {
         "offset": 487,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "30009",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX21",
       "locations": [
        {
         "offset": 636,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3142",
        "type": "GeneOrGeneProduct"
       },
       "text": "HLX1",
       "locations": [
        {
         "offset": 652,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D008050",
        "type": "ChemicalEntity"
       },
       "text": "Lipid A",
       "locations": [
        {
         "offset": 698,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008050",
        "type": "ChemicalEntity"
       },
       "text": "LpA",
       "locations": [
        {
         "offset": 707,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D010457",
        "type": "ChemicalEntity"
       },
       "text": "Peptidoglycan",
       "locations": [
        {
         "offset": 712,
         "length": 13
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D010457",
        "type": "ChemicalEntity"
       },
       "text": "Ppg",
       "locations": [
        {
         "offset": 727,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "113791973",
        "type": "GeneOrGeneProduct"
       },
       "text": "Dermatophagoides pteronyssinus 1",
       "locations": [
        {
         "offset": 767,
         "length": 32
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "113791973",
        "type": "GeneOrGeneProduct"
       },
       "text": "Derp1",
       "locations": [
        {
         "offset": 801,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D010835",
        "type": "ChemicalEntity"
       },
       "text": "phytohemagglutinin",
       "locations": [
        {
         "offset": 820,
         "length": 18
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D010835",
        "type": "ChemicalEntity"
       },
       "text": "PHA",
       "locations": [
        {
         "offset": 840,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "30009",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX21",
       "locations": [
        {
         "offset": 1046,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs17250932",
        "type": "SequenceVariant"
       },
       "text": "rs17250932",
       "locations": [
        {
         "offset": 1065,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "3142",
        "type": "GeneOrGeneProduct"
       },
       "text": "HLX1",
       "locations": [
        {
         "offset": 1080,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs2738751",
        "type": "SequenceVariant"
       },
       "text": "rs2738751",
       "locations": [
        {
         "offset": 1098,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
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     "offset": 0,
     "text": "NEK2 serves as a prognostic biomarker for hepatocellular carcinoma.",
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     "text": "Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a microtubule-associated protein that regulates spindle assembly in human cells and is overexpressed in various malignancies. However, the role of NEK2 in hepatocellular carcinoma (HCC) remains undetermined. We performed RNA-seq of the HCC cell line SMMC-7721 and the normal liver cell line HL-7702 using the Ion Proton System. NEK2 expression was detected using quantitative reverse transcription polymerase chain reaction in two cell lines and 5 matched HCC and adjacent non-tumorous liver tissues. The correlation between survival and NEK2 expression was analyzed in 359 patients with HCC using RNASeqV2 data available from The Cancer Genome Atlas (TCGA) website (https://tcga-data.nci.nih.gov/tcga/). The expression of NEK2, phospho-AKT and MMP-2 was evaluated by immunohistochemistry in 63 cases of HCC and matched adjacent non-tumorous liver tissues. Relationships between protein expression and clinicopathological parameters were assessed, and the correlations between NEK2 with phospho-AKT and MMP-2 expressions were evaluated. A total of 610 differentially expressed genes (DEGs) were revealed in the transcriptome comparison, 297 of which were upregulated and 313 were downregulated in HCC. NEK2, as the most obviously different DEG in cells and tissues from the RNA-seq data, was listed as an HCC candidate biomarker for further verification. NEK2 was overexpressed in HCC cells and tissues (P=0.002, P=0.013) and HCC patients with a high expression of NEK2 had a poor prognosis (P=0.0145). Clinical analysis indicated that the overexpression of NEK2 in HCC was significantly correlated with diolame complete (P<0.001), tumor nodule number (P=0.012) and recurrence (P=0.004). NEK2 expression was positively correlated with the expression of phospho-AKT (r=0.883, P<0.01) and MMP-2 (r=0.781, P<0.01). Overexpression of NEK2 was associated with clinicopathological characteristics and poor patient outcomes, suggesting that NEK2 serves as a prognostic biomarker for HCC. Alteration of NEK2 protein levels may contribute to invasion and metastasis of HCC, which may occur through activation of AKT signaling and promotion of MMP-2 expression.",
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     "text": "Nijmegen breakage syndrome in 13% of age-matched Czech children with primary microcephaly.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 0,
         "length": 26
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "primary microcephaly",
       "locations": [
        {
         "offset": 69,
         "length": 20
        }
       ]
      }
     ]
    },
    {
     "offset": 91,
     "text": "The Nijmegen breakage syndrome is a rare autosomal recessive chromosomal instability disorder characterized by early growth retardation, congenital microcephaly, immunodeficiency, borderline mental development, and a high tendency to lymphoreticular malignancies. Most Nijmegen breakage syndrome patients are of Slavonic origin, and all of them known so far carry a founder homozygous 5 nucleotide deletion in the NBS1 gene. Microcephaly was present in 100% of Nijmegen breakage syndrome patients in a recent large international cooperative study. The frequency of Nijmegen breakage syndrome among children with primary microcephaly was not known. Early correct diagnosis of the syndrome is crucial for appropriate preventive care and therapy. We tested 67 Czech patients of different ages with simple microcephaly for the presence of the most common mutation in the NBS1 gene. Three new Nijmegen breakage syndrome cases were detected in this cohort, representing 4.5% of the cohort. All these newly diagnosed Nijmegen breakage syndrome patients were younger than 10 months at the time of diagnosis. They were all born within a 2.5-year period. Twenty-three of the 67 children in the cohort were born within this 2.5-year period, representing a 13% incidence of Nijmegen breakage syndrome. Frequency of Nijmegen breakage syndrome heterozygotes among infants in the Czech Republic is 1: 130-158 and the birth rate is 90,000 per year, therefore in the time span of 2.5 years, three new Nijmegen breakage syndrome homozygotes are expected to be born. Therefore we assume that by DNA testing of Czech primary microcephalic children it is possible to detect all Nijmegen breakage syndrome patients to be expected. The age at correct diagnosis was lowered from 7.1 years at the time before DNA testing, to well under 1 year of age. All new Nijmegen breakage syndrome patients could receive appropriate preventive care, which should significantly improve their life expectancy and prognosis.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 95,
         "length": 26
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D043171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal recessive chromosomal instability disorder",
       "locations": [
        {
         "offset": 132,
         "length": 52
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D006130",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "growth retardation",
       "locations": [
        {
         "offset": 208,
         "length": 18
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital microcephaly",
       "locations": [
        {
         "offset": 228,
         "length": 23
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D007153",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "immunodeficiency",
       "locations": [
        {
         "offset": 253,
         "length": 16
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lymphoreticular malignancies",
       "locations": [
        {
         "offset": 325,
         "length": 28
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 360,
         "length": 26
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 387,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "c|DEL||5",
        "type": "SequenceVariant"
       },
       "text": "5 nucleotide deletion",
       "locations": [
        {
         "offset": 476,
         "length": 21
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "4683",
        "type": "GeneOrGeneProduct"
       },
       "text": "NBS1",
       "locations": [
        {
         "offset": 505,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Microcephaly",
       "locations": [
        {
         "offset": 516,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 552,
         "length": 26
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 579,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 656,
         "length": 26
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D008831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "primary microcephaly",
       "locations": [
        {
         "offset": 703,
         "length": 20
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 854,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "4683",
        "type": "GeneOrGeneProduct"
       },
       "text": "NBS1",
       "locations": [
        {
         "offset": 958,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 979,
         "length": 26
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 1101,
         "length": 26
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1128,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 1353,
         "length": 26
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 1394,
         "length": 26
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 1575,
         "length": 26
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 1748,
         "length": 26
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1775,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 1925,
         "length": 26
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1952,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D049932",
      "entity2": "4683",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D049932",
      "entity2": "c|DEL||5",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "15198485",
   "passages": [
    {
     "offset": 0,
     "text": "Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Lys198Asn",
       "locations": [
        {
         "offset": 18,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs1800997",
        "type": "SequenceVariant"
       },
       "text": "-134delA",
       "locations": [
        {
         "offset": 32,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "endothelin-1",
       "locations": [
        {
         "offset": 70,
         "length": 12
        }
       ]
      }
     ]
    },
    {
     "offset": 89,
     "text": "Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been reported to be associated with blood pressure (BP). One is the Lys198Asn polymorphism, which showed a positive association with BP in overweight people. Another is the 3A/4A polymorphism (-134delA) located in the 5'-untranslated region. In this study, we investigated the expression of the Lys198Asn polymorphism in ET-1 in vitro, as well as the association between either of the two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys-type) and minor type (Asn-type) preproET-1 in three different cell lines, and measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no significant difference in the levels of ET-1 or big ET-1 between the Asn-type and Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54 hypertensive patients having an amino acid substitution from Lys to Asn at position 198 were not different from those of hypertensives without the substitution. However, we found a significant difference in ET-1 levels between individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET-1 production. Another variant in the EDN1 gene in linkage disequilibrium with the Lys198Asn polymorphism may be responsible for the association with BP, or the interaction between the EDN1 Lys198Asn polymorphism and other factors such as obesity may be involved in the mechanisms elevating BP in vivo.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "Endothelin-1",
       "locations": [
        {
         "offset": 89,
         "length": 12
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 103,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 225,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "EDN1",
       "locations": [
        {
         "offset": 236,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Lys198Asn",
       "locations": [
        {
         "offset": 315,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D050177",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "overweight",
       "locations": [
        {
         "offset": 386,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs1800997",
        "type": "SequenceVariant"
       },
       "text": "-134delA",
       "locations": [
        {
         "offset": 440,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Lys198Asn",
       "locations": [
        {
         "offset": 542,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 568,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 665,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 748,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 811,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 824,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 910,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 922,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Asn-type and Lys-type transfectant",
       "locations": [
        {
         "offset": 939,
         "length": 34
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 1022,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertensive",
       "locations": [
        {
         "offset": 1033,
         "length": 12
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1046,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Lys to Asn at position 198",
       "locations": [
        {
         "offset": 1094,
         "length": 26
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertensives",
       "locations": [
        {
         "offset": 1154,
         "length": 13
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 1240,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Lys198Asn",
       "locations": [
        {
         "offset": 1358,
         "length": 9
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 1405,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "ET-1",
       "locations": [
        {
         "offset": 1418,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "EDN1",
       "locations": [
        {
         "offset": 1458,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Lys198Asn",
       "locations": [
        {
         "offset": 1503,
         "length": 9
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "1906",
        "type": "GeneOrGeneProduct"
       },
       "text": "EDN1",
       "locations": [
        {
         "offset": 1605,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "rs5370",
        "type": "SequenceVariant"
       },
       "text": "Lys198Asn",
       "locations": [
        {
         "offset": 1610,
         "length": 9
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "obesity",
       "locations": [
        {
         "offset": 1659,
         "length": 7
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs5370",
      "entity2": "D050177",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs5370",
      "entity2": "D009765",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "1906",
      "entity2": "D050177",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "1906",
      "entity2": "D009765",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16120104",
   "passages": [
    {
     "offset": 0,
     "text": "A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "8864",
        "type": "GeneOrGeneProduct"
       },
       "text": "hPER2",
       "locations": [
        {
         "offset": 70,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 120,
     "text": "The PERIOD2 (PER2) gene is a key component of the molecular mechanism that generates circadian rhythms in mammals. A missense mutation in the human PER2 gene has previously been linked to advanced sleep phase syndrome (ASPS). We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C-1228T), one in exon 2 in the 5'-untranslated region (5'-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein. Subjects selected from a group of 484 volunteers for extreme morning or evening preference, or intermediate diurnal preference were genotyped with regard to the three polymorphisms (n=35 for each group). Whereas allele frequencies for the other two polymorphisms did not differ significantly between any of the groups, the 111G allele frequency was significantly higher in subjects with extreme morning preference (0.14) than in subjects with extreme evening preference (0.03) (Fisher's exact test, two-sided P value=0.031, odds ratio=5.67). No significant difference in 111G allele frequency was observed between either of these groups and subjects with intermediate diurnal preference. Computer prediction indicated that the C111G polymorphism, which occurs 12 bases upstream from the translation start codon, might alter the secondary structure of the transcript. The PER2 111G allele associates with morning preference and is a potential candidate allele for ASPS.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "8864",
        "type": "GeneOrGeneProduct"
       },
       "text": "PERIOD2",
       "locations": [
        {
         "offset": 124,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "8864",
        "type": "GeneOrGeneProduct"
       },
       "text": "PER2",
       "locations": [
        {
         "offset": 133,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
        {
         "offset": 262,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "8864",
        "type": "GeneOrGeneProduct"
       },
       "text": "PER2",
       "locations": [
        {
         "offset": 268,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C565789",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "advanced sleep phase syndrome",
       "locations": [
        {
         "offset": 308,
         "length": 29
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C565789",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ASPS",
       "locations": [
        {
         "offset": 339,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "8864",
        "type": "GeneOrGeneProduct"
       },
       "text": "hPER2",
       "locations": [
        {
         "offset": 418,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|C|-1228|T",
        "type": "SequenceVariant"
       },
       "text": "C-1228T",
       "locations": [
        {
         "offset": 478,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "c|SUB|C|111|G",
        "type": "SequenceVariant"
       },
       "text": "C111G",
       "locations": [
        {
         "offset": 542,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "c|SUB|G|3853|A",
        "type": "SequenceVariant"
       },
       "text": "G3853A",
       "locations": [
        {
         "offset": 577,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "p|SUB|G||Q",
        "type": "SequenceVariant"
       },
       "text": "glycine to glutamine",
       "locations": [
        {
         "offset": 595,
         "length": 20
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|Allele|G|111",
        "type": "SequenceVariant"
       },
       "text": "111G",
       "locations": [
        {
         "offset": 978,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|Allele|G|111",
        "type": "SequenceVariant"
       },
       "text": "111G",
       "locations": [
        {
         "offset": 1226,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|SUB|C|111|G",
        "type": "SequenceVariant"
       },
       "text": "C111G",
       "locations": [
        {
         "offset": 1382,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "8864",
        "type": "GeneOrGeneProduct"
       },
       "text": "PER2",
       "locations": [
        {
         "offset": 1526,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|Allele|G|111",
        "type": "SequenceVariant"
       },
       "text": "111G",
       "locations": [
        {
         "offset": 1531,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C565789",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ASPS",
       "locations": [
        {
         "offset": 1618,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|Allele|G|111",
      "entity2": "C565789",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "8864",
      "entity2": "C565789",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17003357",
   "passages": [
    {
     "offset": 0,
     "text": "A haplotype-based analysis of the PTPN22 locus in type 1 diabetes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 34,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 50,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 67,
     "text": "A recent addition to the list of widely confirmed type 1 diabetes risk loci is the PTPN22 gene encoding a lymphoid-specific phosphatase (Lyp). However, evidence supporting a role for PTPN22 in type 1 diabetes derives entirely from the study of just one coding single nucleotide polymorphism, 1858C/T. In the current study, the haplotype structure of the PTPN22 region was determined, and individual haplotypes were tested for association with type 1 diabetes in family-based tests. The 1858T risk allele occurred on only a single haplotype that was strongly associated with type 1 diabetes (P = 7.9 x 10(-5)). After controlling for the effects of this allele, two other haplotypes were observed to be weakly associated with type 1 diabetes (P < 0.05). Sequencing of the coding region of PTPN22 on these haplotypes revealed a novel variant (2250G/C) predicted to result in a nonsynonymous amino acid substitution. Analysis of PTPN22 transcripts from a subject heterozygous for this variant indicated that it interfered with normal mRNA splicing, resulting in a premature termination codon after exon 17. These results support the conclusion that the 1858C/T allele is the major risk variant for type 1 diabetes in the PTPN22 locus, but they suggest that additional infrequent coding variants at PTPN22 may also contribute to type 1 diabetes risk.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 117,
         "length": 15
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 150,
         "length": 6
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "lymphoid-specific phosphatase",
       "locations": [
        {
         "offset": 173,
         "length": 29
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "Lyp",
       "locations": [
        {
         "offset": 204,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 250,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 260,
         "length": 15
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs2476601",
        "type": "SequenceVariant"
       },
       "text": "1858C/T",
       "locations": [
        {
         "offset": 359,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 421,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 510,
         "length": 15
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs2476601",
        "type": "SequenceVariant"
       },
       "text": "1858T",
       "locations": [
        {
         "offset": 553,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 641,
         "length": 15
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 791,
         "length": 15
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 854,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs56048322",
        "type": "SequenceVariant"
       },
       "text": "2250G/C",
       "locations": [
        {
         "offset": 907,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 992,
         "length": 6
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs2476601",
        "type": "SequenceVariant"
       },
       "text": "1858C/T",
       "locations": [
        {
         "offset": 1216,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 1261,
         "length": 15
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 1284,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "26191",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN22",
       "locations": [
        {
         "offset": 1361,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 1391,
         "length": 15
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs2476601",
      "entity2": "D003922",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D003922",
      "entity2": "26191",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D003922",
      "entity2": "rs56048322",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17277899",
   "passages": [
    {
     "offset": 0,
     "text": "Polymorphic Alu insertions and the genetic structure of Iberian Basques.",
     "annotations": []
    },
    {
     "offset": 73,
     "text": "Eight Alu sequences (ACE, TPA25, PV92, APO, FXIIIB, D1, A25 and B65) were analyzed in two samples from Navarre and Guipuzcoa provinces (Basque Country, Spain). Alu data for other European, Caucasus and North African populations were compiled from the literature for comparison purposes to assess the genetic relationships of the Basques in a broader geographic context. Results of both MDS plot and AMOVA revealed spatial heterogeneity among these three population clusters clearly defined by geography. On the contrary, no substantial genetic heterogeneity was found between the Basque samples, or between Basques and other Europeans (excluding Caucasus populations). Moreover, the genetic information obtained from Alu data conflicts with hypotheses linking the origin of Basques with populations from North Africa (Berbers) or from the Caucasus region (Georgia). In order to explain the reduced genetic heterogeneity detected by Alu insertions among Basque subpopulations, values of the Wright's F(ST )statistic were estimated for both Alu markers and a set of short tandem repeats (STRs) in terms of two geographical scales: (1) the Basque Country, (2) Europe (including Basques). In the Basque area, estimates of Wahlund's effect for both genetic markers showed no statistical difference between Basque subpopulations. However, when this analysis was performed on a European scale, F(ST) values were significantly higher for Alu insertions than for STR alleles. From these results, we suggest that the spatial heterogeneity of the Basque gene pool identified in previous polymorphism studies is relatively recent and probably caused by a differential process of genetic admixture with non-Basque neighboring populations modulated by the effect of a linguistic barrier to random mating.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1636",
        "type": "GeneOrGeneProduct"
       },
       "text": "ACE",
       "locations": [
        {
         "offset": 94,
         "length": 3
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "-",
        "type": "GeneOrGeneProduct"
       },
       "text": "TPA25",
       "locations": [
        {
         "offset": 99,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "-",
        "type": "GeneOrGeneProduct"
       },
       "text": "PV92",
       "locations": [
        {
         "offset": 106,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "84909",
        "type": "GeneOrGeneProduct"
       },
       "text": "APO",
       "locations": [
        {
         "offset": 112,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2165",
        "type": "GeneOrGeneProduct"
       },
       "text": "FXIIIB",
       "locations": [
        {
         "offset": 117,
         "length": 6
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "-",
        "type": "GeneOrGeneProduct"
       },
       "text": "D1",
       "locations": [
        {
         "offset": 125,
         "length": 2
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "28936",
        "type": "GeneOrGeneProduct"
       },
       "text": "A25",
       "locations": [
        {
         "offset": 129,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "-",
        "type": "GeneOrGeneProduct"
       },
       "text": "B65",
       "locations": [
        {
         "offset": 137,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": []
  },
  {
   "id": "17628794",
   "passages": [
    {
     "offset": 0,
     "text": "Manganese superoxide dismutase (Mn-SOD) gene polymorphisms in urolithiasis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "Manganese superoxide dismutase",
       "locations": [
        {
         "offset": 0,
         "length": 30
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "Mn-SOD",
       "locations": [
        {
         "offset": 32,
         "length": 6
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D052878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "urolithiasis",
       "locations": [
        {
         "offset": 62,
         "length": 12
        }
       ]
      }
     ]
    },
    {
     "offset": 76,
     "text": "Polymorphism in manganese superoxide dismutase gene (Mn-SOD) is a new approach to identify its probable association with urolithiasis. Oxidative stress may be involved in the development of stone formation in the renal system. MnSOD is one of the primary enzymes that directly scavenges potential harmful oxidizing species. A valine (Val) to alanine (Ala) substitution at amino acid 16, occurring in the mitochondrial targeting sequence of the MnSOD gene, has been associated with an increase in urolithiasis risk. This study was conducted to investigate the association of MnSOD gene polymorphism with the risk of urolithiasis. We investigated the MnSOD in 66 stone-forming adults and 72 healthy volunteers. DNA was isolated from peripheral blood and genotyping was performed with PCR-based methods. Then PCR products were cut by BsaW1. Products were run on 3% agarose gel, 246 bp regions were 1-Ala-9, 164 and 82 bp products were determined as 2 Val-9. Chi-square test was used for comparison between patients and controls. In the control group the homozygote Ala allele was significantly higher than in the patient group (P < 0.01). The distribution of Ala/Val and homozygote Val alleles in the patient group was significantly higher than in the control group (P < 0.05). MnSOD genotype determination may provide a tool to identify individuals who are at risk of urolithiasis. This experiment also provides data about antioxidant status and stone formation.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "manganese superoxide dismutase",
       "locations": [
        {
         "offset": 92,
         "length": 30
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "Mn-SOD",
       "locations": [
        {
         "offset": 129,
         "length": 6
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D052878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "urolithiasis",
       "locations": [
        {
         "offset": 197,
         "length": 12
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002137",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stone formation",
       "locations": [
        {
         "offset": 266,
         "length": 15
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "MnSOD",
       "locations": [
        {
         "offset": 303,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "p|SUB|V|16|A",
        "type": "SequenceVariant"
       },
       "text": "valine (Val) to alanine (Ala) substitution at amino acid 16",
       "locations": [
        {
         "offset": 402,
         "length": 59
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "MnSOD",
       "locations": [
        {
         "offset": 520,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D052878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "urolithiasis",
       "locations": [
        {
         "offset": 572,
         "length": 12
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "MnSOD",
       "locations": [
        {
         "offset": 650,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D052878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "urolithiasis",
       "locations": [
        {
         "offset": 691,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "MnSOD",
       "locations": [
        {
         "offset": 725,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D002137",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stone-forming",
       "locations": [
        {
         "offset": 737,
         "length": 13
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D012685",
        "type": "ChemicalEntity"
       },
       "text": "agarose",
       "locations": [
        {
         "offset": 938,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1079,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1186,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1274,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "MnSOD",
       "locations": [
        {
         "offset": 1351,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D052878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "urolithiasis",
       "locations": [
        {
         "offset": 1442,
         "length": 12
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D002137",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stone formation",
       "locations": [
        {
         "offset": 1520,
         "length": 15
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "p|SUB|V|16|A",
      "entity2": "D052878",
      "type": "Positive_Correlation",
      "novel": "Novel"
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     "id": "R1",
     "infons": {
      "entity1": "D052878",
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      "novel": "No"
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      "novel": "No"
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    }
   ]
  },
  {
   "id": "19160446",
   "passages": [
    {
     "offset": 0,
     "text": "P2RX7: A bipolar and unipolar disorder candidate susceptibility gene?",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5027",
        "type": "GeneOrGeneProduct"
       },
       "text": "P2RX7",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D001714,D003866",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bipolar and unipolar disorder",
       "locations": [
        {
         "offset": 9,
         "length": 29
        }
       ]
      }
     ]
    },
    {
     "offset": 70,
     "text": "The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Darier's disease that show linkage across this region. The gene P2RX7 is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The non-synonymous SNP rs2230912 (resulting in amino-acid polymorphism Q460R) showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK case-control sample (bipolar I disorder N = 687, unipolar recurrent major depression N = 1,036, controls N = 1,204). Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7 was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12-linked bipolar-Darier families showed no evidence of rare variants at P2RX7 that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D001714",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bipolar disorder",
       "locations": [
        {
         "offset": 157,
         "length": 16
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D003866,D019964",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "unipolar mood disorder",
       "locations": [
        {
         "offset": 178,
         "length": 22
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D001714",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bipolar disorder",
       "locations": [
        {
         "offset": 253,
         "length": 16
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D007644",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Darier's disease",
       "locations": [
        {
         "offset": 274,
         "length": 16
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "5027",
        "type": "GeneOrGeneProduct"
       },
       "text": "P2RX7",
       "locations": [
        {
         "offset": 338,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001714",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bipolar disorder",
       "locations": [
        {
         "offset": 442,
         "length": 16
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D003866",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "unipolar depression",
       "locations": [
        {
         "offset": 463,
         "length": 19
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs2230912",
        "type": "SequenceVariant"
       },
       "text": "rs2230912",
       "locations": [
        {
         "offset": 507,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs2230912",
        "type": "SequenceVariant"
       },
       "text": "Q460R",
       "locations": [
        {
         "offset": 555,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D001714",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bipolar I disorder",
       "locations": [
        {
         "offset": 716,
         "length": 18
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003865",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "unipolar recurrent major depression",
       "locations": [
        {
         "offset": 744,
         "length": 35
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs2230912",
        "type": "SequenceVariant"
       },
       "text": "rs2230912",
       "locations": [
        {
         "offset": 820,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "5027",
        "type": "GeneOrGeneProduct"
       },
       "text": "P2RX7",
       "locations": [
        {
         "offset": 871,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D019964",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mood disorder",
       "locations": [
        {
         "offset": 909,
         "length": 13
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D001714,D003866",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bipolar or unipolar disorder",
       "locations": [
        {
         "offset": 957,
         "length": 28
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "5027",
        "type": "GeneOrGeneProduct"
       },
       "text": "P2RX7",
       "locations": [
        {
         "offset": 1102,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs2230912",
        "type": "SequenceVariant"
       },
       "text": "rs2230912",
       "locations": [
        {
         "offset": 1176,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "5027",
        "type": "GeneOrGeneProduct"
       },
       "text": "P2RX7",
       "locations": [
        {
         "offset": 1232,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D019964",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mood disorders",
       "locations": [
        {
         "offset": 1281,
         "length": 14
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "5027",
      "entity2": "D003866",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "5027",
      "entity2": "D001714",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "19549709",
   "passages": [
    {
     "offset": 0,
     "text": "Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000068338",
        "type": "ChemicalEntity"
       },
       "text": "everolimus",
       "locations": [
        {
         "offset": 12,
         "length": 10
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D000068338",
        "type": "ChemicalEntity"
       },
       "text": "RAD001",
       "locations": [
        {
         "offset": 24,
         "length": 6
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 35,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D002289",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NSCLC",
       "locations": [
        {
         "offset": 58,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 132,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 149,
     "text": "BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D002289",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "non-small-cell lung cancer",
       "locations": [
        {
         "offset": 213,
         "length": 26
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002289",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NSCLC",
       "locations": [
        {
         "offset": 241,
         "length": 5
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 248,
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       "id": "8",
       "infons": {
        "identifier": "D000068338",
        "type": "ChemicalEntity"
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       "text": "RAD001",
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         "offset": 258,
         "length": 6
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       ]
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       "id": "9",
       "infons": {
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       "text": "mammalian target of rapamycin",
       "locations": [
        {
         "offset": 291,
         "length": 29
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2475",
        "type": "GeneOrGeneProduct"
       },
       "text": "mTOR",
       "locations": [
        {
         "offset": 322,
         "length": 4
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D002289",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "NSCLC",
       "locations": [
        {
         "offset": 359,
         "length": 5
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D002289",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NSCLC",
       "locations": [
        {
         "offset": 392,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 398,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D010984",
        "type": "ChemicalEntity"
       },
       "text": "platinum",
       "locations": [
        {
         "offset": 459,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "epidermal growth factor receptor tyrosine kinase",
       "locations": [
        {
         "offset": 511,
         "length": 48
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D000068338",
        "type": "ChemicalEntity"
       },
       "text": "RAD001",
       "locations": [
        {
         "offset": 593,
         "length": 6
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "toxicity",
       "locations": [
        {
         "offset": 644,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "2475",
        "type": "GeneOrGeneProduct"
       },
       "text": "mTOR",
       "locations": [
        {
         "offset": 745,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 787,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 895,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D005221",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fatigue",
       "locations": [
        {
         "offset": 1164,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D004417",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyspnea",
       "locations": [
        {
         "offset": 1173,
         "length": 7
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D013280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stomatitis",
       "locations": [
        {
         "offset": 1182,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D000740",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anemia",
       "locations": [
        {
         "offset": 1194,
         "length": 6
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D013921",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "thrombocytopenia",
       "locations": [
        {
         "offset": 1206,
         "length": 16
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D011014",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Pneumonitis",
       "locations": [
        {
         "offset": 1224,
         "length": 11
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "207",
        "type": "GeneOrGeneProduct"
       },
       "text": "AKT",
       "locations": [
        {
         "offset": 1364,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "207",
        "type": "GeneOrGeneProduct"
       },
       "text": "pAKT",
       "locations": [
        {
         "offset": 1369,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D000068338",
        "type": "ChemicalEntity"
       },
       "text": "RAD001",
       "locations": [
        {
         "offset": 1442,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D002289",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NSCLC",
       "locations": [
        {
         "offset": 1526,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D000068338",
        "type": "ChemicalEntity"
       },
       "text": "RAD001",
       "locations": [
        {
         "offset": 1547,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D002289",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NSCLC",
       "locations": [
        {
         "offset": 1591,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "2475",
      "entity2": "D002289",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D000068338",
      "entity2": "2475",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D000068338",
      "entity2": "D002289",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "1956",
      "entity2": "D002289",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D010984",
      "entity2": "D002289",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "19891556",
   "passages": [
    {
     "offset": 0,
     "text": "Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000077144",
        "type": "ChemicalEntity"
       },
       "text": "Clopidogrel",
       "locations": [
        {
         "offset": 0,
         "length": 11
        }
       ]
      }
     ]
    },
    {
     "offset": 97,
     "text": "Antiplatelet therapy with clopidogrel is the current standard of care for coronary artery disease patients undergoing a percutaneous coronary intervention. However, approximately 25% of patients experience a subtherapeutic antiplatelet response. Clopidogrel is a prodrug that undergoes hepatic biotransformation by CYP2C19 into its active metabolite. Several studies have reported that, compared with wild-type individuals, CYP2C19 variant allele carriers exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, and are therefore at significantly higher risk of adverse cardiovascular events. Consequently, the US FDA has recently changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics and clinical response. Future studies remain necessary to develop effective personalized therapeutic strategies for CYP2C19 variant allele carriers and other individuals at risk for clopidogrel nonresponsiveness.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D000077144",
        "type": "ChemicalEntity"
       },
       "text": "clopidogrel",
       "locations": [
        {
         "offset": 123,
         "length": 11
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D003324",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "coronary artery disease",
       "locations": [
        {
         "offset": 171,
         "length": 23
        }
       ]
      },
      {
       "id": "3",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 195,
         "length": 8
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
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         "offset": 283,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D000077144",
        "type": "ChemicalEntity"
       },
       "text": "Clopidogrel",
       "locations": [
        {
         "offset": 343,
         "length": 11
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1557",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2C19",
       "locations": [
        {
         "offset": 412,
         "length": 7
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1557",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2C19",
       "locations": [
        {
         "offset": 521,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000077144",
        "type": "ChemicalEntity"
       },
       "text": "clopidogrel",
       "locations": [
        {
         "offset": 606,
         "length": 11
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000077144",
        "type": "ChemicalEntity"
       },
       "text": "clopidogrel",
       "locations": [
        {
         "offset": 805,
         "length": 11
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "1557",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2C19",
       "locations": [
        {
         "offset": 870,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D000077144",
        "type": "ChemicalEntity"
       },
       "text": "clopidogrel",
       "locations": [
        {
         "offset": 890,
         "length": 11
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "1557",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2C19",
       "locations": [
        {
         "offset": 1053,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D000077144",
        "type": "ChemicalEntity"
       },
       "text": "clopidogrel",
       "locations": [
        {
         "offset": 1119,
         "length": 11
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D000077144",
      "entity2": "1557",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D000077144",
      "entity2": "D003324",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "20367983",
   "passages": [
    {
     "offset": 0,
     "text": "Mutation analysis in a Chinese family with multiple endocrine neoplasia type 1.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "multiple endocrine neoplasia type 1",
       "locations": [
        {
         "offset": 43,
         "length": 35
        }
       ]
      }
     ]
    },
    {
     "offset": 80,
     "text": "BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome which is caused by germline mutations of the tumor suppressor gene MEN1. This study aimed to identify mutations in a Chinese pedigree with MEN1. METHODS: A large Chinese family with MEN1 was collected. All of the coded regions and their adjacent sequences of the MEN1 gene were amplified and sequenced. RESULTS: In this family, a heterozygous cytosine insertion in exon 10 (c.1546_1547insC) inducing a frame shift mutation of MEN1 was found in the proband and the other two suffering members of his family. This mutation was linked to a novel single nucleotide polymorphism (SNP) in intron 3 (IVS3 + 18C > T). CONCLUSIONS: The mutation in exon 10 of MEN1 gene might induce development of parathyroid hyperplasia and pituitary adenoma and cosegregate with MEN1 syndrome. The significance of the new found IVS3 + 18C > T of MEN1 needs a further investigation.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Multiple endocrine neoplasia type 1",
       "locations": [
        {
         "offset": 92,
         "length": 35
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 129,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009386",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant cancer syndrome",
       "locations": [
        {
         "offset": 141,
         "length": 34
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 221,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 243,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 315,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 358,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 439,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "c|INS||C",
        "type": "SequenceVariant"
       },
       "text": "cytosine insertion",
       "locations": [
        {
         "offset": 519,
         "length": 18
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "c|INS|1546_1547|C",
        "type": "SequenceVariant"
       },
       "text": "c.1546_1547insC",
       "locations": [
        {
         "offset": 550,
         "length": 15
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 602,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|SUB|C|IVS3+18|T",
        "type": "SequenceVariant"
       },
       "text": "IVS3 + 18C > T",
       "locations": [
        {
         "offset": 769,
         "length": 14
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 826,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D006965",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "parathyroid hyperplasia",
       "locations": [
        {
         "offset": 864,
         "length": 23
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D010911",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pituitary adenoma",
       "locations": [
        {
         "offset": 892,
         "length": 17
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MEN1 syndrome",
       "locations": [
        {
         "offset": 931,
         "length": 13
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|SUB|C|IVS3+18|T",
        "type": "SequenceVariant"
       },
       "text": "IVS3 + 18C > T",
       "locations": [
        {
         "offset": 980,
         "length": 14
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 998,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D009369",
      "entity2": "4221",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|INS||C",
      "entity2": "D018761",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|INS||C",
      "entity2": "D010911",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|INS||C",
      "entity2": "D006965",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "4221",
      "entity2": "D018761",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "4221",
      "entity2": "D010911",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "4221",
      "entity2": "D006965",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "c|INS|1546_1547|C",
      "entity2": "D018761",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "c|INS|1546_1547|C",
      "entity2": "D010911",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "c|INS|1546_1547|C",
      "entity2": "D006965",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "c|INS|1546_1547|C",
      "entity2": "c|SUB|C|IVS3+18|T",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "22180037",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic polymorphism of the glutathione-S-transferase P1 gene (GSTP1) and susceptibility to prostate cancer in the Kashmiri population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "glutathione-S-transferase P1",
       "locations": [
        {
         "offset": 28,
         "length": 28
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 63,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 92,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 136,
     "text": "Glutathione-S-transferase P1 (GSTP1) is a critical enzyme of the phase II detoxification pathway. One of the common functional polymorphisms of GSTP1 is A > G at nucleotide 313, which results in an amino acid substitution (Ile105Val) at the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. To investigate the GSTP1 Ile105Val genotype frequency in prostate cancer cases in the Kashmiri population, we designed a case-control study, in which 50 prostate cancer cases and 45 benign prostate hyperplasia cases were studied for GSTP1 Ile105Val polymorphism, compared to 80 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of GSTP1 Ile105Val in our ethnic Kashmir population, i.e., Ile/Ile, Ile/Val and Val/Val, to be 52.4, 33.3 and 14.3% among prostate cancer cases, 48.5, 37.5 and 14% among benign prostate hyperplasia cases and 73.8, 21.3 and 5% in the control population, respectively. There was a significant association between the GSTP1 Ile/Val genotype and the advanced age group among the cases. We conclude that GSTP1 Ile/Val polymorphism is involved in the risk of prostate cancer development in our population.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "Glutathione-S-transferase P1",
       "locations": [
        {
         "offset": 136,
         "length": 28
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 166,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 280,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "rs1695",
        "type": "SequenceVariant"
       },
       "text": "A > G at nucleotide 313",
       "locations": [
        {
         "offset": 289,
         "length": 23
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs1695",
        "type": "SequenceVariant"
       },
       "text": "Ile105Val",
       "locations": [
        {
         "offset": 359,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 403,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 443,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 469,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs1695",
        "type": "SequenceVariant"
       },
       "text": "Ile105Val",
       "locations": [
        {
         "offset": 475,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 507,
         "length": 15
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 603,
         "length": 15
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "benign prostate hyperplasia",
       "locations": [
        {
         "offset": 632,
         "length": 27
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 683,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs1695",
        "type": "SequenceVariant"
       },
       "text": "Ile105Val",
       "locations": [
        {
         "offset": 689,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 865,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs1695",
        "type": "SequenceVariant"
       },
       "text": "Ile105Val",
       "locations": [
        {
         "offset": 871,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 984,
         "length": 15
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "benign prostate hyperplasia",
       "locations": [
        {
         "offset": 1032,
         "length": 27
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 1177,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs1695",
        "type": "SequenceVariant"
       },
       "text": "Ile/Val",
       "locations": [
        {
         "offset": 1183,
         "length": 7
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "2950",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSTP1",
       "locations": [
        {
         "offset": 1261,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs1695",
        "type": "SequenceVariant"
       },
       "text": "Ile/Val",
       "locations": [
        {
         "offset": 1267,
         "length": 7
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1315,
         "length": 15
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs1695",
      "entity2": "D011470",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs1695",
      "entity2": "D011471",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "2950",
      "entity2": "D011470",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "2950",
      "entity2": "D011471",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "24742750",
   "passages": [
    {
     "offset": 0,
     "text": "Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 16,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QT prolongation",
       "locations": [
        {
         "offset": 111,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 128,
     "text": "Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K(+) channel and Ca(2+) channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2min every 10min for 30min after drug exposure for the vehicle and each drug concentration. IKr and IKs blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca(2+) channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the IKr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 162,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D002121,D026902",
        "type": "ChemicalEntity"
       },
       "text": "K(+) channel and Ca(2+) channel blocker",
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         "offset": 331,
         "length": 39
        }
       ]
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       "id": "4",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QT prolongation",
       "locations": [
        {
         "offset": 509,
         "length": 15
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QT prolongation",
       "locations": [
        {
         "offset": 623,
         "length": 15
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002121",
        "type": "ChemicalEntity"
       },
       "text": "Ca(2+) channel blockers",
       "locations": [
        {
         "offset": 907,
         "length": 23
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D000638",
        "type": "ChemicalEntity"
       },
       "text": "Amiodarone",
       "locations": [
        {
         "offset": 1005,
         "length": 10
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D017374",
        "type": "ChemicalEntity"
       },
       "text": "Paroxetine",
       "locations": [
        {
         "offset": 1017,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D016593",
        "type": "ChemicalEntity"
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       "text": "Terfenadine",
       "locations": [
        {
         "offset": 1029,
         "length": 11
        }
       ]
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       "id": "10",
       "infons": {
        "identifier": "D015283",
        "type": "ChemicalEntity"
       },
       "text": "Citalopram",
       "locations": [
        {
         "offset": 1045,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D016593",
        "type": "ChemicalEntity"
       },
       "text": "Terfenadine",
       "locations": [
        {
         "offset": 1135,
         "length": 11
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D015283",
        "type": "ChemicalEntity"
       },
       "text": "Citalopram",
       "locations": [
        {
         "offset": 1151,
         "length": 10
        }
       ]
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       "id": "13",
       "infons": {
        "identifier": "D016171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Torsade de Pointes",
       "locations": [
        {
         "offset": 1191,
         "length": 18
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D016171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TdP",
       "locations": [
        {
         "offset": 1211,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D016171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TdP",
       "locations": [
        {
         "offset": 1447,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
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    {
     "id": "R0",
     "infons": {
      "entity1": "D015283",
      "entity2": "D016171",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D016593",
      "entity2": "D016171",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "26270232",
   "passages": [
    {
     "offset": 0,
     "text": "Serum levels of chemokines CCL4 and CCL5 in cirrhotic patients indicate the presence of hepatocellular carcinoma.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3576,6347,6348,6351,6352,6374",
        "type": "GeneOrGeneProduct"
       },
       "text": "chemokines",
       "locations": [
        {
         "offset": 16,
         "length": 10
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6351",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL4",
       "locations": [
        {
         "offset": 27,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "6352",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL5",
       "locations": [
        {
         "offset": 36,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D008103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cirrhotic",
       "locations": [
        {
         "offset": 44,
         "length": 9
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 54,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hepatocellular carcinoma",
       "locations": [
        {
         "offset": 88,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 114,
     "text": "BACKGROUND: Most hepatocellular carcinomas (HCCs) are diagnosed at an advanced stage. The prognostic value of serum tumour markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) is limited. The aim of our study is to evaluate the diagnostic value of serum growth factors, apoptotic and inflammatory mediators of cirrhotic patients with and without HCC. METHODS: Serum samples were collected from cirrhotic potential liver transplant patients (LTx) with (n=61) and without HCC (n=78) as well as from healthy controls (HCs; n=39). Serum concentrations of CRP, neopterin and IL-6 as markers of inflammation and thrombopoietin (TPO), GCSF, FGF basic and VEGF, HMGB1, CK-18 (M65) and CK18 fragment (M30) and a panel of proinflammatory chemokines (CCL2, CCL3, CCL4, CCL5, CXCL5 and IL-8) were measured. Chi square, Fisher exact, Mann-Whitney U-tests, ROC curve analysis and forward stepwise logistic regression analyses were applied. RESULTS: Patients with HCC had higher serum TPO and chemokines (P   <0.001 for TPO, CCL4, CCL5 and CXCL5) and lower CCL2 (P=0.008) levels than cirrhotic patients without HCC. Multivariate forward stepwise regression analysis for significant parameters showed that among the studied parameters CCL4 and CCL5 (P=0.001) are diagnostic markers of HCC. Serum levels of TPO and chemokines were lower, whereas M30 was significantly higher in cirrhotic patients than in HCs. CONCLUSIONS: High serum levels of inflammatory chemokines such as CCL4 and CCL5 in the serum of cirrhotic patients indicate the presence of HCC.",
     "annotations": [
      {
       "id": "6",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hepatocellular carcinomas",
       "locations": [
        {
         "offset": 131,
         "length": 25
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCCs",
       "locations": [
        {
         "offset": 158,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumour",
       "locations": [
        {
         "offset": 230,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "174",
        "type": "GeneOrGeneProduct"
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       "text": "alpha-fetoprotein",
       "locations": [
        {
         "offset": 245,
         "length": 17
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "174",
        "type": "GeneOrGeneProduct"
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       "text": "AFP",
       "locations": [
        {
         "offset": 264,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "2147",
        "type": "GeneOrGeneProduct"
       },
       "text": "des-gamma-carboxy prothrombin",
       "locations": [
        {
         "offset": 273,
         "length": 29
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "2147",
        "type": "GeneOrGeneProduct"
       },
       "text": "DCP",
       "locations": [
        {
         "offset": 304,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 417,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cirrhotic",
       "locations": [
        {
         "offset": 443,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 453,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCC",
       "locations": [
        {
         "offset": 479,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D008103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cirrhotic",
       "locations": [
        {
         "offset": 527,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 564,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCC",
       "locations": [
        {
         "offset": 603,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "CRP",
       "locations": [
        {
         "offset": 684,
         "length": 3
        }
       ]
      },
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       "id": "21",
       "infons": {
        "identifier": "D019798",
        "type": "ChemicalEntity"
       },
       "text": "neopterin",
       "locations": [
        {
         "offset": 689,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "3569",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-6",
       "locations": [
        {
         "offset": 703,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammation",
       "locations": [
        {
         "offset": 722,
         "length": 12
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "7066",
        "type": "GeneOrGeneProduct"
       },
       "text": "thrombopoietin",
       "locations": [
        {
         "offset": 739,
         "length": 14
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "7066",
        "type": "GeneOrGeneProduct"
       },
       "text": "TPO",
       "locations": [
        {
         "offset": 755,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "1440",
        "type": "GeneOrGeneProduct"
       },
       "text": "GCSF",
       "locations": [
        {
         "offset": 761,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "2247",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGF basic",
       "locations": [
        {
         "offset": 767,
         "length": 9
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "7422",
        "type": "GeneOrGeneProduct"
       },
       "text": "VEGF",
       "locations": [
        {
         "offset": 781,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "3146",
        "type": "GeneOrGeneProduct"
       },
       "text": "HMGB1",
       "locations": [
        {
         "offset": 787,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "3875",
        "type": "GeneOrGeneProduct"
       },
       "text": "CK-18",
       "locations": [
        {
         "offset": 794,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "3875",
        "type": "GeneOrGeneProduct"
       },
       "text": "CK18",
       "locations": [
        {
         "offset": 810,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "3576,6347,6348,6351,6352,6374",
        "type": "GeneOrGeneProduct"
       },
       "text": "proinflammatory chemokines",
       "locations": [
        {
         "offset": 845,
         "length": 26
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "6347",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL2",
       "locations": [
        {
         "offset": 873,
         "length": 4
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "6348",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL3",
       "locations": [
        {
         "offset": 879,
         "length": 4
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "6351",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL4",
       "locations": [
        {
         "offset": 885,
         "length": 4
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "6352",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL5",
       "locations": [
        {
         "offset": 891,
         "length": 4
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "6374",
        "type": "GeneOrGeneProduct"
       },
       "text": "CXCL5",
       "locations": [
        {
         "offset": 897,
         "length": 5
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "3576",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-8",
       "locations": [
        {
         "offset": 907,
         "length": 4
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Patients",
       "locations": [
        {
         "offset": 1068,
         "length": 8
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCC",
       "locations": [
        {
         "offset": 1082,
         "length": 3
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "7066",
        "type": "GeneOrGeneProduct"
       },
       "text": "TPO",
       "locations": [
        {
         "offset": 1103,
         "length": 3
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "3576,6347,6348,6351,6352,6374",
        "type": "GeneOrGeneProduct"
       },
       "text": "chemokines",
       "locations": [
        {
         "offset": 1111,
         "length": 10
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "7066",
        "type": "GeneOrGeneProduct"
       },
       "text": "TPO",
       "locations": [
        {
         "offset": 1138,
         "length": 3
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "6351",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL4",
       "locations": [
        {
         "offset": 1143,
         "length": 4
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "6352",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL5",
       "locations": [
        {
         "offset": 1149,
         "length": 4
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "6374",
        "type": "GeneOrGeneProduct"
       },
       "text": "CXCL5",
       "locations": [
        {
         "offset": 1158,
         "length": 5
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "6347",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL2",
       "locations": [
        {
         "offset": 1175,
         "length": 4
        }
       ]
      },
      {
       "id": "48",
       "infons": {
        "identifier": "D008103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cirrhotic",
       "locations": [
        {
         "offset": 1202,
         "length": 9
        }
       ]
      },
      {
       "id": "49",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1212,
         "length": 8
        }
       ]
      },
      {
       "id": "50",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCC",
       "locations": [
        {
         "offset": 1229,
         "length": 3
        }
       ]
      },
      {
       "id": "51",
       "infons": {
        "identifier": "6351",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL4",
       "locations": [
        {
         "offset": 1352,
         "length": 4
        }
       ]
      },
      {
       "id": "52",
       "infons": {
        "identifier": "6352",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL5",
       "locations": [
        {
         "offset": 1361,
         "length": 4
        }
       ]
      },
      {
       "id": "53",
       "infons": {
        "identifier": "D006528",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "HCC",
       "locations": [
        {
         "offset": 1402,
         "length": 3
        }
       ]
      },
      {
       "id": "54",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "TPO",
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         "offset": 1423,
         "length": 3
        }
       ]
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       "id": "55",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "chemokines",
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         "length": 10
        }
       ]
      },
      {
       "id": "56",
       "infons": {
        "identifier": "D008103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cirrhotic",
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        {
         "offset": 1494,
         "length": 9
        }
       ]
      },
      {
       "id": "57",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patients",
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        {
         "offset": 1504,
         "length": 8
        }
       ]
      },
      {
       "id": "58",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 1560,
         "length": 12
        }
       ]
      },
      {
       "id": "59",
       "infons": {
        "identifier": "3576,6347,6348,6351,6352,6374",
        "type": "GeneOrGeneProduct"
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       "text": "chemokines",
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         "length": 10
        }
       ]
      },
      {
       "id": "60",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "CCL4",
       "locations": [
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         "offset": 1592,
         "length": 4
        }
       ]
      },
      {
       "id": "61",
       "infons": {
        "identifier": "6352",
        "type": "GeneOrGeneProduct"
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       "text": "CCL5",
       "locations": [
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         "offset": 1601,
         "length": 4
        }
       ]
      },
      {
       "id": "62",
       "infons": {
        "identifier": "D008103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cirrhotic",
       "locations": [
        {
         "offset": 1622,
         "length": 9
        }
       ]
      },
      {
       "id": "63",
       "infons": {
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     "text": "Disease-associated mutations in human BICD2 hyperactivate motility of dynein-dynactin.",
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     "text": "Bicaudal D2 (BICD2) joins dynein with dynactin into a ternary complex (termed DDB) capable of processive movement. Point mutations in the BICD2 gene have been identified in patients with a dominant form of spinal muscular atrophy, but how these mutations cause disease is unknown. To investigate this question, we have developed in vitro motility assays with purified DDB and BICD2's membrane vesicle partner, the GTPase Rab6a. Rab6a-GTP, either in solution or bound to artificial liposomes, released BICD2 from an autoinhibited state and promoted robust dynein-dynactin transport. In these assays, BICD2 mutants showed an enhanced ability to form motile DDB complexes. Increased retrograde transport by BICD2 mutants also was observed in cells using an inducible organelle transport assay. When overexpressed in rat hippocampal neurons, the hyperactive BICD2 mutants decreased neurite growth. Our results reveal that dominant mutations in BICD2 hyperactivate DDB motility and suggest that an imbalance of minus versus plus end-directed microtubule motility in neurons may underlie spinal muscular atrophy.",
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     "text": "Thiamine deficiency activates hypoxia inducible factor-1a to facilitate pro-apoptotic responses in mouse primary astrocytes.",
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     "text": "Thiamine is an essential enzyme cofactor required for proper metabolic function and maintenance of metabolism and energy production in the brain. In developed countries, thiamine deficiency (TD) is most often manifested following chronic alcohol consumption leading to impaired mitochondrial function, oxidative stress, inflammation and excitotoxicity. These biochemical lesions result in apoptotic cell death in both neurons and astrocytes. Comparable histological injuries in patients with hypoxia/ischemia and TD have been described in the thalamus and mammillary bodies, suggesting a congruency between the cellular responses to these stresses. Consistent with hypoxia/ischemia, TD stabilizes and activates Hypoxia Inducible Factor-1a (HIF-1a) under physiological oxygen levels. However, the role of TD-induced HIF-1a in neurological injury is currently unknown. Using Western blot analysis and RT-PCR, we have demonstrated that TD induces HIF-1a expression and activity in primary mouse astrocytes. We observed a time-dependent increase in mRNA and protein expression of the pro-apoptotic and pro-inflammatory HIF-1a target genes MCP1, BNIP3, Nix and Noxa during TD. We also observed apoptotic cell death in TD as demonstrated by PI/Annexin V staining, TUNEL assay, and Cell Death ELISA. Pharmacological inhibition of HIF-1a activity using YC1 and thiamine repletion both reduced expression of pro-apoptotic HIF-1a target genes and apoptotic cell death in TD. These results demonstrate that induction of HIF-1a mediated transcriptional up-regulation of pro-apoptotic/inflammatory signaling contributes to astrocyte cell death during thiamine deficiency.",
     "annotations": [
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        "identifier": "D003345",
        "type": "ChemicalEntity"
       },
       "text": "corticosterone",
       "locations": [
        {
         "offset": 1414,
         "length": 14
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "24111",
        "type": "GeneOrGeneProduct"
       },
       "text": "U-II",
       "locations": [
        {
         "offset": 1513,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 1542,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D001008",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anxiogenic",
       "locations": [
        {
         "offset": 1556,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D003866",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "depressant",
       "locations": [
        {
         "offset": 1572,
         "length": 10
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 1599,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "24111",
        "type": "GeneOrGeneProduct"
       },
       "text": "U-II",
       "locations": [
        {
         "offset": 1630,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D001523",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psychiatric disorders",
       "locations": [
        {
         "offset": 1670,
         "length": 21
        }
       ]
      }
     ]
    }
   ],
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     "id": "R0",
     "infons": {
      "entity1": "24111",
      "entity2": "D001919",
      "type": "Positive_Correlation",
      "novel": "No"
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "24111",
      "entity2": "D006973",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "24111",
      "entity2": "12640",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "24111",
      "entity2": "19109",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "24111",
      "entity2": "D001523",
      "type": "Association",
      "novel": "Novel"
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     "id": "R5",
     "infons": {
      "entity1": "24111",
      "entity2": "D003866",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
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    {
     "id": "R6",
     "infons": {
      "entity1": "24111",
      "entity2": "D001008",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16288199",
   "passages": [
    {
     "offset": 0,
     "text": "The promoter of inducible nitric oxide synthase implicated in glaucoma based on genetic analysis and nuclear factor binding.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4843",
        "type": "GeneOrGeneProduct"
       },
       "text": "nitric oxide synthase",
       "locations": [
        {
         "offset": 26,
         "length": 21
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glaucoma",
       "locations": [
        {
         "offset": 62,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 125,
     "text": "PURPOSE: Nitric oxide has many beneficial functions in the human body at the right amounts, but it can also be hazardous if it is produced in amounts more than needed and has therefore been studied in relation to several neurological and non-neurological disorders. In vitro and in vivo studies demonstrate a connection between the inducible form of Nitric Oxide Synthase, iNOS, and the neuropathological disorder glaucoma, one of the major causes of blindness in the world. In this study, we sought to establish the genetic association between iNOS and primary open angle glaucoma, POAG, and to find the functional element(s) connected with the pathogenesis of the disease. METHODS: Two microsatellites, 1 insertion/deletion, and 8 single nucleotide polymorphisms (SNPs) in the regulatory region of iNOS were genotyped in 200 POAG patients and 200 age-matched controls. Also, the CCTTT-microsatellite was examined for its protein-binding capability in an electrophoretic mobility shift assay, EMSA. RESULTS: There was a significant difference in allele distribution of the CCTTT-microsatellite, between patients and controls. (CCTTT)14, which has been reported to have a higher activity in a reporter-construct, was significantly more abundant in POAG patients, while (CCTTT)10 and (CCTTT)13 were less common. In EMSA, the (CCTTT)14 allele exhibited specific binding of nuclear proteins. CONCLUSIONS: These results, together with other studies on this gene and the CCTTT-microsatellite, establish, for the first time, a genetic association of iNOS with POAG and suggest a regulatory function for the microsatellite.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D009569",
        "type": "ChemicalEntity"
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       "text": "Nitric oxide",
       "locations": [
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         "offset": 134,
         "length": 12
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       ]
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      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 184,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009422",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurological and non-neurological disorders",
       "locations": [
        {
         "offset": 346,
         "length": 43
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4843",
        "type": "GeneOrGeneProduct"
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       "text": "Nitric Oxide Synthase",
       "locations": [
        {
         "offset": 475,
         "length": 21
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4843",
        "type": "GeneOrGeneProduct"
       },
       "text": "iNOS",
       "locations": [
        {
         "offset": 498,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D005901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neuropathological disorder glaucoma",
       "locations": [
        {
         "offset": 512,
         "length": 35
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D001766",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "blindness",
       "locations": [
        {
         "offset": 576,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "4843",
        "type": "GeneOrGeneProduct"
       },
       "text": "iNOS",
       "locations": [
        {
         "offset": 670,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D005902",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "primary open angle glaucoma",
       "locations": [
        {
         "offset": 679,
         "length": 27
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D005902",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "POAG",
       "locations": [
        {
         "offset": 708,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "4843",
        "type": "GeneOrGeneProduct"
       },
       "text": "iNOS",
       "locations": [
        {
         "offset": 925,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D005902",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "POAG",
       "locations": [
        {
         "offset": 952,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 957,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1229,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|DUP||CCTTT|14",
        "type": "SequenceVariant"
       },
       "text": "(CCTTT)14",
       "locations": [
        {
         "offset": 1252,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D005902",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "POAG",
       "locations": [
        {
         "offset": 1373,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1378,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|DUP||CCTTT|10",
        "type": "SequenceVariant"
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       "text": "(CCTTT)10",
       "locations": [
        {
         "offset": 1394,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|DUP||CCTTT|13",
        "type": "SequenceVariant"
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       "text": "(CCTTT)13",
       "locations": [
        {
         "offset": 1408,
         "length": 9
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|DUP||CCTTT|14",
        "type": "SequenceVariant"
       },
       "text": "(CCTTT)14",
       "locations": [
        {
         "offset": 1449,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "4843",
        "type": "GeneOrGeneProduct"
       },
       "text": "iNOS",
       "locations": [
        {
         "offset": 1669,
         "length": 4
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "D005902",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "POAG",
       "locations": [
        {
         "offset": 1679,
         "length": 4
        }
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      "entity1": "c|DUP||CCTTT|14",
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     "id": "R2",
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     "id": "R3",
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      "novel": "No"
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     "id": "R5",
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      "novel": "No"
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      "type": "Association",
      "novel": "No"
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    }
   ]
  },
  {
   "id": "16391785",
   "passages": [
    {
     "offset": 0,
     "text": "Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "81704",
        "type": "GeneOrGeneProduct"
       },
       "text": "DOCK8",
       "locations": [
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         "offset": 50,
         "length": 5
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
        {
         "offset": 64,
         "length": 5
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       ]
      },
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       "id": "2",
       "infons": {
        "identifier": "D008175",
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       "text": "lung cancer",
       "locations": [
        {
         "offset": 70,
         "length": 11
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       ]
      }
     ]
    },
    {
     "offset": 83,
     "text": "A homozygous deletion of the DOCK8 (dedicator of cytokinesis 8) locus at chromosome 9p24 was found in a lung cancer cell line by array-CGH analysis. Cloning of the full-length DOCK8 cDNA led us to define that the DOCK8 gene encodes a protein consisting of 2,099 amino acids. DOCK8 was expressed in a variety of human organs, including the lungs, and was also expressed in type II alveolar, bronchiolar epithelial and bronchial epithelial cells, which are considered as being progenitors for lung cancer cells. DOCK8 expression was reduced in 62/71 (87%) primary lung cancers compared with normal lung tissue, and the reduction occurred irrespective of the histological type of lung cancer. 5-Aza-2'-deoxy-cytidine and/or Trichostatin A treatments induced DOCK8 expression in lung cancer cell lines with reduced DOCK8 expression. Therefore, epigenetic mechanisms, including DNA methylation and histone deacetylation, were indicated to be involved in DOCK8 down-regulation in lung cancer cells. Further screening revealed homozygous deletions of the DOCK8 gene in a gastric and a breast cancer cell line. DOCK family proteins have been shown to play roles in regulation of migration, morphology, adhesion and growth of cells. Thus, the present results suggest that genetic and epigenetic inactivation of DOCK8 is involved in the development and/or progression of lung and other cancers by disturbing such regulations.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "81704",
        "type": "GeneOrGeneProduct"
       },
       "text": "DOCK8",
       "locations": [
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         "offset": 112,
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       ]
      },
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       "id": "4",
       "infons": {
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       "text": "dedicator of cytokinesis 8",
       "locations": [
        {
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         "length": 26
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       ]
      },
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       "id": "5",
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        "identifier": "D008175",
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       "text": "lung cancer",
       "locations": [
        {
         "offset": 187,
         "length": 11
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "81704",
        "type": "GeneOrGeneProduct"
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       "text": "DOCK8",
       "locations": [
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         "offset": 259,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "81704",
        "type": "GeneOrGeneProduct"
       },
       "text": "DOCK8",
       "locations": [
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         "offset": 296,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "81704",
        "type": "GeneOrGeneProduct"
       },
       "text": "DOCK8",
       "locations": [
        {
         "offset": 358,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
        {
         "offset": 394,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 574,
         "length": 11
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "81704",
        "type": "GeneOrGeneProduct"
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       "text": "DOCK8",
       "locations": [
        {
         "offset": 593,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancers",
       "locations": [
        {
         "offset": 645,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008175",
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       "text": "lung cancer",
       "locations": [
        {
         "offset": 760,
         "length": 11
        }
       ]
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       "infons": {
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        "type": "ChemicalEntity"
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       "text": "5-Aza-2'-deoxy-cytidine",
       "locations": [
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         "length": 23
        }
       ]
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       "id": "15",
       "infons": {
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        "type": "ChemicalEntity"
       },
       "text": "Trichostatin A",
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         "offset": 804,
         "length": 14
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       ]
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       "id": "16",
       "infons": {
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       "text": "DOCK8",
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        }
       ]
      },
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       "id": "17",
       "infons": {
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       "text": "lung cancer",
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         "length": 11
        }
       ]
      },
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       "id": "18",
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       "text": "DOCK8",
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        }
       ]
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       "id": "19",
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       "text": "DOCK8",
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      },
      {
       "id": "20",
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       "text": "lung cancer",
       "locations": [
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         "offset": 1057,
         "length": 11
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "81704",
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       "text": "DOCK8",
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         "offset": 1131,
         "length": 5
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       ]
      },
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       "id": "22",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
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         "offset": 1161,
         "length": 13
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "81704",
        "type": "GeneOrGeneProduct"
       },
       "text": "DOCK",
       "locations": [
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         "offset": 1186,
         "length": 4
        }
       ]
      },
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       "id": "24",
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        "identifier": "81704",
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       },
       "text": "DOCK8",
       "locations": [
        {
         "offset": 1385,
         "length": 5
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      },
      {
       "id": "25",
       "infons": {
        "identifier": "D008175,D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung and other cancers",
       "locations": [
        {
         "offset": 1444,
         "length": 22
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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    },
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    },
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      "entity1": "81704",
      "entity2": "D008175",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17250663",
   "passages": [
    {
     "offset": 0,
     "text": "A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "DFNA36",
       "locations": [
        {
         "offset": 24,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D034381",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hearing loss",
       "locations": [
        {
         "offset": 31,
         "length": 12
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "TMC1",
       "locations": [
        {
         "offset": 145,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 151,
     "text": "We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D006319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sensorineural hearing loss",
       "locations": [
        {
         "offset": 282,
         "length": 26
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D034381",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hearing loss",
       "locations": [
        {
         "offset": 314,
         "length": 12
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 429,
         "length": 8
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "TMC1",
       "locations": [
        {
         "offset": 562,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "DFNA36",
       "locations": [
        {
         "offset": 579,
         "length": 6
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs121908072",
        "type": "SequenceVariant"
       },
       "text": "p.D572H",
       "locations": [
        {
         "offset": 678,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs121908072",
        "type": "SequenceVariant"
       },
       "text": "c.G1714C",
       "locations": [
        {
         "offset": 687,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "TMC1",
       "locations": [
        {
         "offset": 705,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "DFNA36",
       "locations": [
        {
         "offset": 807,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs121908072",
        "type": "SequenceVariant"
       },
       "text": "p.D572N",
       "locations": [
        {
         "offset": 824,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs121908072",
        "type": "SequenceVariant"
       },
       "text": "c.G1714A",
       "locations": [
        {
         "offset": 833,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "TMC1",
       "locations": [
        {
         "offset": 924,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "DFNA36",
       "locations": [
        {
         "offset": 961,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D034381",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hearing loss",
       "locations": [
        {
         "offset": 968,
         "length": 12
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D034381",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hearing loss",
       "locations": [
        {
         "offset": 1008,
         "length": 12
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs121908072",
        "type": "SequenceVariant"
       },
       "text": "p.D572H",
       "locations": [
        {
         "offset": 1037,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs121908072",
        "type": "SequenceVariant"
       },
       "text": "p.D572N",
       "locations": [
        {
         "offset": 1080,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "DFNA36",
       "locations": [
        {
         "offset": 1118,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "117531",
        "type": "GeneOrGeneProduct"
       },
       "text": "TMC1",
       "locations": [
        {
         "offset": 1140,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs121908072",
      "entity2": "D034381",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "117531",
      "entity2": "D034381",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17318851",
   "passages": [
    {
     "offset": 0,
     "text": "Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "Interferon regulatory factor 6",
       "locations": [
        {
         "offset": 0,
         "length": 30
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 32,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "2260",
        "type": "GeneOrGeneProduct"
       },
       "text": "fibroblast growth factor receptor 1",
       "locations": [
        {
         "offset": 42,
         "length": 35
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "2260",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGFR1",
       "locations": [
        {
         "offset": 79,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 100,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D000848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tooth agenesis",
       "locations": [
        {
         "offset": 106,
         "length": 14
        }
       ]
      }
     ]
    },
    {
     "offset": 122,
     "text": "Phenotypic characteristics expressed in syndromes give clues to the factors involved in the cause of isolated forms of the same defects. We investigated two genes responsible for craniofacial syndromes, FGFR1 and IRF6, in a collection of families with isolated tooth agenesis. Cheek swab samples were obtained for DNA analysis from 116 case/parent trios. Probands had at least one developmentally missing tooth, excluding third molars. In addition, we studied 89 cases and 50 controls from Ohio to replicate any positive findings. Genotyping was performed by kinetic polymerase chain-reaction or TaqMan assays. Linkage disequilibrium analysis and transmission distortion of the marker alleles were performed. The same variants in the IRF6 gene that are associated with isolated orofacial clefts are also associated with human tooth agenesis (rs861019, P = 0.058; rs17015215-V274I, P = 0.0006; rs7802, P = 0.004). Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. The craniofacial phenotypic characteristics of these syndromes include oral clefts and preferential tooth agenesis of incisors and premolars, besides pits on the lower lips. Also it appears that preferential premolar agenesis is associated with FGFR1 (P = 0.014) and IRF6 (P = 0.002) markers. There were statistically significant data suggesting that IRF6 interacts not only with MSX1 (P = 0.001), but also with TGFA (P = 0.03).",
     "annotations": [
      {
       "id": "6",
       "infons": {
        "identifier": "D019465",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "craniofacial syndromes",
       "locations": [
        {
         "offset": 301,
         "length": 22
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2260",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGFR1",
       "locations": [
        {
         "offset": 325,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 335,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tooth agenesis",
       "locations": [
        {
         "offset": 383,
         "length": 14
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 856,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C566121",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "orofacial clefts",
       "locations": [
        {
         "offset": 900,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 942,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D000848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tooth agenesis",
       "locations": [
        {
         "offset": 948,
         "length": 14
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs861019",
        "type": "SequenceVariant"
       },
       "text": "rs861019",
       "locations": [
        {
         "offset": 964,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs17015215",
        "type": "SequenceVariant"
       },
       "text": "rs17015215",
       "locations": [
        {
         "offset": 985,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs2235371",
        "type": "SequenceVariant"
       },
       "text": "V274I",
       "locations": [
        {
         "offset": 996,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs7802",
        "type": "SequenceVariant"
       },
       "text": "rs7802",
       "locations": [
        {
         "offset": 1015,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 1048,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C536528,C562509",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Van der Woude and popliteal pterygium syndromes",
       "locations": [
        {
         "offset": 1059,
         "length": 47
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "oral clefts",
       "locations": [
        {
         "offset": 1179,
         "length": 11
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D000848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tooth agenesis",
       "locations": [
        {
         "offset": 1208,
         "length": 14
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "C536528,C562509",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pits on the lower lips",
       "locations": [
        {
         "offset": 1258,
         "length": 22
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "2260",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGFR1",
       "locations": [
        {
         "offset": 1353,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 1375,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 1459,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "4487",
        "type": "GeneOrGeneProduct"
       },
       "text": "MSX1",
       "locations": [
        {
         "offset": 1488,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "7039",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFA",
       "locations": [
        {
         "offset": 1520,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D019465",
      "entity2": "2260",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D019465",
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs7802",
      "entity2": "C562509",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs7802",
      "entity2": "C536528",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "rs7802",
      "entity2": "C566121",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "rs7802",
      "entity2": "D000848",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "rs2235371",
      "entity2": "C562509",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "rs2235371",
      "entity2": "C536528",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "rs2235371",
      "entity2": "C566121",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "rs2235371",
      "entity2": "D000848",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "rs17015215",
      "entity2": "C562509",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "rs17015215",
      "entity2": "C536528",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R12",
     "infons": {
      "entity1": "rs17015215",
      "entity2": "C566121",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R13",
     "infons": {
      "entity1": "rs17015215",
      "entity2": "D000848",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R14",
     "infons": {
      "entity1": "rs861019",
      "entity2": "C562509",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R15",
     "infons": {
      "entity1": "rs861019",
      "entity2": "C536528",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R16",
     "infons": {
      "entity1": "rs861019",
      "entity2": "C566121",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R17",
     "infons": {
      "entity1": "rs861019",
      "entity2": "D000848",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R18",
     "infons": {
      "entity1": "2260",
      "entity2": "D000848",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R19",
     "infons": {
      "entity1": "3664",
      "entity2": "7039",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R20",
     "infons": {
      "entity1": "3664",
      "entity2": "4487",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R21",
     "infons": {
      "entity1": "3664",
      "entity2": "C562509",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R22",
     "infons": {
      "entity1": "3664",
      "entity2": "C536528",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R23",
     "infons": {
      "entity1": "3664",
      "entity2": "C566121",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R24",
     "infons": {
      "entity1": "3664",
      "entity2": "D000848",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17951029",
   "passages": [
    {
     "offset": 0,
     "text": "Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Focal dermal hypoplasia",
       "locations": [
        {
         "offset": 0,
         "length": 23
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "p|SUB|E|300|X",
        "type": "SequenceVariant"
       },
       "text": "p.E300X",
       "locations": [
        {
         "offset": 64,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "64840",
        "type": "GeneOrGeneProduct"
       },
       "text": "PORCN",
       "locations": [
        {
         "offset": 80,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 92,
     "text": "BACKGROUND: Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development. OBJECTIVES: To investigate the molecular basis of FDH in a 2-year-old Thai girl who presented at birth with depressed, pale linear scars on the trunk and limbs, sparse brittle hair, syndactyly of the right middle and ring fingers, dental caries and radiological features of osteopathia striata. METHODS: Sequencing of genomic DNA from the affected individual and both parents to search for pathogenic mutations in PORCN gene. RESULTS: DNA sequencing disclosed a heterozygous G>T substitution at nucleotide c.898 within exon 10 (NM_203475.1), converting a glutamic acid residue (GAA) to a premature termination codon (TAA). This mutation, designated p.E300X, was not detected in DNA from either parent or in 100 control chromosomes. CONCLUSION: Identification of this new de novo nonsense mutation confirms the diagnosis of FDH in this child and highlights the clinical importance of PORCN and Wnt signalling pathways in embryogenesis.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Focal dermal hypoplasia",
       "locations": [
        {
         "offset": 104,
         "length": 23
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FDH",
       "locations": [
        {
         "offset": 129,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "OMIM 305600",
       "locations": [
        {
         "offset": 135,
         "length": 11
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D040181",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked dominant disorder",
       "locations": [
        {
         "offset": 154,
         "length": 26
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Goltz syndrome",
       "locations": [
        {
         "offset": 227,
         "length": 14
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FDH",
       "locations": [
        {
         "offset": 243,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypoplastic dermis",
       "locations": [
        {
         "offset": 294,
         "length": 18
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FDH",
       "locations": [
        {
         "offset": 408,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "64840",
        "type": "GeneOrGeneProduct"
       },
       "text": "PORCN",
       "locations": [
        {
         "offset": 438,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FDH",
       "locations": [
        {
         "offset": 633,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003866",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "depressed",
       "locations": [
        {
         "offset": 691,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D003731",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dental caries",
       "locations": [
        {
         "offset": 814,
         "length": 13
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "64840",
        "type": "GeneOrGeneProduct"
       },
       "text": "PORCN",
       "locations": [
        {
         "offset": 997,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|SUB|G|898|T",
        "type": "SequenceVariant"
       },
       "text": "G>T substitution at nucleotide c.898",
       "locations": [
        {
         "offset": 1058,
         "length": 36
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|SUB|E||X",
        "type": "SequenceVariant"
       },
       "text": "glutamic acid residue (GAA) to a premature termination codon (TAA)",
       "locations": [
        {
         "offset": 1138,
         "length": 66
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|SUB|E|300|X",
        "type": "SequenceVariant"
       },
       "text": "p.E300X",
       "locations": [
        {
         "offset": 1232,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D005489",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FDH",
       "locations": [
        {
         "offset": 1406,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "64840",
        "type": "GeneOrGeneProduct"
       },
       "text": "PORCN",
       "locations": [
        {
         "offset": 1466,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "p|SUB|E||X",
      "entity2": "D005489",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|SUB|G|898|T",
      "entity2": "D005489",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D005489",
      "entity2": "64840",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "p|SUB|E|300|X",
      "entity2": "D005489",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19110214",
   "passages": [
    {
     "offset": 0,
     "text": "A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D010009",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "recessive skeletal dysplasia",
       "locations": [
        {
         "offset": 2,
         "length": 28
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D010009",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SEMD",
       "locations": [
        {
         "offset": 32,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "176",
        "type": "GeneOrGeneProduct"
       },
       "text": "aggrecan",
       "locations": [
        {
         "offset": 37,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "176",
        "type": "GeneOrGeneProduct"
       },
       "text": "aggrecan",
       "locations": [
        {
         "offset": 123,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 133,
     "text": "Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G --> A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D010009",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "spondyloepimetaphyseal dysplasia",
       "locations": [
        {
         "offset": 234,
         "length": 32
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D006130",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "short stature",
       "locations": [
        {
         "offset": 291,
         "length": 13
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "176",
        "type": "GeneOrGeneProduct"
       },
       "text": "aggrecan",
       "locations": [
        {
         "offset": 704,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1464",
        "type": "GeneOrGeneProduct"
       },
       "text": "chondroitin sulfate proteoglycan 4",
       "locations": [
        {
         "offset": 717,
         "length": 34
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "176",
        "type": "GeneOrGeneProduct"
       },
       "text": "aggrecan",
       "locations": [
        {
         "offset": 820,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs545688154",
        "type": "SequenceVariant"
       },
       "text": "c.6799G --> A",
       "locations": [
        {
         "offset": 922,
         "length": 13
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs545688154",
        "type": "SequenceVariant"
       },
       "text": "p.D2267N",
       "locations": [
        {
         "offset": 953,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "176",
        "type": "GeneOrGeneProduct"
       },
       "text": "aggrecan",
       "locations": [
        {
         "offset": 1038,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs545688154",
        "type": "SequenceVariant"
       },
       "text": "D2267",
       "locations": [
        {
         "offset": 1052,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "calcium",
       "locations": [
        {
         "offset": 1106,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "176",
        "type": "GeneOrGeneProduct"
       },
       "text": "aggrecan",
       "locations": [
        {
         "offset": 1603,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "3371",
        "type": "GeneOrGeneProduct"
       },
       "text": "tenascin-C",
       "locations": [
        {
         "offset": 1626,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D010009",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal-recessive skeletal dysplasia",
       "locations": [
        {
         "offset": 1665,
         "length": 38
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "176",
        "type": "GeneOrGeneProduct"
       },
       "text": "aggrecan",
       "locations": [
        {
         "offset": 1735,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs545688154",
      "entity2": "D002118",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010009",
      "entity2": "1464",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D010009",
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      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D010009",
      "entity2": "rs545688154",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "176",
      "entity2": "3371",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "176",
      "entity2": "D010009",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19592582",
   "passages": [
    {
     "offset": 0,
     "text": "Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "Matriptase-2",
       "locations": [
        {
         "offset": 0,
         "length": 12
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D007501",
        "type": "ChemicalEntity"
       },
       "text": "iron",
       "locations": [
        {
         "offset": 26,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D018798",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "iron deficiency anemia",
       "locations": [
        {
         "offset": 42,
         "length": 22
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 65,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 132,
     "text": "Mutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C>A and c.468C>T in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "matriptase-2",
       "locations": [
        {
         "offset": 167,
         "length": 12
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "humans",
       "locations": [
        {
         "offset": 204,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C562385",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "iron-refractory iron deficiency anemia",
       "locations": [
        {
         "offset": 234,
         "length": 38
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "C562385",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IRIDA",
       "locations": [
        {
         "offset": 274,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "57817",
        "type": "GeneOrGeneProduct"
       },
       "text": "hepcidin",
       "locations": [
        {
         "offset": 297,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "matriptase-2",
       "locations": [
        {
         "offset": 375,
         "length": 12
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "TMPRSS6",
       "locations": [
        {
         "offset": 389,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C562385",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IRIDA",
       "locations": [
        {
         "offset": 443,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "p|FS|P|686||",
        "type": "SequenceVariant"
       },
       "text": "P686fs",
       "locations": [
        {
         "offset": 498,
         "length": 6
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|INS||CCCC",
        "type": "SequenceVariant"
       },
       "text": "insertion of the four nucleotides CCCC",
       "locations": [
        {
         "offset": 520,
         "length": 38
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|INS|2172_2173|CCCC",
        "type": "SequenceVariant"
       },
       "text": "2172_2173insCCCC",
       "locations": [
        {
         "offset": 571,
         "length": 16
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "c|SUB|C|467|A",
        "type": "SequenceVariant"
       },
       "text": "c.467C>A",
       "locations": [
        {
         "offset": 715,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|SUB|C|468|T",
        "type": "SequenceVariant"
       },
       "text": "c.468C>T",
       "locations": [
        {
         "offset": 728,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|SUB|A|118|D",
        "type": "SequenceVariant"
       },
       "text": "A118D",
       "locations": [
        {
         "offset": 781,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "matriptase-2",
       "locations": [
        {
         "offset": 841,
         "length": 12
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "matriptase-2",
       "locations": [
        {
         "offset": 891,
         "length": 12
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "57817",
        "type": "GeneOrGeneProduct"
       },
       "text": "hepcidin",
       "locations": [
        {
         "offset": 972,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "p|SUB|A|118|D",
        "type": "SequenceVariant"
       },
       "text": "A118D",
       "locations": [
        {
         "offset": 1025,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "matriptase-2",
       "locations": [
        {
         "offset": 1111,
         "length": 12
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "164656",
        "type": "GeneOrGeneProduct"
       },
       "text": "TMPRSS6",
       "locations": [
        {
         "offset": 1186,
         "length": 7
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "C562385",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IRIDA",
       "locations": [
        {
         "offset": 1220,
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       "id": "25",
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       "text": "matriptase-2",
       "locations": [
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         "offset": 1382,
         "length": 12
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      {
       "id": "26",
       "infons": {
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       "text": "iron deficiency",
       "locations": [
        {
         "offset": 1402,
         "length": 15
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  {
   "id": "19841052",
   "passages": [
    {
     "offset": 0,
     "text": "Smoking of crack cocaine as a risk factor for HIV infection among people who use injection drugs.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D016578",
        "type": "ChemicalEntity"
       },
       "text": "crack cocaine",
       "locations": [
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       "id": "1",
       "infons": {
        "identifier": "D015658",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "HIV infection",
       "locations": [
        {
         "offset": 46,
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       ]
      }
     ]
    },
    {
     "offset": 98,
     "text": "BACKGROUND: Little is known about the possible role that smoking crack cocaine has on the incidence of HIV infection. Given the increasing use of crack cocaine, we sought to examine whether use of this illicit drug has become a risk factor for HIV infection. METHODS: We included data from people participating in the Vancouver Injection Drug Users Study who reported injecting illicit drugs at least once in the month before enrolment, lived in the greater Vancouver area, were HIV-negative at enrolment and completed at least 1 follow-up study visit. To determine whether the risk of HIV seroconversion among daily smokers of crack cocaine changed over time, we used Cox proportional hazards regression and divided the study into 3 periods: May 1, 1996-Nov. 30, 1999 (period 1), Dec. 1, 1999-Nov. 30, 2002 (period 2), and Dec. 1, 2002-Dec. 30, 2005 (period 3). RESULTS: Overall, 1048 eligible injection drug users were included in our study. Of these, 137 acquired HIV infection during follow-up. The mean proportion of participants who reported daily smoking of crack cocaine increased from 11.6% in period 1 to 39.7% in period 3. After adjusting for potential confounders, we found that the risk of HIV seroconversion among participants who were daily smokers of crack cocaine increased over time (period 1: hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.57-1.85; period 2: HR 1.68, 95% CI 1.01-2.80; and period 3: HR 2.74, 95% CI 1.06-7.11). INTERPRETATION: Smoking of crack cocaine was found to be an independent risk factor for HIV seroconversion among people who were injection drug users. This finding points to the urgent need for evidence-based public health initiatives targeted at people who smoke crack cocaine.",
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       "id": "2",
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       "text": "crack cocaine",
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       "id": "3",
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       "text": "HIV infection",
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       "id": "4",
       "infons": {
        "identifier": "D016578",
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       "text": "crack cocaine",
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       "id": "5",
       "infons": {
        "identifier": "D015658",
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       "text": "HIV infection",
       "locations": [
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         "offset": 342,
         "length": 13
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D015658",
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       "text": "HIV",
       "locations": [
        {
         "offset": 577,
         "length": 3
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D006679",
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       "text": "HIV seroconversion",
       "locations": [
        {
         "offset": 684,
         "length": 18
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       ]
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      {
       "id": "8",
       "infons": {
        "identifier": "D016578",
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       "text": "crack cocaine",
       "locations": [
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       "id": "9",
       "infons": {
        "identifier": "D015658",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "HIV infection",
       "locations": [
        {
         "offset": 1065,
         "length": 13
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D016578",
        "type": "ChemicalEntity"
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       "text": "crack cocaine",
       "locations": [
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         "offset": 1163,
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       "id": "11",
       "infons": {
        "identifier": "D006679",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "HIV seroconversion",
       "locations": [
        {
         "offset": 1301,
         "length": 18
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       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "D016578",
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       "text": "crack cocaine",
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       "id": "13",
       "infons": {
        "identifier": "D016578",
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       "text": "crack cocaine",
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       "id": "14",
       "infons": {
        "identifier": "D006679",
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       "text": "HIV seroconversion",
       "locations": [
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         "offset": 1641,
         "length": 18
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       ]
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      {
       "id": "15",
       "infons": {
        "identifier": "D016578",
        "type": "ChemicalEntity"
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       "text": "crack cocaine",
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         "offset": 1817,
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  {
   "id": "21666969",
   "passages": [
    {
     "offset": 0,
     "text": "Roles of G1359A polymorphism of the cannabinoid receptor gene (CNR1) on weight loss and adipocytokines after a hypocaloric diet.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs1049353",
        "type": "SequenceVariant"
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       "text": "G1359A",
       "locations": [
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         "offset": 9,
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       "id": "1",
       "infons": {
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       "text": "cannabinoid receptor",
       "locations": [
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         "offset": 36,
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       "id": "2",
       "infons": {
        "identifier": "1268",
        "type": "GeneOrGeneProduct"
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       "text": "CNR1",
       "locations": [
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         "offset": 63,
         "length": 4
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      {
       "id": "3",
       "infons": {
        "identifier": "D015431",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "weight loss",
       "locations": [
        {
         "offset": 72,
         "length": 11
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      }
     ]
    },
    {
     "offset": 129,
     "text": "BACKGROUND: A intragenic biallelic polymorphism (1359 G/A) of the CB1 gene resulting in the substitution of the G to A at nucleotide position 1359 in codon 435 (Thr), was reported as a common polymorphism in Caucasian populations. Intervention studies with this polymorphism have not been realized. OBJECTIVE: We decided to investigate the role of the polymorphism (G1359A) of CB1 receptor gene on adipocytokines response and weight loss secondary to a lifestyle modification (Mediterranean hypocaloric diet and exercise) in obese patients. DESIGN: A population of 94 patients with obesity was analyzed. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined G1359A and A1359A as a group and wild type G1359G as second group, with a dominant model. Results: Forty seven patients (50%) had the genotype G1359G (wild type group) and 47 (50%) patients G1359A (41 patients, 43.6%) or A1359A (6 patients, 6.4%) (mutant type group) had the genotype. In wild and mutant type groups, weight, body mass index, fat mass, waist circumference and systolic blood pressure decreased. In mutant type group, resistin (4.15 1.7 ng/ml vs. 3.90 2.1 ng/ml: P < 0.05), leptin (78.4 69 ng/ml vs 66.2 32 ng/ml: P < 0.05) and IL-6 (1.40 1.9 pg/ml vs 0.81 1.5 pg/ml: P < 0.05) levels decreased after dietary treatment. CONCLUSION: The novel finding of this study is the association of the mutant allele (A1359) with a decrease of resistin, leptin and interleukin-6 secondary to weight loss.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "rs1049353",
        "type": "SequenceVariant"
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       "text": "1359 G/A",
       "locations": [
        {
         "offset": 178,
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      {
       "id": "5",
       "infons": {
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       "text": "CB1",
       "locations": [
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         "offset": 195,
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       "id": "6",
       "infons": {
        "identifier": "rs1049353",
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       "text": "G to A at nucleotide position 1359",
       "locations": [
        {
         "offset": 241,
         "length": 34
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       "id": "7",
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        "identifier": "rs1049353",
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       "id": "9",
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       "id": "10",
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       "locations": [
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         "offset": 555,
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      {
       "id": "11",
       "infons": {
        "identifier": "D009765",
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       "text": "obese",
       "locations": [
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         "offset": 654,
         "length": 5
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       ]
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       "id": "12",
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       "text": "patients",
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       "id": "13",
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       "id": "14",
       "infons": {
        "identifier": "D009765",
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       "text": "obesity",
       "locations": [
        {
         "offset": 711,
         "length": 7
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs1049353",
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       "text": "G1359A",
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         "offset": 947,
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       "id": "16",
       "infons": {
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       "infons": {
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       "text": "patients",
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       "text": "patients",
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       "text": "leptin",
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       "text": "IL-6",
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       "id": "28",
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       "text": "A1359",
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       "id": "29",
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       "id": "30",
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       "text": "leptin",
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       "id": "31",
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       "text": "interleukin-6",
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       "id": "32",
       "infons": {
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      "novel": "No"
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    {
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  {
   "id": "21810259",
   "passages": [
    {
     "offset": 0,
     "text": "HIV-1 Tat activates indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures in a p38 mitogen-activated protein kinase-dependent manner.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "11676",
        "type": "OrganismTaxon"
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       "text": "HIV-1",
       "locations": [
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       ]
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      {
       "id": "1",
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       "text": "Tat",
       "locations": [
        {
         "offset": 6,
         "length": 3
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       ]
      },
      {
       "id": "2",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "indoleamine 2,3 dioxygenase",
       "locations": [
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         "offset": 20,
         "length": 27
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "10090",
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       "text": "murine",
       "locations": [
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         "offset": 51,
         "length": 6
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "26416",
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       "text": "p38 mitogen-activated protein kinase",
       "locations": [
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         "offset": 102,
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     "text": "BACKGROUND: We have established that activation of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) mediates the switch from cytokine-induced sickness behavior to depressive-like behavior. Because human immunodeficiency virus type 1 (HIV-1) Tat protein causes depressive-like behavior in mice, we investigated its ability to activate IDO in organotypic hippocampal slice cultures (OHSCs) derived from neonatal C57BL/6 mice. METHODS: Depressive-like behavior in C57BL/6J mice was assessed by the forced swim test. Expression of cytokines and IDO mRNA in OHSCs was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs). p38 MAPK phosphorylation was analyzed by western blot. RESULTS: Intracerebroventricular (i.c.v.) administration of Tat (40 ng) induced depressive-like behavior in the absence of sickness. Addition of Tat (40 ng/slice) to the medium of OHSCs induced IDO steady-state mRNA that peaked at 6 h. This effect was potentiated by pretreatment with IFNg. Tat also induced the synthesis and release of TNFa and IL-6 protein in the supernatant of the slices and increased expression of the inducible isoform of nitric oxide synthase (iNOS) and the serotonin transporter (SERT). Tat had no effect on endogenous synthesis of IFNg. To explore the mechanisms of Tat-induced IDO expression, slices were pretreated with the p38 mitogen-activated protein kinase (MAPK) inhibitor SB 202190 for 30 min before Tat treatment. SB 202190 significantly decreased IDO expression induced by Tat, and this effect was accompanied by a reduction of Tat-induced expression of TNFa, IL-6, iNOS and SERT. CONCLUSION: These data establish that Tat induces IDO expression via an IFNg-independent mechanism that depends upon activation of p38 MAPK. Targeting IDO itself or the p38 MAPK signaling pathway could provide a novel therapy for comorbid depressive disorders in HIV-1-infected patients.",
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   "id": "28604678",
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     "offset": 0,
     "text": "Dynamic subunit turnover in ESCRT-III assemblies is regulated by Vps4 to mediate membrane remodelling during cytokinesis.",
     "annotations": [
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       "infons": {
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     "offset": 122,
     "text": "The endosomal sorting complex required for transport (ESCRT)-III mediates membrane fission in fundamental cellular processes, including cytokinesis. ESCRT-III is thought to form persistent filaments that over time increase their curvature to constrict membranes. Unexpectedly, we found that ESCRT-III at the midbody of human cells rapidly turns over subunits with cytoplasmic pools while gradually forming larger assemblies. ESCRT-III turnover depended on the ATPase VPS4, which accumulated at the midbody simultaneously with ESCRT-III subunits, and was required for assembly of functional ESCRT-III structures. In vitro, the Vps2/Vps24 subunits of ESCRT-III formed side-by-side filaments with Snf7 and inhibited further polymerization, but the growth inhibition was alleviated by the addition of Vps4 and ATP. High-speed atomic force microscopy further revealed highly dynamic arrays of growing and shrinking ESCRT-III spirals in the presence of Vps4. Continuous ESCRT-III remodelling by subunit turnover might facilitate shape adaptions to variable membrane geometries, with broad implications for diverse cellular processes.",
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       "infons": {
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       "infons": {
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         "offset": 919,
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       "text": "Vps4",
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         "offset": 1069,
         "length": 4
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       "id": "19",
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   ]
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  {
   "id": "16167916",
   "passages": [
    {
     "offset": 0,
     "text": "The effects of short-term raloxifene therapy on fibrinolysis markers: TAFI, tPA, and PAI-1.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D020849",
        "type": "ChemicalEntity"
       },
       "text": "raloxifene",
       "locations": [
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         "offset": 26,
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       "id": "1",
       "infons": {
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       "text": "TAFI",
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         "offset": 70,
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       "id": "2",
       "infons": {
        "identifier": "5327",
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       "text": "tPA",
       "locations": [
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         "offset": 76,
         "length": 3
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       ]
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      {
       "id": "3",
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        "identifier": "5054",
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       "text": "PAI-1",
       "locations": [
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         "offset": 85,
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    {
     "offset": 92,
     "text": "BACKGROUND: Markers of fibrinolysis, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) levels were studied for the evaluation of short-term effects of raloxifene administration in postmenopausal women. METHODS: Thirty-nine postmenopausal women with osteopenia or osteoporosis were included in this prospective, controlled clinical study. Twenty-five women were given raloxifene hydrochloride (60 mg/day) plus calcium (500 mg/day). Age-matched controls (n = 14) were given only calcium. Plasma TAFI, tPA, and PAI-1 antigen levels were measured at baseline and after 3 months of treatment by commercially available ELISA kits. Variations of individuals were assessed by Wilcoxon's test. Relationship between those markers and demographic characteristics were investigated. RESULTS: Three months of raloxifene treatment was associated with a significant decrease in the plasma TAFI antigen concentrations (16% change, P < 0.01), and a significant increase in tPA antigen concentrations (25% change, P < 0.05). A significant correlation was found between baseline TAFI antigen concentrations and the duration of amenorrhea (P < 0.05; r = 0.33). CONCLUSION: We suggest that the increased risk of venous thromboembolism due to raloxifene treatment may be related to increased tPA levels, but not TAFI levels.",
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       "id": "4",
       "infons": {
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       "text": "thrombin-activatable fibrinolysis inhibitor",
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       "text": "TAFI",
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         "offset": 174,
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       "text": "tissue-type plasminogen activator",
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       "id": "7",
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       "text": "plasminogen activator inhibitor-1",
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       "id": "9",
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         "offset": 261,
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       "id": "10",
       "infons": {
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       "text": "raloxifene",
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         "offset": 332,
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       "id": "11",
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       "text": "women",
       "locations": [
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         "offset": 376,
         "length": 5
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       "id": "12",
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       "text": "women",
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       "id": "13",
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       "text": "osteopenia",
       "locations": [
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         "offset": 430,
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       ]
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       "id": "14",
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        "identifier": "D010024",
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       "text": "osteoporosis",
       "locations": [
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         "offset": 444,
         "length": 12
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       "id": "15",
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       "text": "women",
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       "text": "raloxifene hydrochloride",
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       "text": "calcium",
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       "text": "calcium",
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         "offset": 674,
         "length": 4
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       "id": "21",
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       "text": "PAI-1",
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         "offset": 689,
         "length": 5
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       "id": "22",
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         "offset": 1055,
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         "offset": 1137,
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       "id": "25",
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         "offset": 1241,
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       "id": "26",
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        "identifier": "D054556",
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       "text": "venous thromboembolism",
       "locations": [
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         "offset": 1372,
         "length": 22
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       ]
      },
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       "id": "27",
       "infons": {
        "identifier": "D020849",
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       "text": "raloxifene",
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         "offset": 1402,
         "length": 10
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       "id": "28",
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       "text": "tPA",
       "locations": [
        {
         "offset": 1451,
         "length": 3
        }
       ]
      },
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       "id": "29",
       "infons": {
        "identifier": "1361",
        "type": "GeneOrGeneProduct"
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       "text": "TAFI",
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         "offset": 1471,
         "length": 4
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      "novel": "No"
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      "type": "Association",
      "novel": "No"
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    }
   ]
  },
  {
   "id": "16781314",
   "passages": [
    {
     "offset": 0,
     "text": "Ectodermal dysplasia-skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C536183",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Ectodermal dysplasia-skin fragility syndrome",
       "locations": [
        {
         "offset": 0,
         "length": 44
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|DEL888|C",
        "type": "SequenceVariant"
       },
       "text": "888delC",
       "locations": [
        {
         "offset": 87,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "5317",
        "type": "GeneOrGeneProduct"
       },
       "text": "plakophilin 1",
       "locations": [
        {
         "offset": 122,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 137,
     "text": "We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently developed skin fragility, progressive plantar keratoderma, nail dystrophy, and alopecia. Skin biopsy revealed widening of intercellular spaces in the epidermis and a reduced number of small, poorly formed desmosomes. Mutation analysis of the plakophilin 1 gene PKP1 revealed a homozygous deletion of C at nucleotide 888 within exon 5. This mutation differs from the PKP1 gene pathology reported in 8 previously published individuals with this rare genodermatosis. However, all cases show similar clinical features, highlighting the importance of functional plakophilin 1 in maintaining desmosomal adhesion in skin, as well as the role of this protein in aspects of ectodermal development.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inherited disorder",
       "locations": [
        {
         "offset": 169,
         "length": 18
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "5317",
        "type": "GeneOrGeneProduct"
       },
       "text": "plakophilin 1",
       "locations": [
        {
         "offset": 214,
         "length": 13
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C536183",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ectodermal dysplasia-skin fragility syndrome",
       "locations": [
        {
         "offset": 242,
         "length": 44
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C536183",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "skin fragility",
       "locations": [
        {
         "offset": 365,
         "length": 14
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D017499",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "plantar keratoderma",
       "locations": [
        {
         "offset": 393,
         "length": 19
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nail dystrophy",
       "locations": [
        {
         "offset": 414,
         "length": 14
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000505",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "alopecia",
       "locations": [
        {
         "offset": 434,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "5317",
        "type": "GeneOrGeneProduct"
       },
       "text": "plakophilin 1",
       "locations": [
        {
         "offset": 597,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "5317",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKP1",
       "locations": [
        {
         "offset": 616,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|DEL888|C",
        "type": "SequenceVariant"
       },
       "text": "deletion of C at nucleotide 888",
       "locations": [
        {
         "offset": 643,
         "length": 31
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "5317",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKP1",
       "locations": [
        {
         "offset": 721,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D012873",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "genodermatosis",
       "locations": [
        {
         "offset": 803,
         "length": 14
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "5317",
        "type": "GeneOrGeneProduct"
       },
       "text": "plakophilin 1",
       "locations": [
        {
         "offset": 912,
         "length": 13
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D030342",
      "entity2": "5317",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "5317",
      "entity2": "D012873",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|DEL888|C",
      "entity2": "D012873",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "C536183",
      "entity2": "5317",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "C536183",
      "entity2": "c|DEL888|C",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16843501",
   "passages": [
    {
     "offset": 0,
     "text": "DNA damage and repair in gastric cancer--a correlation with the hOGG1 and RAD51 genes polymorphisms.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D013274",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "gastric cancer",
       "locations": [
        {
         "offset": 25,
         "length": 14
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4968",
        "type": "GeneOrGeneProduct"
       },
       "text": "hOGG1",
       "locations": [
        {
         "offset": 64,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "5888",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAD51",
       "locations": [
        {
         "offset": 74,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 101,
     "text": "The cell's susceptibility to mutagens and its ability to repair DNA lesions are important for cancer induction, promotion and progression. Both the mutagens' sensitivity and the efficacy of DNA repair may be affected by variation in several genes, including DNA repair genes. The hOGG1 gene encodes glycosylase of base excision repair and RAD51 specifies a key protein in homologues recombination repair. Both can be involved in the repair of oxidative DNA lesions, which can contribute to stomach cancer. In the present work we determined the level of basal and oxidative DNA damage and the kinetics of removal of DNA damage induced by hydrogen peroxide in peripheral blood lymphocytes of 30 gastric cancer patients and 30 healthy individuals. The metrics from DNA damage and repair study were correlated with the genotypes of common polymorphisms of the hOGG1 and RAD51 genes: a G-->C transversion at 1245 position of the hOGG1 gene producing a Ser-->Cys substitution at the codon 326 (the Ser326Cys polymorphism) and a G-->C substitution at position 135 (5'-untranslated region) of the RAD51 gene (the G135C polymorphism). DNA damage and repair were evaluated by alkaline single cell gel electrophoresis (comet assay) assisted by DNA repair enzymes: endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg), preferentially recognizing oxidized DNA bases. The genotypes of the polymorphism were determined by restriction fragment length polymorphism PCR. We observed a strong association between gastric cancer occurrence, impaired DNA repair in human lymphocytes and the G/C genotype of the G135C polymorphism of the RAD51 gene. Moreover, there was a strong correlation between that genotype and stomach cancer occurrence in subjects with high level of oxidatively damaged DNA. We did not observe any correlation between the Ser1245Cys polymorphism of the hOGG1 gene and gastric cancer, including subjects with impaired DNA repair and/or high levels of endogenous oxidative DNA lesions. Therefore, our result suggest that the G135C polymorphism of the RAD51 gene may be linked with gastric cancer by the modulation of the cellular response to oxidative stress and this polymorphism may be a useful additional marker in this disease along with the genetic or/and environmental indicators of oxidative stress.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 195,
         "length": 6
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "4968",
        "type": "GeneOrGeneProduct"
       },
       "text": "hOGG1",
       "locations": [
        {
         "offset": 381,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "5888",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAD51",
       "locations": [
        {
         "offset": 440,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D013274",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stomach cancer",
       "locations": [
        {
         "offset": 591,
         "length": 14
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D006861",
        "type": "ChemicalEntity"
       },
       "text": "hydrogen peroxide",
       "locations": [
        {
         "offset": 738,
         "length": 17
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D013274",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "gastric cancer",
       "locations": [
        {
         "offset": 794,
         "length": 14
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 809,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "4968",
        "type": "GeneOrGeneProduct"
       },
       "text": "hOGG1",
       "locations": [
        {
         "offset": 957,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "5888",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAD51",
       "locations": [
        {
         "offset": 967,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs1052133",
        "type": "SequenceVariant"
       },
       "text": "G-->C transversion at 1245 position",
       "locations": [
        {
         "offset": 982,
         "length": 35
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "4968",
        "type": "GeneOrGeneProduct"
       },
       "text": "hOGG1",
       "locations": [
        {
         "offset": 1025,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs1052133",
        "type": "SequenceVariant"
       },
       "text": "Ser-->Cys substitution at the codon 326",
       "locations": [
        {
         "offset": 1048,
         "length": 39
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs1052133",
        "type": "SequenceVariant"
       },
       "text": "Ser326Cys",
       "locations": [
        {
         "offset": 1093,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "g|SUB|G|135|C",
        "type": "SequenceVariant"
       },
       "text": "G-->C substitution at position 135",
       "locations": [
        {
         "offset": 1123,
         "length": 34
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "5888",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAD51",
       "locations": [
        {
         "offset": 1190,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "g|SUB|G|135|C",
        "type": "SequenceVariant"
       },
       "text": "G135C",
       "locations": [
        {
         "offset": 1206,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "4913",
        "type": "GeneOrGeneProduct"
       },
       "text": "endonuclease III",
       "locations": [
        {
         "offset": 1354,
         "length": 16
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "4913",
        "type": "GeneOrGeneProduct"
       },
       "text": "Nth",
       "locations": [
        {
         "offset": 1372,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "79661",
        "type": "GeneOrGeneProduct"
       },
       "text": "formamidopyrimidine-DNA glycosylase",
       "locations": [
        {
         "offset": 1381,
         "length": 35
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "79661",
        "type": "GeneOrGeneProduct"
       },
       "text": "Fpg",
       "locations": [
        {
         "offset": 1418,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D013274",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "gastric cancer",
       "locations": [
        {
         "offset": 1611,
         "length": 14
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1661,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "g|SUB|G||C",
        "type": "SequenceVariant"
       },
       "text": "G/C",
       "locations": [
        {
         "offset": 1687,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "g|SUB|G|135|C",
        "type": "SequenceVariant"
       },
       "text": "G135C",
       "locations": [
        {
         "offset": 1707,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "5888",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAD51",
       "locations": [
        {
         "offset": 1733,
         "length": 5
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D013274",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stomach cancer",
       "locations": [
        {
         "offset": 1812,
         "length": 14
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "rs1052133",
        "type": "SequenceVariant"
       },
       "text": "Ser1245Cys",
       "locations": [
        {
         "offset": 1941,
         "length": 10
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "4968",
        "type": "GeneOrGeneProduct"
       },
       "text": "hOGG1",
       "locations": [
        {
         "offset": 1972,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D013274",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "gastric cancer",
       "locations": [
        {
         "offset": 1987,
         "length": 14
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "g|SUB|G|135|C",
        "type": "SequenceVariant"
       },
       "text": "G135C",
       "locations": [
        {
         "offset": 2142,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "5888",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAD51",
       "locations": [
        {
         "offset": 2168,
         "length": 5
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D013274",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "gastric cancer",
       "locations": [
        {
         "offset": 2198,
         "length": 14
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "4968",
      "entity2": "D013274",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "g|SUB|G|135|C",
      "entity2": "D013274",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "g|SUB|G||C",
      "entity2": "D013274",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D013274",
      "entity2": "5888",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17221831",
   "passages": [
    {
     "offset": 0,
     "text": "The G51S purine nucleoside phosphorylase polymorphism is associated with cognitive decline in Alzheimer's disease patients.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs1049564",
        "type": "SequenceVariant"
       },
       "text": "G51S",
       "locations": [
        {
         "offset": 4,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4860",
        "type": "GeneOrGeneProduct"
       },
       "text": "purine nucleoside phosphorylase",
       "locations": [
        {
         "offset": 9,
         "length": 31
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D003072",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cognitive decline",
       "locations": [
        {
         "offset": 73,
         "length": 17
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alzheimer's disease",
       "locations": [
        {
         "offset": 94,
         "length": 19
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 114,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 124,
     "text": "Alzheimer's disease (AD) is a polygenic and multifactorial complex disease, whose etiopathology is still unclear, however several genetic factors have shown to increase the risk of developing the disease. Purine nucleotides and nucleosides play an important role in the brain. Besides their role in neurotransmission and neuromodulation, they are involved in trophic factor release, apoptosis, and inflammatory responses. These mediators may also have a pivotal role in the control of neurodegenerative processes associated with AD. In this report the distribution of the exonic G/A single nucleotide polymorphism (SNP) in purine nucleoside phosphorylase (PNP) gene, resulting in the amino acid substitution serine to glycine at position 51 (G51S), was investigated in a large population of AD patients (n=321) and non-demented control (n=208). The PNP polymorphism distribution was not different between patients and controls. The polymorphism distribution was also analyzed in AD patients stratified according to differential progressive rate of cognitive decline during a 2-year follow-up. An increased representation of the PNP AA genotype was observed in AD patients with fast cognitive deterioration in comparison with that from patients with slow deterioration rate. Our findings suggest that the G51S PNP polymorphism is associated with a faster rate of cognitive decline in AD patients, highlighting the important role of purine metabolism in the progression of this neurodegenerative disorder.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alzheimer's disease",
       "locations": [
        {
         "offset": 124,
         "length": 19
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 145,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 522,
         "length": 12
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 653,
         "length": 2
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs1049564",
        "type": "SequenceVariant"
       },
       "text": "G/A",
       "locations": [
        {
         "offset": 703,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "4860",
        "type": "GeneOrGeneProduct"
       },
       "text": "purine nucleoside phosphorylase",
       "locations": [
        {
         "offset": 747,
         "length": 31
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "4860",
        "type": "GeneOrGeneProduct"
       },
       "text": "PNP",
       "locations": [
        {
         "offset": 780,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs1049564",
        "type": "SequenceVariant"
       },
       "text": "serine to glycine at position 51",
       "locations": [
        {
         "offset": 832,
         "length": 32
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs1049564",
        "type": "SequenceVariant"
       },
       "text": "G51S",
       "locations": [
        {
         "offset": 866,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 915,
         "length": 2
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 918,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "4860",
        "type": "GeneOrGeneProduct"
       },
       "text": "PNP",
       "locations": [
        {
         "offset": 973,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1029,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 1103,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1106,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D003072",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cognitive decline",
       "locations": [
        {
         "offset": 1172,
         "length": 17
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "4860",
        "type": "GeneOrGeneProduct"
       },
       "text": "PNP",
       "locations": [
        {
         "offset": 1252,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 1284,
         "length": 2
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1287,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D003072",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cognitive deterioration",
       "locations": [
        {
         "offset": 1306,
         "length": 23
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1359,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs1049564",
        "type": "SequenceVariant"
       },
       "text": "G51S",
       "locations": [
        {
         "offset": 1428,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "4860",
        "type": "GeneOrGeneProduct"
       },
       "text": "PNP",
       "locations": [
        {
         "offset": 1433,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D003072",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cognitive decline",
       "locations": [
        {
         "offset": 1486,
         "length": 17
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 1507,
         "length": 2
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1510,
         "length": 8
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D019636",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurodegenerative disorder",
       "locations": [
        {
         "offset": 1600,
         "length": 26
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "4860",
      "entity2": "D000544",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D019636",
      "entity2": "4860",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D019636",
      "entity2": "rs1049564",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D003072",
      "entity2": "4860",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "rs1049564",
      "entity2": "D003072",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "rs1049564",
      "entity2": "D000544",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17286451",
   "passages": [
    {
     "offset": 0,
     "text": "Retinoblastoma in India : microsatellite analysis and its application in genetic counseling.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Retinoblastoma",
       "locations": [
        {
         "offset": 0,
         "length": 14
        }
       ]
      }
     ]
    },
    {
     "offset": 93,
     "text": "OBJECTIVES: This study was conducted with two objectives. The first was to estimate the frequency of loss of heterozygosity (LOH) of the RB1 gene as a mechanism in disease causation in tumors of patients from India. The second objective was to employ RB1 molecular deletion and microsatellite-based linkage analysis as laboratory tools, while counseling families with a history of retinoblastoma (RB). METHODS: DNA was extracted from peripheral blood and tumors of 54 RB patients and their relatives. Eight fluorescent microsatellite markers, both intragenic and flanking the RB1 gene, were used. After PCR amplification, samples were run on an ABI PRISM 310 genetic analyzer for LOH, deletion detection, and haplotype generation. RESULTS: LOH was found in conjunction with tumor formation in 72.9% of RB patients (39/54 patients; p=0.001; 95% CI 0.6028, 0.8417); however, we could not associate various other clinical parameters of RB patients with the presence or absence of RB1 LOH. Seven germline deletions (13% of RB patients) were identified, and the maternal allele was more frequently lost (p=0.01). A disease co-segregating haplotype was detected in two hereditary autosomal dominant cases. CONCLUSION: LOH of the RB1 gene could play an important role in tumor formation. Large deletions involving RB1 were observed, and a disease co-segregating haplotype was used for indirect genetic testing. This is the first report from India where molecular testing has been applied for RB families in conjunction with genetic counseling. In tertiary ophthalmic practice in India, there is an emerging trend towards the application of genetical knowledge in clinical practice.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 230,
         "length": 3
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumors",
       "locations": [
        {
         "offset": 278,
         "length": 6
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 288,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 344,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "retinoblastoma",
       "locations": [
        {
         "offset": 474,
         "length": 14
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RB",
       "locations": [
        {
         "offset": 490,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumors",
       "locations": [
        {
         "offset": 548,
         "length": 6
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RB",
       "locations": [
        {
         "offset": 561,
         "length": 2
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 564,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 669,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 867,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RB",
       "locations": [
        {
         "offset": 895,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 898,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 914,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RB",
       "locations": [
        {
         "offset": 1026,
         "length": 2
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1029,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 1070,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RB",
       "locations": [
        {
         "offset": 1112,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1115,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 1316,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1357,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 1400,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D012175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RB",
       "locations": [
        {
         "offset": 1578,
         "length": 2
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "5925",
      "entity2": "D012175",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "5925",
      "entity2": "D009369",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17327131",
   "passages": [
    {
     "offset": 0,
     "text": "Molecular analysis of the CYP2F1 gene: identification of a frequent non-functional allelic variant.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 26,
         "length": 6
        }
       ]
      }
     ]
    },
    {
     "offset": 100,
     "text": "The CYP2F1 is a human cytochrome P450 that is selectively expressed in lung tissue and involved in the metabolism of various pneumotoxicants with potential carcinogenic effects. In the present study, we report the first systematic investigation of the genetic polymorphism of this enzyme. We analyzed the nucleotidic sequence of the CYP2F1 gene in DNA samples from 90 French Caucasians consisting in 44 patients with lung cancer and 46 control individuals, using single-strand conformation polymorphism analysis of PCR products (PCR-SSCP). We identified 24 novel mutations distributed in the promoter region of the gene, as well as in the coding regions and their flanking intronic sequences. In addition to the wild-type CYP2F1*1 allele, seven allelic variant, CYP2F1*2A, *2B, *3, *4, *5A, *5B and *6, were characterized. The most frequent allelic variant, CYP2F1*2A (25.6%), harbors a combination of 9 mutations, including 2 missense mutations (Asp218Asn and Gln266His) and a 1-bp insertion (c.14_15insC) that creates a premature stop codon in exon 2, probably leading to the synthesis of a severely truncated protein with no catalytic activity. The identification of around 7% of homozygotes for the frameshift mutation in our Caucasian population suggests the existence of an interindividual variation of the CYP2F1 activity and, consequently, the possibility of interindividual differences in the toxic response to some pneumotoxicants and in the susceptibility to certain chemically induced diseases. However, our preliminary results did not show any evidence that the CYP2F1 genetic polymorphism has implications in the pathogenesis of lung cancer.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 104,
         "length": 6
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 116,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "cytochrome P450",
       "locations": [
        {
         "offset": 122,
         "length": 15
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "carcinogenic",
       "locations": [
        {
         "offset": 256,
         "length": 12
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 433,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 503,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 517,
         "length": 11
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 822,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 862,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 958,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs305974",
        "type": "SequenceVariant"
       },
       "text": "Asp218Asn",
       "locations": [
        {
         "offset": 1047,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs75405062",
        "type": "SequenceVariant"
       },
       "text": "Gln266His",
       "locations": [
        {
         "offset": 1061,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs11399890",
        "type": "SequenceVariant"
       },
       "text": "1-bp insertion",
       "locations": [
        {
         "offset": 1078,
         "length": 14
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs11399890",
        "type": "SequenceVariant"
       },
       "text": "c.14_15insC",
       "locations": [
        {
         "offset": 1094,
         "length": 11
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 1413,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "1572",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2F1",
       "locations": [
        {
         "offset": 1675,
         "length": 6
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 1743,
         "length": 11
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1572",
      "entity2": "D009369",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19234905",
   "passages": [
    {
     "offset": 0,
     "text": "Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson's disease.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "idiopathic Parkinson's disease",
       "locations": [
        {
         "offset": 77,
         "length": 30
        }
       ]
      }
     ]
    },
    {
     "offset": 109,
     "text": "A prospective, randomized, double-blind pilot study to compare the results of stereotactic unilateral pallidotomy and subthalamotomy in advanced idiopathic Parkinson's disease (PD) refractory to medical treatment was designed. Ten consecutive patients (mean age, 58.4 +/- 6.8 years; 7 men, 3 women) with similar characteristics at the duration of disease (mean disease time, 8.4 +/- 3.5 years), disabling motor fluctuations (Hoehn _ Yahr stage 3-5 in off-drug phases) and levodopa-induced dyskinesias were selected. All patients had bilateral symptoms and their levodopa equivalent dosing were analysed. Six patients were operated on in the globus pallidus interna (GPi) and four in the subthalamic nucleus (STN). Clinical evaluation included the use of the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn_Yahr score and Schwab England activities of daily living (ADL) score in 'on'- and 'off'-drug conditions before surgery and 6 months after surgery. There was statistically significant improvement in all contralateral major parkinsonian motor signs in all patients followed for 6 months. Levodopa equivalent daily intake was significantly reduced in the STN group. Changes in UPDRS, Hoehn _ Yahr and Schwab England ADL scores were similar in both groups. Cognitive functions were unchanged in both groups. Complications were observed in two patients: one had a left homonymous hemianopsia after pallidotomy and another one developed left hemiballistic movements 3 days after subthalamotomy which partly improved within 1 month with Valproate 1000 mg/day. The findings of this study suggest that lesions of the unilateral STN and GPi are equally effective treatment for patients with advanced PD refractory to medical treatment.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "idiopathic Parkinson's disease",
       "locations": [
        {
         "offset": 254,
         "length": 30
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 286,
         "length": 2
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 352,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 394,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 401,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 581,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesias",
       "locations": [
        {
         "offset": 598,
         "length": 11
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 629,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 671,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 717,
         "length": 8
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Parkinson's Disease",
       "locations": [
        {
         "offset": 875,
         "length": 19
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "parkinsonian",
       "locations": [
        {
         "offset": 1145,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1177,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "Levodopa",
       "locations": [
        {
         "offset": 1209,
         "length": 8
        }
       ]
      },
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       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1462,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D006423",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "homonymous hemianopsia",
       "locations": [
        {
         "offset": 1487,
         "length": 22
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D014635",
        "type": "ChemicalEntity"
       },
       "text": "Valproate",
       "locations": [
        {
         "offset": 1653,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1790,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 1813,
         "length": 2
        }
       ]
      }
     ]
    }
   ],
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    {
     "id": "R0",
     "infons": {
      "entity1": "D007980",
      "entity2": "D004409",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "19365571",
   "passages": [
    {
     "offset": 0,
     "text": "Macular corneal dystrophy in a Chinese family related with novel mutations of CHST6.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Macular corneal dystrophy",
       "locations": [
        {
         "offset": 0,
         "length": 25
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4166",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHST6",
       "locations": [
        {
         "offset": 78,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 85,
     "text": "PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea. METHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion. RESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C, were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 (p.Q298X) and a missense mutation at codon 358, tyrosine to histidine (p.Y358H). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects. CONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "4166",
        "type": "GeneOrGeneProduct"
       },
       "text": "carbohydrate sulfotransferase gene",
       "locations": [
        {
         "offset": 123,
         "length": 34
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "4166",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHST6",
       "locations": [
        {
         "offset": 159,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "macular corneal dystrophy",
       "locations": [
        {
         "offset": 192,
         "length": 25
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MCD",
       "locations": [
        {
         "offset": 219,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4166",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHST6",
       "locations": [
        {
         "offset": 649,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007501",
        "type": "ChemicalEntity"
       },
       "text": "iron",
       "locations": [
        {
         "offset": 846,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|C|892|T",
        "type": "SequenceVariant"
       },
       "text": "c.892C>T",
       "locations": [
        {
         "offset": 1117,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "c|SUB|T|1072|C",
        "type": "SequenceVariant"
       },
       "text": "c.1072T>C",
       "locations": [
        {
         "offset": 1130,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "4166",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHST6",
       "locations": [
        {
         "offset": 1170,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1185,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "p|SUB|Q|298|X",
        "type": "SequenceVariant"
       },
       "text": "stop codon for glutamine at codon 298",
       "locations": [
        {
         "offset": 1251,
         "length": 37
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "p|SUB|Q|298|X",
        "type": "SequenceVariant"
       },
       "text": "p.Q298X",
       "locations": [
        {
         "offset": 1290,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|SUB|Y|358|H",
        "type": "SequenceVariant"
       },
       "text": "codon 358, tyrosine to histidine",
       "locations": [
        {
         "offset": 1326,
         "length": 32
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "p|SUB|Y|358|H",
        "type": "SequenceVariant"
       },
       "text": "p.Y358H",
       "locations": [
        {
         "offset": 1360,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "4166",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHST6",
       "locations": [
        {
         "offset": 1625,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D007632",
        "type": "ChemicalEntity"
       },
       "text": "keratan sulfate",
       "locations": [
        {
         "offset": 1682,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D007632",
        "type": "ChemicalEntity"
       },
       "text": "KS",
       "locations": [
        {
         "offset": 1699,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "1277",
        "type": "GeneOrGeneProduct"
       },
       "text": "collagen",
       "locations": [
        {
         "offset": 1825,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D003317",
      "entity2": "c|SUB|T|1072|C",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D003317",
      "entity2": "c|SUB|C|892|T",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D003317",
      "entity2": "4166",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D003317",
      "entity2": "p|SUB|Y|358|H",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D003317",
      "entity2": "p|SUB|Q|298|X",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D007632",
      "entity2": "c|SUB|T|1072|C",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D007632",
      "entity2": "c|SUB|C|892|T",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "D007632",
      "entity2": "4166",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "D007632",
      "entity2": "p|SUB|Y|358|H",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "D007632",
      "entity2": "D003317",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "D007632",
      "entity2": "p|SUB|Q|298|X",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19642243",
   "passages": [
    {
     "offset": 0,
     "text": "Acute renal failure in patients with AIDS on tenofovir while receiving prolonged vancomycin course for osteomyelitis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D058186",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Acute renal failure",
       "locations": [
        {
         "offset": 0,
         "length": 19
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 23,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D000163",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AIDS",
       "locations": [
        {
         "offset": 37,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D000068698",
        "type": "ChemicalEntity"
       },
       "text": "tenofovir",
       "locations": [
        {
         "offset": 45,
         "length": 9
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D014640",
        "type": "ChemicalEntity"
       },
       "text": "vancomycin",
       "locations": [
        {
         "offset": 81,
         "length": 10
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D010019",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "osteomyelitis",
       "locations": [
        {
         "offset": 103,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 118,
     "text": "Renal failure developed after a prolonged course of vancomycin therapy in 2 patients who were receiving tenofovir disoproxil fumarate as part of an antiretroviral regimen. Tenofovir has been implicated in the development of Fanconi syndrome and renal insufficiency because of its effects on the proximal renal tubule. Vancomycin nephrotoxicity is infrequent but may result from coadministration with a nephrotoxic agent. Clinicians should be aware that tenofovir may raise the risk of renal failure during prolonged administration of vancomycin.",
     "annotations": [
      {
       "id": "6",
       "infons": {
        "identifier": "D051437",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Renal failure",
       "locations": [
        {
         "offset": 118,
         "length": 13
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D014640",
        "type": "ChemicalEntity"
       },
       "text": "vancomycin",
       "locations": [
        {
         "offset": 170,
         "length": 10
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 194,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000068698",
        "type": "ChemicalEntity"
       },
       "text": "tenofovir disoproxil fumarate",
       "locations": [
        {
         "offset": 222,
         "length": 29
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000068698",
        "type": "ChemicalEntity"
       },
       "text": "Tenofovir",
       "locations": [
        {
         "offset": 290,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D005198",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Fanconi syndrome",
       "locations": [
        {
         "offset": 342,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D051437",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "renal insufficiency",
       "locations": [
        {
         "offset": 363,
         "length": 19
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D014640",
        "type": "ChemicalEntity"
       },
       "text": "Vancomycin",
       "locations": [
        {
         "offset": 436,
         "length": 10
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nephrotoxicity",
       "locations": [
        {
         "offset": 447,
         "length": 14
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D007674",
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       },
       "text": "nephrotoxic",
       "locations": [
        {
         "offset": 520,
         "length": 11
        }
       ]
      },
      {
       "id": "16",
       "infons": {
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       "text": "tenofovir",
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         "offset": 571,
         "length": 9
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       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D051437",
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       },
       "text": "renal failure",
       "locations": [
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         "offset": 603,
         "length": 13
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D014640",
        "type": "ChemicalEntity"
       },
       "text": "vancomycin",
       "locations": [
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         "offset": 652,
         "length": 10
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
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      "entity2": "D051437",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010019",
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      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D000068698",
      "entity2": "D005198",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D000068698",
      "entity2": "D051437",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D000068698",
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      "type": "Drug_Interaction",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D000068698",
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      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "19672862",
   "passages": [
    {
     "offset": 0,
     "text": "Protein kinase C alpha-dependent signaling mediates endometrial cancer cell growth and tumorigenesis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5578",
        "type": "GeneOrGeneProduct"
       },
       "text": "Protein kinase C alpha",
       "locations": [
        {
         "offset": 0,
         "length": 22
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D016889",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "endometrial cancer",
       "locations": [
        {
         "offset": 52,
         "length": 18
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumorigenesis",
       "locations": [
        {
         "offset": 87,
         "length": 13
        }
       ]
      }
     ]
    },
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     "text": "BACKGROUND: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance. METHODS: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. RESULTS: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model <or= 0.009, effect sizes 8/8%, rs6232: pdominant model <or= 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p >or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom <or= 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. CONCLUSIONS: Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.",
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     "text": "Inhibitory effect of emodin on fatty acid synthase, colon cancer proliferation and apoptosis.",
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     "text": "Fatty acid synthase (FASN) is a key anabolic enzyme for de novo fatty acid synthesis, which is important in the development of colon carcinoma. The high expression of FASN is considered a promising molecular target for colon cancer therapy. Emodin, a naturally occurring anthraquinone, exhibits an anticancer effect in various types of human cancer, including colon cancer; however, the molecular mechanisms remain to be fully elucidated. Cell viability was evaluated using a Cell Counting Kit-8 assay. The apoptosis rate of cells was quantified via flow cytometry following Annexin V/propidium iodide staining. FASN activity was measured by monitoring oxidation of nicotinamide adenine dinucleotide phosphate at a wavelength of 340 nm, and intracellular free fatty acid levels were detected using a Free Fatty Acid Quantification kit. Western blot analysis and reverse transcription-polymerase chain reaction were used to detect target gene and protein expression. The present study was performed to investigate whether the gene expression of FASN and its enzymatic activity are regulated by emodin in a human colon cancer cell line. Emodin markedly inhibited the proliferation of HCT116 cells and a higher protein level of FASN was expressed, compared with that in SW480, SNU-C2A or SNU-C5 cells. Emodin significantly downregulated the protein expression of FASN in HCT116 cells, which was caused by protein degradation due to elevated protein ubiquitination. Emodin also inhibited intracellular FASN enzymatic activity and reduced the levels of intracellular free fatty acids. Emodin enhanced antiproliferation and apoptosis in a dose- and time-dependent manner. The combined treatment of emodin and cerulenin, a commercial FASN inhibitor, had an additive effect on these activities. Palmitate, the final product of the FASN reaction, rescued emodin-induced viability and apoptosis. In addition, emodin altered FASN-involved signaling pathways, including phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinases/extracellular signal-regulated kinases 1/2. These results suggested that emodin-regulated cell growth and apoptosis were mediated by inhibiting FASN and provide a molecular basis for colon cancer therapy.",
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       "text": "mitogen-activated protein kinases/extracellular signal-regulated kinases 1/2",
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       "id": "50",
       "infons": {
        "identifier": "D015179",
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       "text": "colon cancer",
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  {
   "id": "28747658",
   "passages": [
    {
     "offset": 0,
     "text": "A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "11676",
        "type": "OrganismTaxon"
       },
       "text": "HIV-1",
       "locations": [
        {
         "offset": 75,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "p17",
       "locations": [
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         "offset": 96,
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     "offset": 101,
     "text": "Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s.",
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       "id": "2",
       "infons": {
        "identifier": "D006679",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "HIV-1-seropositive",
       "locations": [
        {
         "offset": 140,
         "length": 18
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 159,
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       ]
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       "id": "4",
       "infons": {
        "identifier": "D008223",
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       "text": "lymphoma",
       "locations": [
        {
         "offset": 173,
         "length": 8
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       ]
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       "id": "5",
       "infons": {
        "identifier": "155348",
        "type": "GeneOrGeneProduct"
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       "text": "p17",
       "locations": [
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         "offset": 186,
         "length": 3
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       ]
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       "id": "6",
       "infons": {
        "identifier": "D008223",
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       "text": "lymphomagenesis",
       "locations": [
        {
         "offset": 272,
         "length": 15
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "155348",
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       "text": "p17",
       "locations": [
        {
         "offset": 392,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "p|SUB|S|75|X",
        "type": "SequenceVariant"
       },
       "text": "S75X",
       "locations": [
        {
         "offset": 422,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "p|SUB|R|76|G",
        "type": "SequenceVariant"
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       "text": "Arginine (R) to Glycine (G) mutation at position 76",
       "locations": [
        {
         "offset": 456,
         "length": 51
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "155348",
        "type": "GeneOrGeneProduct"
       },
       "text": "p17",
       "locations": [
        {
         "offset": 532,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "p|SUB|R|76|G",
        "type": "SequenceVariant"
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       "text": "R76G",
       "locations": [
        {
         "offset": 535,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "p|SUB|S|75|X",
        "type": "SequenceVariant"
       },
       "text": "S75X",
       "locations": [
        {
         "offset": 552,
         "length": 4
        }
       ]
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       "id": "13",
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       "locations": [
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         "offset": 688,
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       "id": "14",
       "infons": {
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       "text": "PI3K",
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       ]
      },
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       "id": "15",
       "infons": {
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       "text": "Akt",
       "locations": [
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         "offset": 698,
         "length": 3
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       ]
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        "identifier": "842",
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       "text": "CASP-7",
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       "id": "18",
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         "offset": 791,
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       "id": "19",
       "infons": {
        "identifier": "4869",
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       "locations": [
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         "offset": 799,
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       "text": "MAPK8",
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       "id": "24",
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        "identifier": "D009369",
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       "text": "cancer",
       "locations": [
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         "offset": 855,
         "length": 6
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       "id": "25",
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       "id": "26",
       "infons": {
        "identifier": "1017",
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       "text": "CDK2",
       "locations": [
        {
         "offset": 881,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "1024",
        "type": "GeneOrGeneProduct"
       },
       "text": "CDK8",
       "locations": [
        {
         "offset": 887,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "1111",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHEK1",
       "locations": [
        {
         "offset": 893,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "11200",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHEK2",
       "locations": [
        {
         "offset": 900,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "2932",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSK-3 beta",
       "locations": [
        {
         "offset": 907,
         "length": 10
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "4869",
        "type": "GeneOrGeneProduct"
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       "text": "NPM",
       "locations": [
        {
         "offset": 919,
         "length": 3
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       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "5058",
        "type": "GeneOrGeneProduct"
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       "text": "PAK1",
       "locations": [
        {
         "offset": 924,
         "length": 4
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       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "5494",
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       "text": "PP2C-alpha",
       "locations": [
        {
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         "length": 10
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       ]
      },
      {
       "id": "34",
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        "type": "SequenceVariant"
       },
       "text": "R to G mutation at position 76",
       "locations": [
        {
         "offset": 962,
         "length": 30
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "155348",
        "type": "GeneOrGeneProduct"
       },
       "text": "p17",
       "locations": [
        {
         "offset": 1145,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "p|SUB|R|76|G",
        "type": "SequenceVariant"
       },
       "text": "R76G",
       "locations": [
        {
         "offset": 1149,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "p|SUB|S|75|X",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "p|SUB|R|76|G",
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      "novel": "Novel"
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      "novel": "No"
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     "id": "R7",
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     "id": "R10",
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      "novel": "No"
     }
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      "type": "Association",
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      "novel": "No"
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    }
   ]
  },
  {
   "id": "16410744",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic alterations in primary glioblastomas in Japan.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 31,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 55,
     "text": "Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 99,
         "length": 13
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumors",
       "locations": [
        {
         "offset": 153,
         "length": 6
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 182,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 330,
         "length": 13
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 356,
         "length": 8
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "7157",
        "type": "GeneOrGeneProduct"
       },
       "text": "TP53",
       "locations": [
        {
         "offset": 407,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 440,
         "length": 13
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "5728",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTEN",
       "locations": [
        {
         "offset": 458,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 546,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "1029",
        "type": "GeneOrGeneProduct"
       },
       "text": "p16",
       "locations": [
        {
         "offset": 593,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 714,
         "length": 13
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 817,
         "length": 13
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 898,
         "length": 13
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 964,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1029",
        "type": "GeneOrGeneProduct"
       },
       "text": "p16",
       "locations": [
        {
         "offset": 987,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "7157",
        "type": "GeneOrGeneProduct"
       },
       "text": "TP53",
       "locations": [
        {
         "offset": 1060,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "1029",
        "type": "GeneOrGeneProduct"
       },
       "text": "p16",
       "locations": [
        {
         "offset": 1079,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 1105,
         "length": 13
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastoma",
       "locations": [
        {
         "offset": 1228,
         "length": 12
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1241,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 1335,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 1383,
         "length": 13
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 1426,
         "length": 13
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "p|SUB|Q|787|Q",
        "type": "SequenceVariant"
       },
       "text": "codon 787 CAG/CAA",
       "locations": [
        {
         "offset": 1499,
         "length": 17
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "p|SUB|Q||Q",
        "type": "SequenceVariant"
       },
       "text": "Gln/Gln",
       "locations": [
        {
         "offset": 1518,
         "length": 7
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 1530,
         "length": 13
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 1675,
         "length": 13
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glioblastomas",
       "locations": [
        {
         "offset": 1833,
         "length": 13
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
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       "text": "EGFR",
       "locations": [
        {
         "offset": 2068,
         "length": 4
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       ]
      }
     ]
    }
   ],
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      "novel": "Novel"
     }
    },
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     "id": "R1",
     "infons": {
      "entity1": "p|SUB|Q|787|Q",
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      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "7157",
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      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "7157",
      "entity2": "D005909",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "1956",
      "entity2": "1029",
      "type": "Negative_Correlation",
      "novel": "No"
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    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D005909",
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      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D005909",
      "entity2": "1956",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16526029",
   "passages": [
    {
     "offset": 0,
     "text": "Evaluation of RGS4 as a candidate gene for schizophrenia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5999",
        "type": "GeneOrGeneProduct"
       },
       "text": "RGS4",
       "locations": [
        {
         "offset": 14,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenia",
       "locations": [
        {
         "offset": 43,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 58,
     "text": "Several studies have suggested that the regulator of G-protein signaling 4 (RGS4) may be a positional and functional candidate gene for schizophrenia. Three single nucleotide polymorphisms (SNP) located at the promoter region (SNP4 and SNP7) and the intron 1 (SNP18) of RGS4 have been verified in different ethnic groups. Positive results have been reported in these SNPs with different numbers of SNP combinatory haplotypes. In this study, these three SNP markers were genotyped in 218 schizophrenia pedigrees of Taiwan (864 individuals) for association analysis. Among these three SNPs, neither SNP4, SNP7, SNP18 has shown significant association with schizophrenia in single locus association analysis, nor any compositions of the three SNP haplotypes has shown significantly associations with the DSM-IV diagnosed schizophrenia. Our results fail to support the RGS4 as a candidate gene for schizophrenia when evaluated from these three SNP markers.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "5999",
        "type": "GeneOrGeneProduct"
       },
       "text": "regulator of G-protein signaling 4",
       "locations": [
        {
         "offset": 98,
         "length": 34
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "5999",
        "type": "GeneOrGeneProduct"
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       "text": "RGS4",
       "locations": [
        {
         "offset": 134,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "schizophrenia",
       "locations": [
        {
         "offset": 194,
         "length": 13
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "5999",
        "type": "GeneOrGeneProduct"
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       "text": "RGS4",
       "locations": [
        {
         "offset": 328,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "schizophrenia",
       "locations": [
        {
         "offset": 545,
         "length": 13
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "schizophrenia",
       "locations": [
        {
         "offset": 712,
         "length": 13
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "schizophrenia",
       "locations": [
        {
         "offset": 876,
         "length": 13
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "5999",
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       "text": "RGS4",
       "locations": [
        {
         "offset": 923,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "schizophrenia",
       "locations": [
        {
         "offset": 952,
         "length": 13
        }
       ]
      }
     ]
    }
   ],
   "relations": []
  },
  {
   "id": "17065198",
   "passages": [
    {
     "offset": 0,
     "text": "Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV-specific tandem CC to TT mutations of the p53 gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D012878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "skin cancer",
       "locations": [
        {
         "offset": 12,
         "length": 11
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 74,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "c|SUB|C||T",
        "type": "SequenceVariant"
       },
       "text": "CC to TT",
       "locations": [
        {
         "offset": 123,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "7157",
        "type": "GeneOrGeneProduct"
       },
       "text": "p53",
       "locations": [
        {
         "offset": 149,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 159,
     "text": "Immunosuppressed renal transplant recipients (RTRs) are predisposed to non-melanoma skin cancers (NMSCs), predominantly squamous cell carcinomas (SCCs). We have analyzed skin lesions from RTRs with aggressive tumors for p53 gene modifications, the presence of Human Papillomas Virus (HPV) DNA in relation to the p53 codon 72 genotype and polymorphisms of the XPD repair gene. We detected 24 p53 mutations in 15/25 (60%) NMSCs, 1 deletion and 23 base substitutions, the majority (78%) being UV-specific C to T transitions at bipyrimidine sites. Importantly, 35% (6/17) are tandem mutations, including 4 UV signature CC to TT transitions possibly linked to modulated DNA repair caused by the immunosuppressive drug cyclosporin A (CsA). We found 8 p53 mutations in 7/17 (41%) precancerous actinic keratosis (AK), suggesting that p53 mutations are early events in RTR skin carcinogenesis. Immunohistochemical analysis shows a good correlation between p53 accumulation and mutations. HPV DNA was detected in 78% of skin lesions (60% Basal Cell Carcinomas, 82%AK and 79% SCCs). Thus, immunosuppression has increased the risk of infections by HPVs, predominantly epidermodysplasia verruciformis, speculated to play a role in skin cancer development. No association is found between HPV status and p53 mutation. Moreover, p53 codon 72 or frequencies of three XPD genotypes of RTRs are comparable with control populations. The p53 mutation spectrum, presenting a high level of CC to TT mutations, shows that the UV component of sunlight is the major risk factor and modulated DNA repair by immunosuppressive drug treatment may be significant in the skin carcinogenesis of RTRs.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D012878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "non-melanoma skin cancers",
       "locations": [
        {
         "offset": 230,
         "length": 25
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D012878",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NMSCs",
       "locations": [
        {
         "offset": 257,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002294",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "squamous cell carcinomas",
       "locations": [
        {
         "offset": 279,
         "length": 24
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D002294",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SCCs",
       "locations": [
        {
         "offset": 305,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012871",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "skin lesions",
       "locations": [
        {
         "offset": 329,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D009369",
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     "offset": 0,
     "text": "Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D013575",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Syncope",
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         "offset": 0,
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       "infons": {
        "identifier": "D008133",
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       "text": "QT prolongation",
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         "length": 15
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       "text": "patients",
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     "text": "BACKGROUND: Methadone is prescribed to heroin addicts to decrease illicit opioid use. Prolongation of the QT interval in the ECG of patients with torsade de pointes (TdP) has been reported in methadone users. As heroin addicts sometimes faint while using illicit drugs, doctors might attribute too many episodes of syncope to illicit drug use and thereby underestimate the incidence of TdP in this special population, and the high mortality in this population may, in part, be caused by the proarrhythmic effect of methadone. METHODS: In this cross-sectional study interview, ECGs and blood samples were collected in a population of adult heroin addicts treated with methadone or buprenorphine on a daily basis. Of the patients at the Drug Addiction Service in the municipal of Copenhagen, 450 (approximately 52%) were included. The QT interval was estimated from 12 lead ECGs. All participants were interviewed about any experience of syncope. The association between opioid dose and QT, and methadone dose and reporting of syncope was assessed using multivariate linear regression and logistic regression, respectively. RESULTS: Methadone dose was associated with longer QT interval of 0.140 ms/mg (p = 0.002). No association between buprenorphine and QTc was found. Among the subjects treated with methadone, 28% men and 32% women had prolonged QTc interval. None of the subjects treated with buprenorphine had QTc interval >0.440 s((1/2)). A 50 mg higher methadone dose was associated with a 1.2 (95% CI 1.1 to 1.4) times higher odds for syncope. CONCLUSIONS: Methadone is associated with QT prolongation and higher reporting of syncope in a population of heroin addicts.",
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       "infons": {
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       "text": "Prolongation of the QT interval",
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       "infons": {
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       "text": "torsade de pointes",
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         "length": 18
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       "id": "11",
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       "id": "15",
       "infons": {
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       "text": "TdP",
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       "text": "longer QT interval",
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       "text": "men",
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       "id": "30",
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       "text": "women",
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       "text": "prolonged QTc interval",
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   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D016171",
      "entity2": "D008691",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D002047",
      "entity2": "D006556",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D002047",
      "entity2": "D008691",
      "type": "Comparison",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D008691",
      "entity2": "D000701",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D008691",
      "entity2": "D006556",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D008691",
      "entity2": "D008133",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D008691",
      "entity2": "D013575",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18945288",
   "passages": [
    {
     "offset": 0,
     "text": "R58fs mutation in the HGD gene in a family with alkaptonuria in the UAE.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "p|FS|R|58||",
        "type": "SequenceVariant"
       },
       "text": "R58fs",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "3081",
        "type": "GeneOrGeneProduct"
       },
       "text": "HGD",
       "locations": [
        {
         "offset": 22,
         "length": 3
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D000474",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "alkaptonuria",
       "locations": [
        {
         "offset": 48,
         "length": 12
        }
       ]
      }
     ]
    },
    {
     "offset": 73,
     "text": "This study was conducted to determine the prevalence of alkaptonuria in the UAE population and to identify the genotype of affected individuals. In a 3 stage sampling technique 2981 pupils from Government schools in Al Ain and private schools in Dubai were selected to take part in the study, of whom 2857 provided urine samples. Urine collected was analysed for homogentisic acid by gas chromatography-mass spectrometry. Genomic DNA was isolated from the white blood cells of all family members of the affected case following standard established protocols. Specific PRC primers were designed to amplify all 14 exons of the HGD gene with the flanking intronic sequences including the splice site sequences. 2857 children returned a viable urine sample, of which one was highly positive for homogentisic acid. All 12 members of this girl's family were studied and one, a 22 year old brother, was found to excrete HGA. Another, a sister who had not provided a urine sample, was discovered by genetic testing. There were no complaints of joint pain or other symptoms in any member of this family. Parents were first cousins. We found a single nucleotide deletion c.342delA, located in exon 3, which resulted in a frameshift at amino acid position 58 (p.Arg58fs or p.R58fs). Alkaptonuria may be more common than it is thought to be with an allele prevalence estimated at 0.0107 (95% CI 0.000392-0.03473). The R58fs mutation is old, perhaps having occurred several thousand years ago, and has spread over a large geographical area.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D000474",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "alkaptonuria",
       "locations": [
        {
         "offset": 129,
         "length": 12
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D006713",
        "type": "ChemicalEntity"
       },
       "text": "homogentisic acid",
       "locations": [
        {
         "offset": 436,
         "length": 17
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "3081",
        "type": "GeneOrGeneProduct"
       },
       "text": "HGD",
       "locations": [
        {
         "offset": 698,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D006713",
        "type": "ChemicalEntity"
       },
       "text": "homogentisic acid",
       "locations": [
        {
         "offset": 864,
         "length": 17
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D006713",
        "type": "ChemicalEntity"
       },
       "text": "HGA",
       "locations": [
        {
         "offset": 986,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D018771",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "joint pain",
       "locations": [
        {
         "offset": 1109,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "c|DEL|342|A",
        "type": "SequenceVariant"
       },
       "text": "c.342delA",
       "locations": [
        {
         "offset": 1234,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "p|FS|R|58||",
        "type": "SequenceVariant"
       },
       "text": "p.Arg58fs",
       "locations": [
        {
         "offset": 1322,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "p|FS|R|58||",
        "type": "SequenceVariant"
       },
       "text": "p.R58fs",
       "locations": [
        {
         "offset": 1335,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D000474",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alkaptonuria",
       "locations": [
        {
         "offset": 1345,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "p|FS|R|58||",
        "type": "SequenceVariant"
       },
       "text": "R58fs",
       "locations": [
        {
         "offset": 1479,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "3081",
      "entity2": "D006713",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "3081",
      "entity2": "D000474",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "p|FS|R|58||",
      "entity2": "D000474",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|DEL|342|A",
      "entity2": "D000474",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19306381",
   "passages": [
    {
     "offset": 0,
     "text": "Neuregulin-1 beta and neuregulin-1 alpha differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "Neuregulin-1 beta",
       "locations": [
        {
         "offset": 0,
         "length": 17
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "neuregulin-1 alpha",
       "locations": [
        {
         "offset": 22,
         "length": 18
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "malignant peripheral nerve sheath tumor",
       "locations": [
        {
         "offset": 93,
         "length": 39
        }
       ]
      }
     ]
    },
    {
     "offset": 140,
     "text": "Malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy associated with neurofibromatosis Type 1 (NF1). These Schwann cell lineage-derived sarcomas aggressively invade adjacent nerve and soft tissue, frequently precluding surgical resection. Little is known regarding the mechanisms underlying this invasive behavior. We have shown that MPNSTs express neuregulin-1 (NRG-1) beta isoforms, which promote Schwann cell migration during development, and NRG-1 alpha isoforms, whose effects on Schwann cells are poorly understood. Hypothesizing that NRG-1 beta and/or NRG-1 alpha promote MPNST invasion, we found that NRG-1 beta promoted MPNST migration in a substrate-specific manner, markedly enhancing migration on laminin but not on collagen type I or fibronectin. The NRG-1 receptors erbB3 and erbB4 were present in MPNST invadopodia (processes mediating invasion), partially colocalized with focal adhesion kinase and the laminin receptor beta(1)-integrin and coimmunoprecipitated with beta(1)-integrin. NRG-1 beta stimulated human and murine MPNST cell migration and invasion in a concentration-dependent manner in three-dimensional migration assays, acting as a chemotactic factor. Both baseline and NRG-1 beta-induced migration were erbB-dependent and required the action of MEK 1/2, SAPK/JNK, PI-3 kinase, Src family kinases and ROCK-I/II. In contrast, NRG-1 alpha had no effect on the migration and invasion of some MPNST lines and inhibited the migration of others. While NRG-1 beta potently and persistently activated Erk 1/2, SAPK/JNK, Akt and Src family kinases, NRG-1 alpha did not activate Akt and activated these other kinases with kinetics distinct from those evident in NRG-1 beta-stimulated cells. These findings suggest that NRG-1 beta enhances MPNST migration and that NRG-1 beta and NRG-1 alpha differentially modulate this process.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Malignant peripheral nerve sheath tumors",
       "locations": [
        {
         "offset": 140,
         "length": 40
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPNSTs",
       "locations": [
        {
         "offset": 182,
         "length": 6
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "malignancy",
       "locations": [
        {
         "offset": 210,
         "length": 10
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4763",
        "type": "GeneOrGeneProduct"
       },
       "text": "neurofibromatosis Type 1",
       "locations": [
        {
         "offset": 237,
         "length": 24
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "4763",
        "type": "GeneOrGeneProduct"
       },
       "text": "NF1",
       "locations": [
        {
         "offset": 263,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012509",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sarcomas",
       "locations": [
        {
         "offset": 304,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPNSTs",
       "locations": [
        {
         "offset": 502,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "neuregulin-1 (NRG-1) beta",
       "locations": [
        {
         "offset": 517,
         "length": 25
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 alpha",
       "locations": [
        {
         "offset": 614,
         "length": 11
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 beta",
       "locations": [
        {
         "offset": 709,
         "length": 10
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 alpha",
       "locations": [
        {
         "offset": 727,
         "length": 11
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPNST",
       "locations": [
        {
         "offset": 747,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 beta",
       "locations": [
        {
         "offset": 777,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPNST",
       "locations": [
        {
         "offset": 797,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "16777",
        "type": "GeneOrGeneProduct"
       },
       "text": "laminin",
       "locations": [
        {
         "offset": 877,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "1277,1278",
        "type": "GeneOrGeneProduct"
       },
       "text": "collagen type I",
       "locations": [
        {
         "offset": 896,
         "length": 15
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "2335",
        "type": "GeneOrGeneProduct"
       },
       "text": "fibronectin",
       "locations": [
        {
         "offset": 915,
         "length": 11
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1",
       "locations": [
        {
         "offset": 932,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "13867,2065",
        "type": "GeneOrGeneProduct"
       },
       "text": "erbB3",
       "locations": [
        {
         "offset": 948,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "13869,2066",
        "type": "GeneOrGeneProduct"
       },
       "text": "erbB4",
       "locations": [
        {
         "offset": 958,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPNST",
       "locations": [
        {
         "offset": 980,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "5747",
        "type": "GeneOrGeneProduct"
       },
       "text": "focal adhesion kinase",
       "locations": [
        {
         "offset": 1057,
         "length": 21
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "3688",
        "type": "GeneOrGeneProduct"
       },
       "text": "laminin receptor",
       "locations": [
        {
         "offset": 1087,
         "length": 16
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "3688",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta(1)-integrin",
       "locations": [
        {
         "offset": 1104,
         "length": 16
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "3688",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta(1)-integrin",
       "locations": [
        {
         "offset": 1151,
         "length": 16
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 beta",
       "locations": [
        {
         "offset": 1169,
         "length": 10
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1191,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "murine",
       "locations": [
        {
         "offset": 1201,
         "length": 6
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPNST",
       "locations": [
        {
         "offset": 1208,
         "length": 5
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 beta",
       "locations": [
        {
         "offset": 1367,
         "length": 10
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "13867,13869,2065,2066",
        "type": "GeneOrGeneProduct"
       },
       "text": "erbB",
       "locations": [
        {
         "offset": 1401,
         "length": 4
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "26395,26396,5604,5605",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEK 1/2",
       "locations": [
        {
         "offset": 1443,
         "length": 7
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "26419,5599",
        "type": "GeneOrGeneProduct"
       },
       "text": "SAPK",
       "locations": [
        {
         "offset": 1452,
         "length": 4
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "26419,5599",
        "type": "GeneOrGeneProduct"
       },
       "text": "JNK",
       "locations": [
        {
         "offset": 1457,
         "length": 3
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "30955,5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PI-3 kinase",
       "locations": [
        {
         "offset": 1462,
         "length": 11
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "20779,6714",
        "type": "GeneOrGeneProduct"
       },
       "text": "Src family kinases",
       "locations": [
        {
         "offset": 1475,
         "length": 18
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "19877,19878,6093,9475",
        "type": "GeneOrGeneProduct"
       },
       "text": "ROCK-I/II",
       "locations": [
        {
         "offset": 1498,
         "length": 9
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 alpha",
       "locations": [
        {
         "offset": 1522,
         "length": 11
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "D018319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPNST",
       "locations": [
        {
         "offset": 1586,
         "length": 5
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 beta",
       "locations": [
        {
         "offset": 1643,
         "length": 10
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "26413,26417,5594,5595",
        "type": "GeneOrGeneProduct"
       },
       "text": "Erk 1/2",
       "locations": [
        {
         "offset": 1690,
         "length": 7
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "26419,5599",
        "type": "GeneOrGeneProduct"
       },
       "text": "SAPK",
       "locations": [
        {
         "offset": 1699,
         "length": 4
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "26419,5599",
        "type": "GeneOrGeneProduct"
       },
       "text": "JNK",
       "locations": [
        {
         "offset": 1704,
         "length": 3
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "11651,207",
        "type": "GeneOrGeneProduct"
       },
       "text": "Akt",
       "locations": [
        {
         "offset": 1709,
         "length": 3
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "20779,6714",
        "type": "GeneOrGeneProduct"
       },
       "text": "Src family kinases",
       "locations": [
        {
         "offset": 1717,
         "length": 18
        }
       ]
      },
      {
       "id": "48",
       "infons": {
        "identifier": "3084",
        "type": "GeneOrGeneProduct"
       },
       "text": "NRG-1 alpha",
       "locations": [
        {
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     "text": "Exploratory investigation on functional significance of ETS2 and SIM2 genes in Down syndrome.",
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     "text": "Calbindin-D28k (CB), one of the major calcium-binding and buffering proteins, has a critical role in preventing a neuronal death as well as maintaining calcium homeostasis. Although marked reductions of CB expression have been observed in the brains of mice and humans with Alzheimer disease (AD), it is unknown whether these changes contribute to AD-related dysfunction. To determine the pathogenic importance of CB depletions in AD models, we crossed 5 familial AD mutations (5XFAD; Tg) mice with CB knock-out (CBKO) mice and generated a novel line CBKO.5XFAD (CBKOTg) mice. We first identified the change of signaling pathways and differentially expressed proteins globally by removing CB in Tg mice using mass spectrometry and antibody microarray. Immunohistochemistry showed that CBKOTg mice had significant neuronal loss in the subiculum area without changing the magnitude (number) of amyloid b-peptide (Ab) plaques deposition and elicited significant apoptotic features and mitochondrial dysfunction compared with Tg mice. Moreover, CBKOTg mice reduced levels of phosphorylated mitogen-activated protein kinase (extracellular signal-regulated kinase) 1/2 and cAMP response element-binding protein at Ser-133 and synaptic molecules such as N-methyl-D-aspartate receptor 1 (NMDA receptor 1), NMDA receptor 2A, PSD-95 and synaptophysin in the subiculum compared with Tg mice. Importantly, this is the first experimental evidence that removal of CB from amyloid precursor protein/presenilin transgenic mice aggravates AD pathogenesis, suggesting that CB has a critical role in AD pathogenesis.",
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       "text": "OCT4A",
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         "offset": 1635,
         "length": 5
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       "infons": {
        "identifier": "CVCL_0479",
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       "text": "PA-1",
       "locations": [
        {
         "offset": 1675,
         "length": 4
        }
       ]
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       "id": "31",
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       "text": "p21Cip1",
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        {
         "offset": 1778,
         "length": 7
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       "id": "32",
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        "identifier": "5562",
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       "text": "AMPK",
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         "offset": 1803,
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   ]
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  {
   "id": "26411452",
   "passages": [
    {
     "offset": 0,
     "text": "Putative Prostate Cancer Risk SNP in an Androgen Receptor-Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Prostate Cancer",
       "locations": [
        {
         "offset": 9,
         "length": 15
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       "infons": {
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        {
         "offset": 40,
         "length": 17
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       ]
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       "id": "2",
       "infons": {
        "identifier": "79083",
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       "text": "Melanophilin",
       "locations": [
        {
         "offset": 78,
         "length": 12
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       ]
      },
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       "id": "3",
       "infons": {
        "identifier": "367",
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       "text": "Androgen Receptor",
       "locations": [
        {
         "offset": 135,
         "length": 17
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       ]
      }
     ]
    },
    {
     "offset": 167,
     "text": "Genome-wide association studies have identified genomic loci, whose single-nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-immunoprecipitation-coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor-binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary AR-binding motif, which is enriched in the neighborhood of canonical androgen-responsive elements. T>G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor-suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 288,
         "length": 15
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PCa",
       "locations": [
        {
         "offset": 305,
         "length": 3
        }
       ]
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       "id": "6",
       "infons": {
        "identifier": "7113",
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       "text": "TMPRSS2",
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        {
         "offset": 484,
         "length": 7
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       "infons": {
        "identifier": "2078",
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       "text": "ERG",
       "locations": [
        {
         "offset": 492,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "CVCL_2025",
        "type": "CellLine"
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       "text": "DUCaP",
       "locations": [
        {
         "offset": 524,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PCa",
       "locations": [
        {
         "offset": 550,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "367",
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       },
       "text": "androgen receptor",
       "locations": [
        {
         "offset": 640,
         "length": 17
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "367",
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       "text": "AR",
       "locations": [
        {
         "offset": 673,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "367",
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       "text": "AR",
       "locations": [
        {
         "offset": 763,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs11891426",
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       "text": "rs11891426",
       "locations": [
        {
         "offset": 780,
         "length": 10
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       ]
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      {
       "id": "14",
       "infons": {
        "identifier": "rs11891426",
        "type": "SequenceVariant"
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       "text": "T>G",
       "locations": [
        {
         "offset": 791,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "79083",
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       },
       "text": "melanophilin",
       "locations": [
        {
         "offset": 815,
         "length": 12
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "79083",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLPH",
       "locations": [
        {
         "offset": 834,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
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       "text": "AR",
       "locations": [
        {
         "offset": 878,
         "length": 2
        }
       ]
      },
      {
       "id": "18",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "androgen",
       "locations": [
        {
         "offset": 947,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs11891426",
        "type": "SequenceVariant"
       },
       "text": "T>G",
       "locations": [
        {
         "offset": 977,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 1037,
         "length": 2
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 1048,
         "length": 2
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "79083",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLPH",
       "locations": [
        {
         "offset": 1090,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate tumors",
       "locations": [
        {
         "offset": 1106,
         "length": 15
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       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "367",
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       "text": "AR",
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        {
         "offset": 1227,
         "length": 2
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "79083",
        "type": "GeneOrGeneProduct"
       },
       "text": "melanophilin",
       "locations": [
        {
         "offset": 1246,
         "length": 12
        }
       ]
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       "id": "26",
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        "type": "OrganismTaxon"
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       "text": "patients",
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        {
         "offset": 1287,
         "length": 8
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       ]
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       "id": "27",
       "infons": {
        "identifier": "D011471",
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       "text": "PCa",
       "locations": [
        {
         "offset": 1313,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1343,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 1413,
         "length": 2
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PCa",
       "locations": [
        {
         "offset": 1442,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D000728",
        "type": "ChemicalEntity"
       },
       "text": "androgen",
       "locations": [
        {
         "offset": 1488,
         "length": 8
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "79083",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLPH",
       "locations": [
        {
         "offset": 1525,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
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      "novel": "No"
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      "type": "Bind",
      "novel": "Novel"
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    }
   ]
  },
  {
   "id": "27941998",
   "passages": [
    {
     "offset": 0,
     "text": "Voltage-Dependent Anion Channel 1(VDAC1) Participates the Apoptosis of the Mitochondrial Dysfunction in Desminopathy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7416,83529",
        "type": "GeneOrGeneProduct"
       },
       "text": "Voltage-Dependent Anion Channel 1",
       "locations": [
        {
         "offset": 0,
         "length": 33
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "7416,83529",
        "type": "GeneOrGeneProduct"
       },
       "text": "VDAC1",
       "locations": [
        {
         "offset": 34,
         "length": 5
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D028361",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Mitochondrial Dysfunction",
       "locations": [
        {
         "offset": 75,
         "length": 25
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Desminopathy",
       "locations": [
        {
         "offset": 104,
         "length": 12
        }
       ]
      }
     ]
    },
    {
     "offset": 118,
     "text": "Desminopathies caused by the mutation in the gene coding for desmin are genetically protein aggregation myopathies. Mitochondrial dysfunction is one of pathological changes in the desminopathies at the earliest stage. The molecular mechanisms of mitochondria dysfunction in desminopathies remain exclusive. VDAC1 regulates mitochondrial uptake across the outer membrane and mitochondrial outer membrane permeabilization (MOMP). Relationships between desminopathies and Voltage-dependent anion channel 1 (VDAC1) remain unclear. Here we successfully constructed the desminopathy rat model, evaluated with conventional stains, containing hematoxylin and eosin (HE), Gomori Trichrome (MGT), (PAS), red oil (ORO), NADH-TR, SDH staining and immunohistochemistry. Immunofluorescence results showed that VDAC1 was accumulated in the desmin highly stained area of muscle fibers of desminopathy patients or desminopathy rat model compared to the normal ones. Meanwhile apoptosis related proteins bax and ATF2 were involved in desminopathy patients and desminopathy rat model, but not bcl-2, bcl-xl or HK2.VDAC1 and desmin are closely relevant in the tissue splices of deminopathies patients and rats with desminopathy at protein lever. Moreover, apoptotic proteins are also involved in the desminopathies, like bax, ATF2, but not bcl-2, bcl-xl or HK2. This pathological analysis presents the correlation between VDAC1 and desmin, and apoptosis related proteins are correlated in the desminopathy. Furthermore, we provide a rat model of desminopathy for the investigation of desmin related myopathy.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Desminopathies",
       "locations": [
        {
         "offset": 118,
         "length": 14
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1674",
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       "text": "desmin",
       "locations": [
        {
         "offset": 179,
         "length": 6
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009135",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myopathies",
       "locations": [
        {
         "offset": 222,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D028361",
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       },
       "text": "Mitochondrial dysfunction",
       "locations": [
        {
         "offset": 234,
         "length": 25
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "desminopathies",
       "locations": [
        {
         "offset": 298,
         "length": 14
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D028361",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mitochondria dysfunction",
       "locations": [
        {
         "offset": 364,
         "length": 24
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "desminopathies",
       "locations": [
        {
         "offset": 392,
         "length": 14
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "7416",
        "type": "GeneOrGeneProduct"
       },
       "text": "VDAC1",
       "locations": [
        {
         "offset": 425,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "desminopathies",
       "locations": [
        {
         "offset": 568,
         "length": 14
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "7416",
        "type": "GeneOrGeneProduct"
       },
       "text": "Voltage-dependent anion channel 1",
       "locations": [
        {
         "offset": 587,
         "length": 33
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "7416",
        "type": "GeneOrGeneProduct"
       },
       "text": "VDAC1",
       "locations": [
        {
         "offset": 622,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "C563319",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "desminopathy",
       "locations": [
        {
         "offset": 682,
         "length": 12
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
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     "text": "BACKGROUND AND OBJECTIVES: The low prevalence of the C282Y mutation of the HFE gene in Japan means that the genetic background of hemochromatosis in Japanese patients remains unclear. In a previous report, we showed that 3 patients from one family had an AVAQ 594-597 deletion of the transferrin receptor (TfR2) gene. This suggests that the TfR2 gene is involved in hemochromatosis in Japanese patients. DESIGN AND METHODS: Nine patients clinically diagnosed with hemochromatosis were included in the study. DNA was extracted from whole blood samples collected with informed consent. The HFE and TfR2 genes were analyzed by sequencing the coding region and splicing sites. RESULTS: There were no mutations in the HFE gene. In the TfR2 gene, 2 novel mutations, 1469T->G (L490R) and 1665delC (V561X), were found in 2 patients. A known variation, 714C-> (I238M), was also found in the patient with L490R. The patient homozygous for both L490R and I238M presented with a mild manifestation of hemochromatosis at the age of 41 years. His liver was cirrhotic with parenchymal iron deposits and the result of a glucose tolerance test was compatible with diabetes mellitus. The patient homozygous for V561X had severe iron overload with the triad of cirrhosis, diabetes mellitus and skin pigmentation at the age of 58 years. INTERPRETATION AND CONCLUSIONS: Taken together with the previous report, 5 of our 12 patients with hemochromatosis manifesting in middle age had mutations in the TfR2 gene. Thus, TfR2 plays a role in the pathogenesis of hemochromatosis in Japan.",
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       "id": "33",
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       "text": "hemochromatosis",
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       "id": "37",
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       "id": "38",
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       "text": "diabetes mellitus",
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       "id": "39",
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       "id": "40",
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       "id": "41",
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       "text": "skin pigmentation",
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       "id": "49",
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    {
     "offset": 0,
     "text": "Succinylcholine-induced masseter muscle rigidity during bronchoscopic removal of a tracheal foreign body.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "D013390",
        "type": "ChemicalEntity"
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     "text": "Masseter muscle rigidity during general anesthesia is considered an early warning sign of a possible episode of malignant hyperthermia. The decision whether to continue or discontinue the procedure depends on the urgency of the surgery and severity of masseter muscle rigidity. Here, we describe a case of severe masseter muscle rigidity (jaw of steel) after succinylcholine (Sch) administration during general anesthetic management for rigid bronchoscopic removal of a tracheal foreign body. Anesthesia was continued uneventfully with propofol infusion while all facilities were available to detect and treat malignant hyperthermia.",
     "annotations": [
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       "text": "masseter muscle rigidity",
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       "text": "malignant hyperthermia",
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     "offset": 0,
     "text": "Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan.",
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       "infons": {
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     "offset": 94,
     "text": "Non-syndromic deafness is genetically heterogeneous. We previously reported that mutations of transmembrane channel-like gene 1 (TMC1) cause non-syndromic recessive deafness at the DFNB7/B11 locus on chromosome 9q13-q21 in nine Pakistani families. The goal of this study was to define the identities, origins and frequencies of TMC1 mutations in an expanded cohort of 557 large Pakistani families segregating recessive deafness. We screened affected family members for homozygosity at short-tandem repeats flanking known autosomal recessive (DFNB) deafness loci, followed by TMC1 sequence analysis in families segregating deafness linked to DFNB7/B11. We identified 10 new families segregating DFNB7/B11 deafness and TMC1 mutations, including three novel alleles. Overall, 9 different TMC1 mutations account for deafness in 19 (3.4%) of the 557 Pakistani families. A single mutation, p.R34X, causes deafness in 10 (1.8%) of the families. Genotype analysis of p.R34X-linked markers indicates that it arose from a common founder. We also detected p.R34X among normal control samples of African-American and northern European origins, raising the possibility that p.R34X and other mutations of TMC1 are prevalent contributors to the genetic load of deafness across a variety of populations and continents.",
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       "text": "transmembrane channel-like gene 1",
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   "id": "18410548",
   "passages": [
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     "offset": 0,
     "text": "Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9049",
        "type": "GeneOrGeneProduct"
       },
       "text": "Aryl hydrocarbon receptor interacting protein",
       "locations": [
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       "id": "1",
       "infons": {
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       "id": "2",
       "infons": {
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       "text": "pituitary adenomas",
       "locations": [
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     "text": "OBJECTIVE: Pituitary adenomas occur rarely in childhood and adolescence. Pituitary adenoma predisposition (PAP) has been recently associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The aim of the study was to examine the proportion of germline AIP mutations in apparently sporadic paediatric pituitary adenomas. DESIGN: Genomic DNA was analysed for mutations in the AIP gene, by PCR amplification and direct sequencing. PATIENTS: A population-based cohort consisting of 36 apparently sporadic paediatric pituitary adenoma patients, referred to two medical centres in Italy, was included in the study. Patients were either less than 18 years at diagnosis, or showed clinical evidence of adenoma development before the age of 18 years. RESULTS: A heterozygous in-frame deletion Y248del (c.742_744delTAC) was identified in one GH-secreting adenoma patient. Loss of heterozygosity (LOH) analysis of tumour DNA revealed the loss of the wild-type allele. First degree relatives carrying the mutation were clinically unaffected. CONCLUSIONS: While mutations were absent in non-GH-secreting adenoma patients, germline AIP mutations can be found in children and adolescents with GH-secreting tumours, even in the absence of family history. The present study reports the AIP mutation analysis results on patients of a single ethnic origin. Clearly, further studies are needed to improve our knowledge on the role of AIP in paediatric pituitary adenomas.",
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       "text": "PATIENTS",
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       "id": "11",
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     "offset": 0,
     "text": "Curcumin decreases specificity protein expression in bladder cancer cells.",
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     "text": "Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. In this study, 10 to 25 micromol/L curcumin inhibited 253JB-V and KU7 bladder cancer cell growth, and this was accompanied by induction of apoptosis and decreased expression of the proapoptotic protein survivin and the angiogenic proteins vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Because expression of survivin, VEGF, and VEGFR1 are dependent on specificity protein (Sp) transcription factors, we also investigated the effects of curcumin on Sp protein expression as an underlying mechanism for the apoptotic and antiangiogenic activity of this compound. The results show that curcumin induced proteasome-dependent down-regulation of Sp1, Sp3, and Sp4 in 253JB-V and KU7 cells. Moreover, using RNA interference with small inhibitory RNAs for Sp1, Sp3, and Sp4, we observed that curcumin-dependent inhibition of nuclear factor kappaB (NF-kappaB)-dependent genes, such as bcl-2, survivin, and cyclin D1, was also due, in part, to loss of Sp proteins. Curcumin also decreased bladder tumor growth in athymic nude mice bearing KU7 cells as xenografts and this was accompanied by decreased Sp1, Sp3, and Sp4 protein levels in tumors. These results show for the first time that one of the underlying mechanisms of action of curcumin as a cancer chemotherapeutic agent is due, in part, to decreased expression of Sp transcription factors in bladder cancer cells.",
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       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 89,
         "length": 28
        }
       ]
      }
     ]
    },
    {
     "offset": 228,
     "text": "OBJECTIVE: We examined the genetic association of the promoter insertion/deletion (indel) in IRF5 gene with systemic lupus erythematosus (SLE) in distinct populations and assessed its role in gene expression. METHODS: Four IRF5 polymorphisms were genotyped in 1488 SLE patients and 1466 controls. Gene expression was analyzed by quantitative real-time PCR using RNA from peripheral blood mononuclear cells (PBMC). RESULTS: The promoter indel and rs2070197 had independent genetic effects, which accounted for the association of rs2004640 and rs10954213. Gene expression analysis revealed that rs10954213 exerted the greatest influence on IRF5 transcript levels. CONCLUSION: We corroborated the association of the promoter indel with SLE in 5 different populations and revealed that rs10954213 is the main single-nucleotide polymorphism responsible for altered IRF5 expression in PBMC.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 321,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 336,
         "length": 28
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 366,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 451,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 493,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 497,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs2070197",
        "type": "SequenceVariant"
       },
       "text": "rs2070197",
       "locations": [
        {
         "offset": 674,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs2004640",
        "type": "SequenceVariant"
       },
       "text": "rs2004640",
       "locations": [
        {
         "offset": 756,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs10954213",
        "type": "SequenceVariant"
       },
       "text": "rs10954213",
       "locations": [
        {
         "offset": 770,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs10954213",
        "type": "SequenceVariant"
       },
       "text": "rs10954213",
       "locations": [
        {
         "offset": 821,
         "length": 10
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 866,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 961,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs10954213",
        "type": "SequenceVariant"
       },
       "text": "rs10954213",
       "locations": [
        {
         "offset": 1010,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "3663",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF5",
       "locations": [
        {
         "offset": 1088,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs2004640",
      "entity2": "rs10954213",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D008180",
      "entity2": "3663",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D008180",
      "entity2": "rs10954213",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "21496008",
   "passages": [
    {
     "offset": 0,
     "text": "Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "Aristaless-related homeobox",
       "locations": [
        {
         "offset": 56,
         "length": 27
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 85,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 96,
     "text": "ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)(7)'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 96,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 138,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "brain and genital malformations",
       "locations": [
        {
         "offset": 175,
         "length": 31
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intellectual disability",
       "locations": [
        {
         "offset": 224,
         "length": 23
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ID",
       "locations": [
        {
         "offset": 249,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 254,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C019529",
        "type": "ChemicalEntity"
       },
       "text": "polyalanine",
       "locations": [
        {
         "offset": 324,
         "length": 11
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "C019529",
        "type": "ChemicalEntity"
       },
       "text": "pA",
       "locations": [
        {
         "offset": 337,
         "length": 2
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ID",
       "locations": [
        {
         "offset": 474,
         "length": 2
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 509,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|INS|304|GCG(7)",
        "type": "SequenceVariant"
       },
       "text": "c.304ins(GCG)(7)",
       "locations": [
        {
         "offset": 524,
         "length": 16
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|DUP|429_452||",
        "type": "SequenceVariant"
       },
       "text": "c.429_452dup",
       "locations": [
        {
         "offset": 563,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|DUP||24|",
        "type": "SequenceVariant"
       },
       "text": "dup24bp",
       "locations": [
        {
         "offset": 577,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 660,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 847,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|DUP||24|",
        "type": "SequenceVariant"
       },
       "text": "dup24bp",
       "locations": [
        {
         "offset": 971,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|DUP||24|",
        "type": "SequenceVariant"
       },
       "text": "dup24bp",
       "locations": [
        {
         "offset": 1016,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|DUP||27|",
        "type": "SequenceVariant"
       },
       "text": "dup27bp",
       "locations": [
        {
         "offset": 1045,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|DUP||33|",
        "type": "SequenceVariant"
       },
       "text": "dup33bp",
       "locations": [
        {
         "offset": 1054,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|SUB|G|1074|T",
        "type": "SequenceVariant"
       },
       "text": "c.1074G>T",
       "locations": [
        {
         "offset": 1147,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 1197,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1250,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "170302",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARX",
       "locations": [
        {
         "offset": 1375,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|G|1074|T",
      "entity2": "D008607",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|DUP||33|",
      "entity2": "D008607",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|DUP||27|",
      "entity2": "D008607",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "170302",
      "entity2": "C019529",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "170302",
      "entity2": "D008607",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "c|DUP||24|",
      "entity2": "D008607",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "c|DUP|429_452||",
      "entity2": "D008607",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "c|INS|304|GCG(7)",
      "entity2": "D008607",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "24768818",
   "passages": [
    {
     "offset": 0,
     "text": "Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4921,780",
        "type": "GeneOrGeneProduct"
       },
       "text": "collagen receptor",
       "locations": [
        {
         "offset": 52,
         "length": 17
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "780",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDR1",
       "locations": [
        {
         "offset": 70,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 134,
     "text": "The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and aD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a b-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "4921,780",
        "type": "GeneOrGeneProduct"
       },
       "text": "discoidin domain receptors",
       "locations": [
        {
         "offset": 138,
         "length": 26
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "4921,780",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDRs",
       "locations": [
        {
         "offset": 166,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "780",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDR1",
       "locations": [
        {
         "offset": 173,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4921",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDR2",
       "locations": [
        {
         "offset": 182,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4921,780",
        "type": "GeneOrGeneProduct"
       },
       "text": "receptor tyrosine kinases",
       "locations": [
        {
         "offset": 215,
         "length": 25
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1277",
        "type": "GeneOrGeneProduct"
       },
       "text": "collagen",
       "locations": [
        {
         "offset": 293,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "780",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDR1",
       "locations": [
        {
         "offset": 326,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "4921",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDR2",
       "locations": [
        {
         "offset": 335,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 386,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D005355",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fibrosis",
       "locations": [
        {
         "offset": 412,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D050197",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atherosclerosis",
       "locations": [
        {
         "offset": 422,
         "length": 15
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 442,
         "length": 6
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "4921,780",
        "type": "GeneOrGeneProduct"
       },
       "text": "receptor tyrosine kinases",
       "locations": [
        {
         "offset": 492,
         "length": 25
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 540,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D000068877",
        "type": "ChemicalEntity"
       },
       "text": "imatinib",
       "locations": [
        {
         "offset": 553,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C545373",
        "type": "ChemicalEntity"
       },
       "text": "ponatinib",
       "locations": [
        {
         "offset": 566,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "-",
        "type": "ChemicalEntity"
       },
       "text": "DDR1-IN-1",
       "locations": [
        {
         "offset": 620,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C545373",
        "type": "ChemicalEntity"
       },
       "text": "Ponatinib",
       "locations": [
        {
         "offset": 631,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "780",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDR1",
       "locations": [
        {
         "offset": 699,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "4921",
        "type": "GeneOrGeneProduct"
       },
       "text": "DDR2",
       "locations": [
        {
         "offset": 708,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 759,
         "length": 5
        }
       ]
      },
      {
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     "id": "R15",
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  {
   "id": "28368423",
   "passages": [
    {
     "offset": 0,
     "text": "Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to Btk inhibition.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "17869",
        "type": "GeneOrGeneProduct"
       },
       "text": "Myc",
       "locations": [
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         "offset": 0,
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       "id": "1",
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       "text": "B-cell receptor",
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       "id": "2",
       "infons": {
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       "text": "precancerous",
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         "offset": 42,
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       ]
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       "id": "3",
       "infons": {
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       "text": "Btk",
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     "text": "Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells. Utilizing the Eu-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Eu-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79a, Btk, Plcg2 and Erk1/2. Notably, Myc-overexpressing B cells maintained elevated BCR signaling despite treatment with ibrutinib, a Bruton's tyrosine kinase inhibitor. Furthermore, PI3K/Akt pathway signaling was also increased in Eu-myc B cells, and this increase was partially suppressed with ibrutinib. In addition, experiments with Btk-null B cells revealed off-target effects of ibrutinib on BCR signaling. Our data show that in pre-malignant B cells, Myc overexpression is sufficient to activate BCR and PI3K/Akt signaling pathways and further enhances signaling following BCR ligation. Therefore, our results indicate that precancerous B cells have already acquired enhanced survival and growth capabilities before transformation, and that elevated MYC levels confer resistance to pharmacologic inhibitors of BCR signaling, which has significant implications for B-NHL treatment.",
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       "id": "6",
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         "offset": 240,
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       "id": "7",
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       "id": "15",
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       "text": "BCR",
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       "text": "Bruton's tyrosine kinase",
       "locations": [
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       "text": "PI3K",
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       "text": "myc",
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       "id": "43",
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       "id": "45",
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       "text": "MYC",
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       "id": "46",
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       "id": "47",
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       "text": "B-NHL",
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  {
   "id": "28416580",
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    {
     "offset": 0,
     "text": "A TSPO ligand attenuates brain injury after intracerebral hemorrhage.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "12257",
        "type": "GeneOrGeneProduct"
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       "text": "TSPO",
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      },
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       "id": "1",
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       "text": "brain injury",
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      {
       "id": "2",
       "infons": {
        "identifier": "D002543",
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       "text": "intracerebral hemorrhage",
       "locations": [
        {
         "offset": 44,
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    {
     "offset": 70,
     "text": "Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. After ICH, the immediate infiltration of leukocytes and activation of microglia are accompanied by a rapid up-regulation of the 18-kDa translocator protein (TSPO). TSPO ligands have shown anti-inflammatory and neuroprotective properties in models of CNS injury. In this study, we determined the impact of a TSPO ligand, etifoxine, on brain injury and inflammation in 2 mouse models of ICH. TSPO was up-regulated in Iba1(+) cells from brains of patients with ICH and in CD11b(+)CD45(int) cells from mice subjected to collagenase-induced ICH. Etifoxine significantly reduced neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In collagenase-induced ICH mice, the protection of etifoxine was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6 and TNF-a. Etifoxine improved blood-brain barrier integrity and diminished cell death. Notably, the protective effect of etifoxine was abolished in mice depleted of microglia by using a colony-stimulating factor 1 receptor inhibitor. These results indicate that the TSPO ligand etifoxine attenuates brain injury and inflammation after ICH. TSPO may be a viable therapeutic target that requires further investigations in ICH.-Li, M., Ren, H., Sheth, K. N., Shi, F.-D., Liu, Q. A TSPO ligand attenuates brain injury after intracerebral hemorrhage.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "D002543",
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       "text": "Intracerebral hemorrhage",
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         "length": 12
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       "id": "10",
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     "text": "IL-17-producing gd T (gdT17) cells are critical components of the innate immune system. However, the gene networks that control their development are unclear. Here we show that HEB (HeLa E-box binding protein, encoded by Tcf12) is required for the generation of a newly defined subset of fetal-derived CD73- gdT17 cells. HEB is required in immature CD24+CD73- gd T cells for the expression of Sox4, Sox13, and Rorc, and these genes are repressed by acute expression of the HEB antagonist Id3. HEB-deficiency also affects mature CD73+ gd T cells, which are defective in RORgt expression and IL-17 production. Additionally, the fetal TCRg chain repertoire is altered, and peripheral Vg4 gd T cells are mostly restricted to the IFNg-producing phenotype in HEB-deficient mice. Therefore, our work identifies HEB-dependent pathways for the development of CD73+ and CD73- gdT17 cells, and provides mechanistic evidence for control of the gdT17 gene network by HEB.",
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       "text": "IL-17",
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         "offset": 252,
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        "identifier": "21406",
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        "identifier": "23959",
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       "text": "CD73",
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         "offset": 429,
         "length": 4
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       "id": "10",
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        "identifier": "20677",
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       "text": "Sox4",
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         "offset": 468,
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       "id": "11",
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       "text": "Sox13",
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         "offset": 485,
         "length": 4
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       "id": "13",
       "infons": {
        "identifier": "21406",
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       "text": "HEB",
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         "offset": 548,
         "length": 3
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       "id": "14",
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       "text": "Id3",
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         "offset": 563,
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        "identifier": "21406",
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       "text": "HEB",
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       "text": "CD73",
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         "offset": 603,
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       "text": "IL-17",
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         "offset": 665,
         "length": 5
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       "id": "19",
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       "text": "TCRg",
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         "offset": 707,
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       "text": "Vg4",
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         "offset": 756,
         "length": 3
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       "id": "21",
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       "text": "IFNg",
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         "offset": 800,
         "length": 4
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       "id": "22",
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        "identifier": "21406",
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       "text": "HEB",
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         "offset": 828,
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       "text": "mice",
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        "identifier": "21406",
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       "text": "HEB",
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         "offset": 879,
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       "id": "25",
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       "text": "CD73",
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       ]
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       "id": "26",
       "infons": {
        "identifier": "23959",
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       "text": "CD73",
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         "offset": 935,
         "length": 4
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       ]
      },
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       "id": "27",
       "infons": {
        "identifier": "21406",
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       "text": "HEB",
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         "offset": 1029,
         "length": 3
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  {
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    {
     "offset": 0,
     "text": "Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene.",
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      {
       "id": "0",
       "infons": {
        "identifier": "D016543",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Primary malignant lymphoma of the brain",
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       "text": "p14",
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       "id": "2",
       "infons": {
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       "text": "tumor",
       "locations": [
        {
         "offset": 88,
         "length": 5
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    {
     "offset": 111,
     "text": "Ten primary central nervous system lymphomas (PCNSL, brain lymphomas) were examined for p14 gene exon 1beta deletion, mutation and methylation by Southern blot analysis, nucleotide analysis of polymerase chain reaction clones and Southern blot-based methylation assay. In Southern blot analysis, from the signal densities of the hybridized bands and their similarities to those of exons 2 and 3 in our previous quantitative study, we found that exon 1beta was homozygously deleted in four cases, hemizygously deleted in five cases and not deleted in one case. Thus, the same deletion patterns covered the entire p14 gene for all cases except for one case, which suggested the hemizygous deletion of exons 1beta and 2 and homozygous deletion of exon 3. In addition, although exon 1beta mutation is rare in various tumors, we detected a missense mutation (L50R) in one case with a hemizygous deletion. Methylation of the 5'CpG island of the p14 gene was not suggested for any case without homozygous deletion. Our observation of frequent p14 gene abnormalities (90%) and inactivation (40-60%) was in striking contrast to the same pathological subtype of systemic lymphoma in which p14 gene abnormalities and inactivation were infrequent, suggesting a difference in carcinogenesis between PCNSL and systemic lymphoma.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D016543",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "primary central nervous system lymphomas",
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       "infons": {
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       "text": "PCNSL",
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         "offset": 157,
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       "id": "5",
       "infons": {
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       "text": "brain lymphomas",
       "locations": [
        {
         "offset": 164,
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       ]
      },
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       "id": "6",
       "infons": {
        "identifier": "11102",
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       "text": "p14",
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       "id": "7",
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        "identifier": "11102",
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       "text": "p14",
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         "offset": 723,
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumors",
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       ]
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       "id": "9",
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        "identifier": "p|SUB|L|50|R",
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       "text": "L50R",
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         "offset": 965,
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       ]
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       "id": "10",
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        "identifier": "11102",
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       "text": "p14",
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         "offset": 1050,
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       ]
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       "id": "11",
       "infons": {
        "identifier": "11102",
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       "text": "p14",
       "locations": [
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         "offset": 1147,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008223",
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       "text": "systemic lymphoma",
       "locations": [
        {
         "offset": 1263,
         "length": 17
        }
       ]
      },
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       "id": "13",
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        "identifier": "11102",
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       "text": "p14",
       "locations": [
        {
         "offset": 1290,
         "length": 3
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      },
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       "id": "14",
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       "text": "carcinogenesis",
       "locations": [
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         "offset": 1374,
         "length": 14
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       ]
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       "id": "15",
       "infons": {
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       "text": "PCNSL",
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         "offset": 1397,
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       "text": "systemic lymphoma",
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   "passages": [
    {
     "offset": 0,
     "text": "Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "C535741",
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       "text": "Congenital disorder of glycosylation Ic",
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    {
     "offset": 90,
     "text": "We describe a new cause of congenital disorder of glycosylation-Ic (CDG-Ic) in a young girl with a rather mild CDG phenotype. Her cells accumulated lipid-linked oligosaccharides lacking three glucose residues, and sequencing of the ALG6 gene showed what initially appeared to be a homozygous novel point mutation (338G>A). However, haplotype analysis showed that the patient does not carry any paternal DNA markers extending 33kb in the telomeric direction from the ALG6 region, and microsatellite analysis extended the abnormal region to at least 2.5Mb. We used high-resolution karyotyping to confirm a deletion (10-12Mb) [del(1)(p31.2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation.",
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       "id": "2",
       "infons": {
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       "text": "congenital disorder of glycosylation-Ic",
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       "text": "CDG-Ic",
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       "text": "CDG",
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       "infons": {
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       "text": "lipid-linked oligosaccharides",
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       "text": "glucose",
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       "text": "ALG6",
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       "text": "338G>A",
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       "text": "patient",
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       "text": "ALG6",
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       "text": "deletion (10-12Mb)",
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       "text": "del(1)(p31.2p32.3)",
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       "text": "CDG",
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         "offset": 849,
         "length": 3
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       ]
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       "id": "14",
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       "text": "CDG-Ic",
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         "length": 6
        }
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     "id": "R3",
     "infons": {
      "entity1": "c|DEL||10-12MB",
      "entity2": "D018981",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "c|DEL||10-12MB",
      "entity2": "C535741",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "29929",
      "entity2": "D018981",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "29929",
      "entity2": "C535741",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16506214",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic variation in the COX-2 gene and the association with prostate cancer risk.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4513",
        "type": "GeneOrGeneProduct"
       },
       "text": "COX-2",
       "locations": [
        {
         "offset": 25,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 61,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 83,
     "text": "COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case-control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI=0.64-0.96) and 0.65 (95% CI=0.45-0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p=0.036, global simulated p-value=0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "4513",
        "type": "GeneOrGeneProduct"
       },
       "text": "COX-2",
       "locations": [
        {
         "offset": 83,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D016718",
        "type": "ChemicalEntity"
       },
       "text": "arachidonic acid",
       "locations": [
        {
         "offset": 126,
         "length": 16
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D011453",
        "type": "ChemicalEntity"
       },
       "text": "prostaglandins",
       "locations": [
        {
         "offset": 146,
         "length": 14
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D011453",
        "type": "ChemicalEntity"
       },
       "text": "prostaglandins",
       "locations": [
        {
         "offset": 166,
         "length": 14
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4513",
        "type": "GeneOrGeneProduct"
       },
       "text": "COX-2",
       "locations": [
        {
         "offset": 193,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammation",
       "locations": [
        {
         "offset": 215,
         "length": 12
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D010146",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pain",
       "locations": [
        {
         "offset": 232,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "4513",
        "type": "GeneOrGeneProduct"
       },
       "text": "COX-2",
       "locations": [
        {
         "offset": 406,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 428,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "carcinogenesis",
       "locations": [
        {
         "offset": 434,
         "length": 14
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 473,
         "length": 15
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "4513",
        "type": "GeneOrGeneProduct"
       },
       "text": "COX-2",
       "locations": [
        {
         "offset": 542,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 573,
         "length": 15
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer prostate",
       "locations": [
        {
         "offset": 652,
         "length": 15
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "4513",
        "type": "GeneOrGeneProduct"
       },
       "text": "COX-2",
       "locations": [
        {
         "offset": 804,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 968,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|SUB|T|+3100|G",
        "type": "SequenceVariant"
       },
       "text": "+3100 T/G",
       "locations": [
        {
         "offset": 1163,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|SUB|C|+8365|T",
        "type": "SequenceVariant"
       },
       "text": "+8365 C/T",
       "locations": [
        {
         "offset": 1177,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|SUB|T|+3100|G",
        "type": "SequenceVariant"
       },
       "text": "+3100 T/G",
       "locations": [
        {
         "offset": 1354,
         "length": 9
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|SUB|C|+8365|T",
        "type": "SequenceVariant"
       },
       "text": "+8365 C/T",
       "locations": [
        {
         "offset": 1368,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1471,
         "length": 15
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammation",
       "locations": [
        {
         "offset": 1570,
         "length": 12
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate carcinogenesis",
       "locations": [
        {
         "offset": 1598,
         "length": 23
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "4513",
        "type": "GeneOrGeneProduct"
       },
       "text": "COX-2",
       "locations": [
        {
         "offset": 1661,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1694,
         "length": 15
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|C|+8365|T",
      "entity2": "D011471",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|SUB|T|+3100|G",
      "entity2": "c|SUB|C|+8365|T",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|SUB|T|+3100|G",
      "entity2": "D011471",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D011453",
      "entity2": "D010146",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D011453",
      "entity2": "D007249",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D016718",
      "entity2": "D011453",
      "type": "Conversion",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "4513",
      "entity2": "D010146",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "4513",
      "entity2": "D007249",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "4513",
      "entity2": "D011453",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "4513",
      "entity2": "D016718",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "4513",
      "entity2": "D011471",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "4513",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "16801510",
   "passages": [
    {
     "offset": 0,
     "text": "Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "long QT syndrome",
       "locations": [
        {
         "offset": 13,
         "length": 16
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 64,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 106,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 133,
     "text": "BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "long QT syndrome",
       "locations": [
        {
         "offset": 158,
         "length": 16
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "Methadone",
       "locations": [
        {
         "offset": 211,
         "length": 9
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "inpatient",
       "locations": [
        {
         "offset": 290,
         "length": 9
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QT interval prolongation",
       "locations": [
        {
         "offset": 326,
         "length": 24
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 356,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 593,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 627,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 647,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 734,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 753,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 876,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 902,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QT prolongation",
       "locations": [
        {
         "offset": 1022,
         "length": 15
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 1058,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1080,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QTc prolongation",
       "locations": [
        {
         "offset": 1108,
         "length": 16
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1212,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 1235,
         "length": 9
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D016171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "torsades de pointes",
       "locations": [
        {
         "offset": 1261,
         "length": 19
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 1338,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 1497,
         "length": 9
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "1576",
        "type": "GeneOrGeneProduct"
       },
       "text": "cytochrome P-450 3A4",
       "locations": [
        {
         "offset": 1513,
         "length": 20
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D007008",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypokalemia",
       "locations": [
        {
         "offset": 1558,
         "length": 11
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QT interval prolongation",
       "locations": [
        {
         "offset": 1612,
         "length": 24
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "methadone",
       "locations": [
        {
         "offset": 1640,
         "length": 9
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1662,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D008691",
        "type": "ChemicalEntity"
       },
       "text": "Methadone",
       "locations": [
        {
         "offset": 1733,
         "length": 9
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D065692",
        "type": "ChemicalEntity"
       },
       "text": "cytochrome P-450 3A4 inhibitors",
       "locations": [
        {
         "offset": 1761,
         "length": 31
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D011188",
        "type": "ChemicalEntity"
       },
       "text": "potassium",
       "locations": [
        {
         "offset": 1794,
         "length": 9
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "QT prolongation",
       "locations": [
        {
         "offset": 1844,
         "length": 15
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D008133",
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   "id": "23864035",
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    {
     "offset": 0,
     "text": "Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes.",
     "annotations": [
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       "id": "0",
       "infons": {
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     "text": "Bortezomib (bort)-dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort-dex. The median number of bort-dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was peripheral neuropathy, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort-dex a single line of prior therapy. Bort-dex was an effective salvage treatment for MM patients, particularly for those in first relapse.",
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       "text": "peripheral neuropathy",
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     "offset": 0,
     "text": "Metalloprotease-disintegrin ADAM12 actively promotes the stem cell-like phenotype in claudin-low breast cancer.",
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     "text": "BACKGROUND: ADAM12 is upregulated in human breast cancers and is a predictor of chemoresistance in estrogen receptor-negative tumors. ADAM12 is induced during epithelial-to-mesenchymal transition, a feature associated with claudin-low breast tumors, which are enriched in cancer stem cell (CSC) markers. It is currently unknown whether ADAM12 plays an active role in promoting the CSC phenotype in breast cancer cells. METHODS: ADAM12 expression was downregulated in representative claudin-low breast cancer cell lines, SUM159PT and Hs578T, using siRNA transfection or inducible shRNA expression. Cell characteristics commonly associated with the CSC phenotype in vitro (cell migration, invasion, anoikis resistance, mammosphere formation, ALDH activity, and expression of the CD44 and CD24 cell surface markers) and in vivo (tumor formation in mice using limiting dilution transplantation assays) were evaluated. RNA sequencing was performed to identify global gene expression changes after ADAM12 knockdown. RESULTS: We found that sorted SUM159PT cell populations with high ADAM12 levels had elevated expression of CSC markers and an increased ability to form mammospheres. ADAM12 knockdown reduced cell migration and invasion, decreased anoikis resistance, and compromised mammosphere formation. ADAM12 knockdown also diminished ALDEFLUOR(+) and CD44(hi)/CD24(-/lo) CSC-enriched populations in vitro and reduced tumorigenesis in mice in vivo. RNA sequencing identified a significant overlap between ADAM12- and Epidermal Growth Factor Receptor (EGFR)-regulated genes. Consequently, ADAM12 knockdown lowered the basal activation level of EGFR, and this effect was abolished by batimastat, a metalloproteinase inhibitor. Furthermore, incubation of cells with exogenously added EGF prevented the downregulation of CD44(hi)/CD24(-/lo) cell population by ADAM12 knockdown. CONCLUSIONS: These results indicate that ADAM12 actively supports the CSC phenotype in claudin-low breast cancer cells via modulation of the EGFR pathway.",
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     "text": "The goal of this study was to perform 5-alpha-reductase type 2 gene (SRD5A2) analysis in a male pseudohermaphrodite (MPH) patient with normal testosterone (T) production and normal androgen receptor (AR) gene coding sequences. A patient of Chinese origin with ambiguous genitalia at 14 months, a 46,XY karyotype, and normal T secretion under human chorionic gonadotropin (hCG) stimulation underwent a gonadectomy at 20 months. Exons 1-8 of the AR gene and exons 1-5 of the SRD5A2 gene were sequenced from peripheral blood DNA. AR gene coding sequences were normal. SRD5A2 gene analysis revealed 2 consecutive mutations in exon 4, each located in a different allele: 1) a T nucleotide deletion, which predicts a frameshift mutation from codon 219, and 2) a missense mutation at codon 227, where the substitution of guanine (CGA) by adenine (CAA) predicts a glutamine replacement of arginine (R227Q). Testes located in the inguinal canal showed a normal morphology for age. The patient was a compound heterozygote for SRD5A2 mutations, carrying 2 mutations in exon 4. The patient showed an R227Q mutation that has been described in an Asian population and MPH patients, along with a novel frameshift mutation, Tdel219. Testis morphology showed that, during early infancy, the 5-alpha-reductase enzyme deficiency may not have affected interstitial or tubular development.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-alpha-reductase type 2",
       "locations": [
        {
         "offset": 153,
         "length": 24
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 184,
         "length": 6
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D058490",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "male pseudohermaphrodite",
       "locations": [
        {
         "offset": 206,
         "length": 24
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D058490",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPH",
       "locations": [
        {
         "offset": 232,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 237,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D013739",
        "type": "ChemicalEntity"
       },
       "text": "testosterone",
       "locations": [
        {
         "offset": 257,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D013739",
        "type": "ChemicalEntity"
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       "text": "T",
       "locations": [
        {
         "offset": 271,
         "length": 1
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "androgen receptor",
       "locations": [
        {
         "offset": 296,
         "length": 17
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 315,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 344,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D013739",
        "type": "ChemicalEntity"
       },
       "text": "T",
       "locations": [
        {
         "offset": 439,
         "length": 1
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D006063",
        "type": "ChemicalEntity"
       },
       "text": "human chorionic gonadotropin",
       "locations": [
        {
         "offset": 457,
         "length": 28
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D006063",
        "type": "ChemicalEntity"
       },
       "text": "hCG",
       "locations": [
        {
         "offset": 487,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 559,
         "length": 2
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 588,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "AR",
       "locations": [
        {
         "offset": 642,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 680,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|DEL|CODON219|T",
        "type": "SequenceVariant"
       },
       "text": "T nucleotide deletion, which predicts a frameshift mutation from codon 219",
       "locations": [
        {
         "offset": 786,
         "length": 74
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs9332964",
        "type": "SequenceVariant"
       },
       "text": "guanine (CGA) by adenine (CAA)",
       "locations": [
        {
         "offset": 929,
         "length": 30
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs9332964",
        "type": "SequenceVariant"
       },
       "text": "glutamine replacement of arginine",
       "locations": [
        {
         "offset": 971,
         "length": 33
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs9332964",
        "type": "SequenceVariant"
       },
       "text": "R227Q",
       "locations": [
        {
         "offset": 1006,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1091,
         "length": 7
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 1131,
         "length": 6
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1185,
         "length": 7
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "rs9332964",
        "type": "SequenceVariant"
       },
       "text": "R227Q",
       "locations": [
        {
         "offset": 1203,
         "length": 5
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D058490",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MPH",
       "locations": [
        {
         "offset": 1269,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1273,
         "length": 8
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "c|DEL|CODON219|T",
        "type": "SequenceVariant"
       },
       "text": "Tdel219",
       "locations": [
        {
         "offset": 1323,
         "length": 7
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "5-alpha-reductase",
       "locations": [
        {
         "offset": 1389,
         "length": 17
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D013739",
      "entity2": "D006063",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|DEL|CODON219|T",
      "entity2": "D058490",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs9332964",
      "entity2": "D058490",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "6716",
      "entity2": "D058490",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15583840",
   "passages": [
    {
     "offset": 0,
     "text": "Tumor associated antigen recognition by autologous serum in patients with breast cancer.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Tumor",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 60,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 74,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 89,
     "text": "Breast cancer accounts for 30-40% of all deaths from cancers in females. In an effort to identify tumor associated antigens that may be useful for immunotherapy, we utilized serological analysis of recombinant cDNA expression libraries (SEREX) technique to identify breast cancer-associated antigens. SEREX screening of cDNA expression libraries derived from 3 breast cancer patients identified a total of 88 positive clones (bcg-1 to bcg-88), including 27 hitherto unknown sequences. The cDNA sequences and mRNA expression patterns were characterized. Seroreactivity of the SEREX clones were determined in sera from 75 breast cancer patients, 75 colon cancer patients, and 25 healthy donors. Expression analysis on a cDNA panel from 17 different normal tissues by reverse transcription-PCR (RT-PCR) revealed tissue restricted mRNA expression of 2 of the 27 unknown antigens. Bcg-72 is expressed only in breast, prostate and thymus, while bcg-84 is expressed at moderate levels in testis, spleen and breast. The other 25 unknown antigens were expressed in most other tissues. Serologic assay revealed that 7 out of the 88 clones showed reactivity to at least one serum from either 75 breast or 75 colon cancer patients. These clones did not react with sera from a panel of 25 healthy adult individuals. Our results demonstrate the utility of the SEREX approach for the identification of potential tumor associated antigens in human breast cancer.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Breast cancer",
       "locations": [
        {
         "offset": 89,
         "length": 13
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancers",
       "locations": [
        {
         "offset": 142,
         "length": 7
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 187,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 355,
         "length": 13
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 450,
         "length": 13
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 464,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 709,
         "length": 13
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 723,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colon cancer",
       "locations": [
        {
         "offset": 736,
         "length": 12
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 749,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colon cancer",
       "locations": [
        {
         "offset": 1286,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1299,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1486,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1515,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 1521,
         "length": 13
        }
       ]
      }
     ]
    }
   ],
   "relations": []
  },
  {
   "id": "15623763",
   "passages": [
    {
     "offset": 0,
     "text": "TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFBI",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C537881,D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lattice and granular corneal dystrophies",
       "locations": [
        {
         "offset": 29,
         "length": 40
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 80,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 90,
     "text": "PURPOSE: To identify mutations in the TGFBI gene in Indian patients with lattice corneal dystrophy (LCD) or granular corneal dystrophy (GCD) and to look for genotype-phenotype correlations. METHODS: Thirty-seven unrelated patients were studied, 18 with LCD and 19 with GCD. The diagnosis of LCD or GCD was made on the basis of clinical and/or histopathological evaluation. Exons and flanking intron sequences of the TGFBI gene were amplified by PCR with specific primers. PCR products were screened by the method of single-strand conformation polymorphism followed by sequencing. Mutations were confirmed by screening at least 100 unrelated normal control subjects. RESULTS: Mutations were identified in 14 of 18 patients with LCD and in all 19 patients with GCD. In LCD, three novel heterozygous mutations found were glycine-594-valine (Gly594Val) in 2 of 18 patients, valine-539-aspartic acid (Val539Asp) in 1 patient, and deletion of valine 624, valine 625 (Val624-Val625del) in 1 patient. In addition, mutation of arginine 124-to-cysteine (Arg124Cys) was found in 8 of 18 patients and histidine 626-to-arginine (His626Arg) in 2 of 18 patients. Atypical clinical features for LCD were noted in patients with the Gly594Val and Val624-Val625del mutations. In GCD, 18 patients with GCD type I had a mutation of arginine 555-to-tryptophan (Arg555Trp) and 1 patient with GCD type III (Reis-Bucklers dystrophy), had the Arg124Leu mutation. Seven novel single-nucleotide polymorphisms (SNPs) were also found, of which a change of leucine 269 to phenylalanine (Leu269Phe) was found in 12 of 18 patients with the Arg555Trp mutation. CONCLUSIONS: Arg124Cys and Arg555Trp appear to be the predominant mutations causing LCD and GCD, respectively, in the population studied. The novel mutations identified in this study are associated with distinct phenotypes.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFBI",
       "locations": [
        {
         "offset": 128,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 149,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lattice corneal dystrophy",
       "locations": [
        {
         "offset": 163,
         "length": 25
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD",
       "locations": [
        {
         "offset": 190,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "granular corneal dystrophy",
       "locations": [
        {
         "offset": 198,
         "length": 26
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GCD",
       "locations": [
        {
         "offset": 226,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 312,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD",
       "locations": [
        {
         "offset": 343,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GCD",
       "locations": [
        {
         "offset": 359,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD",
       "locations": [
        {
         "offset": 381,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GCD",
       "locations": [
        {
         "offset": 388,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFBI",
       "locations": [
        {
         "offset": 506,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 803,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD",
       "locations": [
        {
         "offset": 817,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 835,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003317",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GCD",
       "locations": [
        {
         "offset": 849,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD",
       "locations": [
        {
         "offset": 857,
         "length": 3
        }
       ]
      },
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        "type": "SequenceVariant"
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       "text": "glycine-594-valine",
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      },
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       "id": "21",
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      },
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       "id": "27",
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       "id": "32",
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        "identifier": "p|SUB|H|626|R",
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       "id": "33",
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        "identifier": "p|SUB|H|626|R",
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       "id": "39",
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      },
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       "id": "44",
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       "text": "patient",
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      },
      {
       "id": "45",
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        "identifier": "C535476",
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       ]
      },
      {
       "id": "46",
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        "identifier": "C535476",
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       "text": "Reis-Bucklers dystrophy",
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  {
   "id": "17033686",
   "passages": [
    {
     "offset": 0,
     "text": "A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "10084",
        "type": "GeneOrGeneProduct"
       },
       "text": "PQBP1",
       "locations": [
        {
         "offset": 32,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008850",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microphthalmia",
       "locations": [
        {
         "offset": 62,
         "length": 14
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D008831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microcephaly",
       "locations": [
        {
         "offset": 78,
         "length": 12
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mental retardation",
       "locations": [
        {
         "offset": 96,
         "length": 18
        }
       ]
      }
     ]
    },
    {
     "offset": 116,
     "text": "X-linked mental retardation has been traditionally divided into syndromic (S-XLMR) and non-syndromic forms (NS-XLMR), although the borderlines between these phenotypes begin to vanish and mutations in a single gene, for example PQBP1, can cause S-XLMR as well as NS-XLMR. Here, we report two maternal cousins with an apparently X-linked phenotype of mental retardation (MR), microphthalmia, choroid coloboma, microcephaly, renal hypoplasia, and spastic paraplegia. By multipoint linkage analysis with markers spanning the entire X-chromosome we mapped the disease locus to a 28-Mb interval between Xp11.4 and Xq12, including the BCOR gene. A missense mutation in BCOR was described in a family with Lenz microphthalmia syndrome, a phenotype showing substantial overlapping features with that described in the two cousins. However, no mutation in the BCOR gene was found in both patients. Subsequent mutation analysis of PQBP1, located within the delineated linkage interval in Xp11.23, revealed a 2-bp deletion, c.461_462delAG, that cosegregated with the disease. Notably, the same mutation is associated with the Hamel cerebropalatocardiac syndrome, another form of S-XLMR. Haplotype analysis suggests a germline mosaicism of the 2-bp deletion in the maternal grandmother of both affected individuals. In summary, our findings demonstrate for the first time that mutations in PQBP1 are associated with an S-XLMR phenotype including microphthalmia, thereby further extending the clinical spectrum of phenotypes associated with PQBP1 mutations.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked mental retardation",
       "locations": [
        {
         "offset": 116,
         "length": 27
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLMR",
       "locations": [
        {
         "offset": 193,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLMR",
       "locations": [
        {
         "offset": 227,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "10084",
        "type": "GeneOrGeneProduct"
       },
       "text": "PQBP1",
       "locations": [
        {
         "offset": 344,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLMR",
       "locations": [
        {
         "offset": 363,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLMR",
       "locations": [
        {
         "offset": 382,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked phenotype of mental retardation",
       "locations": [
        {
         "offset": 444,
         "length": 40
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MR",
       "locations": [
        {
         "offset": 486,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008850",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microphthalmia",
       "locations": [
        {
         "offset": 491,
         "length": 14
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "choroid coloboma",
       "locations": [
        {
         "offset": 507,
         "length": 16
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microcephaly",
       "locations": [
        {
         "offset": 525,
         "length": 12
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "renal hypoplasia",
       "locations": [
        {
         "offset": 539,
         "length": 16
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D010264",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "spastic paraplegia",
       "locations": [
        {
         "offset": 561,
         "length": 18
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "54880",
        "type": "GeneOrGeneProduct"
       },
       "text": "BCOR",
       "locations": [
        {
         "offset": 745,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "54880",
        "type": "GeneOrGeneProduct"
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       "text": "BCOR",
       "locations": [
        {
         "offset": 779,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C537464",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Lenz microphthalmia syndrome",
       "locations": [
        {
         "offset": 815,
         "length": 28
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "54880",
        "type": "GeneOrGeneProduct"
       },
       "text": "BCOR",
       "locations": [
        {
         "offset": 966,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 994,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "10084",
        "type": "GeneOrGeneProduct"
       },
       "text": "PQBP1",
       "locations": [
        {
         "offset": 1036,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs606231195",
        "type": "SequenceVariant"
       },
       "text": "c.461_462delAG",
       "locations": [
        {
         "offset": 1128,
         "length": 14
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "C537761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hamel cerebropalatocardiac syndrome",
       "locations": [
        {
         "offset": 1230,
         "length": 35
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLMR",
       "locations": [
        {
         "offset": 1285,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "10084",
        "type": "GeneOrGeneProduct"
       },
       "text": "PQBP1",
       "locations": [
        {
         "offset": 1493,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLMR",
       "locations": [
        {
         "offset": 1524,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D008850",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microphthalmia",
       "locations": [
        {
         "offset": 1549,
         "length": 14
        }
       ]
      },
      {
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     "text": "Interaction between warfarin and levofloxacin: case series.",
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     "text": "Rapid reversal of anticoagulation reduces hemorrhage volume in a mouse model of warfarin-associated intracerebral hemorrhage.",
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     "text": "Warfarin-associated intracerebral hemorrhage (W-ICH) is a severe type of stroke. There is no consensus on the optimal treatment for W-ICH. Using a mouse model, we tested whether the rapid reversal of anticoagulation using human prothrombin complex concentrate (PCC) can reduce hemorrhagic blood volume. Male CD-1 mice were treated with warfarin (2 mg/kg over 24 h), resulting in a mean (+/-s.d.) International Normalized Ratio of 3.5+/-0.9. First, we showed that an intravenous administration of human PCC rapidly reversed anticoagulation in mice. Second, a stereotactic injection of collagenase was administered to induce hemorrhage in the right striatum. Forty-five minutes later, the animals were randomly treated with PCC (100 U/kg) or saline i.v. (n=12 per group). Twenty-four hours after hemorrhage induction, hemorrhagic blood volume was quantified using a photometric hemoglobin assay. The mean hemorrhagic blood volume was reduced in PCC-treated animals (6.5+/-3.1 microL) compared with saline controls (15.3+/-11.2 microL, P=0.015). In the saline group, 45% of the mice developed large hematomas (i.e., >15 microL). In contrast, such extensive lesions were never found in the PCC group. We provide experimental data suggesting PCC to be an effective acute treatment for W-ICH in terms of reducing hemorrhagic blood volume. Future studies are needed to assess the therapeutic potential emerging from our finding for human W-ICH.",
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     "text": "FGFR4 Gly388Arg polymorphism and prostate cancer risk in Scottish men.",
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     "text": "Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan.",
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       "id": "9",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "prostate cancer",
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         "offset": 477,
         "length": 15
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       ]
      },
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       "id": "10",
       "infons": {
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       "text": "patients",
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         "length": 8
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       "text": "prostate cancer",
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       "text": "patients",
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       "infons": {
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       "text": "BPH",
       "locations": [
        {
         "offset": 581,
         "length": 3
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       ]
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       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 585,
         "length": 8
        }
       ]
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       "id": "15",
       "infons": {
        "identifier": "2264",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGFR4",
       "locations": [
        {
         "offset": 711,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D011471",
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       "text": "prostate cancer",
       "locations": [
        {
         "offset": 840,
         "length": 15
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       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 944,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BPH",
       "locations": [
        {
         "offset": 987,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 1067,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D011470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BPH",
       "locations": [
        {
         "offset": 1078,
         "length": 3
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1082,
         "length": 8
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       ]
      },
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       "id": "22",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
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         "offset": 1107,
         "length": 6
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       ]
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       "infons": {
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       "text": "Gly(388)Arg",
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         "offset": 1179,
         "length": 11
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        "identifier": "2264",
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       "text": "FGFR4",
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         "offset": 1194,
         "length": 5
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       ]
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       "id": "25",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1241,
         "length": 15
        }
       ]
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       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "men",
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         "offset": 1269,
         "length": 3
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   "id": "20335448",
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    {
     "offset": 0,
     "text": "A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain.",
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       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
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         "offset": 42,
         "length": 5
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       ]
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       "id": "1",
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       "text": "glucocorticoid receptor",
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         "offset": 48,
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      {
       "id": "2",
       "infons": {
        "identifier": "C564221",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "glucocorticoid resistance",
       "locations": [
        {
         "offset": 91,
         "length": 25
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       ]
      }
     ]
    },
    {
     "offset": 175,
     "text": "CONTEXT: Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by partial insensitivity to glucocorticoids, caused by mutations in the glucocorticoid receptor (GR) gene. Most of the reported cases are adults, demonstrating symptoms associated with mineralocorticoid and/or adrenal androgen excess caused by compensatively increased secretion of the adrenocorticotropic hormone. PATIENT: We identified a new 2-yr-old female case of generalized glucocorticoid resistance syndrome. The patient (TJ) presented with a generalized seizure associated with hypoglycemia and hypokalemia. She also had hypertension and premature pubarche, whereas dexamethasone effectively suppressed these clinical manifestations. RESULTS: The patient's GR gene had a heterozygotic mutation (G-->A) at nucleotide position 2141 (exon 8), which resulted in substitution of arginine by glutamine at amino acid position 714 in the ligand-binding domain (LBD) of the GR alpha. Molecular analysis revealed that the mutant receptor had significantly impaired transactivation activity with a 2-fold reduction in affinity to ligand. It showed attenuated transactivation of the activation function (AF)-2 and reduced binding to a p160 nuclear receptor coactivator. Computer-based structural analysis revealed that replacement of arginine by glutamine at position 714 transmitted a conformational change to the LBD and the AF-2 transactivation surface, resulting in a decreased binding affinity to ligand and to the LXXLL coactivator motif. CONCLUSIONS: Dexamethasone treatment is effective in controlling the premature pubarche, hypoglycemia, hypertension, and hypokalemia in this child case, wherein arginine 714 plays a key role in the proper formation of the ligand-binding pocket and the AF-2 surface of the GR alpha LBD.",
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       "id": "3",
       "infons": {
        "identifier": "C564221",
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       "text": "glucocorticoid resistance",
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       "text": "glucocorticoid receptor",
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       "text": "mineralocorticoid",
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       "text": "androgen",
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       "text": "PATIENT",
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         "offset": 601,
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       ]
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      {
       "id": "10",
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       "text": "glucocorticoid resistance",
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         "length": 25
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       "text": "patient",
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        {
         "offset": 748,
         "length": 7
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       ]
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       "infons": {
        "identifier": "D007003",
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       "text": "hypoglycemia",
       "locations": [
        {
         "offset": 772,
         "length": 12
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D007008",
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       "text": "hypokalemia",
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        {
         "offset": 789,
         "length": 11
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       ]
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       "id": "15",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "hypertension",
       "locations": [
        {
         "offset": 815,
         "length": 12
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "C567552",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "premature pubarche",
       "locations": [
        {
         "offset": 832,
         "length": 18
        }
       ]
      },
      {
       "id": "17",
       "infons": {
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       "text": "dexamethasone",
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       "text": "patient",
       "locations": [
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       "id": "19",
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        "identifier": "2908",
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       "text": "GR",
       "locations": [
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         "length": 2
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       ]
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       "id": "20",
       "infons": {
        "identifier": "c|SUB|G|2141|A",
        "type": "SequenceVariant"
       },
       "text": "(G-->A) at nucleotide position 2141",
       "locations": [
        {
         "offset": 988,
         "length": 35
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|SUB|R|714|Q",
        "type": "SequenceVariant"
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       "text": "arginine by glutamine at amino acid position 714",
       "locations": [
        {
         "offset": 1068,
         "length": 48
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "2908",
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       "text": "GR alpha",
       "locations": [
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         "offset": 1159,
         "length": 8
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "8648",
        "type": "GeneOrGeneProduct"
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       "text": "p160 nuclear receptor coactivator",
       "locations": [
        {
         "offset": 1417,
         "length": 33
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "c|SUB|R|714|Q",
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       "text": "arginine by glutamine at position 714",
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       ]
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       "id": "25",
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       "text": "Dexamethasone",
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      {
       "id": "26",
       "infons": {
        "identifier": "C567552",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "premature pubarche",
       "locations": [
        {
         "offset": 1796,
         "length": 18
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D007003",
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       "text": "hypoglycemia",
       "locations": [
        {
         "offset": 1816,
         "length": 12
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "hypertension",
       "locations": [
        {
         "offset": 1830,
         "length": 12
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D007008",
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       "text": "hypokalemia",
       "locations": [
        {
         "offset": 1848,
         "length": 11
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       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "c|Allele|R|714",
        "type": "SequenceVariant"
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       "text": "arginine 714",
       "locations": [
        {
         "offset": 1888,
         "length": 12
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       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "2908",
        "type": "GeneOrGeneProduct"
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       "text": "GR alpha",
       "locations": [
        {
         "offset": 1999,
         "length": 8
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  {
   "id": "21695597",
   "passages": [
    {
     "offset": 0,
     "text": "MHC region and risk of systemic lupus erythematosus in African American women.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "3123,720",
        "type": "GeneOrGeneProduct"
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       "text": "MHC",
       "locations": [
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       "text": "systemic lupus erythematosus",
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       "text": "women",
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     "text": "The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case-control study (380 cases, 765 age-matched controls) nested within the prospective Black Women's Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6 10(-5)) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 10(-4)), rs2071349 (OR = 1.53, p = 1.0 10(-3)), and rs2844580 (OR = 1.43, p = 1.3 10(-3)), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "3123,720",
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       "text": "major histocompatibility complex",
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       "infons": {
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       "text": "MHC",
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     "offset": 0,
     "text": "Plasminogen activator inhibitor type 1 serum levels and 4G/5G gene polymorphism in morbidly obese Hispanic patients with non-alcoholic fatty liver disease.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5054",
        "type": "GeneOrGeneProduct"
       },
       "text": "Plasminogen activator inhibitor type 1",
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       },
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         "length": 5
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       ]
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       "id": "2",
       "infons": {
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       "text": "patients",
       "locations": [
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         "offset": 107,
         "length": 8
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       "locations": [
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     "text": "BACKGROUND: The plasminogen activator inhibitor type-1 (PAI-1) has been implicated in the regulation of fibrinolysis and extracellular matrix components. The single base pair guanine insertion/deletion polymorphism (4G/5G) within the promoter region of the PAI-1 gene influences PAI-1 synthesis and may modulate hepatic fibrogenesis. AIM: To evaluate the influence of PAI-1 serum levels and 4G/5G polymorphism on the risk of liver fibrosis associated to non-alcoholic fatty liver disease (NAFLD) in morbidly obese patients. MATERIAL AND METHODS: Case-control study of 50 obese patients undergoing bariatric surgery and 71 non-obese subjects matched by age and sex. Anthropometric and biochemical measurements were performed, including PAI-1 serum levels. Genomic DNA was obtained to assess the presence of 4G/5G polymorphism. RESULTS: BMI, insulinemia, triglycerides, HOMA-IR, hypertension and diabetes were significantly higher in obese patients compared to control subjects. PAI-1 serum levels observed in obese patients were significantly lower (10.63 4.82) compared to controls (14.26 11.4; p < 0.05). No differences were observed in the PAI-1 4G/5G promoter genotypes frequencies (p = 0.12). No differences were observed in PAI-1 plasma levels among obese patients with liver fibrosis (10.64 4.35) compared to patients without liver fibrosis (10.61 5.2; p = 0.985). PAI-1 4G/5G promoter genotypes frequencies were similar in patients with or without liver fibrosis associated to NASH (p = 0.6). CONCLUSIONS: Morbidly obese patients had significantly lower PAI-1 serum levels with similar PAI-1 4G/5G genotypes frequencies compared to non-obese subjects. The frequency of 4G/5G genotypes in Chilean Hispanic healthy subjects was similar to that described in other populations. No association was found between PAI-1 serum levels or 4G/5G genotype with liver fibrosis in obese patients.",
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      "type": "Positive_Correlation",
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     "id": "R1",
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  {
   "id": "28468941",
   "passages": [
    {
     "offset": 0,
     "text": "Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "857",
        "type": "GeneOrGeneProduct"
       },
       "text": "caveolin-1",
       "locations": [
        {
         "offset": 9,
         "length": 10
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4086,4090,4093",
        "type": "GeneOrGeneProduct"
       },
       "text": "Smad",
       "locations": [
        {
         "offset": 29,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "rs587777017",
        "type": "SequenceVariant"
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       "text": "adenine 474 deletion",
       "locations": [
        {
         "offset": 88,
         "length": 20
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "rs587777017",
        "type": "SequenceVariant"
       },
       "text": "c.474delA",
       "locations": [
        {
         "offset": 119,
         "length": 9
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patient",
       "locations": [
        {
         "offset": 133,
         "length": 7
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       ]
      },
      {
       "id": "5",
       "infons": {
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        "type": "DiseaseOrPhenotypicFeature"
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       "text": "pulmonary hypertension",
       "locations": [
        {
         "offset": 192,
         "length": 22
        }
       ]
      }
     ]
    },
    {
     "offset": 216,
     "text": "A heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFb receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation.",
     "annotations": [
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       "id": "6",
       "infons": {
        "identifier": "857",
        "type": "GeneOrGeneProduct"
       },
       "text": "caveolin-1",
       "locations": [
        {
         "offset": 231,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs587777017",
        "type": "SequenceVariant"
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       "text": "c.474delA",
       "locations": [
        {
         "offset": 242,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pulmonary arterial hypertension",
       "locations": [
        {
         "offset": 308,
         "length": 31
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 341,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "857",
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       },
       "text": "caveolin-1",
       "locations": [
        {
         "offset": 383,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "857",
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       "text": "caveolin-1",
       "locations": [
        {
         "offset": 555,
         "length": 10
        }
       ]
      },
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       "id": "12",
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       "text": "patient",
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         "offset": 582,
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        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs587777017",
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       },
       "text": "c.474delA",
       "locations": [
        {
         "offset": 681,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "857",
        "type": "GeneOrGeneProduct"
       },
       "text": "caveolin-1",
       "locations": [
        {
         "offset": 745,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
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        "identifier": "12389",
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       "text": "caveolin-1",
       "locations": [
        {
         "offset": 759,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "10090",
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       "text": "mouse",
       "locations": [
        {
         "offset": 775,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
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        "identifier": "857",
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       "text": "caveolin-1",
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         "length": 10
        }
       ]
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       "id": "18",
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        {
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       "id": "19",
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       "text": "type I TGFb receptors",
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       "id": "23",
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        {
         "offset": 1306,
         "length": 9
        }
       ]
      },
      {
       "id": "24",
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        "identifier": "rs587777017",
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        {
         "offset": 1355,
         "length": 9
        }
       ]
      },
      {
       "id": "25",
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        "identifier": "857",
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        {
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "4086,4090,4093",
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       "text": "Smad",
       "locations": [
        {
         "offset": 1516,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "4086,4090,4093",
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       "text": "Smad",
       "locations": [
        {
         "offset": 1558,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "PAH",
       "locations": [
        {
         "offset": 1655,
         "length": 3
        }
       ]
      },
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       "id": "29",
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        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 1662,
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       ]
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       "id": "30",
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        "identifier": "857",
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       "text": "caveolin-1",
       "locations": [
        {
         "offset": 1676,
         "length": 10
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "rs587777017",
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       "text": "c.474delA",
       "locations": [
        {
         "offset": 1687,
         "length": 9
        }
       ]
      }
     ]
    }
   ],
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   ]
  },
  {
   "id": "15191352",
   "passages": [
    {
     "offset": 0,
     "text": "Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D018382",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "thyroid hormone resistance",
       "locations": [
        {
         "offset": 15,
         "length": 26
        }
       ]
      },
      {
       "id": "1",
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       "text": "patient",
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        {
         "offset": 47,
         "length": 7
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       ]
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       "text": "T3 receptor",
       "locations": [
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         "offset": 94,
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       ]
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     ]
    },
    {
     "offset": 112,
     "text": "Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta). We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S (1123T-->G) was present either on both alleles or in a hemizygous form with complete deletion of the second allele. The I280S mutation was recently reported in a heterozygous patient. The severe phenotype with seriously impaired intellectual development, hyperkinetic behaviour, tachycardia, hearing and visual impairment is probably due to the dominant negative effect of the I280S mutant protein and the absence of any functional TR-beta.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D018382",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Resistance to thyroid hormone syndrome",
       "locations": [
        {
         "offset": 112,
         "length": 38
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D018382",
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       },
       "text": "RTH",
       "locations": [
        {
         "offset": 152,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
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       "text": "Patients",
       "locations": [
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         "offset": 227,
         "length": 8
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D018382",
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       "text": "RTH",
       "locations": [
        {
         "offset": 241,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
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        "identifier": "D013971",
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       "text": "thyrotoxicosis",
       "locations": [
        {
         "offset": 323,
         "length": 14
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D007037",
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       },
       "text": "hypothyroidism",
       "locations": [
        {
         "offset": 353,
         "length": 14
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "7068",
        "type": "GeneOrGeneProduct"
       },
       "text": "thyroid hormone receptor beta",
       "locations": [
        {
         "offset": 436,
         "length": 29
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "7068",
        "type": "GeneOrGeneProduct"
       },
       "text": "TR-beta",
       "locations": [
        {
         "offset": 472,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 495,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D018382",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RTH",
       "locations": [
        {
         "offset": 508,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "7068",
        "type": "GeneOrGeneProduct"
       },
       "text": "TR-beta",
       "locations": [
        {
         "offset": 563,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|SUB|I|280|S",
        "type": "SequenceVariant"
       },
       "text": "I280S",
       "locations": [
        {
         "offset": 612,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "g|SUB|T|1123|G",
        "type": "SequenceVariant"
       },
       "text": "1123T-->G",
       "locations": [
        {
         "offset": 619,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "p|SUB|I|280|S",
        "type": "SequenceVariant"
       },
       "text": "I280S",
       "locations": [
        {
         "offset": 738,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 793,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "impaired intellectual development",
       "locations": [
        {
         "offset": 838,
         "length": 33
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D006948",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperkinetic",
       "locations": [
        {
         "offset": 873,
         "length": 12
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D013610",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tachycardia",
       "locations": [
        {
         "offset": 897,
         "length": 11
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D006311,D014786",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hearing and visual impairment",
       "locations": [
        {
         "offset": 910,
         "length": 29
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "p|SUB|I|280|S",
        "type": "SequenceVariant"
       },
       "text": "I280S",
       "locations": [
        {
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     "text": "The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism.",
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     "text": "PURPOSE: In the present study, we aimed to substantiate the putative significance of angiotensin I-converting enzyme (ACE) on gastric cancer biology by investigating the influence of its gene polymorphism on gastric cancer progression. EXPERIMENTAL DESIGN: Genomic DNA was purified from peripheral blood mononuclear cells or tissue specimens. Amplified ACE gene fragments were separated on agarose gels. D or I alleles were identified by the presence of 190- or 490-bp fragments, respectively. Local expression of ACE was investigated by immunohistochemistry. RESULTS: Twenty-four of 113 (21%) gastric cancer patients had the II, 57 (51%) the ID, and 32 (28%) the DD genotype. The distribution of the ACE genotypes did not differ significantly from the control group of 189 patients without gastric cancer. However, the ACE genotypes correlated with the number of lymph node metastases and the Unio Internationale Contra Cancrum (UICC) tumor stage. Patients with the II genotype had a highly significantly smaller number of lymph node metastases (P < 0.001) and a significantly lower UICC tumor stage (P = 0.01) than patients with the DD genotype. No correlation was found between tumor type, tumor location, local tumor growth, distant metastases, and the ACE genotype. The expression of ACE in gastric cancer was investigated by immunohistochemistry in 100 of 113 patients. ACE was expressed by endothelial cells in all (100%) specimens and by tumor cells in 56 (56%) specimens. CONCLUSIONS: Our study shows that ACE is expressed locally in gastric cancer and that the gene polymorphism influences metastatic behavior.",
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     "text": "Distinct patterns of germ-line deletions in MLH1 and MSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC).",
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     "text": "A relatively high frequency of germ-line genomic rearrangements in MLH1 and MSH2 has been reported among Lynch Syndrome (HNPCC) patients from different ethnic populations. To investigate the underlying molecular mechanisms, we characterized the DNA breakpoints of 11 germ-line deletions, six for MLH1 and five for MSH2. Distinct deletion patterns were found for the two genes. The five cases of MSH2 deletions result exclusively from intragenic unequal recombination mediated by repetitive Alu sequences. In contrast, five out of the six MLH1 deletions are due to recombinations involving sequences of no significant homology (P=0.015). A detailed analysis of the DNA breakpoints in the two genes, previously characterized by other groups, validated the observation that Alu-mediated unequal recombination is the main type of deletion in MSH2 (n=34), but not in MLH1 (n=21) (P<0.0001). Plotting the distribution of known DNA breakpoints among the introns of the two genes showed that, the highest breakpoint density is co-localized with the highest Alu density. Our study suggests that Alu is a promoting factor for the genomic recombinations in both MLH1 and MSH2, and the local Alu density may be involved in shaping the deletion pattern.",
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        "identifier": "54820",
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       "text": "NDE1",
       "locations": [
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         "offset": 128,
         "length": 4
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     "offset": 134,
     "text": "We have previously reported a robust association between an allelic haplotype of 'Disrupted in Schizophrenia 1' (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.",
     "annotations": [
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       "id": "3",
       "infons": {
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       "text": "Disrupted in Schizophrenia 1",
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         "offset": 216,
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       "id": "4",
       "infons": {
        "identifier": "27185",
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       "text": "DISC1",
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         "offset": 247,
         "length": 5
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       "id": "5",
       "infons": {
        "identifier": "D012559",
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       "text": "schizophrenia",
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       "id": "6",
       "infons": {
        "identifier": "D012559",
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       "text": "schizophrenia",
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         "offset": 310,
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       "id": "7",
       "infons": {
        "identifier": "27185",
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       "text": "DISC1",
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       "text": "DISC1",
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       "id": "9",
       "infons": {
        "identifier": "D012559",
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       "text": "schizophrenia",
       "locations": [
        {
         "offset": 466,
         "length": 13
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       ]
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       "id": "10",
       "infons": {
        "identifier": "27185",
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       "text": "DISC1",
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         "offset": 691,
         "length": 5
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       ]
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       "id": "11",
       "infons": {
        "identifier": "54820",
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       "text": "NDE1",
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         "offset": 915,
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       "id": "12",
       "infons": {
        "identifier": "27185",
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       "text": "DISC1",
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         "offset": 972,
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       "id": "13",
       "infons": {
        "identifier": "54820",
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       "text": "NDE1",
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         "offset": 1110,
         "length": 4
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       "id": "14",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "schizophrenia",
       "locations": [
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         "offset": 1167,
         "length": 13
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       "id": "15",
       "infons": {
        "identifier": "27185",
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       "text": "DISC1",
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         "offset": 1547,
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       "id": "16",
       "infons": {
        "identifier": "D012559",
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       "text": "schizophrenia",
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         "offset": 1600,
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     "offset": 0,
     "text": "Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors.",
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       "id": "0",
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       "text": "prolactin receptor",
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       "text": "women",
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       "text": "benign breast tumors",
       "locations": [
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     ]
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     "offset": 108,
     "text": "There is currently no known genetic disease linked to prolactin (Prl) or its receptor (PrlR) in humans. Given the essential role of this hormonal system in breast physiology, we reasoned that genetic anomalies of Prl/PrlR genes may be related to the occurrence of breast diseases with high proliferative potential. Multiple fibroadenomas (MFA) are benign breast tumors which appear most frequently in young women, including at puberty, when Prl has well-recognized proliferative actions on the breast. In a prospective study involving 74 MFA patients and 170 control subjects, we identified four patients harboring a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile(146)-->Leu substitution in its extracellular domain. This sole substitution was sufficient to confer constitutive activity to the receptor variant (PrlR(I146L)), as assessed in three reconstituted cell models (Ba/F3, HEK293 and MCF-7 cells) by Prl-independent (i) PrlR tyrosine phosphorylation, (ii) activation of signal transducer and activator of transcription 5 (STAT5) signaling, (iii) transcriptional activity toward a Prl-responsive reporter gene, and (iv) cell proliferation and protection from cell death. Constitutive activity of PrlR(I146L) in the breast sample from a patient was supported by increased STAT5 signaling. This is a unique description of a functional mutation of the PrlR associated with a human disease. Hallmarks of constitutive activity were all reversed by a specific PrlR antagonist, which opens potential therapeutic approaches for MFA, or any other disease that could be associated with this mutation in future.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "D030342",
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       "text": "genetic disease",
       "locations": [
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         "offset": 136,
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       "text": "prolactin",
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       "id": "5",
       "infons": {
        "identifier": "5617",
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       "text": "Prl",
       "locations": [
        {
         "offset": 173,
         "length": 3
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       ]
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       "id": "6",
       "infons": {
        "identifier": "5618",
        "type": "GeneOrGeneProduct"
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       "text": "PrlR",
       "locations": [
        {
         "offset": 195,
         "length": 4
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       ]
      },
      {
       "id": "7",
       "infons": {
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       "text": "humans",
       "locations": [
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         "offset": 204,
         "length": 6
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       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "5617",
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       "text": "Prl",
       "locations": [
        {
         "offset": 321,
         "length": 3
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       ]
      },
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       "id": "9",
       "infons": {
        "identifier": "5618",
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       "text": "PrlR",
       "locations": [
        {
         "offset": 325,
         "length": 4
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001941",
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       },
       "text": "breast diseases",
       "locations": [
        {
         "offset": 372,
         "length": 15
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D018226",
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       },
       "text": "Multiple fibroadenomas",
       "locations": [
        {
         "offset": 423,
         "length": 22
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       ]
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       "id": "12",
       "infons": {
        "identifier": "D018226",
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       "text": "MFA",
       "locations": [
        {
         "offset": 447,
         "length": 3
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       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "D001943",
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       "text": "benign breast tumors",
       "locations": [
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         "length": 20
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       ]
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       "id": "14",
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       "text": "women",
       "locations": [
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         "offset": 515,
         "length": 5
        }
       ]
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      {
       "id": "15",
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        "identifier": "5617",
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       "text": "Prl",
       "locations": [
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         "offset": 549,
         "length": 3
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       ]
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       "id": "16",
       "infons": {
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       "text": "MFA",
       "locations": [
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       "text": "patients",
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       "text": "patients",
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       ]
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       "id": "19",
       "infons": {
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       "text": "PrlR",
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         "offset": 786,
         "length": 4
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       ]
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       "id": "20",
       "infons": {
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       "text": "Ile(146)-->Leu",
       "locations": [
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       ]
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       "id": "21",
       "infons": {
        "identifier": "19116",
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       "text": "PrlR",
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         "length": 4
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       "id": "22",
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       "text": "I146L",
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       "text": "Ba/F3",
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       "text": "HEK293",
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       "text": "MCF-7",
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         "length": 5
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       "id": "26",
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       "text": "Prl",
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         "offset": 1054,
         "length": 3
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       "id": "27",
       "infons": {
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       "text": "PrlR",
       "locations": [
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         "length": 4
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       ]
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      {
       "id": "28",
       "infons": {
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       "text": "signal transducer and activator of transcription 5",
       "locations": [
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         "length": 50
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       ]
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       "id": "29",
       "infons": {
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       "text": "STAT5",
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         "offset": 1176,
         "length": 5
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       ]
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       "id": "30",
       "infons": {
        "identifier": "5617",
        "type": "GeneOrGeneProduct"
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       "text": "Prl",
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         "offset": 1234,
         "length": 3
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       "id": "31",
       "infons": {
        "identifier": "5618",
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       "text": "PrlR",
       "locations": [
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         "offset": 1349,
         "length": 4
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       ]
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       "id": "32",
       "infons": {
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       "text": "I146L",
       "locations": [
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       "id": "33",
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       "text": "patient",
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       "id": "34",
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       "text": "STAT5",
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         "offset": 1424,
         "length": 5
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       ]
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       "id": "35",
       "infons": {
        "identifier": "5618",
        "type": "GeneOrGeneProduct"
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       "text": "PrlR",
       "locations": [
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         "offset": 1502,
         "length": 4
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       ]
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       "id": "36",
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       "text": "human",
       "locations": [
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         "offset": 1525,
         "length": 5
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       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "-",
        "type": "ChemicalEntity"
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       "text": "PrlR antagonist",
       "locations": [
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         "offset": 1607,
         "length": 15
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       ]
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       "id": "38",
       "infons": {
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       "text": "MFA",
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         "offset": 1673,
         "length": 3
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      "novel": "Novel"
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    {
     "id": "R7",
     "infons": {
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      "type": "Bind",
      "novel": "No"
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    {
     "id": "R8",
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      "type": "Association",
      "novel": "Novel"
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    }
   ]
  },
  {
   "id": "19346865",
   "passages": [
    {
     "offset": 0,
     "text": "Reversible inferior colliculus lesion in metronidazole-induced encephalopathy: magnetic resonance findings on diffusion-weighted and fluid attenuated inversion recovery imaging.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inferior colliculus lesion",
       "locations": [
        {
         "offset": 11,
         "length": 26
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008795",
        "type": "ChemicalEntity"
       },
       "text": "metronidazole",
       "locations": [
        {
         "offset": 41,
         "length": 13
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "encephalopathy",
       "locations": [
        {
         "offset": 63,
         "length": 14
        }
       ]
      }
     ]
    },
    {
     "offset": 178,
     "text": "OBJECTIVE: This is to present reversible inferior colliculus lesions in metronidazole-induced encephalopathy, to focus on the diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) imaging. MATERIALS AND METHODS: From November 2005 to September 2007, 8 patients (5 men and 3 women) were diagnosed as having metronidazole-induced encephalopathy (age range; 43-78 years). They had been taking metronidazole (total dosage, 45-120 g; duration, 30 days to 2 months) to treat the infection in various organs. Initial brain magnetic resonance imaging (MRI) were obtained after the hospitalization, including DWI (8/8), apparent diffusion coefficient (ADC) map (4/8), FLAIR (7/8), and T2-weighted image (8/8). Follow-up MRIs were performed on 5 patients from third to 14th days after discontinuation of metronidazole administration. Findings of initial and follow-up MRIs were retrospectively evaluated by 2 neuroradiologists by consensus, to analyze the presence of abnormal signal intensities, their locations, and signal changes on follow-up images. RESULTS: Initial MRIs showed abnormal high signal intensities on DWI and FLAIR (or T2-weighted image) at the dentate nucleus (8/8), inferior colliculus (6/8), corpus callosum (2/8), pons (2/8), medulla (1/8), and bilateral cerebral white matter (1/8). High-signal intensity lesions on DWI tended to show low signal intensity on ADC map (3/4), but in one patient, high signal intensity was shown at bilateral dentate nuclei on not only DWI but also ADC map. All the lesions in dentate, inferior colliculus, pons, and medullas had been resolved completely on follow-up MRIs in 5 patients, but in 1 patient of them, corpus callosal lesion persisted. CONCLUSIONS: Reversible inferior colliculus lesions could be considered as the characteristic for metronidazole-induced encephalopathy, next to the dentate nucleus involvement.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "inferior colliculus lesions",
       "locations": [
        {
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         "length": 27
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       ]
      },
      {
       "id": "4",
       "infons": {
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       "text": "metronidazole",
       "locations": [
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         "offset": 250,
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       ]
      },
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       "id": "5",
       "infons": {
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       "text": "encephalopathy",
       "locations": [
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         "offset": 272,
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       ]
      },
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       "id": "6",
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       "text": "patients",
       "locations": [
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       ]
      },
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       "id": "7",
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        "type": "OrganismTaxon"
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       "text": "men",
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         "offset": 469,
         "length": 3
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       ]
      },
      {
       "id": "8",
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        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "women",
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         "offset": 479,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008795",
        "type": "ChemicalEntity"
       },
       "text": "metronidazole",
       "locations": [
        {
         "offset": 511,
         "length": 13
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "encephalopathy",
       "locations": [
        {
         "offset": 533,
         "length": 14
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D008795",
        "type": "ChemicalEntity"
       },
       "text": "metronidazole",
       "locations": [
        {
         "offset": 595,
         "length": 13
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D007239",
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       },
       "text": "infection",
       "locations": [
        {
         "offset": 678,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 941,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008795",
        "type": "ChemicalEntity"
       },
       "text": "metronidazole",
       "locations": [
        {
         "offset": 999,
         "length": 13
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       ]
      },
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       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patient",
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         "offset": 1603,
         "length": 7
        }
       ]
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       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
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         "offset": 1826,
         "length": 8
        }
       ]
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       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1845,
         "length": 7
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "callosal lesion",
       "locations": [
        {
         "offset": 1869,
         "length": 15
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inferior colliculus lesions",
       "locations": [
        {
         "offset": 1920,
         "length": 27
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D008795",
        "type": "ChemicalEntity"
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       "text": "metronidazole",
       "locations": [
        {
         "offset": 1994,
         "length": 13
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "encephalopathy",
       "locations": [
        {
         "offset": 2016,
         "length": 14
        }
       ]
      }
     ]
    }
   ],
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     "infons": {
      "entity1": "D008795",
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      "novel": "No"
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    {
     "id": "R1",
     "infons": {
      "entity1": "D008795",
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      "type": "Positive_Correlation",
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   ]
  },
  {
   "id": "19889778",
   "passages": [
    {
     "offset": 0,
     "text": "Differential impact of immune escape mutations G145R and P120T on the replication of lamivudine-resistant hepatitis B virus e antigen-positive and -negative strains.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "p|SUB|G|145|R",
        "type": "SequenceVariant"
       },
       "text": "G145R",
       "locations": [
        {
         "offset": 47,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|SUB|P|120|T",
        "type": "SequenceVariant"
       },
       "text": "P120T",
       "locations": [
        {
         "offset": 57,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "lamivudine",
       "locations": [
        {
         "offset": 85,
         "length": 10
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D006513",
        "type": "ChemicalEntity"
       },
       "text": "hepatitis B virus e antigen",
       "locations": [
        {
         "offset": 106,
         "length": 27
        }
       ]
      }
     ]
    },
    {
     "offset": 166,
     "text": "Immune escape variants of the hepatitis B virus (HBV) represent an emerging clinical challenge, because they can be associated with vaccine escape, HBV reactivation, and failure of diagnostic tests. Recent data suggest a preferential selection of immune escape mutants in distinct peripheral blood leukocyte compartments of infected individuals. We therefore systematically analyzed the functional impact of the most prevalent immune escape variants, the sG145R and sP120T mutants, on the viral replication efficacy and antiviral drug susceptibility of common treatment-associated mutants with resistance to lamivudine (LAM) and/or HBeAg negativity. Replication-competent HBV strains with sG145R or sP120T and LAM resistance (rtM204I or rtL180M/rtM204V) were generated on an HBeAg-positive and an HBeAg-negative background with precore (PC) and basal core promoter (BCP) mutants. The sG145R mutation strongly reduced HBsAg levels and was able to fully restore the impaired replication of LAM-resistant HBV mutants to the levels of wild-type HBV, and PC or BCP mutations further enhanced viral replication. Although the sP120T substitution also impaired HBsAg secretion, it did not enhance the replication of LAM-resistant clones. However, the concomitant occurrence of HBeAg negativity (PC/BCP), sP120T, and LAM resistance resulted in the restoration of replication to levels of wild-type HBV. In all clones with combined immune escape and LAM resistance mutations, the nucleotide analogues adefovir and tenofovir remained effective in suppressing viral replication in vitro. These findings reveal the differential impact of immune escape variants on the replication and drug susceptibility of complex HBV mutants, supporting the need of close surveillance and treatment adjustment in response to the selection of distinct mutational patterns.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "hepatitis B virus",
       "locations": [
        {
         "offset": 196,
         "length": 17
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "HBV",
       "locations": [
        {
         "offset": 215,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "HBV",
       "locations": [
        {
         "offset": 314,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "p|SUB|G|145|R",
        "type": "SequenceVariant"
       },
       "text": "G145R",
       "locations": [
        {
         "offset": 622,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|P|120|T",
        "type": "SequenceVariant"
       },
       "text": "P120T",
       "locations": [
        {
         "offset": 633,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "lamivudine",
       "locations": [
        {
         "offset": 774,
         "length": 10
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "LAM",
       "locations": [
        {
         "offset": 786,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D006513",
        "type": "ChemicalEntity"
       },
       "text": "HBeAg",
       "locations": [
        {
         "offset": 798,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "HBV",
       "locations": [
        {
         "offset": 838,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "p|SUB|G|145|R",
        "type": "SequenceVariant"
       },
       "text": "G145R",
       "locations": [
        {
         "offset": 856,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|SUB|P|120|T",
        "type": "SequenceVariant"
       },
       "text": "P120T",
       "locations": [
        {
         "offset": 866,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "LAM",
       "locations": [
        {
         "offset": 876,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "p|SUB|M|204|I",
        "type": "SequenceVariant"
       },
       "text": "M204I",
       "locations": [
        {
         "offset": 894,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|SUB|L|180|M",
        "type": "SequenceVariant"
       },
       "text": "L180M",
       "locations": [
        {
         "offset": 905,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|SUB|M|204|V",
        "type": "SequenceVariant"
       },
       "text": "M204V",
       "locations": [
        {
         "offset": 913,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D006513",
        "type": "ChemicalEntity"
       },
       "text": "HBeAg",
       "locations": [
        {
         "offset": 941,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D006513",
        "type": "ChemicalEntity"
       },
       "text": "HBeAg",
       "locations": [
        {
         "offset": 963,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "944568",
        "type": "GeneOrGeneProduct"
       },
       "text": "precore",
       "locations": [
        {
         "offset": 994,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "944568",
        "type": "GeneOrGeneProduct"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 1003,
         "length": 2
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "p|SUB|G|145|R",
        "type": "SequenceVariant"
       },
       "text": "G145R",
       "locations": [
        {
         "offset": 1051,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D006514",
        "type": "ChemicalEntity"
       },
       "text": "HBsAg",
       "locations": [
        {
         "offset": 1083,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "LAM",
       "locations": [
        {
         "offset": 1154,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "HBV",
       "locations": [
        {
         "offset": 1168,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "HBV",
       "locations": [
        {
         "offset": 1207,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "944568",
        "type": "GeneOrGeneProduct"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 1216,
         "length": 2
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "c|SUB|P|120|T",
        "type": "SequenceVariant"
       },
       "text": "P120T",
       "locations": [
        {
         "offset": 1286,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D006514",
        "type": "ChemicalEntity"
       },
       "text": "HBsAg",
       "locations": [
        {
         "offset": 1319,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "LAM",
       "locations": [
        {
         "offset": 1374,
         "length": 3
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D006513",
        "type": "ChemicalEntity"
       },
       "text": "HBeAg",
       "locations": [
        {
         "offset": 1435,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "944568",
        "type": "GeneOrGeneProduct"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 1453,
         "length": 2
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "c|SUB|P|120|T",
        "type": "SequenceVariant"
       },
       "text": "P120T",
       "locations": [
        {
         "offset": 1463,
         "length": 5
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "LAM",
       "locations": [
        {
         "offset": 1474,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "HBV",
       "locations": [
        {
         "offset": 1555,
         "length": 3
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "LAM",
       "locations": [
        {
         "offset": 1606,
         "length": 3
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "C053001",
        "type": "ChemicalEntity"
       },
       "text": "adefovir",
       "locations": [
        {
         "offset": 1657,
         "length": 8
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "D000068698",
        "type": "ChemicalEntity"
       },
       "text": "tenofovir",
       "locations": [
        {
         "offset": 1670,
         "length": 9
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "10407",
        "type": "OrganismTaxon"
       },
       "text": "HBV",
       "locations": [
        {
         "offset": 1868,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
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      "novel": "Novel"
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    },
    {
     "id": "R1",
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      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "944568",
      "entity2": "D006513",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|SUB|P|120|T",
      "entity2": "D006514",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "c|SUB|P|120|T",
      "entity2": "D006513",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D019259",
      "entity2": "c|SUB|P|120|T",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D019259",
      "entity2": "D006513",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "p|SUB|G|145|R",
      "entity2": "D006514",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "p|SUB|G|145|R",
      "entity2": "D019259",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "D006513",
      "entity2": "p|SUB|G|145|R",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "20583543",
   "passages": [
    {
     "offset": 0,
     "text": "Molecular diagnosis of 46,XY DSD and identification of a novel 8 nucleotide deletion in exon 1 of the SRD5A2 gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D058490",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "46,XY DSD",
       "locations": [
        {
         "offset": 23,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|DEL||8",
        "type": "SequenceVariant"
       },
       "text": "8 nucleotide deletion",
       "locations": [
        {
         "offset": 63,
         "length": 21
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 102,
         "length": 6
        }
       ]
      }
     ]
    },
    {
     "offset": 115,
     "text": "Phenotypic presentation of 46,XY DSD depends on the underlying defects. Defect in androgen action on the target tissues or production of active metabolite share common morphological features. Molecular study may help differentiating these abnormalities with precision. Mutational analysis of androgen receptor (AR) and SRD5A2 genes was performed in 29 patients with 46,XY DSD, by PCR-SSCP. The amplicons that showed an aberrant migration in SSCP were subjected to sequencing. Interestingly, six patients from 4 unrelated families (a pair of sibs, uncle/nephew and other two isolated) were identified with mutations in SRD5A2 gene. In five patients p.R246Q missense mutation was detected, of which four were homozygous and one was compound heterozygous: g.80_87delT CGCGAAG (p.A27fsX132) and p.R246Q. Another patient with isolated micropenis harbored a heterozygous p.G196S missense mutation. No AR gene mutation was detected. In conclusion, our study suggests that p.R246Q mutation is common amongst patients with SRD5A2 gene defect from the Northern states of India. Also, it records a novel deletion in exon 1 of SRD5A2 gene in a patient with severe hypospadias.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D058490",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "46,XY DSD",
       "locations": [
        {
         "offset": 142,
         "length": 9
        }
       ]
      },
      {
       "id": "4",
       "infons": {
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       "text": "androgen receptor",
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         "offset": 407,
         "length": 17
        }
       ]
      },
      {
       "id": "5",
       "infons": {
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       },
       "text": "AR",
       "locations": [
        {
         "offset": 426,
         "length": 2
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 434,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 467,
         "length": 8
        }
       ]
      },
      {
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     "text": "Cytostatic and anti-angiogenic effects of temsirolimus in refractory mantle cell lymphoma.",
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     "text": "Mantle cell lymphoma (MCL) is a rare and aggressive type of B-cell non-Hodgkin's lymphoma. Patients become progressively refractory to conventional chemotherapy, and their prognosis is poor. However, a 38% remission rate has been recently reported in refractory MCL treated with temsirolimus, a mTOR inhibitor.Here we had the opportunity to study a case of refractory MCL who had tumor regression two months after temsirolimus treatment, and a progression-free survival of 10 months. In this case, lymph node biopsies were performed before and six months after temsirolimus therapy. Comparison of the two biopsies showed that temsirolimus inhibited tumor cell proliferation through cell cycle arrest, but did not induce any change in the number of apoptotic tumor cells. Apart from this cytostatic effect, temsirolimus had an antiangiogenic effect with decrease of tumor microvessel density and of VEGF expression. Moreover, numerous patchy, well-limited fibrotic areas, compatible with post-necrotic tissue repair, were found after 6-month temsirolimus therapy. Thus, temsirolimus reduced tumor burden through associated cytostatic and anti-angiogenic effects.This dual effect of temsirolimus on tumor tissue could contribute to its recently reported efficiency in refractory MCL resistant to conventional chemotherapy.",
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       "text": "tumor",
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       "id": "15",
       "infons": {
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       "text": "tumor",
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       "text": "VEGF",
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       "text": "MCL",
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  {
   "id": "24477591",
   "passages": [
    {
     "offset": 0,
     "text": "The -930A>G polymorphism of the CYBA gene is associated with premature coronary artery disease. A case-control study and gene-risk factors interactions.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs9932581",
        "type": "SequenceVariant"
       },
       "text": "-930A>G",
       "locations": [
        {
         "offset": 4,
         "length": 7
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "1535",
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       "text": "CYBA",
       "locations": [
        {
         "offset": 32,
         "length": 4
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D003324",
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       "text": "coronary artery disease",
       "locations": [
        {
         "offset": 71,
         "length": 23
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       ]
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     ]
    },
    {
     "offset": 153,
     "text": "Reactive oxygen species (ROS) are involved in the pathogenesis of atherosclerosis and coronary artery disease (CAD). NADPH oxidases are the main source of ROS in the vasculature. p22phox is a critical component of vascular NADPH oxidases and is encoded by the CYBA (cytochrome b245 alpha) gene. The -930A>G CYBA polymorphism (rs9932581:A>G) modulates the activity of the CYBA promoter, and influences CYBA transcriptional activity. The aim of the present study was to analyze a possible association between the -930A>G polymorphism and CAD and to search for gene-traditional risk factors interactions. 480 subjects were studied: 240 patients with premature CAD, 240 age and sex matched blood donors. The -930A>G polymorphism was genotyped using the TaqMan - Pre-designed SNP Genotyping Assay (Applied Biosystems). The -930G allele carrier state was a risk factor for CAD (OR 2.03, 95% CI 1.21-3.44, P=0.007). A synergistic effect of the -930G allele with overweight/obesity (BMI --25) and cigarette smoking was found. The estimated CAD risk for BMI --25 and the -930G allele interaction was about 160% greater than that predicted by assuming additivity of the effects, and about 40% greater for interaction of cigarette smoking and the -930G allele. Overweight/obesity was a risk factor for CAD only in the -930G allele carriers (P<10(-10)) but not in the AA homozygotes (P=1.00). In conclusion the -930A>G CYBA polymorphism is associated with CAD in the Polish population. The -930G allele carriers are particularly at risk of consequences of obesity and tobacco smoke exposure.",
     "annotations": [
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       "id": "3",
       "infons": {
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       "text": "Reactive oxygen species",
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         "offset": 153,
         "length": 23
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       "id": "4",
       "infons": {
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       "text": "ROS",
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         "offset": 178,
         "length": 3
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       "id": "5",
       "infons": {
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       "text": "atherosclerosis",
       "locations": [
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         "offset": 219,
         "length": 15
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D003324",
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       "text": "coronary artery disease",
       "locations": [
        {
         "offset": 239,
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      },
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       "id": "7",
       "infons": {
        "identifier": "D003324",
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       "text": "CAD",
       "locations": [
        {
         "offset": 264,
         "length": 3
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "1666",
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       "text": "NADPH oxidases",
       "locations": [
        {
         "offset": 270,
         "length": 14
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       ]
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       "id": "9",
       "infons": {
        "identifier": "D017382",
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       "text": "ROS",
       "locations": [
        {
         "offset": 308,
         "length": 3
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       ]
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      {
       "id": "10",
       "infons": {
        "identifier": "1535",
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       "text": "p22phox",
       "locations": [
        {
         "offset": 332,
         "length": 7
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       ]
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      {
       "id": "11",
       "infons": {
        "identifier": "1666",
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       "text": "NADPH oxidases",
       "locations": [
        {
         "offset": 376,
         "length": 14
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "1535",
        "type": "GeneOrGeneProduct"
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       "text": "CYBA",
       "locations": [
        {
         "offset": 413,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "1535",
        "type": "GeneOrGeneProduct"
       },
       "text": "cytochrome b245 alpha",
       "locations": [
        {
         "offset": 419,
         "length": 21
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs9932581",
        "type": "SequenceVariant"
       },
       "text": "-930A>G",
       "locations": [
        {
         "offset": 452,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1535",
        "type": "GeneOrGeneProduct"
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       "text": "CYBA",
       "locations": [
        {
         "offset": 460,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs9932581",
        "type": "SequenceVariant"
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       "text": "rs9932581",
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        {
         "offset": 479,
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       ]
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       "id": "17",
       "infons": {
        "identifier": "rs9932581",
        "type": "SequenceVariant"
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       "text": "A>G",
       "locations": [
        {
         "offset": 489,
         "length": 3
        }
       ]
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      {
       "id": "18",
       "infons": {
        "identifier": "1535",
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       "text": "CYBA",
       "locations": [
        {
         "offset": 524,
         "length": 4
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       ]
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      {
       "id": "19",
       "infons": {
        "identifier": "1535",
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       "text": "CYBA",
       "locations": [
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         "offset": 554,
         "length": 4
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       "id": "20",
       "infons": {
        "identifier": "rs9932581",
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       "text": "-930A>G",
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        {
         "offset": 664,
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      {
       "id": "21",
       "infons": {
        "identifier": "D003324",
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       "text": "CAD",
       "locations": [
        {
         "offset": 689,
         "length": 3
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       "id": "22",
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       "text": "patients",
       "locations": [
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       "id": "23",
       "infons": {
        "identifier": "D003324",
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       "text": "CAD",
       "locations": [
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         "offset": 810,
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       "id": "24",
       "infons": {
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       "text": "-930A>G",
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       "id": "25",
       "infons": {
        "identifier": "rs9932581",
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       "text": "-930G",
       "locations": [
        {
         "offset": 971,
         "length": 5
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       ]
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      {
       "id": "26",
       "infons": {
        "identifier": "D003324",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "CAD",
       "locations": [
        {
         "offset": 1020,
         "length": 3
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       ]
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       "id": "27",
       "infons": {
        "identifier": "rs9932581",
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       "text": "-930G",
       "locations": [
        {
         "offset": 1090,
         "length": 5
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       ]
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      {
       "id": "28",
       "infons": {
        "identifier": "D050177",
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       "text": "overweight",
       "locations": [
        {
         "offset": 1108,
         "length": 10
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       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "obesity",
       "locations": [
        {
         "offset": 1119,
         "length": 7
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       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D003324",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CAD",
       "locations": [
        {
         "offset": 1185,
         "length": 3
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       ]
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      {
       "id": "31",
       "infons": {
        "identifier": "rs9932581",
        "type": "SequenceVariant"
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       "text": "-930G",
       "locations": [
        {
         "offset": 1215,
         "length": 5
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       ]
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       "id": "32",
       "infons": {
        "identifier": "rs9932581",
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       "text": "-930G",
       "locations": [
        {
         "offset": 1389,
         "length": 5
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       "id": "33",
       "infons": {
        "identifier": "D050177",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Overweight",
       "locations": [
        {
         "offset": 1403,
         "length": 10
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       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "obesity",
       "locations": [
        {
         "offset": 1414,
         "length": 7
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       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D003324",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "CAD",
       "locations": [
        {
         "offset": 1444,
         "length": 3
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       "id": "36",
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        "identifier": "rs9932581",
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       "text": "-930G",
       "locations": [
        {
         "offset": 1460,
         "length": 5
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       "id": "37",
       "infons": {
        "identifier": "rs9932581",
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       "text": "-930A>G",
       "locations": [
        {
         "offset": 1552,
         "length": 7
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       ]
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      {
       "id": "38",
       "infons": {
        "identifier": "1535",
        "type": "GeneOrGeneProduct"
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       "text": "CYBA",
       "locations": [
        {
         "offset": 1560,
         "length": 4
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       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "D003324",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "CAD",
       "locations": [
        {
         "offset": 1597,
         "length": 3
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       "id": "40",
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       "text": "-930G",
       "locations": [
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         "offset": 1631,
         "length": 5
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       "id": "41",
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        "identifier": "D009765",
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       "text": "obesity",
       "locations": [
        {
         "offset": 1697,
         "length": 7
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       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "4097",
        "type": "OrganismTaxon"
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       "text": "tobacco",
       "locations": [
        {
         "offset": 1709,
         "length": 7
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    {
     "offset": 0,
     "text": "GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake or Hypertrophic Growth in Mouse Skeletal Muscle.",
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       "text": "Mouse",
       "locations": [
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     ]
    },
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     "text": "GLUT4 is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine whether GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [(3)H]-2-deoxy-d-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes. To assess which transporters mediate overload-induced glucose uptake, chemical inhibitors were used. The facilitative GLUT inhibitor cytochalasin B, but not the sodium-dependent glucose cotransport inhibitor phloridzin, prevented overload-induced uptake demonstrating that GLUTs mediate this effect. To assess which GLUT, hexose competition experiments were performed. Overload-induced [(3)H]-2-deoxy-d-glucose uptake was not inhibited by d-fructose, demonstrating that the fructose-transporting GLUT2, GLUT5, GLUT8, and GLUT12 do not mediate this effect. To assess additional GLUTs, immunoblots were performed. Overload increased GLUT1, GLUT3, GLUT6, and GLUT10 protein levels twofold to fivefold. Collectively, these results demonstrate that GLUT4 is not necessary for overload-induced muscle glucose uptake or hypertrophic growth and suggest that GLUT1, GLUT3, GLUT6, and/or GLUT10 mediate overload-induced glucose uptake.",
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     "text": "Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma.",
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     "text": "Pediatric high-grade gliomas represent 8-12% of all primary tumors of the nervous system in children. Five-year survival for these pediatric aggressive tumors is poor (15-35%) indicating the need to develop better treatments for pediatric high-grade gliomas. In this work we used SF188 and SJ-GBM2 cell lines to study the function of the ubiquitin carboxyl-terminal esterase L1 (UCHL1), a deubiquitinase de-regulated in several cancers, in pediatric high-grade gliomas. UCHL1 depletion in SF188 and SJ-GBM2 glioma cells was associated with decreased cell proliferation and invasion, along with a reduced ability to grow in soft agar and to form spheres (i.e. self-renewal measure). A 70% reduction in Wnt signaling was also observed in the SF188 and SJ-GBM2 UCHL1 knockdowns (KDs) using a TCF-dependent TOPflash reporter assay. Transcriptome comparisons of UCHL1 KDs versus vector control identified a list of 306 differentially expressed genes (at least 2-fold change; p    <0.05) which included genes known to be involved in cancer like ACTA2, POSTN, LIF, FBXL7, FBXW11, GDF15, HEY2, but also potential novel genes such us IGLL5, ABCA4, AQP3, AQP4, CALB1, and ALK. Bioinformatics gene ontology (GO) analysis of these 306 genes revealed significant enrichment in \"signal peptides\", \"extracellular matrix\"and \"secreted proteins\" GO Terms. \"Angiogenesis and blood vessel development\", \"neuron differentiation/development\", cell adhesion\", and \"cell migration\" also showed significant enrichment in our GO analysis. Top canonical pathways identified by Ingenuity Pathway Analysis (IPA) included \"Clathrin-mediated Endocytosis Signaling\" (p = 5.14x10-4), \"Virus Entry via Endocytic Pathways\" (p = 6.15x 10-4), and \"High Mobility Group-Box 1 (HMGB1) Signaling\" (p = 6.15x10-4). While FGF2, IL1B, TNF and PDGFB were predicted as top upstream regulators (p    < 2x10-16) of the UCHL1 KD-associated transcriptome. Aberrant expression of UCHL1 in pediatric high-grade gliomas may promote cell invasion, transformation, and self-renewal properties, at least in part, by modulating Wnt/Beta catenin activity. UCHL1 might act as an oncogene in glioma within the gene network that imparts stem-like characteristics to these cancer cells.",
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     "text": "Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients with X-linked intellectual disability.",
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       "id": "21",
       "infons": {
        "identifier": "8473",
        "type": "GeneOrGeneProduct"
       },
       "text": "O-GlcNAc",
       "locations": [
        {
         "offset": 1130,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "8473",
        "type": "GeneOrGeneProduct"
       },
       "text": "O-GlcNAcylation",
       "locations": [
        {
         "offset": 1235,
         "length": 15
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "10724",
        "type": "GeneOrGeneProduct"
       },
       "text": "O-GlcNAcase",
       "locations": [
        {
         "offset": 1270,
         "length": 11
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "c|SUB|T463-6|G",
        "type": "SequenceVariant"
       },
       "text": "c.463-6T>G",
       "locations": [
        {
         "offset": 1317,
         "length": 10
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1436,
         "length": 7
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "8473",
        "type": "GeneOrGeneProduct"
       },
       "text": "OGT",
       "locations": [
        {
         "offset": 1477,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "rs1114167891",
        "type": "SequenceVariant"
       },
       "text": "p.Arg284Pro",
       "locations": [
        {
         "offset": 1493,
         "length": 11
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "3054",
        "type": "GeneOrGeneProduct"
       },
       "text": "host cell factor 1",
       "locations": [
        {
         "offset": 1689,
         "length": 18
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLID",
       "locations": [
        {
         "offset": 1737,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "8473",
        "type": "GeneOrGeneProduct"
       },
       "text": "O-GlcNAc",
       "locations": [
        {
         "offset": 1787,
         "length": 8
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "3054",
        "type": "GeneOrGeneProduct"
       },
       "text": "host cell factor 1",
       "locations": [
        {
         "offset": 1812,
         "length": 18
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLID",
       "locations": [
        {
         "offset": 1874,
         "length": 4
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "8473",
        "type": "GeneOrGeneProduct"
       },
       "text": "OGT",
       "locations": [
        {
         "offset": 1899,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|T463-6|G",
      "entity2": "D038901",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "3054",
      "entity2": "D038901",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs1114167891",
      "entity2": "D038901",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "8473",
      "entity2": "D019636",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "8473",
      "entity2": "D003147",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "8473",
      "entity2": "D038901",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15523499",
   "passages": [
    {
     "offset": 0,
     "text": "Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "153,154,155",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta adrenergic receptor",
       "locations": [
        {
         "offset": 27,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 98,
     "text": "The beta-adrenergic receptors (beta-AR) are G protein-coupled receptors activated by epinephrine and norepinephrine and are involved in a variety of their physiological functions. Previously, three beta-AR genes (ADRB1, ADRB2 and ADRB3) were resequenced, identifying polymorphisms that were used in genetic association studies of cardiovascular and metabolic disorders. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: ADRB1 Arg389Gly and Gly49Ser, ADRB2 Arg16Gly and Gln27Glu, and ADRB3 Arg64Trp provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for each beta-AR gene that included the known functional markers and also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 27 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations and for each gene, a single block with little evidence of historical recombination was observed. For each gene, haplotype captured most of the information content of each functional locus, even if that locus was not genotyped, and presumably haplotype would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using beta-AR gene haplotype maps and marker panels as tools for linkage studies on beta-AR function.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "153,154,155",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-adrenergic receptors",
       "locations": [
        {
         "offset": 102,
         "length": 25
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "153,154,155",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-AR",
       "locations": [
        {
         "offset": 129,
         "length": 7
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D004837",
        "type": "ChemicalEntity"
       },
       "text": "epinephrine",
       "locations": [
        {
         "offset": 183,
         "length": 11
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009638",
        "type": "ChemicalEntity"
       },
       "text": "norepinephrine",
       "locations": [
        {
         "offset": 199,
         "length": 14
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "153,154,155",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-AR",
       "locations": [
        {
         "offset": 296,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "153",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRB1",
       "locations": [
        {
         "offset": 311,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "154",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRB2",
       "locations": [
        {
         "offset": 318,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "155",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRB3",
       "locations": [
        {
         "offset": 328,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D002318,D008659",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiovascular and metabolic disorders",
       "locations": [
        {
         "offset": 428,
         "length": 38
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "153",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRB1",
       "locations": [
        {
         "offset": 584,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "p|SUB|R|389|G",
        "type": "SequenceVariant"
       },
       "text": "Arg389Gly",
       "locations": [
        {
         "offset": 590,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "p|SUB|G|49|S",
        "type": "SequenceVariant"
       },
       "text": "Gly49Ser",
       "locations": [
        {
         "offset": 604,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "154",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRB2",
       "locations": [
        {
         "offset": 614,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|SUB|R|16|G",
        "type": "SequenceVariant"
       },
       "text": "Arg16Gly",
       "locations": [
        {
         "offset": 620,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "p|SUB|Q|27|E",
        "type": "SequenceVariant"
       },
       "text": "Gln27Glu",
       "locations": [
        {
         "offset": 633,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "155",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRB3",
       "locations": [
        {
         "offset": 647,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|SUB|R|64|W",
        "type": "SequenceVariant"
       },
       "text": "Arg64Trp",
       "locations": [
        {
         "offset": 653,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "153,154,155",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-AR",
       "locations": [
        {
         "offset": 788,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "153,154,155",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-AR",
       "locations": [
        {
         "offset": 1479,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "153,154,155",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-AR",
       "locations": [
        {
         "offset": 1557,
         "length": 7
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D008659",
      "entity2": "p|SUB|R|64|W",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D008659",
      "entity2": "p|SUB|Q|27|E",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D008659",
      "entity2": "p|SUB|R|16|G",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D008659",
      "entity2": "p|SUB|G|49|S",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D008659",
      "entity2": "p|SUB|R|389|G",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D008659",
      "entity2": "155",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D008659",
      "entity2": "154",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "D008659",
      "entity2": "153",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "D002318",
      "entity2": "p|SUB|R|64|W",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "D002318",
      "entity2": "p|SUB|Q|27|E",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "D002318",
      "entity2": "p|SUB|R|16|G",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "D002318",
      "entity2": "p|SUB|G|49|S",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R12",
     "infons": {
      "entity1": "D002318",
      "entity2": "p|SUB|R|389|G",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R13",
     "infons": {
      "entity1": "D002318",
      "entity2": "155",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R14",
     "infons": {
      "entity1": "D002318",
      "entity2": "154",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R15",
     "infons": {
      "entity1": "D002318",
      "entity2": "153",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R16",
     "infons": {
      "entity1": "155",
      "entity2": "D009638",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R17",
     "infons": {
      "entity1": "155",
      "entity2": "D004837",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R18",
     "infons": {
      "entity1": "154",
      "entity2": "D009638",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R19",
     "infons": {
      "entity1": "154",
      "entity2": "D004837",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R20",
     "infons": {
      "entity1": "153",
      "entity2": "D009638",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R21",
     "infons": {
      "entity1": "153",
      "entity2": "D004837",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "15770495",
   "passages": [
    {
     "offset": 0,
     "text": "New mutations, hotspots, and founder effects in Brazilian patients with steroid 5alpha-reductase deficiency type 2.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 58,
         "length": 8
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C535830",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "steroid 5alpha-reductase deficiency type 2",
       "locations": [
        {
         "offset": 72,
         "length": 42
        }
       ]
      }
     ]
    },
    {
     "offset": 116,
     "text": "Mutations of the steroid 5alpha-reductase type 2 (SRD5A2) gene in 46,XY subjects cause masculinization defects of varying degrees, due to reduced or impaired enzymatic activity. In this study, sequence abnormalities of the SRD5A2 gene were assessed by polymerase chain reaction with specific primers and automated sequencing analysis in DNA samples from 20 patients with suspected steroid 5alpha-reductase type 2 deficiency from 18 Brazilian families. Eleven subjects presented SRD5A2 homozygous single-base mutations (two first cousins and four unrelated patients with G183S, two with R246W, one with del642T, one with G196S, and one with 217_218insC plus the A49T variant in heterozygosis), whereas four were compound heterozygotes (one with Q126R/IVS3+1G>A, one with Q126R/del418T, and two brothers with Q126R/G158R). Three patients were heterozygous for A207D, G196S, and R266W substitutions. The V89L polymorphism was found in heterozygosis in one of them (with A207D) and in one case with an otherwise normal gene sequence. The A49T variant was also detected in heterozygosis in the second case without other sequencing abnormalities. Four patients harbor yet non-described SRD5A2 gene mutations: a single nucleotide deletion (del642T), a G158R amino acid substitution, a splice junction mutation (IVS3+1G>A), and the insertion of a cytosine (217_218insC) occurring at a CCCC motif. This is the first report of a single-nucleotide insertion in the coding sequence of the SRD5A2 gene. In addition to these new mutations, this investigation reveals the prevalence of G183S substitution among a subset of African-Brazilian patients and presents evidences of the recurrence of already known mutations.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "steroid 5alpha-reductase type 2",
       "locations": [
        {
         "offset": 133,
         "length": 31
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 166,
         "length": 6
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 339,
         "length": 6
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 473,
         "length": 8
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C535830",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "steroid 5alpha-reductase type 2 deficiency",
       "locations": [
        {
         "offset": 497,
         "length": 42
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6716",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRD5A2",
       "locations": [
        {
         "offset": 594,
         "length": 6
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 672,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs121434247",
        "type": "SequenceVariant"
       },
       "text": "G183S",
       "locations": [
        {
         "offset": 686,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs121434244",
        "type": "SequenceVariant"
       },
       "text": "R246W",
       "locations": [
        {
         "offset": 702,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|DEL|642|T",
        "type": "SequenceVariant"
       },
       "text": "del642T",
       "locations": [
        {
         "offset": 718,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs121434250",
        "type": "SequenceVariant"
       },
       "text": "G196S",
       "locations": [
        {
         "offset": 736,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|INS|217_218|C",
        "type": "SequenceVariant"
       },
       "text": "217_218insC",
       "locations": [
        {
         "offset": 756,
         "length": 11
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs9282858",
        "type": "SequenceVariant"
       },
       "text": "A49T",
       "locations": [
        {
         "offset": 777,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs368386747",
        "type": "SequenceVariant"
       },
       "text": "Q126R",
       "locations": [
        {
         "offset": 860,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|SUB|G|IVS3+1|A",
        "type": "SequenceVariant"
       },
       "text": "IVS3+1G>A",
       "locations": [
        {
         "offset": 866,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs368386747",
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     "text": "Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells.",
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     "text": "OBJECTIVES: SLCO1B1*5 and SLCO1B1*15 have been reported to reduce the clearance of pravastatin in healthy volunteers. However, there remains controversy in the effects of SLCO1B1*5 on the activity of OATP1B1 in vitro. In addition, the effect of SLCO1B1*15 on the function of OATP1B1 has not been studied using cDNA-expression systems. Object of the present study was to study the influence of SLCO1B1*5, *15 and *15+C1007G, a novel haplotype found in a patient with pravastatin-induced myopathy, on the functional properties of OATP1B1 by transient expression systems of HEK293 and HeLa cells using endogenous conjugates and statins as substrates. METHODS: Transporting assays for endogenous substrates were performed using tritium labeled estradiol-17beta-D-glucuronide and estrone-3-sulfate. Quantitation of pravastatin, atorvastatin, cerivastatin and simvastatin were carried out using HPLC tandem mass spectrometry. RESULTS: The transporting activities of cells expressing SLCO1B1*5, *15 and *15+C1007G decreased significantly but those of SLCO1B1*1b, *1a+C1007G and *1b+C1007G were not altered for all of the substrates tested except for simvastatin. Kinetic analysis of pravastatin and atorvastatin showed that Km values were not altered but Vmax values decreased significantly in cells expressing SLCO1B1*5, *15 and *15+C1007G. Immunocytochemical study showed that SLCO1B1*5, *15 and *15+C1007G proteins are localized not only at the plasma membrane but also in the intracellular space. CONCLUSIONS: These findings suggest that 521T>C, existing commonly in SLCO1B1*5, *15 and *15+C1007G, is the key single nucleotide polymorphism (SNP) that determines the functional properties of SLCO1B1*5, *15 and *15+C1007G allelic proteins and that decreased activities of these variant proteins are mainly caused by a sorting error produced by this SNP.",
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     "id": "R9",
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      "novel": "No"
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    },
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     "id": "R10",
     "infons": {
      "entity1": "D017035",
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      "novel": "No"
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   ]
  },
  {
   "id": "16737910",
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    {
     "offset": 0,
     "text": "Identification of the nuclear localization motif in the ETV6 (TEL) protein.",
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      {
       "id": "0",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 56,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "TEL",
       "locations": [
        {
         "offset": 62,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 76,
     "text": "ETV6, or Translocation-Ets-Leukemia (TEL), is an ETS family transcriptional repressor that is essential for establishing hematopoiesis in neonatal bone marrow, and is frequently a target of chromosomal translocations in human cancer. ETV6 is predominantly a nuclear phosphoprotein that represses transcription by binding directly to the promoters of target genes. The nuclear localization mechanism of ETV6, however, is not well understood. In this report, we provide evidence that a nuclear localization signal (NLS) exists in the C-terminal region of ETV6. ETV6 proteins with mutations outside of amino acids 332-452 localize to the nucleus, whereas proteins with mutations within amino acids 332-452 remain in the cytoplasm. Furthermore, when a fragment of ETV6 comprised of amino acids 332-452 was fused to cytoplasmic beta-galactosidase protein, the fusion protein was able to enter the nucleus. These results strongly indicate that residues 332-452 mediate nuclear localization of ETV6.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 76,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "Translocation-Ets-Leukemia",
       "locations": [
        {
         "offset": 85,
         "length": 26
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "TEL",
       "locations": [
        {
         "offset": 113,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 296,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 302,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 310,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 478,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 629,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 635,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 836,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "2720",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-galactosidase",
       "locations": [
        {
         "offset": 899,
         "length": 18
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "2120",
        "type": "GeneOrGeneProduct"
       },
       "text": "ETV6",
       "locations": [
        {
         "offset": 1063,
         "length": 4
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       ]
      }
     ]
    }
   ],
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  {
   "id": "16822828",
   "passages": [
    {
     "offset": 0,
     "text": "Genotyping of five chinese patients with 17alpha-hydroxylase deficiency diagnosed through high-performance liquid chromatography serum adrenal profile: identification of two novel CYP17 mutations.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
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         "offset": 27,
         "length": 8
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C538237",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "17alpha-hydroxylase deficiency",
       "locations": [
        {
         "offset": 41,
         "length": 30
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "1586",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP17",
       "locations": [
        {
         "offset": 180,
         "length": 5
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       ]
      }
     ]
    },
    {
     "offset": 197,
     "text": "CONTEXT: 17alpha-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia caused by CYP17 gene mutations. OBJECTIVE: Five Chinese patients with 17alpha-hydroxylase deficiency were genotyped. PATIENTS: The five patients derived from four families living in Shandong Province, China. The diagnosis of 17alpha-hydroxylase deficiency was initially established through HPLC serum adrenal profiles in Qilu Hospital, China, from 1983-1993. RESULTS: Three CYP17 gene mutations were identified from these patients. Among them, V311fs and Y329fs are two novel frame-shifting mutations. V311fs is an 8-bp nucleotide (TTAAATGG) deletion in exon 5. Y329fs is a deletion-insertion combined mutation (TAC-->AA) at codon 329 in exon 6. Two homozygotes for Y329fs and one compound heterozygote for Y329fs and V311fs were identified from three different families. Two homozygous sisters for the D487_S488_F489 deletion were identified. CONCLUSION: The results confirmed the diagnostic value of the HPLC serum adrenal profile for 17alpha-hydroxylase deficiency. The D487_S488_F489 deletion had been identified in two previously genotyped Chinese families. In our present study, a third Chinese family with this mutation was identified, suggesting that this mutation is a prevalent CYP17 mutation in the Chinese population. The identification of Y329fs mutation in addition to three previously identified mutations at codon 329 suggests that codon 329 is an unstable point of the CYP17 gene. The mutations identified from our five patients appear to be random, but the recurrence of the Y329fs mutation may be attributed to a founder effect. Our studies suggest that 17alpha-hydroxylase deficiency may not be rare in the Chinese population.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "C538237",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "17alpha-Hydroxylase deficiency",
       "locations": [
        {
         "offset": 206,
         "length": 30
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000312",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital adrenal hyperplasia",
       "locations": [
        {
         "offset": 255,
         "length": 30
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1586",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP17",
       "locations": [
        {
         "offset": 296,
         "length": 5
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       ]
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       "id": "6",
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        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 342,
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       ]
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       "id": "7",
       "infons": {
        "identifier": "C538237",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "17alpha-hydroxylase deficiency",
       "locations": [
        {
         "offset": 356,
         "length": 30
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "PATIENTS",
       "locations": [
        {
         "offset": 403,
         "length": 8
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
        {
         "offset": 422,
         "length": 8
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "C538237",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "17alpha-hydroxylase deficiency",
       "locations": [
        {
         "offset": 511,
         "length": 30
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1586",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP17",
       "locations": [
        {
         "offset": 660,
         "length": 5
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 708,
         "length": 8
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       ]
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       "id": "13",
       "infons": {
        "identifier": "p|FS|V|311||",
        "type": "SequenceVariant"
       },
       "text": "V311fs",
       "locations": [
        {
         "offset": 730,
         "length": 6
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|FS|Y|329||",
        "type": "SequenceVariant"
       },
       "text": "Y329fs",
       "locations": [
        {
         "offset": 741,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "p|FS|V|311||",
        "type": "SequenceVariant"
       },
       "text": "V311fs",
       "locations": [
        {
         "offset": 788,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|DEL||TTAAATGG",
        "type": "SequenceVariant"
       },
       "text": "8-bp nucleotide (TTAAATGG) deletion",
       "locations": [
        {
         "offset": 801,
         "length": 35
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|FS|Y|329||",
        "type": "SequenceVariant"
       },
       "text": "Y329fs",
       "locations": [
        {
         "offset": 848,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|SUB|TAC|CODON329|AA",
        "type": "SequenceVariant"
       },
       "text": "(TAC-->AA) at codon 329",
       "locations": [
        {
         "offset": 897,
         "length": 23
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "p|FS|Y|329||",
        "type": "SequenceVariant"
       },
       "text": "Y329fs",
       "locations": [
        {
         "offset": 952,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "p|FS|Y|329||",
        "type": "SequenceVariant"
       },
       "text": "Y329fs",
       "locations": [
        {
         "offset": 993,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "p|FS|V|311||",
        "type": "SequenceVariant"
       },
       "text": "V311fs",
       "locations": [
        {
         "offset": 1004,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "p|DEL|487_489|DSF",
        "type": "SequenceVariant"
       },
       "text": "D487_S488_F489 deletion",
       "locations": [
        {
         "offset": 1089,
         "length": 23
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "C538237",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "17alpha-hydroxylase deficiency",
       "locations": [
        {
         "offset": 1223,
         "length": 30
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "p|DEL|487_489|DSF",
        "type": "SequenceVariant"
       },
       "text": "D487_S488_F489 deletion",
       "locations": [
        {
         "offset": 1259,
         "length": 23
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "1586",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP17",
       "locations": [
        {
         "offset": 1474,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "p|FS|Y|329||",
        "type": "SequenceVariant"
       },
       "text": "Y329fs",
       "locations": [
        {
         "offset": 1538,
         "length": 6
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "1586",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP17",
       "locations": [
        {
         "offset": 1672,
         "length": 5
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1723,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "p|FS|Y|329||",
        "type": "SequenceVariant"
       },
       "text": "Y329fs",
       "locations": [
        {
         "offset": 1779,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "C538237",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "17alpha-hydroxylase deficiency",
       "locations": [
        {
         "offset": 1859,
         "length": 30
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "1586",
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "p|DEL|487_489|DSF",
      "entity2": "C538237",
      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|SUB|TAC|CODON329|AA",
      "entity2": "C538237",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|DEL||TTAAATGG",
      "entity2": "C538237",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "p|FS|Y|329||",
      "entity2": "C538237",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "p|FS|V|311||",
      "entity2": "C538237",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17351238",
   "passages": [
    {
     "offset": 0,
     "text": "A dramatic drop in blood pressure following prehospital GTN administration.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D007022",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drop in blood pressure",
       "locations": [
        {
         "offset": 11,
         "length": 22
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D005996",
        "type": "ChemicalEntity"
       },
       "text": "GTN",
       "locations": [
        {
         "offset": 56,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 76,
     "text": "A male in his sixties with no history of cardiac chest pain awoke with chest pain following an afternoon sleep. The patient did not self medicate. The patient's observations were within normal limits, he was administered oxygen via a face mask and glyceryl trinitrate (GTN). Several minutes after the GTN the patient experienced a sudden drop in blood pressure and heart rate, this was rectified by atropine sulphate and a fluid challenge. There was no further deterioration in the patient's condition during transport to hospital. There are very few documented case like this in the prehospital scientific literature. The cause appears to be the Bezold-Jarish reflex, stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre. Prehospital care providers who are managing any patient with a syncopal episode that fails to recover within a reasonable time frame should consider the Bezold-Jarisch reflex as the cause and manage the patient accordingly.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D002637",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chest pain",
       "locations": [
        {
         "offset": 125,
         "length": 10
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D002637",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chest pain",
       "locations": [
        {
         "offset": 147,
         "length": 10
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 192,
         "length": 7
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 227,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D010100",
        "type": "ChemicalEntity"
       },
       "text": "oxygen",
       "locations": [
        {
         "offset": 297,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D005996",
        "type": "ChemicalEntity"
       },
       "text": "glyceryl trinitrate",
       "locations": [
        {
         "offset": 324,
         "length": 19
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D005996",
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         "length": 3
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       "id": "9",
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        "identifier": "D005996",
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       "text": "patient",
       "locations": [
        {
         "offset": 385,
         "length": 7
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D007022",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drop in blood pressure",
       "locations": [
        {
         "offset": 414,
         "length": 22
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D001285",
        "type": "ChemicalEntity"
       },
       "text": "atropine sulphate",
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         "offset": 475,
         "length": 17
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        "type": "OrganismTaxon"
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       "text": "patient",
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         "offset": 901,
         "length": 7
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       "id": "15",
       "infons": {
        "identifier": "D013575",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "syncopal episode",
       "locations": [
        {
         "offset": 916,
         "length": 16
        }
       ]
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      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patient",
       "locations": [
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         "offset": 1056,
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     "id": "R0",
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     "id": "R1",
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  {
   "id": "18189233",
   "passages": [
    {
     "offset": 0,
     "text": "RNASEL and RNASEL-inhibitor variation and prostate cancer risk in Afro-Caribbeans.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6041",
        "type": "GeneOrGeneProduct"
       },
       "text": "RNASEL",
       "locations": [
        {
         "offset": 0,
         "length": 6
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6041",
        "type": "GeneOrGeneProduct"
       },
       "text": "RNASEL",
       "locations": [
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         "offset": 11,
         "length": 6
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       ]
      },
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       "id": "2",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 42,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 83,
     "text": "BACKGROUND: Afro-Caribbeans from Tobago are at high risk of developing prostate cancer. This elevated risk of prostate cancer is shared by populations of African ancestry living in diverse environments in the Western hemisphere. Variation in the ribonuclease L (RNASEL) gene has recently been reported to be associated with an increased risk of prostate cancer. However, whether RNASEL variation contributes to the increased risk of prostate cancer observed in populations of African ancestry remains unclear. METHODS: We resequenced the positional candidate gene RNASEL in 48 prostate cancer cases and genotyped the previously reported R462Q and D541E polymorphisms in 230 prostate cancer cases and 458 controls. We also examined the inhibitor of RNASEL (ABCE1) for variation associated with prostate cancer risk. RESULTS: We found no evidence of association between R462Q and D541E polymorphisms and prostate cancer risk in our case/control analysis. A novel variant (K294E) was identified in a single heterozygous individual with prostate cancer. We also observed a 20 bp insertion/deletion polymorphism 1,109 bp upstream of the initiation codon, but this variant was not associated with prostate cancer. We identified 16 single nucleotide polymorphisms in the ABCE1 gene, only 3 of which had a minor allele frequency >5%. A common A/G transition -1,071 bp from the transcriptional start site was genotyped and showed no evidence of association with prostate cancer. CONCLUSIONS: Our results suggest that common variation in the putative prostate cancer susceptibility gene, RNASEL, or its inhibitor does not contribute significantly to prostate cancer risk in this Afro-Caribbean population.",
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       "id": "3",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "prostate cancer",
       "locations": [
        {
         "offset": 154,
         "length": 15
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      },
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       "id": "4",
       "infons": {
        "identifier": "D011471",
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       "text": "prostate cancer",
       "locations": [
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       ]
      },
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       "id": "5",
       "infons": {
        "identifier": "6041",
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       "text": "ribonuclease L",
       "locations": [
        {
         "offset": 329,
         "length": 14
        }
       ]
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       "id": "6",
       "infons": {
        "identifier": "6041",
        "type": "GeneOrGeneProduct"
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       "text": "RNASEL",
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         "offset": 345,
         "length": 6
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       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "D011471",
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       "text": "prostate cancer",
       "locations": [
        {
         "offset": 428,
         "length": 15
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "6041",
        "type": "GeneOrGeneProduct"
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       "text": "RNASEL",
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         "offset": 462,
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       ]
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       "id": "9",
       "infons": {
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       "text": "prostate cancer",
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         "offset": 516,
         "length": 15
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "6041",
        "type": "GeneOrGeneProduct"
       },
       "text": "RNASEL",
       "locations": [
        {
         "offset": 647,
         "length": 6
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D011471",
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       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 660,
         "length": 15
        }
       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "rs486907",
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       },
       "text": "R462Q",
       "locations": [
        {
         "offset": 720,
         "length": 5
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "rs627928",
        "type": "SequenceVariant"
       },
       "text": "D541E",
       "locations": [
        {
         "offset": 730,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 757,
         "length": 15
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "6041",
        "type": "GeneOrGeneProduct"
       },
       "text": "RNASEL",
       "locations": [
        {
         "offset": 831,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "6059",
        "type": "GeneOrGeneProduct"
       },
       "text": "ABCE1",
       "locations": [
        {
         "offset": 839,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 876,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs486907",
        "type": "SequenceVariant"
       },
       "text": "R462Q",
       "locations": [
        {
         "offset": 951,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs627928",
        "type": "SequenceVariant"
       },
       "text": "D541E",
       "locations": [
        {
         "offset": 961,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 985,
         "length": 15
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs143544690",
        "type": "SequenceVariant"
       },
       "text": "K294E",
       "locations": [
        {
         "offset": 1053,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D011471",
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       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1116,
         "length": 15
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|INDEL|1109|20",
        "type": "SequenceVariant"
       },
       "text": "20 bp insertion/deletion polymorphism 1,109 bp upstream of the initiation codon",
       "locations": [
        {
         "offset": 1152,
         "length": 79
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1274,
         "length": 15
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "6059",
        "type": "GeneOrGeneProduct"
       },
       "text": "ABCE1",
       "locations": [
        {
         "offset": 1347,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "c|SUB|A|-1071|G",
        "type": "SequenceVariant"
       },
       "text": "A/G transition -1,071 bp",
       "locations": [
        {
         "offset": 1418,
         "length": 24
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1536,
         "length": 15
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1624,
         "length": 15
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "6041",
        "type": "GeneOrGeneProduct"
       },
       "text": "RNASEL",
       "locations": [
        {
         "offset": 1661,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 1723,
         "length": 15
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "rs143544690",
      "entity2": "D011471",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D011471",
      "entity2": "rs627928",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D011471",
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      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
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      "novel": "No"
     }
    },
    {
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    }
   ]
  },
  {
   "id": "18483878",
   "passages": [
    {
     "offset": 0,
     "text": "Exaggerated expression of inflammatory mediators in vasoactive intestinal polypeptide knockout (VIP-/-) mice with cyclophosphamide (CYP)-induced cystitis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 26,
         "length": 12
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "vasoactive intestinal polypeptide",
       "locations": [
        {
         "offset": 52,
         "length": 33
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 96,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 104,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
       },
       "text": "cyclophosphamide",
       "locations": [
        {
         "offset": 114,
         "length": 16
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
       },
       "text": "CYP",
       "locations": [
        {
         "offset": 132,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D003556",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cystitis",
       "locations": [
        {
         "offset": 145,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 155,
     "text": "Vasoactive intestinal polypeptide (VIP) is an immunomodulatory neuropeptide distributed in micturition pathways. VIP(-/-) mice exhibit altered bladder function and neurochemical properties in micturition pathways after cyclophosphamide (CYP)-induced cystitis. Given VIP's role as an anti-inflammatory mediator, we hypothesized that VIP(-/-) mice would exhibit enhanced inflammatory mediator expression after cystitis. A mouse inflammatory cytokine and receptor RT2 profiler array was used to determine regulated transcripts in the urinary bladder of wild type (WT) and VIP(-/-) mice with or without CYP-induced cystitis (150 mg/kg; i.p.; 48 h). Four binary comparisons were made: WT control versus CYP treatment (48 h), VIP(-/-) control versus CYP treatment (48 h), WT control versus VIP(-/-) control, and WT with CYP treatment (48 h) versus VIP(-/-) with CYP treatment (48 h). The genes presented represent (1) greater than 1.5-fold change in either direction and (2) the p value is less than 0.05 for the comparison being made. Several regulated genes were validated using enzyme-linked immunoassays including IL-1beta and CXCL1. CYP treatment significantly (p < or = 0.001) increased expression of CXCL1 and IL-1beta in the urinary bladder of WT and VIP(-/-) mice, but expression in VIP(-/-) mice with CYP treatment was significantly (p < or = 0.001) greater (4.2- to 13-fold increase) than that observed in WT urinary bladder (3.6- to 5-fold increase). The data suggest that in VIP(-/-) mice with bladder inflammation, inflammatory mediators are increased above that observed in WT with CYP. This shift in balance may contribute to increased bladder dysfunction in VIP(-/-) mice with bladder inflammation and altered neurochemical expression in micturition pathways.",
     "annotations": [
      {
       "id": "7",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "Vasoactive intestinal polypeptide",
       "locations": [
        {
         "offset": 155,
         "length": 33
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 190,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 268,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 277,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
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       "text": "cyclophosphamide",
       "locations": [
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         "offset": 374,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
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       "text": "CYP",
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         "length": 3
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003556",
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       "text": "cystitis",
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         "offset": 405,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
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       "text": "VIP",
       "locations": [
        {
         "offset": 421,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 443,
         "length": 12
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 487,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 496,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 524,
         "length": 12
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D003556",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cystitis",
       "locations": [
        {
         "offset": 563,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 575,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 581,
         "length": 12
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 724,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 733,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
       },
       "text": "CYP",
       "locations": [
        {
         "offset": 754,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D003556",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cystitis",
       "locations": [
        {
         "offset": 766,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
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       "text": "CYP",
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       "id": "45",
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        "identifier": "D003556",
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       "text": "bladder inflammation",
       "locations": [
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         "offset": 1656,
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       ]
      },
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       "id": "46",
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         "offset": 1678,
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       ]
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         "offset": 1746,
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       ]
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       "id": "48",
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        "identifier": "D001745",
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       "text": "bladder dysfunction",
       "locations": [
        {
         "offset": 1801,
         "length": 19
        }
       ]
      },
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       "id": "49",
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       "text": "mice",
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         "offset": 1833,
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       ]
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       "id": "51",
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       "text": "bladder inflammation",
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     "offset": 0,
     "text": "mToR inhibitors-induced proteinuria: mechanisms, significance, and management.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "-",
        "type": "ChemicalEntity"
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       "text": "mToR inhibitors",
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       "id": "1",
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       "locations": [
        {
         "offset": 24,
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     ]
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     "offset": 79,
     "text": "Massive urinary protein excretion has been observed after conversion from calcineurin inhibitors to mammalian target of rapamycin (mToR) inhibitors, especially sirolimus, in renal transplant recipients with chronic allograft nephropathy. Because proteinuria is a major predictive factor of poor transplantation outcome, many studies focused on this adverse event during the past years. Whether proteinuria was due to sirolimus or only a consequence of calcineurin inhibitors withdrawal remained unsolved until high range proteinuria has been observed during sirolimus therapy in islet transplantation and in patients who received sirolimus de novo. Podocyte injury and focal segmental glomerulosclerosis have been related to mToR inhibition in some patients, but the pathways underlying these lesions remain hypothetic. We discuss herein the possible mechanisms and the significance of mToR blockade-induced proteinuria.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D065095",
        "type": "ChemicalEntity"
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       "text": "calcineurin inhibitors",
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       ]
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       "text": "mammalian target of rapamycin (mToR) inhibitors",
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       "id": "4",
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       "text": "sirolimus",
       "locations": [
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         "offset": 239,
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       ]
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       "infons": {
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       "text": "chronic allograft nephropathy",
       "locations": [
        {
         "offset": 286,
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       ]
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       "text": "proteinuria",
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       ]
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       "id": "7",
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       "text": "proteinuria",
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       "text": "sirolimus",
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       "text": "calcineurin inhibitors",
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       "id": "10",
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        "identifier": "D011507",
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       "text": "proteinuria",
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       ]
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       "text": "sirolimus",
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       ]
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       "id": "12",
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       "text": "patients",
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       ]
      },
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       "infons": {
        "identifier": "D020123",
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       "text": "sirolimus",
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       "text": "glomerulosclerosis",
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         "offset": 764,
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       "text": "patients",
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       "infons": {
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       "text": "proteinuria",
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    }
   ]
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  {
   "id": "18791947",
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    {
     "offset": 0,
     "text": "A case of Bernard-Soulier Syndrome due to a homozygous four bases deletion (TGAG) of GPIbalpha gene: lack of GPIbalpha but absence of bleeding.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Bernard-Soulier Syndrome",
       "locations": [
        {
         "offset": 10,
         "length": 24
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|DEL||TGAG",
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       "text": "deletion (TGAG)",
       "locations": [
        {
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         "length": 15
        }
       ]
      },
      {
       "id": "2",
       "infons": {
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       "text": "GPIbalpha",
       "locations": [
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         "offset": 85,
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       "id": "3",
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       "text": "GPIbalpha",
       "locations": [
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       ]
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      {
       "id": "4",
       "infons": {
        "identifier": "D006470",
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       "text": "bleeding",
       "locations": [
        {
         "offset": 134,
         "length": 8
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     ]
    },
    {
     "offset": 144,
     "text": "More than 20 DNA mutations with different inheritance pattern have been described in patients with Bernard-Soulier Syndrome (BSS), leading to abnormal or absent synthesis and/or expression of GPIbalpha. Clinical phenotype shows considerable variation between individuals, such as bleeding, platelet count and the percentage of large platelets. We describe in a BSS patient the first case of homozygous four bases deletion (TGAG) in the gpIbalpha gene coding sequence, leading to a premature stop codon. In the propositus, blood smears revealed giant platelets (30 x 10(9) platelets/L), and platelet agglutination to ristocetin was absent. Propositus' parents are consanguineous. His father and paternal grandmother showed a mild thrombocytopenia (108 x 10(9)/L and 120 x 10(9)/L platelets respectively) while mothers and sister's referred normal platelet counts. The surface expression of GPIbalpha was practically undetectable by flow-cytometry and western blot in the patient and was reduced in the father. Proband's DNA analysis revealed a homozygous four-base-pair deletion (TGAG), starting from the last base of the codon for Ser39, leading to a coding frame shift with a new termination codon after 11 novel amino acids. The same mutation was seen in heterozygosis in both parents. This is the first report of GPIbalpha TGAG deletion in homozygous state even if the defect has already been described in a case of compound heterozygosis. Surprisingly, the propositus does not report any spontaneous bleeding tendency.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 229,
         "length": 8
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001606",
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       },
       "text": "Bernard-Soulier Syndrome",
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         "offset": 243,
         "length": 24
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       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "D001606",
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       "text": "BSS",
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         "offset": 269,
         "length": 3
        }
       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "2811",
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       "text": "GPIbalpha",
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         "offset": 336,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D006470",
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       "text": "bleeding",
       "locations": [
        {
         "offset": 424,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001606",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BSS",
       "locations": [
        {
         "offset": 505,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
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       },
       "text": "patient",
       "locations": [
        {
         "offset": 509,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
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        "identifier": "c|DEL||TGAG",
        "type": "SequenceVariant"
       },
       "text": "deletion (TGAG)",
       "locations": [
        {
         "offset": 557,
         "length": 15
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "2811",
        "type": "GeneOrGeneProduct"
       },
       "text": "gpIbalpha",
       "locations": [
        {
         "offset": 580,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D012310",
        "type": "ChemicalEntity"
       },
       "text": "ristocetin",
       "locations": [
        {
         "offset": 760,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D013921",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "thrombocytopenia",
       "locations": [
        {
         "offset": 873,
         "length": 16
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "2811",
        "type": "GeneOrGeneProduct"
       },
       "text": "GPIbalpha",
       "locations": [
        {
         "offset": 1033,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1114,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|DEL||TGAG",
        "type": "SequenceVariant"
       },
       "text": "deletion (TGAG)",
       "locations": [
        {
         "offset": 1213,
         "length": 15
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "2811",
        "type": "GeneOrGeneProduct"
       },
       "text": "GPIbalpha",
       "locations": [
        {
         "offset": 1460,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|DEL||TGAG",
        "type": "SequenceVariant"
       },
       "text": "TGAG deletion",
       "locations": [
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         "offset": 1470,
         "length": 13
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      },
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       "id": "21",
       "infons": {
        "identifier": "D006470",
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       "text": "bleeding tendency",
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    {
     "offset": 0,
     "text": "Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma.",
     "annotations": [
      {
       "id": "0",
       "infons": {
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       "text": "UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit",
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       "id": "1",
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       "text": "GNPTG",
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       "text": "patients",
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       "id": "3",
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        "identifier": "C565367",
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       "text": "mucolipidosis III gamma",
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     "offset": 190,
     "text": "Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.T286M) and nonsense (p.W111X) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site (c.610-2A>G). Three microdeletions were also identified, two of which (c.611delG and c.640_667del28) were located within the coding region whereas one (c.609+28_610-16del) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 (p.G204_K247del) or the retention of introns 8 and 9 (p.G204VfsX28). RT-PCR analysis, performed on a patient homozygous for the intronic deletion (c.609+28_610-16del), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment.",
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       "id": "4",
       "infons": {
        "identifier": "D009081",
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       "text": "Mucolipidosis type III",
       "locations": [
        {
         "offset": 190,
         "length": 22
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009081",
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       "text": "MLIII",
       "locations": [
        {
         "offset": 214,
         "length": 5
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D030342",
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       "text": "autosomal recessive disorder",
       "locations": [
        {
         "offset": 227,
         "length": 28
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       ]
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       "id": "7",
       "infons": {
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       "text": "patients",
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      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009081",
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       "text": "MLIII",
       "locations": [
        {
         "offset": 398,
         "length": 5
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "84572",
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       "text": "GNPTG",
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         "offset": 415,
         "length": 5
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       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "rs193302860",
        "type": "SequenceVariant"
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       "text": "p.T286M",
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       ]
      },
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       "id": "11",
       "infons": {
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        "type": "SequenceVariant"
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       "text": "p.W111X",
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        {
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs193302855",
        "type": "SequenceVariant"
       },
       "text": "AG-dinucleotide",
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        {
         "offset": 553,
         "length": 15
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "rs193302855",
        "type": "SequenceVariant"
       },
       "text": "c.610-2A>G",
       "locations": [
        {
         "offset": 607,
         "length": 10
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs193302856",
        "type": "SequenceVariant"
       },
       "text": "c.611delG",
       "locations": [
        {
         "offset": 677,
         "length": 9
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs193302859",
        "type": "SequenceVariant"
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       "text": "c.640_667del28",
       "locations": [
        {
         "offset": 691,
         "length": 14
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|DEL|609+28_610-16|",
        "type": "SequenceVariant"
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       "text": "c.609+28_610-16del",
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       ]
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       "id": "17",
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        "identifier": "rs193302855",
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       "text": "c.610-2A>G",
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         "length": 10
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       ]
      },
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       "id": "18",
       "infons": {
        "identifier": "p|DEL|204_247|",
        "type": "SequenceVariant"
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       "text": "p.G204_K247del",
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         "offset": 1005,
         "length": 14
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       ]
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      {
       "id": "19",
       "infons": {
        "identifier": "p|FS|G|204|V|28",
        "type": "SequenceVariant"
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       "text": "p.G204VfsX28",
       "locations": [
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         "offset": 1058,
         "length": 12
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       ]
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      {
       "id": "20",
       "infons": {
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       "text": "patient",
       "locations": [
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         "offset": 1105,
         "length": 7
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      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|DEL|609+28_610-16|",
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       "text": "c.609+28_610-16del",
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       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "84572",
        "type": "GeneOrGeneProduct"
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       "text": "GNPTG",
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         "offset": 1193,
         "length": 5
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      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|DEL|609+28_610-16|",
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       "text": "c.609+28_610-16del",
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       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1335,
         "length": 7
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       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D000841",
        "type": "ChemicalEntity"
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       "text": "anisomycin",
       "locations": [
        {
         "offset": 1407,
         "length": 10
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "g|DEL||33",
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       },
       "text": "33-bp genomic deletion",
       "locations": [
        {
         "offset": 1512,
         "length": 22
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "84572",
        "type": "GeneOrGeneProduct"
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       "text": "GNPTG",
       "locations": [
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         "offset": 1584,
         "length": 5
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "p|FS|G|204|V|17",
        "type": "SequenceVariant"
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       "text": "p.G204VfsX17",
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         "offset": 1656,
         "length": 12
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       ]
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      {
       "id": "29",
       "infons": {
        "identifier": "84572",
        "type": "GeneOrGeneProduct"
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       "text": "GNPTG",
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         "offset": 1721,
         "length": 5
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       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "84572",
        "type": "GeneOrGeneProduct"
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       "text": "GNPTG",
       "locations": [
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         "offset": 2083,
         "length": 5
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      }
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  {
   "id": "20331935",
   "passages": [
    {
     "offset": 0,
     "text": "A cross-sectional evaluation of the effect of risperidone and selective serotonin reuptake inhibitors on bone mineral density in boys.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D018967",
        "type": "ChemicalEntity"
       },
       "text": "risperidone",
       "locations": [
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         "offset": 46,
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "D017367",
        "type": "ChemicalEntity"
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       "text": "selective serotonin reuptake inhibitors",
       "locations": [
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         "offset": 62,
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    },
    {
     "offset": 135,
     "text": "OBJECTIVE: The aim of the present study was to investigate the effect of risperidone-induced hyperprolactinemia on trabecular bone mineral density (BMD) in children and adolescents. METHOD: Medically healthy 7- to 17-year-old males chronically treated, in a naturalistic setting, with risperidone were recruited for this cross-sectional study through child psychiatry outpatient clinics between November 2005 and June 2007. Anthropometric measurements and laboratory testing were conducted. The clinical diagnoses were based on chart review, and developmental and treatment history was obtained from the medical record. Volumetric BMD of the ultradistal radius was measured using peripheral quantitative computed tomography, and areal BMD of the lumbar spine was estimated using dual-energy x-ray absorptiometry. RESULTS: Hyperprolactinemia was present in 49% of 83 boys (n = 41) treated with risperidone for a mean of 2.9 years. Serum testosterone concentration increased with pubertal status but was not affected by hyperprolactinemia. As expected, bone mineral content and BMD increased with sexual maturity. After adjusting for the stage of sexual development and height and BMI z scores, serum prolactin was negatively associated with trabecular volumetric BMD at the ultradistal radius (P < .03). Controlling for relevant covariates, we also found treatment with selective serotonin reuptake inhibitors (SSRIs) to be associated with lower trabecular BMD at the radius (P = .03) and BMD z score at the lumbar spine (P < .05). These findings became more marked when the analysis was restricted to non-Hispanic white patients. Of 13 documented fractures, 3 occurred after risperidone and SSRIs were started, and none occurred in patients with hyperprolactinemia. CONCLUSIONS: This is the first study to link risperidone-induced hyperprolactinemia and SSRI treatment to lower BMD in children and adolescents. Future research should evaluate the longitudinal course of this adverse event to determine its temporal stability and whether a higher fracture rate ensues.",
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       "id": "10",
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       "text": "patients",
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       "id": "14",
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       "text": "patients",
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     "offset": 0,
     "text": "The GALT rush: high carrier frequency of an unusual deletion mutation of the GALT gene in the Ashkenazi population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "2592",
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       "text": "GALT",
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         "offset": 4,
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       "id": "1",
       "infons": {
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       "text": "GALT",
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         "offset": 77,
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     "text": "Classic galactosemia is an autosomal recessive disorder of galactose metabolism manifesting in the first weeks of life following exposure to a milk-based diet. Despite the benefit of avoidance of lactose, many patients suffer from long-term complications including neurological deficits and ovarian failure. To date, over 230 mutations have been described in the GALT gene resulting in galactosemia. Recently, an unusual mutation was characterized causing a 5.5 kb deletion, with a relatively high carrier rate in subjects of Ashkenazi Jewish (AJ) descent. The aim of this study was to estimate the carrier frequency of this mutation in the AJ population in Israel. For this purpose we developed a high-throughput methodology to genotype both normal and deleted alleles using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer and Multiplex PCR. DNA samples of 760 anonymous AJ subjects were submitted for analysis, subsequently detecting six individuals heterozygous for the GALT deletion mutation, giving a carrier frequency of 1 in 127 (0.79%). Based on these results, we suggest that the method described here provides a basis for genetic screening and prenatal counseling and can potentially reduce the morbidity and mortality associated with delayed diagnosis of galactosemia in this patient population.",
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      {
       "id": "2",
       "infons": {
        "identifier": "D005693",
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       "text": "Classic galactosemia",
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       "id": "3",
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       "text": "autosomal recessive disorder of galactose metabolism",
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       "text": "ovarian failure",
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       "text": "GALT",
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     "text": "Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin.",
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     "text": "Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in AD.",
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     "text": "PURPOSE: Although the existence of cancer stem cells (CSC) in adenoid cystic carcinoma (ACC) has been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization. Our objective was to isolate CSC from ACC and provide insight into signaling pathways that support their propagation. EXPERIMENTAL DESIGN: To isolate CSC from ACC and characterize them, we used ROCK inhibitor-supplemented cell culture, immunomagnetic cell sorting, andin vitro/in vivoassays for CSC viability and tumorigenicity. RESULTS: We identified in ACC CD133-positive CSC that expressed NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. CD133(+)ACC cells produced activated NOTCH1 (N1ICD) and generated CD133(-)cells that expressed JAG1 as well as neural differentiation factors NR2F1, NR2F2, and p27Kip1. Knockdowns of NOTCH1, SOX10, and their common effector FABP7 had negative effects on each other, inhibited spheroidogenesis, and induced cell death pointing at their essential roles in CSC maintenance. Downstream effects of FABP7 knockdown included suppression of a broad spectrum of genes involved in proliferation, ribosome biogenesis, and metabolism. Among proliferation-linked NOTCH1/FABP7 targets, we identified SKP2 and its substrate p27Kip1. A g-secretase inhibitor, DAPT, selectively depleted CD133(+)cells, suppressed N1ICD and SKP2, induced p27Kip1, inhibited ACC growthin vivo, and sensitized CD133(+)cells to radiation. CONCLUSIONS: These results establish in the majority of ACC the presence of a previously uncharacterized population of CD133(+)cells with neural stem properties, which are driven by SOX10, NOTCH1, and FABP7. Sensitivity of these cells to Notch inhibition and their dependence on SKP2 offer new opportunities for targeted ACC therapies.",
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       "text": "cancer",
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  {
   "id": "18235024",
   "passages": [
    {
     "offset": 0,
     "text": "Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C563678",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Cone dystrophy with supernormal rod response",
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    {
     "offset": 93,
     "text": "PURPOSE: Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior RESULTS: Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. results. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS: The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2.",
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       "id": "2",
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        "identifier": "C563678",
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       "text": "PDE6H",
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        {
         "offset": 374,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "169522",
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       "text": "KCNV2",
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         "offset": 387,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C563678",
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       "text": "CDSRR",
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        {
         "offset": 416,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
        {
         "offset": 490,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "C563678",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CDSRR",
       "locations": [
        {
         "offset": 504,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 558,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "5146",
        "type": "GeneOrGeneProduct"
       },
       "text": "PDE6C",
       "locations": [
        {
         "offset": 826,
         "length": 5
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "169522",
        "type": "GeneOrGeneProduct"
       },
       "text": "KCNV2",
       "locations": [
        {
         "offset": 836,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "5149",
        "type": "GeneOrGeneProduct"
       },
       "text": "PDE6H",
       "locations": [
        {
         "offset": 995,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "169522",
        "type": "GeneOrGeneProduct"
       },
       "text": "KCNV2",
       "locations": [
        {
         "offset": 1020,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1049,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C563678",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CDSRR",
       "locations": [
        {
         "offset": 1351,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003117",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "color vision defects",
       "locations": [
        {
         "offset": 1432,
         "length": 20
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D001284",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atrophy",
       "locations": [
        {
         "offset": 1526,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1555,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1628,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "C563678",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cone dystrophy with supernormal rod response",
       "locations": [
        {
         "offset": 1688,
         "length": 44
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "169522",
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       "text": "KCNV2",
       "locations": [
        {
         "offset": 1769,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
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     "id": "R0",
     "infons": {
      "entity1": "C563678",
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "C563678",
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      "novel": "No"
     }
    }
   ]
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  {
   "id": "19779499",
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    {
     "offset": 0,
     "text": "Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "779",
        "type": "GeneOrGeneProduct"
       },
       "text": "CACNA1S",
       "locations": [
        {
         "offset": 6,
         "length": 7
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypokalemic periodic paralysis",
       "locations": [
        {
         "offset": 49,
         "length": 30
        }
       ]
      }
     ]
    },
    {
     "offset": 108,
     "text": "Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant disorder, which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. A major disease-causing gene for HypoPP has been identified as CACNA1S, which encodes the skeletal muscle calcium channel alpha-subunit with four transmembrane domains (I-IV), each with six transmembrane segments (S1-S6). To date, all CACNA1S mutations identified in HypoPP patients are located within the voltage-sensor S4 segment. In this study we report a novel CACNA1S mutation in a new region of the protein, the S3 segment of domain III. We characterized a four-generation South American family with HypoPP. Genetic analysis identified a novel V876E mutation in all HypoPP patients in the family, but not in normal family members or 160 control people. Clinical analysis indicates that mutation V876E is associated with a severe outcome as characterized by a very early age of onset, complete penetrance and a severe prognosis including death. These results identify a new mutation in CACNA1S and expand the spectrum of CACNA1S mutations associated with HypoPP.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hypokalaemic periodic paralysis",
       "locations": [
        {
         "offset": 108,
         "length": 31
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HypoPP",
       "locations": [
        {
         "offset": 141,
         "length": 6
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant disorder",
       "locations": [
        {
         "offset": 155,
         "length": 27
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D018908",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "muscle weakness",
       "locations": [
        {
         "offset": 230,
         "length": 15
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D011188",
        "type": "ChemicalEntity"
       },
       "text": "potassium",
       "locations": [
        {
         "offset": 286,
         "length": 9
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HypoPP",
       "locations": [
        {
         "offset": 336,
         "length": 6
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "779",
        "type": "GeneOrGeneProduct"
       },
       "text": "CACNA1S",
       "locations": [
        {
         "offset": 366,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "779",
        "type": "GeneOrGeneProduct"
       },
       "text": "skeletal muscle calcium channel alpha-subunit",
       "locations": [
        {
         "offset": 393,
         "length": 45
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "779",
        "type": "GeneOrGeneProduct"
       },
       "text": "CACNA1S",
       "locations": [
        {
         "offset": 538,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HypoPP",
       "locations": [
        {
         "offset": 570,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 577,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "779",
        "type": "GeneOrGeneProduct"
       },
       "text": "CACNA1S",
       "locations": [
        {
         "offset": 668,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HypoPP",
       "locations": [
        {
         "offset": 809,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs267606698",
        "type": "SequenceVariant"
       },
       "text": "V876E",
       "locations": [
        {
         "offset": 853,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HypoPP",
       "locations": [
        {
         "offset": 875,
         "length": 6
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 882,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs267606698",
        "type": "SequenceVariant"
       },
       "text": "V876E",
       "locations": [
        {
         "offset": 1004,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D003643",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "death",
       "locations": [
        {
         "offset": 1146,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "779",
        "type": "GeneOrGeneProduct"
       },
       "text": "CACNA1S",
       "locations": [
        {
         "offset": 1194,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "779",
        "type": "GeneOrGeneProduct"
       },
       "text": "CACNA1S",
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        {
         "offset": 1229,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D020514",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HypoPP",
       "locations": [
        {
         "offset": 1263,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D018908",
      "entity2": "D011188",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D020514",
      "entity2": "779",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "779",
      "entity2": "D003643",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs267606698",
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     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D003643",
      "entity2": "rs267606698",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19811499",
   "passages": [
    {
     "offset": 0,
     "text": "Independent and cooperative roles of tumor necrosis factor-alpha, nuclear factor-kappaB, and bone morphogenetic protein-2 in regulation of metastasis and osteomimicry of prostate cancer cells and differentiation and mineralization of MC3T3-E1 osteoblast-like cells.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "21926,7124",
        "type": "GeneOrGeneProduct"
       },
       "text": "tumor necrosis factor-alpha",
       "locations": [
        {
         "offset": 37,
         "length": 27
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "18033,4790",
        "type": "GeneOrGeneProduct"
       },
       "text": "nuclear factor-kappaB",
       "locations": [
        {
         "offset": 66,
         "length": 21
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "12156,650",
        "type": "GeneOrGeneProduct"
       },
       "text": "bone morphogenetic protein-2",
       "locations": [
        {
         "offset": 93,
         "length": 28
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009362",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "metastasis",
       "locations": [
        {
         "offset": 139,
         "length": 10
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 170,
         "length": 15
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "CVCL_0409",
        "type": "CellLine"
       },
       "text": "MC3T3-E1",
       "locations": [
        {
         "offset": 234,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 266,
     "text": "The molecular mechanisms involved in prostate cancer (PC) metastasis and bone remodeling are poorly understood. We recently reported that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) mediates transcriptional regulation and activation of bone morphogenetic protein (BMP)-2 signaling by nuclear factor (NF)-kappaB in bone metastatic prostate cancer cells. In the present study, we demonstrate that NF-kappaB, whether activated by recombinant human tumor necrosis factor (TNF)-alpha or by ectopic expression of the p65 subunit, is involved in extracellular matrix adhesion and invasion of osteotropic PC-3 and C4-2B, but not LNCaP, cells. The enhanced metastatic potential was associated with transcriptional upregulation of osteopontin, osteocalcin, and collagen IA1 in osteotropic PC cells, suggesting their role in osteomimicry of PC cells. Unlike BMP-4, BMP-2 protein enhanced the invasive properties of C4-2B cells, but not in LNCaP cells. Also, this effect was nullified by Noggin. In addition, BMP-2 mediates TNF-alpha-induced invasion of C4-2B cells in a NF-kappaB-dependent fashion. TNF-alpha or conditioned media (CM) of TNF-alpha-stimulated C4-2B cells upregulated BMP-2 and BMP-dependent Smad transcripts and inhibited receptor activator of NF-kappaB ligand transcripts in RAW 264.7 preosteoclast cells, respectively, implying that this factor may contribute to suppression of osteoclastogenesis via direct and paracrine mechanisms. In contrast, CM of TNF-alpha-stimulate or BMP2-stimulated C4-2B cells induced in vitro mineralization of MC3T3-E1 osteoblast cells in a BMP-2-dependent and NF-kappaB-dependent manner, respectively. Taken together, the results suggest that mutual interactions between these factors may be pivotal not only in enhancing the osteomimicry and metastatic potential of PC cells, but also in bone remodeling and in shifting the balance from osteoclastogenesis towards osteoblastogenesis.",
     "annotations": [
      {
       "id": "6",
       "infons": {
        "identifier": "D009362,D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer (PC) metastasis",
       "locations": [
        {
         "offset": 303,
         "length": 31
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "207",
        "type": "GeneOrGeneProduct"
       },
       "text": "phosphoinositide 3-kinase (PI3K)/protein kinase B",
       "locations": [
        {
         "offset": 404,
         "length": 49
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "207",
        "type": "GeneOrGeneProduct"
       },
       "text": "Akt",
       "locations": [
        {
         "offset": 455,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "650",
        "type": "GeneOrGeneProduct"
       },
       "text": "bone morphogenetic protein (BMP)-2",
       "locations": [
        {
         "offset": 514,
         "length": 34
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "4790",
        "type": "GeneOrGeneProduct"
       },
       "text": "nuclear factor (NF)-kappaB",
       "locations": [
        {
         "offset": 562,
         "length": 26
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prostate cancer",
       "locations": [
        {
         "offset": 608,
         "length": 15
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "4790",
        "type": "GeneOrGeneProduct"
       },
       "text": "NF-kappaB",
       "locations": [
        {
         "offset": 673,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 717,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "7124",
        "type": "GeneOrGeneProduct"
       },
       "text": "tumor necrosis factor (TNF)-alpha",
       "locations": [
        {
         "offset": 723,
         "length": 33
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "5970",
        "type": "GeneOrGeneProduct"
       },
       "text": "p65",
       "locations": [
        {
         "offset": 789,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "CVCL_0035",
        "type": "CellLine"
       },
       "text": "PC-3",
       "locations": [
        {
         "offset": 875,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "CVCL_4784",
        "type": "CellLine"
       },
       "text": "C4-2B",
       "locations": [
        {
         "offset": 884,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "CVCL_0395",
        "type": "CellLine"
       },
       "text": "LNCaP",
       "locations": [
        {
         "offset": 899,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6696",
        "type": "GeneOrGeneProduct"
       },
       "text": "osteopontin",
       "locations": [
        {
         "offset": 999,
         "length": 11
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "632",
        "type": "GeneOrGeneProduct"
       },
       "text": "osteocalcin",
       "locations": [
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         "offset": 1012,
         "length": 11
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "1277",
        "type": "GeneOrGeneProduct"
       },
       "text": "collagen IA1",
       "locations": [
        {
         "offset": 1029,
         "length": 12
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 1057,
         "length": 2
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D011471",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PC",
       "locations": [
        {
         "offset": 1108,
         "length": 2
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "652",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP-4",
       "locations": [
        {
         "offset": 1125,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "650",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP-2",
       "locations": [
        {
         "offset": 1132,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "CVCL_4784",
        "type": "CellLine"
       },
       "text": "C4-2B",
       "locations": [
        {
         "offset": 1182,
         "length": 5
        }
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  {
   "id": "20801104",
   "passages": [
    {
     "offset": 0,
     "text": "Association study of polymorphisms in the promoter region of DRD4 with schizophrenia, depression, and heroin addiction.",
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       "id": "0",
       "infons": {
        "identifier": "1815",
        "type": "GeneOrGeneProduct"
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       "text": "DRD4",
       "locations": [
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         "offset": 61,
         "length": 4
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       "id": "1",
       "infons": {
        "identifier": "D012559",
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       "text": "schizophrenia",
       "locations": [
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         "offset": 71,
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       "id": "2",
       "infons": {
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         "offset": 86,
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       "id": "3",
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       "locations": [
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         "offset": 102,
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     ]
    },
    {
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     "text": "This study investigated the possible association between three functional polymorphisms in the promoter region of the dopamine D4 receptor (DRD4) gene and schizophrenia, depression, and heroin addiction. Genomic DNA was isolated from the venous blood leukocytes of 322 unrelated patients with schizophrenia, 156 patients with depression, 300 patients with heroin addiction, and 300 healthy unrelated individuals. Polymorphisms in the promoter region of DRD4 (-120 bp duplication, -616C/G, and -521C/T) were genotyped using allele-specific polymerase chain reaction analysis. Genotype and allele were analyzed using SPSS 11.5 software. Results of this analysis indicated that there is a strong finding of -120 bp duplication allele frequencies with schizophrenia (p=0.008) and weak finding with -1240 L/S and for paranoid schizophrenia (p=0.022). Interestingly, there is a stronger finding with -521 C/T allele frequencies with heroin dependence (p=0.0002). These observations strongly suggest that the -120-bp duplication polymorphism of DRD4 is associated with schizophrenia and that the -521 C/T polymorphism is associated with heroin addiction.",
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        "identifier": "1815",
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       "text": "dopamine D4 receptor",
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         "offset": 238,
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       "id": "5",
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       "text": "DRD4",
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         "length": 4
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      },
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       "id": "6",
       "infons": {
        "identifier": "D012559",
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       "text": "schizophrenia",
       "locations": [
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         "offset": 275,
         "length": 13
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       "id": "7",
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        "identifier": "D003866",
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         "offset": 290,
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      },
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       "id": "8",
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       "text": "heroin addiction",
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         "offset": 306,
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       ]
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       "id": "9",
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       "text": "patients",
       "locations": [
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         "offset": 399,
         "length": 8
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       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "D012559",
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         "offset": 413,
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       "id": "11",
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       "text": "patients",
       "locations": [
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         "offset": 432,
         "length": 8
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       "id": "12",
       "infons": {
        "identifier": "D003866",
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       "text": "depression",
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         "offset": 446,
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       "id": "13",
       "infons": {
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       "text": "patients",
       "locations": [
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      },
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       "id": "14",
       "infons": {
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       "text": "heroin addiction",
       "locations": [
        {
         "offset": 476,
         "length": 16
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1815",
        "type": "GeneOrGeneProduct"
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       "text": "DRD4",
       "locations": [
        {
         "offset": 573,
         "length": 4
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|DUP|-120||",
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       "text": "-120 bp duplication",
       "locations": [
        {
         "offset": 579,
         "length": 19
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       ]
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      {
       "id": "17",
       "infons": {
        "identifier": "rs747302",
        "type": "SequenceVariant"
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       "text": "-616C/G",
       "locations": [
        {
         "offset": 600,
         "length": 7
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       ]
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       "id": "18",
       "infons": {
        "identifier": "rs1800955",
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       "text": "-521C/T",
       "locations": [
        {
         "offset": 613,
         "length": 7
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       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|DUP|-120||",
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       "text": "-120 bp duplication",
       "locations": [
        {
         "offset": 824,
         "length": 19
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "schizophrenia",
       "locations": [
        {
         "offset": 868,
         "length": 13
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "p|SUB|L|-1240|S",
        "type": "SequenceVariant"
       },
       "text": "-1240 L/S",
       "locations": [
        {
         "offset": 914,
         "length": 9
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       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D012563",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "paranoid schizophrenia",
       "locations": [
        {
         "offset": 932,
         "length": 22
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       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "rs1800955",
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       "text": "-521 C/T",
       "locations": [
        {
         "offset": 1014,
         "length": 8
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      },
      {
       "id": "24",
       "infons": {
        "identifier": "D006556",
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       "text": "heroin dependence",
       "locations": [
        {
         "offset": 1047,
         "length": 17
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       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "c|DUP|-120||",
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       "text": "-120-bp duplication",
       "locations": [
        {
         "offset": 1122,
         "length": 19
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       ]
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      {
       "id": "26",
       "infons": {
        "identifier": "1815",
        "type": "GeneOrGeneProduct"
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       "text": "DRD4",
       "locations": [
        {
         "offset": 1158,
         "length": 4
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      },
      {
       "id": "27",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenia",
       "locations": [
        {
         "offset": 1182,
         "length": 13
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs1800955",
        "type": "SequenceVariant"
       },
       "text": "-521 C/T",
       "locations": [
        {
         "offset": 1209,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D006556",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "heroin addiction",
       "locations": [
        {
         "offset": 1250,
         "length": 16
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   "relations": [
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     "infons": {
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   ]
  },
  {
   "id": "21080147",
   "passages": [
    {
     "offset": 0,
     "text": "Novel CRELD1 gene mutations in patients with atrioventricular septal defect.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "78987",
        "type": "GeneOrGeneProduct"
       },
       "text": "CRELD1",
       "locations": [
        {
         "offset": 6,
         "length": 6
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 31,
         "length": 8
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C562831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atrioventricular septal defect",
       "locations": [
        {
         "offset": 45,
         "length": 30
        }
       ]
      }
     ]
    },
    {
     "offset": 77,
     "text": "BACKGROUND: Atrioventricular septal defects (AVSDs) occur as clinical defects of several different syndromes, as autosomal dominant defects, and as sporadically occurring malformations. Consequently, there is genetic heterogeneity, but until recently, little is known about the genes involving in the pathogenesis of AVSD. CRELD1 gene, a novel cell adhesion molecule, is a candidate gene for AVSD. METHODS: This study included 133 patients with AVSD and 200 healthy controls. Peripheral blood samples were collected and genomic DNA was extracted from the leukocytes. CRELD1 was amplified by polymerase chain reaction (PCR) with specific primers. The sequences of PCR products were compared between the patients and controls. RESULTS: In a patient, a C-to-G transition was identified at nucleotide 857 in exon 8 that resulted in a substitution of alanine for proline at amino acid 286 in the first calcium-binding EGF domain. This patient had an isolated partial AVSD and the mutation was inherited from her mother. Another mutation was detected in a patient with a partial AVSD and evidence of Down syndrome. The heterozygous c.973G>A transition in exon 9 resulted in a substitution of lysine for glutamic acid at amino acid 325 (E325K) in the second calcium-binding EGF domain. CONCLUSIONS: Two novel CRELD1 mutations were identified in the calcium-binding EGF domain in patients with AVSD. CRELD1 is likely to be an AVSD-susceptibility gene and CRELD1 mutations may increase the risk of developing a heart defect rather than being a direct causative mutation.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "C562831",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Atrioventricular septal defects",
       "locations": [
        {
         "offset": 89,
         "length": 31
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       ]
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     "text": "Impact of CCR5delta32 host genetic background and disease progression on HIV-1 intrahost evolutionary processes: efficient hypothesis testing through hierarchical phylogenetic models.",
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     "text": "Late-onset scleroderma renal crisis induced by tacrolimus and prednisolone: a case report.",
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     "text": "Scleroderma renal crisis (SRC) is a rare complication of systemic sclerosis (SSc) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose corticosteroid use is recognized as a major risk factor for SRC. Furthermore, there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with SSc. In this article, we report a patient with SRC induced by tacrolimus and corticosteroids. The aim of this work is to call attention to the risk of tacrolimus use in patients with SSc.",
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     "text": "Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib.",
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     "text": "BACKGROUND: Sorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking. METHODS: We used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used. RESULTS: We observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival. CONCLUSION: These findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.",
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     "text": "BACKGROUND: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies. METHODS: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations. RESULTS: We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions. CONCLUSIONS: Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.",
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       "text": "infarcted heart",
       "locations": [
        {
         "offset": 63,
         "length": 15
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "19211",
        "type": "GeneOrGeneProduct"
       },
       "text": "Pten",
       "locations": [
        {
         "offset": 96,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "11651",
        "type": "GeneOrGeneProduct"
       },
       "text": "Akt",
       "locations": [
        {
         "offset": 101,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 125,
     "text": "The transforming growth factor (TGF)-b-inducible early gene-1 (TIEG1) plays a crucial role in modulating cell apoptosis and proliferation in a number of diseases, including pancreatic cancer, leukaemia and osteoporosis. However, the functional role of TIEG1 in the heart has not been fully defined. In this study, we first investigated the role of TIEG1 in ischaemic heart disease. For in vitro experiments, cardiomyocytes were isolated from both TIEG1 knockout (KO) and wile-type (WT) mice, and the apoptotic ratios were evaluated after a 48-h ischaemic insult. A cell proliferation assay was performed after 7 days of incubation under normoxic conditions. In addition, the angiogenic capacity of endothelial cells was determined by tube formation assay. For in vivo experiments, a model of myocardial infarction (MI) was established using both TIEG1 KO and WT mice. Echocardiography was performed at 3 and 28 days post-MI, whereas the haemodynamics test was performed 28 days post-MI. Histological analyses of apoptosis, proliferation, angiogenesis and infarct zone assessments were performed using terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) staining, BrdU immunostaining, a-smooth muscle actin (a-SMA)/CD31 immunostaining and Masson's trichrome staining, respectively. Changes in the expression of related proteins caused by TIEG1 deficiency were confirmed using both reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Our results demonstrated that the absence of TIEG1 prevented cardiomyocytes from undergoing apoptosis and promoted higher proliferation; it stimulated the proliferation of endothelial cells in vitro and in vivo. Improved cardiac function and less scar formation were observed in TIEG1 KO mice, and we also observed the altered expression of phosphatase and tensin homolog (Pten), Akt and Bcl-2/Bax, as well as vascular endothelial growth factor (VEGF). On the whole, our findings indicate that the absence of TIEG1 plays a cardioprotective role in ischaemic heart disease by promoting changes in Pten/Akt signalling.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "transforming growth factor (TGF)-b-inducible early gene-1",
       "locations": [
        {
         "offset": 129,
         "length": 57
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 188,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 298,
         "length": 17
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "leukaemia",
       "locations": [
        {
         "offset": 317,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D010024",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "osteoporosis",
       "locations": [
        {
         "offset": 331,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 377,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 473,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D017202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischaemic heart disease",
       "locations": [
        {
         "offset": 482,
         "length": 23
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 572,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 611,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D009203",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocardial infarction",
       "locations": [
        {
         "offset": 917,
         "length": 21
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D009203",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MI",
       "locations": [
        {
         "offset": 940,
         "length": 2
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 971,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
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       "text": "mice",
       "locations": [
        {
         "offset": 987,
         "length": 4
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009203",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "MI",
       "locations": [
        {
         "offset": 1046,
         "length": 2
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       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D009203",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "MI",
       "locations": [
        {
         "offset": 1108,
         "length": 2
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D007238",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "infarct",
       "locations": [
        {
         "offset": 1180,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "1791",
        "type": "GeneOrGeneProduct"
       },
       "text": "terminal deoxynucleotidyltransferase",
       "locations": [
        {
         "offset": 1226,
         "length": 36
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "C027078",
        "type": "ChemicalEntity"
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       "text": "dUTP",
       "locations": [
        {
         "offset": 1272,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "11475",
        "type": "GeneOrGeneProduct"
       },
       "text": "a-smooth muscle actin",
       "locations": [
        {
         "offset": 1335,
         "length": 21
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "11475",
        "type": "GeneOrGeneProduct"
       },
       "text": "a-SMA",
       "locations": [
        {
         "offset": 1358,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "18613",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD31",
       "locations": [
        {
         "offset": 1365,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 1488,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 1674,
         "length": 5
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 1908,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 1917,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "19211",
        "type": "GeneOrGeneProduct"
       },
       "text": "phosphatase and tensin homolog",
       "locations": [
        {
         "offset": 1970,
         "length": 30
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "19211",
        "type": "GeneOrGeneProduct"
       },
       "text": "Pten",
       "locations": [
        {
         "offset": 2002,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "11651",
        "type": "GeneOrGeneProduct"
       },
       "text": "Akt",
       "locations": [
        {
         "offset": 2009,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "12043",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bcl-2",
       "locations": [
        {
         "offset": 2017,
         "length": 5
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "12028",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bax",
       "locations": [
        {
         "offset": 2023,
         "length": 3
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "22339",
        "type": "GeneOrGeneProduct"
       },
       "text": "vascular endothelial growth factor",
       "locations": [
        {
         "offset": 2039,
         "length": 34
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "22339",
        "type": "GeneOrGeneProduct"
       },
       "text": "VEGF",
       "locations": [
        {
         "offset": 2075,
         "length": 4
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "21847",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIEG1",
       "locations": [
        {
         "offset": 2138,
         "length": 5
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D017202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischaemic heart disease",
       "locations": [
        {
         "offset": 2177,
         "length": 23
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "19211",
        "type": "GeneOrGeneProduct"
       },
       "text": "Pten",
       "locations": [
        {
         "offset": 2225,
         "length": 4
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "11651",
        "type": "GeneOrGeneProduct"
       },
       "text": "Akt",
       "locations": [
        {
         "offset": 2230,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
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     "id": "R0",
     "infons": {
      "entity1": "1791",
      "entity2": "C027078",
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      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "11651",
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      "novel": "No"
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    {
     "id": "R2",
     "infons": {
      "entity1": "19211",
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      "novel": "No"
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    },
    {
     "id": "R3",
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      "novel": "No"
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    },
    {
     "id": "R4",
     "infons": {
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      "novel": "No"
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      "novel": "No"
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    },
    {
     "id": "R7",
     "infons": {
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      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
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      "novel": "No"
     }
    },
    {
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   ]
  },
  {
   "id": "16001362",
   "passages": [
    {
     "offset": 0,
     "text": "An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "OMIM:604121",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant cerebellar ataxia",
       "locations": [
        {
         "offset": 3,
         "length": 36
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9138",
        "type": "GeneOrGeneProduct"
       },
       "text": "Rho guanine-nucleotide exchange-factor",
       "locations": [
        {
         "offset": 207,
         "length": 38
        }
       ]
      }
     ]
    },
    {
     "offset": 255,
     "text": "Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia (chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C-->T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called \"puratrophin-1\" (Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1--normally expressed in a wide range of cells, including epithelial hair cells in the cochlea--was aggregated in Purkinje cells of the chromosome 16q22.1-linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region (UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "OMIM:604121",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Autosomal dominant cerebellar ataxia",
       "locations": [
        {
         "offset": 255,
         "length": 36
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "OMIM:604121",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ADCA",
       "locations": [
        {
         "offset": 293,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D019636",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurodegenerative disorders",
       "locations": [
        {
         "offset": 327,
         "length": 27
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D001259",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "degenerative ataxia",
       "locations": [
        {
         "offset": 442,
         "length": 19
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "OMIM:604121",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ADCA",
       "locations": [
        {
         "offset": 489,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D002524",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebellar ataxia",
       "locations": [
        {
         "offset": 534,
         "length": 17
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D034381",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sensorineural hearing impairment",
       "locations": [
        {
         "offset": 609,
         "length": 32
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D001259",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ataxia",
       "locations": [
        {
         "offset": 665,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 791,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|SUB|C||T",
        "type": "SequenceVariant"
       },
       "text": "C-->T",
       "locations": [
        {
         "offset": 858,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "25894",
        "type": "GeneOrGeneProduct"
       },
       "text": "DKFZP434I216",
       "locations": [
        {
         "offset": 994,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "25894",
        "type": "GeneOrGeneProduct"
       },
       "text": "puratrophin-1",
       "locations": [
        {
         "offset": 1030,
         "length": 13
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "25894",
        "type": "GeneOrGeneProduct"
       },
       "text": "Purkinje cell atrophy associated protein-1",
       "locations": [
        {
         "offset": 1046,
         "length": 42
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "25894",
        "type": "GeneOrGeneProduct"
       },
       "text": "puratrophin-1",
       "locations": [
        {
         "offset": 1107,
         "length": 13
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9138",
        "type": "GeneOrGeneProduct"
       },
       "text": "guanine-nucleotide exchange factor",
       "locations": [
        {
         "offset": 1243,
         "length": 34
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9138",
        "type": "GeneOrGeneProduct"
       },
       "text": "GEF",
       "locations": [
        {
         "offset": 1279,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "387",
        "type": "GeneOrGeneProduct"
       },
       "text": "Rho GTPases",
       "locations": [
        {
         "offset": 1288,
         "length": 11
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "25894",
        "type": "GeneOrGeneProduct"
       },
       "text": "puratrophin-1",
       "locations": [
        {
         "offset": 1368,
         "length": 13
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "60",
        "type": "GeneOrGeneProduct"
       },
       "text": "actin",
       "locations": [
        {
         "offset": 1413,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "25894",
        "type": "GeneOrGeneProduct"
       },
       "text": "Puratrophin-1",
       "locations": [
        {
         "offset": 1452,
         "length": 13
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "OMIM:604121",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ADCA",
       "locations": [
        {
         "offset": 1626,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "25894",
        "type": "GeneOrGeneProduct"
       },
       "text": "puratrophin-1",
       "locations": [
        {
         "offset": 1686,
         "length": 13
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1903,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9138",
        "type": "GeneOrGeneProduct"
       },
       "text": "GEF",
       "locations": [
        {
         "offset": 2048,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D013132",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebellar degeneration",
       "locations": [
        {
         "offset": 2079,
         "length": 23
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "humans",
       "locations": [
        {
         "offset": 2106,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "60",
      "entity2": "25894",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "9138",
      "entity2": "D013132",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "OMIM:604121",
      "entity2": "25894",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "OMIM:604121",
      "entity2": "c|SUB|C||T",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "OMIM:604121",
      "entity2": "9138",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16158428",
   "passages": [
    {
     "offset": 0,
     "text": "Delineation of the clinical phenotype associated with OPHN1 mutations based on the clinical and neuropsychological evaluation of three families.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4983",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPHN1",
       "locations": [
        {
         "offset": 54,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 145,
     "text": "Recent reports have demonstrated that mutations in the OPHN1 gene were responsible for a syndromic rather than non-specific mental retardation. Abnormalities of the posterior fossa with cerebellar hypoplasia have been demonstrated in all male patients reported to date. We report here a new family with X-linked mental retardation due to mutation in OPHN1 and present unpublished data about two families previously reported, concerning the facial and psychological phenotype of affected males and carrier females. Our study confirms that cerebellar hypoplasia is a hallmark of this syndrome. In addition, affected males display facial similarities that can help the diagnosis. Most carrier females have mild mental retardation and subtle facial changes.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "4983",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPHN1",
       "locations": [
        {
         "offset": 200,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mental retardation",
       "locations": [
        {
         "offset": 269,
         "length": 18
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C562568",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebellar hypoplasia",
       "locations": [
        {
         "offset": 331,
         "length": 21
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 388,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D038901",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked mental retardation",
       "locations": [
        {
         "offset": 448,
         "length": 27
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4983",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPHN1",
       "locations": [
        {
         "offset": 495,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "C562568",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebellar hypoplasia",
       "locations": [
        {
         "offset": 683,
         "length": 21
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mental retardation",
       "locations": [
        {
         "offset": 853,
         "length": 18
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "4983",
      "entity2": "D038901",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "4983",
      "entity2": "C562568",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D008607",
      "entity2": "4983",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "16786513",
   "passages": [
    {
     "offset": 0,
     "text": "McArdle disease: the mutation spectrum of PYGM in a large Italian cohort.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D006012",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "McArdle disease",
       "locations": [
        {
         "offset": 0,
         "length": 15
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "5837",
        "type": "GeneOrGeneProduct"
       },
       "text": "PYGM",
       "locations": [
        {
         "offset": 42,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 74,
     "text": "Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D006012",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Deficiency of the muscle isozyme of glycogen phosphorylase",
       "locations": [
        {
         "offset": 74,
         "length": 58
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D006012",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "McArdle disease",
       "locations": [
        {
         "offset": 149,
         "length": 15
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D006012",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Glycogen storage disease type V",
       "locations": [
        {
         "offset": 168,
         "length": 31
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D006012",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GSD-V",
       "locations": [
        {
         "offset": 201,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal recessive disorder",
       "locations": [
        {
         "offset": 225,
         "length": 28
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D006003",
        "type": "ChemicalEntity"
       },
       "text": "glycogen",
       "locations": [
        {
         "offset": 257,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009120",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cramps",
       "locations": [
        {
         "offset": 358,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D009212",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myoglobinuria",
       "locations": [
        {
         "offset": 380,
         "length": 13
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "5837",
        "type": "GeneOrGeneProduct"
       },
       "text": "PYGM",
       "locations": [
        {
         "offset": 424,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D006012",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GSD-V",
       "locations": [
        {
         "offset": 456,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 462,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 520,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "5837",
        "type": "GeneOrGeneProduct"
       },
       "text": "PYGM",
       "locations": [
        {
         "offset": 574,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs760654579",
        "type": "SequenceVariant"
       },
       "text": "c.475G>A",
       "locations": [
        {
         "offset": 703,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs760654579",
        "type": "SequenceVariant"
       },
       "text": "p.G159R",
       "locations": [
        {
         "offset": 713,
         "length": 7
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|SUB|C|689|G",
        "type": "SequenceVariant"
       },
       "text": "c.689C>G",
       "locations": [
        {
         "offset": 722,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|SUB|P|230|R",
        "type": "SequenceVariant"
       },
       "text": "p.P230R",
       "locations": [
        {
         "offset": 732,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|SUB|C|1094|T",
        "type": "SequenceVariant"
       },
       "text": "c.1094C>T",
       "locations": [
        {
         "offset": 741,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "p|SUB|A|365|E",
        "type": "SequenceVariant"
       },
       "text": "p.A365E",
       "locations": [
        {
         "offset": 752,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|SUB|C|1151|A",
        "type": "SequenceVariant"
       },
       "text": "c.1151C>A",
       "locations": [
        {
         "offset": 761,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "p|SUB|A|384|D",
        "type": "SequenceVariant"
       },
       "text": "p.A384D",
       "locations": [
        {
         "offset": 772,
         "length": 7
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs750700202",
        "type": "SequenceVariant"
       },
       "text": "c.1182C>T,",
       "locations": [
        {
         "offset": 781,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs750700202",
        "type": "SequenceVariant"
       },
       "text": "p.R428C",
       "locations": [
        {
         "offset": 792,
         "length": 7
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs759977194",
        "type": "SequenceVariant"
       },
       "text": "c.1471C>T",
       "locations": [
        {
         "offset": 801,
         "length": 9
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs759977194",
        "type": "SequenceVariant"
       },
       "text": "p.R491C",
       "locations": [
        {
         "offset": 812,
         "length": 7
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "c|SUB|A|2444|C",
        "type": "SequenceVariant"
       },
       "text": "c.2444A>C",
       "locations": [
        {
         "offset": 821,
         "length": 9
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "p|SUB|D|815|A",
        "type": "SequenceVariant"
       },
       "text": "p.D815A",
       "locations": [
        {
         "offset": 832,
         "length": 7
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "c|SUB|G|2477|C",
        "type": "SequenceVariant"
       },
       "text": "c.2477G>C",
       "locations": [
        {
         "offset": 841,
         "length": 9
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "p|SUB|W|826|S",
        "type": "SequenceVariant"
       },
       "text": "p.W826S",
       "locations": [
        {
         "offset": 852,
         "length": 7
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "c|SUB|G|1475|A",
        "type": "SequenceVariant"
       },
       "text": "c.1475G>A",
       "locations": [
        {
         "offset": 886,
         "length": 9
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "p|SUB|W|492|X",
        "type": "SequenceVariant"
       },
       "text": "p.W492X",
       "locations": [
        {
         "offset": 897,
         "length": 7
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "c|SUB|A|1627|T",
        "type": "SequenceVariant"
       },
       "text": "c.1627A>T",
       "locations": [
        {
         "offset": 906,
         "length": 9
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "p|SUB|K|543|X",
        "type": "SequenceVariant"
       },
       "text": "p.K543X",
       "locations": [
        {
         "offset": 917,
         "length": 7
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "c|SUB|C|855+1|C",
        "type": "SequenceVariant"
       },
       "text": "c.855 +1G>C",
       "locations": [
        {
         "offset": 955,
         "length": 11
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "c|SUB|G|1092+1|A",
        "type": "SequenceVariant"
       },
       "text": "c.1092 +1G>A",
       "locations": [
        {
         "offset": 968,
         "length": 12
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "c|SUB|G|1093-1|T",
        "type": "SequenceVariant"
       },
       "text": "c. 1093-1G>T",
       "locations": [
        {
         "offset": 982,
         "length": 12
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "c|SUB|G|1239+1|A",
        "type": "SequenceVariant"
       },
       "text": "c.1239 +1G>A",
       "locations": [
        {
         "offset": 996,
         "length": 12
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "c|SUB|G|2380+1|A",
        "type": "SequenceVariant"
       },
       "text": "c.2380 +1G>A",
       "locations": [
        {
         "offset": 1010,
         "length": 12
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "c|DEL|715_717|GTC",
        "type": "SequenceVariant"
       },
       "text": "c.715_717delGTC",
       "locations": [
        {
         "offset": 1045,
         "length": 15
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "p|DEL|239|V",
        "type": "SequenceVariant"
       },
       "text": "p.V239del",
       "locations": [
        {
         "offset": 1062,
         "length": 9
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "c|DEL|304|A",
        "type": "SequenceVariant"
       },
       "text": "c.304delA",
       "locations": [
        {
         "offset": 1073,
         "length": 9
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "p|FS|N|102|D|4",
        "type": "SequenceVariant"
       },
       "text": "p.N102DfsX4",
       "locations": [
        {
         "offset": 1084,
         "length": 11
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "c|DEL|1970_2177|",
        "type": "SequenceVariant"
       },
       "text": "c.1970_2177del",
       "locations": [
        {
         "offset": 1097,
         "length": 14
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "p|DEL|657_726|",
        "type": "SequenceVariant"
       },
       "text": "p.V657_G726",
       "locations": [
        {
         "offset": 1113,
         "length": 11
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "c|DEL|2113_2114|GG",
        "type": "SequenceVariant"
       },
       "text": "c.2113_2114delGG",
       "locations": [
        {
         "offset": 1126,
         "length": 16
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "p|FS|G|705|R|16",
        "type": "SequenceVariant"
       },
       "text": "p.G705RfsX16",
       "locations": [
        {
         "offset": 1144,
         "length": 12
        }
       ]
      },
      {
       "id": "48",
       "infons": {
        "identifier": "rs116987552",
        "type": "SequenceVariant"
       },
       "text": "p.R50X",
       "locations": [
        {
         "offset": 1308,
         "length": 6
        }
       ]
      },
      {
       "id": "49",
       "infons": {
        "identifier": "9606",
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     "text": "OBJECTIVE: A randomised, double-blind study to compare the gastrointestinal (GI) tolerability, safety and efficacy of etoricoxib and diclofenac in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: A total of 4086 patients (mean age 60.8 years) diagnosed with RA were enrolled and received etoricoxib 90 mg daily (n = 2032) or diclofenac 75 mg twice daily (n = 2054). Use of gastroprotective agents and low-dose aspirin was allowed. The prespecified primary end point consisted of the cumulative rate of patient discontinuations due to clinical and laboratory GI adverse experiences (AEs). General safety was also assessed, including adjudicated thrombotic cardiovascular event data. Efficacy was evaluated using the Patient Global Assessment of Disease Status (PGADS; 0-4 point scale). RESULTS: Mean (SD; maximum) duration of treatment was 19.3 (10.3; 32.9) and 19.1 (10.4; 33.1) months in the etoricoxib and diclofenac groups, respectively. The cumulative discontinuation rate due to GI AEs was significantly lower with etoricoxib than diclofenac (5.2 vs 8.5 events per 100 patient-years, respectively; hazard ratio 0.62 (95% CI: 0.47, 0.81; p<or=0.001)). The incidence of discontinuations for hypertension-related and oedema-related AEs were significantly higher with etoricoxib (2.5% and 1.1% respectively) compared with diclofenac (1.5% and 0.4% respectively; p<0.001 for hypertension and p<0.01 for oedema). Etoricoxib and diclofenac treatment resulted in similar efficacy (PGADS mean changes from baseline -0.62 vs -0.58, respectively). CONCLUSIONS: Etoricoxib 90 mg demonstrated a significantly lower risk for discontinuing treatment due to GI AEs compared with diclofenac 150 mg. Discontinuations from renovascular AEs, although less common than discontinuations from GI AEs, were significantly higher with etoricoxib.",
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 31,
         "length": 8
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       ]
      },
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       "text": "congenital heart disease",
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         "offset": 45,
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     "offset": 71,
     "text": "Recent studies have reported germline mutations in GATA4 gene in some types of congenital heart disease (CHD). However, the prevalence of GATA4 mutations in CHD and the correlation between the GATA4 genotype and CHD phenotype have not been extensively studied. We screened germline mutations in the coding exons and the flanking intron sequences of the GATA4 gene in 486 CHD patients by denaturing high-performance liquid chromatography (DHPLC), and confirmed the mutations by sequencing. Nine distinct mutations including one small deletion mutation (46delS), two small insertion mutations (118-119insA and 125-126insAA), and six non-synonymous mutations (A6V, P163S, E359K, P407Q, S429T and A442V) were identified in 12 of the 486 patients (nine with ventricular septal defect, two with Tetralogy of Fallot, and one with endocardial cushion defect). Of them, two patients carrying E359K mutation were from two generations in one family with ventricular septal defect (VSD). Interestingly, a nucleotide insertion of c.1146+25insA in exon 6 was detected in five VSD patients, but not in 486 normal healthy controls. Our findings are useful in understanding the prevalence of GATA4 mutations and the correlation between the GATA4 genotype and the CHD phenotype in Chinese patients.",
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       "text": "GATA4",
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       "text": "congenital heart disease",
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       "infons": {
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       "text": "CHD",
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       ]
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       "text": "ventricular septal defect",
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       "text": "VSD",
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       "id": "30",
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       "id": "31",
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       "text": "VSD",
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       "id": "32",
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       "text": "patients",
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       "id": "33",
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       "text": "GATA4",
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       "id": "35",
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   "id": "18768591",
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    {
     "offset": 0,
     "text": "Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome.",
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       "infons": {
        "identifier": "20393",
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       "text": "Serum- and glucocorticoid-inducible kinase 1",
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     "text": "Doxorubicin-induced nephropathy leads to epithelial sodium channel (ENaC)-dependent volume retention and renal fibrosis. The aldosterone-sensitive serum- and glucocorticoid-inducible kinase SGK1 has been shown to participate in the stimulation of ENaC and to mediate renal fibrosis following mineralocorticoid and salt excess. The present study was performed to elucidate the role of SGK1 in the volume retention and fibrosis during nephrotic syndrome. To this end, doxorubicin (15 mug/g body wt) was injected intravenously into gene-targeted mice lacking SGK1 (sgk1(-/-)) and their wild-type littermates (sgk1(+/+)). Doxorubicin treatment resulted in heavy proteinuria (>100 mg protein/mg crea) in 15/44 of sgk1(+/+) and 15/44 of sgk1(-/-) mice leading to severe nephrotic syndrome with ascites, lipidemia, and hypoalbuminemia in both genotypes. Plasma aldosterone levels increased in nephrotic mice of both genotypes and was followed by increased SGK1 protein expression in sgk1(+/+) mice. Urinary sodium excretion reached signficantly lower values in sgk1(+/+) mice (15 +/- 5 mumol/mg crea) than in sgk1(-/-) mice (35 +/- 5 mumol/mg crea) and was associated with a significantly higher body weight gain in sgk1(+/+) compared with sgk1(-/-) mice (+6.6 +/- 0.7 vs. +4.1 +/- 0.8 g). During the course of nephrotic syndrome, serum urea concentrations increased significantly faster in sgk1(-/-) mice than in sgk1(+/+) mice leading to uremia and a reduced median survival in sgk1(-/-) mice (29 vs. 40 days in sgk1(+/+) mice). In conclusion, gene-targeted mice lacking SGK1 showed blunted volume retention, yet were not protected against renal fibrosis during experimental nephrotic syndrome.",
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       "text": "sodium",
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     "text": "BACKGROUND AND PURPOSE: Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA). METHODS: We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB. RESULTS: In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4-42.5; P<0.001). CONCLUSIONS: The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Cerebral microbleeds",
       "locations": [
        {
         "offset": 159,
         "length": 20
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 181,
         "length": 2
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intracerebral hemorrhage",
       "locations": [
        {
         "offset": 216,
         "length": 24
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 242,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D005343",
        "type": "ChemicalEntity"
       },
       "text": "antithrombotic drugs",
       "locations": [
        {
         "offset": 306,
         "length": 20
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 372,
         "length": 2
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 434,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D002544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic stroke",
       "locations": [
        {
         "offset": 442,
         "length": 15
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D002544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IS",
       "locations": [
        {
         "offset": 459,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "transient ischemic attack",
       "locations": [
        {
         "offset": 463,
         "length": 25
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TIA",
       "locations": [
        {
         "offset": 490,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 590,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TIA",
       "locations": [
        {
         "offset": 600,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 631,
         "length": 2
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 695,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D002544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IS",
       "locations": [
        {
         "offset": 742,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TIA",
       "locations": [
        {
         "offset": 745,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 758,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic",
       "locations": [
        {
         "offset": 765,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 898,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 931,
         "length": 2
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 973,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D002544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IS",
       "locations": [
        {
         "offset": 986,
         "length": 2
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TIA",
       "locations": [
        {
         "offset": 989,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 994,
         "length": 2
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 1019,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D002544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IS",
       "locations": [
        {
         "offset": 1026,
         "length": 2
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TIA",
       "locations": [
        {
         "offset": 1029,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D014859",
        "type": "ChemicalEntity"
       },
       "text": "warfarin",
       "locations": [
        {
         "offset": 1223,
         "length": 8
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 1287,
         "length": 2
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D014859",
        "type": "ChemicalEntity"
       },
       "text": "warfarin",
       "locations": [
        {
         "offset": 1293,
         "length": 8
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 1325,
         "length": 3
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D014859",
        "type": "ChemicalEntity"
       },
       "text": "warfarin",
       "locations": [
        {
         "offset": 1377,
         "length": 8
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D002544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IS",
       "locations": [
        {
         "offset": 1397,
         "length": 2
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TIA",
       "locations": [
        {
         "offset": 1400,
         "length": 3
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 1489,
         "length": 2
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 1531,
         "length": 3
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "D002544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IS",
       "locations": [
        {
         "offset": 1626,
         "length": 2
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "D002546",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TIA",
       "locations": [
        {
         "offset": 1629,
         "length": 3
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 1756,
         "length": 2
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 1836,
         "length": 3
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 1906,
         "length": 2
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "D014859",
        "type": "ChemicalEntity"
       },
       "text": "warfarin",
       "locations": [
        {
         "offset": 1912,
         "length": 8
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 1932,
         "length": 3
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MB",
       "locations": [
        {
         "offset": 1975,
         "length": 2
        }
       ]
      },
      {
       "id": "48",
       "infons": {
        "identifier": "D014859",
        "type": "ChemicalEntity"
       },
       "text": "warfarin",
       "locations": [
        {
         "offset": 1999,
         "length": 8
        }
       ]
      },
      {
       "id": "49",
       "infons": {
        "identifier": "D002543",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ICH",
       "locations": [
        {
         "offset": 2019,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D005343",
      "entity2": "D002543",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D002543",
      "entity2": "D014859",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "21070631",
   "passages": [
    {
     "offset": 0,
     "text": "The dopamine b-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1621",
        "type": "GeneOrGeneProduct"
       },
       "text": "dopamine b-hydroxylase",
       "locations": [
        {
         "offset": 4,
         "length": 22
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs1611115",
        "type": "SequenceVariant"
       },
       "text": "-1021C/T",
       "locations": [
        {
         "offset": 27,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alzheimer's disease",
       "locations": [
        {
         "offset": 80,
         "length": 19
        }
       ]
      }
     ]
    },
    {
     "offset": 126,
     "text": "BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine b-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alzheimer's disease",
       "locations": [
        {
         "offset": 218,
         "length": 19
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 239,
         "length": 2
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1621",
        "type": "GeneOrGeneProduct"
       },
       "text": "Dopamine b-hydroxylase",
       "locations": [
        {
         "offset": 244,
         "length": 22
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1621",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBH",
       "locations": [
        {
         "offset": 268,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D004298",
        "type": "ChemicalEntity"
       },
       "text": "dopamine",
       "locations": [
        {
         "offset": 301,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009638",
        "type": "ChemicalEntity"
       },
       "text": "noradrenaline",
       "locations": [
        {
         "offset": 313,
         "length": 13
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs1611115",
        "type": "SequenceVariant"
       },
       "text": "-1021T",
       "locations": [
        {
         "offset": 385,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs1611115",
        "type": "SequenceVariant"
       },
       "text": "rs1611115",
       "locations": [
        {
         "offset": 400,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1621",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBH",
       "locations": [
        {
         "offset": 414,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 447,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "3552",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL1A",
       "locations": [
        {
         "offset": 476,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "3569",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL6",
       "locations": [
        {
         "offset": 485,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 518,
         "length": 2
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 566,
         "length": 2
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "1621",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBH",
       "locations": [
        {
         "offset": 576,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs1611115",
        "type": "SequenceVariant"
       },
       "text": "-1021T",
       "locations": [
        {
         "offset": 580,
         "length": 6
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D000544",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AD",
       "locations": [
        {
         "offset": 669,
         "length": 2
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "1621",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBH",
       "locations": [
        {
         "offset": 786,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "3552",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL1A",
       "locations": [
        {
         "offset": 791,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "3569",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL6",
       "locations": [
        {
         "offset": 800,
         "length": 3
        }
       ]
      },
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     "offset": 0,
     "text": "Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.",
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       "id": "0",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
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     "text": "BACKGROUND: To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer. METHODS: We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI). RESULTS: The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00-3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48-0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence. CONCLUSION: Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors. IMPACT: This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis.",
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      "entity1": "1401",
      "entity2": "D011471",
      "type": "Association",
      "novel": "Novel"
     }
    },
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     "id": "R5",
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    }
   ]
  },
  {
   "id": "27292643",
   "passages": [
    {
     "offset": 0,
     "text": "Negative Selection and Chromosome Instability Induced by Mad2 Overexpression Delay Breast Cancer but Facilitate Oncogene-Independent Outgrowth.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D043171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Chromosome Instability",
       "locations": [
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         "offset": 23,
         "length": 22
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       ]
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       "id": "1",
       "infons": {
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       "text": "Mad2",
       "locations": [
        {
         "offset": 57,
         "length": 4
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001943",
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       "text": "Breast Cancer",
       "locations": [
        {
         "offset": 83,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 144,
     "text": "Chromosome instability (CIN) is associated with poor survival and therapeutic outcome in a number of malignancies. Despite this correlation, CIN can also lead to growth disadvantages. Here, we show that simultaneous overexpression of the mitotic checkpoint protein Mad2 with Kras(G12D) or Her2 in mammary glands of adult mice results in mitotic checkpoint overactivation and a delay in tumor onset. Time-lapse imaging of organotypic cultures and pathologic analysis prior to tumor establishment reveals error-prone mitosis, mitotic arrest, and cell death. Nonetheless, Mad2 expression persists and increases karyotype complexity in Kras tumors. Faced with the selective pressure of oncogene withdrawal, Mad2-positive tumors have a higher frequency of developing persistent subclones that avoid remission and continue to grow.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D043171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Chromosome instability",
       "locations": [
        {
         "offset": 144,
         "length": 22
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D043171",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "CIN",
       "locations": [
        {
         "offset": 168,
         "length": 3
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009369",
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       },
       "text": "malignancies",
       "locations": [
        {
         "offset": 245,
         "length": 12
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D043171",
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       },
       "text": "CIN",
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        {
         "offset": 285,
         "length": 3
        }
       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "56150",
        "type": "GeneOrGeneProduct"
       },
       "text": "Mad2",
       "locations": [
        {
         "offset": 409,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "16653",
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       },
       "text": "Kras",
       "locations": [
        {
         "offset": 419,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "16653",
        "type": "GeneOrGeneProduct"
       },
       "text": "G12D",
       "locations": [
        {
         "offset": 424,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "13866",
        "type": "GeneOrGeneProduct"
       },
       "text": "Her2",
       "locations": [
        {
         "offset": 433,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 465,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 530,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 619,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "56150",
        "type": "GeneOrGeneProduct"
       },
       "text": "Mad2",
       "locations": [
        {
         "offset": 713,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "16653",
        "type": "GeneOrGeneProduct"
       },
       "text": "Kras",
       "locations": [
        {
         "offset": 776,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumors",
       "locations": [
        {
         "offset": 781,
         "length": 6
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "56150",
        "type": "GeneOrGeneProduct"
       },
       "text": "Mad2",
       "locations": [
        {
         "offset": 847,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumors",
       "locations": [
        {
         "offset": 861,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
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      "novel": "Novel"
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    },
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     "id": "R4",
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      "type": "Association",
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    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D043171",
      "entity2": "56150",
      "type": "Positive_Correlation",
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     }
    }
   ]
  },
  {
   "id": "28512644",
   "passages": [
    {
     "offset": 0,
     "text": "Analysis of Serum Cytokines and Single-Nucleotide Polymorphisms of SOD1, SOD2, and CAT in Erysipelas Patients.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6647",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD1",
       "locations": [
        {
         "offset": 67,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD2",
       "locations": [
        {
         "offset": 73,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "847",
        "type": "GeneOrGeneProduct"
       },
       "text": "CAT",
       "locations": [
        {
         "offset": 83,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Erysipelas",
       "locations": [
        {
         "offset": 90,
         "length": 10
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Patients",
       "locations": [
        {
         "offset": 101,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 111,
     "text": "Increased free radical production had been documented in group A (beta-hemolytic) streptococcus infection cases. Comparing 71 erysipelas patients to 55 age-matched healthy individuals, we sought for CAT, SOD1, and SOD2 single polymorphism mutation (SNPs) interactions with erysipelas' predisposition and serum cytokine levels in the acute and recovery phases of erysipelas infection. Whereas female patients had a higher predisposition to erysipelas, male patients were prone to having a facial localization of the infection. The presence of SOD1 G7958, SOD2 T2734, and CAT C262 alleles was linked to erysipelas' predisposition. T and C alleles of SOD2 T2734C individually were linked to patients with bullous and erythematous erysipelas, respectively. G and A alleles of SOD1 G7958A individually were associated with lower limbs and higher body part localizations of the infection, respectively. Serum levels of IL-1beta, CCL11, IL-2Ralpha, CXCL9, TRAIL, PDGF-BB, and CCL4 were associated with symptoms accompanying the infection, while IL-6, IL-9, IL-10, IL-13, IL-15, IL-17, G-CSF, and VEGF were associated with predisposition and recurrence of erysipelas. While variations of IL-1beta, IL-7, IL-8, IL-17, CCL5, and HGF were associated with the SOD2 T2734C SNP, variations of PDFG-BB and CCL2 were associated with the CAT C262T SNP.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D013290",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "streptococcus infection",
       "locations": [
        {
         "offset": 193,
         "length": 23
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "erysipelas",
       "locations": [
        {
         "offset": 237,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
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       },
       "text": "patients",
       "locations": [
        {
         "offset": 248,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "847",
        "type": "GeneOrGeneProduct"
       },
       "text": "CAT",
       "locations": [
        {
         "offset": 310,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "6647",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD1",
       "locations": [
        {
         "offset": 315,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD2",
       "locations": [
        {
         "offset": 325,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "erysipelas",
       "locations": [
        {
         "offset": 384,
         "length": 10
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "erysipelas infection",
       "locations": [
        {
         "offset": 473,
         "length": 20
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 510,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "erysipelas",
       "locations": [
        {
         "offset": 550,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 567,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D007239",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "infection",
       "locations": [
        {
         "offset": 626,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "6647",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD1",
       "locations": [
        {
         "offset": 653,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|Aelle|G|7958",
        "type": "SequenceVariant"
       },
       "text": "G7958",
       "locations": [
        {
         "offset": 658,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD2",
       "locations": [
        {
         "offset": 665,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|Aelle|T|2734",
        "type": "SequenceVariant"
       },
       "text": "T2734",
       "locations": [
        {
         "offset": 670,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "847",
        "type": "GeneOrGeneProduct"
       },
       "text": "CAT",
       "locations": [
        {
         "offset": 681,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "c|Aelle|C|262",
        "type": "SequenceVariant"
       },
       "text": "C262",
       "locations": [
        {
         "offset": 685,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "erysipelas",
       "locations": [
        {
         "offset": 712,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "6648",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD2",
       "locations": [
        {
         "offset": 759,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "c|SYB|T2734|C",
        "type": "SequenceVariant"
       },
       "text": "T2734C",
       "locations": [
        {
         "offset": 764,
         "length": 6
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 799,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "erythematous erysipelas",
       "locations": [
        {
         "offset": 825,
         "length": 23
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "6647",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOD1",
       "locations": [
        {
         "offset": 883,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "rs4998557",
        "type": "SequenceVariant"
       },
       "text": "G7958A",
       "locations": [
        {
         "offset": 888,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D007239",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "infection",
       "locations": [
        {
         "offset": 983,
         "length": 9
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "3553",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-1beta",
       "locations": [
        {
         "offset": 1024,
         "length": 8
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "6356",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL11",
       "locations": [
        {
         "offset": 1034,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "3559",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-2Ralpha",
       "locations": [
        {
         "offset": 1041,
         "length": 10
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "4283",
        "type": "GeneOrGeneProduct"
       },
       "text": "CXCL9",
       "locations": [
        {
         "offset": 1053,
         "length": 5
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "8743",
        "type": "GeneOrGeneProduct"
       },
       "text": "TRAIL",
       "locations": [
        {
         "offset": 1060,
         "length": 5
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "5155",
        "type": "GeneOrGeneProduct"
       },
       "text": "PDGF-BB",
       "locations": [
        {
         "offset": 1067,
         "length": 7
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "6351",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCL4",
       "locations": [
        {
         "offset": 1080,
         "length": 4
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D007239",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "infection",
       "locations": [
        {
         "offset": 1132,
         "length": 9
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "3569",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-6",
       "locations": [
        {
         "offset": 1149,
         "length": 4
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "3578",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-9",
       "locations": [
        {
         "offset": 1155,
         "length": 4
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-10",
       "locations": [
        {
         "offset": 1161,
         "length": 5
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "3596",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-13",
       "locations": [
        {
         "offset": 1168,
         "length": 5
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "3600",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-15",
       "locations": [
        {
         "offset": 1175,
         "length": 5
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "3605",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-17",
       "locations": [
        {
         "offset": 1182,
         "length": 5
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "1440",
        "type": "GeneOrGeneProduct"
       },
       "text": "G-CSF",
       "locations": [
        {
         "offset": 1189,
         "length": 5
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "7422",
        "type": "GeneOrGeneProduct"
       },
       "text": "VEGF",
       "locations": [
        {
         "offset": 1200,
         "length": 4
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "D004886",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "erysipelas",
       "locations": [
        {
         "offset": 1259,
         "length": 10
        }
       ]
      },
      {
       "id": "48",
       "infons": {
        "identifier": "3553",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-1beta",
       "locations": [
        {
         "offset": 1291,
         "length": 8
        }
       ]
      },
      {
       "id": "49",
       "infons": {
        "identifier": "3574",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-7",
       "locations": [
        {
         "offset": 1301,
         "length": 4
        }
       ]
      },
      {
       "id": "50",
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     "text": "An Ag-globin G->A gene polymorphism associated with b(0)39 thalassemia globin gene and high fetal hemoglobin production.",
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     "text": "BACKGROUND: Increase of the expression of g-globin gene and high production of fetal hemoglobin (HbF) in b-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify b-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea). METHODS: Ag-globin gene sequencing was performed on genomic DNA isolated from a total of 75 b-thalassemia patients, including 31 b(0)39/b(0)39, 33 b(0)39/b(+)IVSI-110, 9 b(+)IVSI-110/b(+)IVSI-110, one b(0)IVSI-1/b(+)IVSI-6 and one b(0)39/b(+)IVSI-6. RESULTS: The results show that the rs368698783 polymorphism is present in b-thalassemia patients in the 5'UTR sequence (+25) of the Ag-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This Ag(+25 G->A) polymorphism is associated with the Gg-globin-XmnI polymorphism and both are linked with the b(0)39-globin gene, but not with the b(+)IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the Ag(+25 G->A) and Gg-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from b(0)39/b(0)39 thalassemia patients. CONCLUSIONS: As a potential explanation of our findings, we hypothesize that in b-thalassemia the Gg-globin-XmnI/Ag-globin-(G->A) genotype is frequently under genetic linkage with b(0)-thalassemia mutations, but not with the b(+)-thalassemia mutation here studied (i.e. b(+)IVSI-110) and that this genetic combination has been selected within the population of b(0)-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the Ag-globin gene associated in b(0)39 thalassemia patients with high HbF in erythroid precursor cells.",
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       "text": "b(0)-thalassemia",
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         "length": 16
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       ]
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       "id": "43",
       "infons": {
        "identifier": "D017086",
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       "text": "b(+)-thalassemia",
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        {
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         "length": 16
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       "id": "44",
       "infons": {
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       "text": "b(0)-thalassemia",
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       "id": "45",
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        "identifier": "3040,3048",
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       "text": "HbF",
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         "offset": 2022,
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       "text": "rs368698783",
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       "id": "48",
       "infons": {
        "identifier": "rs368698783",
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       "text": "+25 G->A",
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         "offset": 2085,
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       ]
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       "id": "49",
       "infons": {
        "identifier": "3047",
        "type": "GeneOrGeneProduct"
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       "text": "Ag-globin",
       "locations": [
        {
         "offset": 2115,
         "length": 9
        }
       ]
      },
      {
       "id": "50",
       "infons": {
        "identifier": "D017086",
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       "text": "b(0)39 thalassemia",
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        {
         "offset": 2144,
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       ]
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       "id": "51",
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       "text": "patients",
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       "infons": {
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       "text": "HbF",
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         "offset": 2182,
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  {
   "id": "15122711",
   "passages": [
    {
     "offset": 0,
     "text": "POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
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       "text": "POLG",
       "locations": [
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      {
       "id": "1",
       "infons": {
        "identifier": "D002549",
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       "text": "Alpers' syndrome",
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         "offset": 31,
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       "id": "2",
       "infons": {
        "identifier": "D028361",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "mitochondrial DNA depletion",
       "locations": [
        {
         "offset": 52,
         "length": 27
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       ]
      }
     ]
    },
    {
     "offset": 81,
     "text": "Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D002549",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alpers' syndrome",
       "locations": [
        {
         "offset": 81,
         "length": 16
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009422",
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       },
       "text": "neurogenetic disorder",
       "locations": [
        {
         "offset": 109,
         "length": 21
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D028361",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "mitochondrial DNA depletion",
       "locations": [
        {
         "offset": 215,
         "length": 27
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "5428",
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       "text": "DNA polymerase gamma",
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       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
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       "text": "POLG",
       "locations": [
        {
         "offset": 319,
         "length": 4
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012640",
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       "text": "seizures",
       "locations": [
        {
         "offset": 356,
         "length": 8
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D019636",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurodegeneration",
       "locations": [
        {
         "offset": 366,
         "length": 17
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D008107",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "liver disease",
       "locations": [
        {
         "offset": 389,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D002549",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alpers' syndrome",
       "locations": [
        {
         "offset": 434,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "POLG",
       "locations": [
        {
         "offset": 531,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs121918047",
        "type": "SequenceVariant"
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       "text": "Glu873Stop",
       "locations": [
        {
         "offset": 556,
         "length": 10
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs113994095",
        "type": "SequenceVariant"
       },
       "text": "G1681A",
       "locations": [
        {
         "offset": 689,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs113994095",
        "type": "SequenceVariant"
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       "text": "Ala467Thr",
       "locations": [
        {
         "offset": 730,
         "length": 9
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
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       "text": "POLG",
       "locations": [
        {
         "offset": 756,
         "length": 4
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     "id": "R6",
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     "id": "R7",
     "infons": {
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      "novel": "No"
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    {
     "id": "R8",
     "infons": {
      "entity1": "5428",
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      "type": "Association",
      "novel": "No"
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    }
   ]
  },
  {
   "id": "15817013",
   "passages": [
    {
     "offset": 0,
     "text": "People aged over 75 in atrial fibrillation on warfarin: the rate of major hemorrhage and stroke in more than 500 patient-years of follow-up.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D001281",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atrial fibrillation",
       "locations": [
        {
         "offset": 23,
         "length": 19
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D014859",
        "type": "ChemicalEntity"
       },
       "text": "warfarin",
       "locations": [
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         "offset": 46,
         "length": 8
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D006470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hemorrhage",
       "locations": [
        {
         "offset": 74,
         "length": 10
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 89,
         "length": 6
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 113,
         "length": 7
        }
       ]
      }
     ]
    },
    {
     "offset": 141,
     "text": "OBJECTIVES: To determine the incidence of major hemorrhage and stroke in people aged 76 and older with atrial fibrillation on adjusted-dose warfarin who had been recently been admitted to hospital. DESIGN: A retrospective observational cohort study. SETTING: A major healthcare network involving four tertiary hospitals. PARTICIPANTS: Two hundred thirty-five patients aged 76 and older admitted to a major healthcare network between July 1, 2001, and June 30, 2002, with atrial fibrillation on warfarin were enrolled. MEASUREMENTS: Information regarding major bleeding episodes, strokes, and warfarin use was obtained from patients, relatives, primary physicians, and medical records. RESULTS: Two hundred twenty-eight patients (42% men) with a mean age of 81.1 (range 76-94) were included in the analysis. Total follow-up on warfarin was 530 years (mean 28 months). There were 53 major hemorrhages, for an annual rate of 10.0%, including 24 (45.3%) life-threatening and five (9.4%) fatal bleeds. The annual stroke rate after initiation of warfarin was 2.6%. CONCLUSION: The rate of major hemorrhage was high in this old, frail group, but excluding fatalities, resulted in no long-term sequelae, and the stroke rate on warfarin was low, demonstrating how effective warfarin treatment is.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D006470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hemorrhage",
       "locations": [
        {
         "offset": 189,
         "length": 10
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      },
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       "id": "6",
       "infons": {
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       "text": "stroke",
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      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001281",
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       "text": "atrial fibrillation",
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         "offset": 244,
         "length": 19
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       ]
      },
      {
       "id": "8",
       "infons": {
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       "text": "warfarin",
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       "id": "9",
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       "text": "patients",
       "locations": [
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         "offset": 500,
         "length": 8
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001281",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "atrial fibrillation",
       "locations": [
        {
         "offset": 612,
         "length": 19
        }
       ]
      },
      {
       "id": "11",
       "infons": {
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       "text": "warfarin",
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         "offset": 635,
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      },
      {
       "id": "12",
       "infons": {
        "identifier": "D006470",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "bleeding",
       "locations": [
        {
         "offset": 701,
         "length": 8
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "strokes",
       "locations": [
        {
         "offset": 720,
         "length": 7
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D014859",
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       "text": "warfarin",
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         "offset": 733,
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       "id": "15",
       "infons": {
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       "text": "patients",
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         "offset": 764,
         "length": 8
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       ]
      },
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       "id": "16",
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       "text": "patients",
       "locations": [
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         "offset": 860,
         "length": 8
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       ]
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      {
       "id": "17",
       "infons": {
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       "text": "men",
       "locations": [
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         "offset": 874,
         "length": 3
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       "id": "18",
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       "text": "warfarin",
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       "id": "19",
       "infons": {
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       "text": "hemorrhages",
       "locations": [
        {
         "offset": 1028,
         "length": 11
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       ]
      },
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       "id": "20",
       "infons": {
        "identifier": "D006470",
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       "text": "bleeds",
       "locations": [
        {
         "offset": 1130,
         "length": 6
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       ]
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       "id": "21",
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        "identifier": "D020521",
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       "text": "stroke",
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       "text": "hemorrhage",
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     "text": "Disruption of a synaptotagmin (SYT14) associated with neurodevelopmental abnormalities.",
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     "text": "We report cytogenetic and molecular studies of a de novo, apparently balanced t(1;3)(q32.1;q25.1) identified in a 12-year-old female (designated DGAP128) with cerebral atrophy, macrocephaly seizures, and developmental delay. A combination of fluorescence in situ hybridization (FISH) and Southern blot analysis demonstrated disruption of a synaptotagmin gene (SYT14) at the 1q32 breakpoint. Expression of SYT14 in human brain was confirmed using Northern analysis. Because members of the synaptotagmin family of proteins function as sensors that link changes in calcium levels with a variety of biological processes, including neurotransmission and hormone-responsiveness, SYT14 is an intriguing candidate gene for the abnormal development in this child. This is the first known constitutional rearrangement of SYT14, and further systematic genetic analysis and clinical studies of DGAP128 may offer unique insights into the role of SYT14 in neurodevelopment.",
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     "text": "Isoproterenol induces primary loss of dystrophin in rat hearts: correlation with myocardial injury.",
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     "text": "The mechanism of isoproterenol-induced myocardial damage is unknown, but a mismatch of oxygen supply vs. demand following coronary hypotension and myocardial hyperactivity is the best explanation for the complex morphological alterations observed. Severe alterations in the structural integrity of the sarcolemma of cardiomyocytes have been demonstrated to be caused by isoproterenol. Taking into account that the sarcolemmal integrity is stabilized by the dystrophin-glycoprotein complex (DGC) that connects actin and laminin in contractile machinery and extracellular matrix and by integrins, this study tests the hypothesis that isoproterenol affects sarcolemmal stability through changes in the DGC and integrins. We found different sensitivity of the DGC and integrin to isoproterenol subcutaneous administration. Immunofluorescent staining revealed that dystrophin is the most sensitive among the structures connecting the actin in the cardiomyocyte cytoskeleton and the extracellular matrix. The sarcomeric actin dissolution occurred after the reduction or loss of dystrophin. Subsequently, after lysis of myofilaments, gamma-sarcoglycan, beta-dystroglycan, beta1-integrin, and laminin alpha-2 expressions were reduced followed by their breakdown, as epiphenomena of the myocytolytic process. In conclusion, administration of isoproterenol to rats results in primary loss of dystrophin, the most sensitive among the structural proteins that form the DGC that connects the extracellular matrix and the cytoskeleton in cardiomyocyte. These changes, related to ischaemic injury, explain the severe alterations in the structural integrity of the sarcolemma of cardiomyocytes and hence severe and irreversible injury induced by isoproterenol.",
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  {
   "id": "20415560",
   "passages": [
    {
     "offset": 0,
     "text": "Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D014810",
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       "text": "Vitamin E",
       "locations": [
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       "id": "1",
       "infons": {
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       "text": "cardiovascular disease",
       "locations": [
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         "offset": 18,
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       "id": "2",
       "infons": {
        "identifier": "D003920",
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       "text": "diabetes mellitus",
       "locations": [
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       "id": "3",
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    },
    {
     "offset": 113,
     "text": "AIMS: Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. MATERIALS & METHODS: We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). RESULTS: Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40-0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. CONCLUSION: A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.",
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       ]
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       "text": "vitamin E",
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  {
   "id": "20523265",
   "passages": [
    {
     "offset": 0,
     "text": "Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3075",
        "type": "GeneOrGeneProduct"
       },
       "text": "complement factor H",
       "locations": [
        {
         "offset": 21,
         "length": 19
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "717",
        "type": "GeneOrGeneProduct"
       },
       "text": "C2",
       "locations": [
        {
         "offset": 42,
         "length": 2
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "629",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFB",
       "locations": [
        {
         "offset": 46,
         "length": 3
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "718",
        "type": "GeneOrGeneProduct"
       },
       "text": "C3",
       "locations": [
        {
         "offset": 55,
         "length": 2
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "age-related macular degeneration",
       "locations": [
        {
         "offset": 62,
         "length": 32
        }
       ]
      }
     ]
    },
    {
     "offset": 124,
     "text": "PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population. METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis. RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen. CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD.",
     "annotations": [
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       "id": "5",
       "infons": {
        "identifier": "3075",
        "type": "GeneOrGeneProduct"
       },
       "text": "complement factor H",
       "locations": [
        {
         "offset": 176,
         "length": 19
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3075",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFH",
       "locations": [
        {
         "offset": 197,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "629,717",
        "type": "GeneOrGeneProduct"
       },
       "text": "C2/BF",
       "locations": [
        {
         "offset": 203,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "718",
        "type": "GeneOrGeneProduct"
       },
       "text": "C3",
       "locations": [
        {
         "offset": 214,
         "length": 2
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "age-related macular degeneration",
       "locations": [
        {
         "offset": 259,
         "length": 32
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AMD",
       "locations": [
        {
         "offset": 293,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 500,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AMD",
       "locations": [
        {
         "offset": 518,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 526,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D005128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drusen",
       "locations": [
        {
         "offset": 545,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "3075",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFH",
       "locations": [
        {
         "offset": 652,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "717",
        "type": "GeneOrGeneProduct"
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       "text": "C2",
       "locations": [
        {
         "offset": 672,
         "length": 2
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "629",
        "type": "GeneOrGeneProduct"
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       "text": "CFB",
       "locations": [
        {
         "offset": 676,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "718",
        "type": "GeneOrGeneProduct"
       },
       "text": "C3",
       "locations": [
        {
         "offset": 686,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "3078",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFHR1",
       "locations": [
        {
         "offset": 780,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "10878",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFHR3",
       "locations": [
        {
         "offset": 790,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs3753394",
        "type": "SequenceVariant"
       },
       "text": "rs3753394",
       "locations": [
        {
         "offset": 906,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs800292",
        "type": "SequenceVariant"
       },
       "text": "rs800292",
       "locations": [
        {
         "offset": 930,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs1061170",
        "type": "SequenceVariant"
       },
       "text": "rs1061170",
       "locations": [
        {
         "offset": 953,
         "length": 9
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs1329428",
        "type": "SequenceVariant"
       },
       "text": "rs1329428",
       "locations": [
        {
         "offset": 982,
         "length": 9
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "3075",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFH",
       "locations": [
        {
         "offset": 1009,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AMD",
       "locations": [
        {
         "offset": 1055,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AMD",
       "locations": [
        {
         "offset": 1176,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs2274700",
        "type": "SequenceVariant"
       },
       "text": "rs2274700",
       "locations": [
        {
         "offset": 1298,
         "length": 9
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "rs1410996",
        "type": "SequenceVariant"
       },
       "text": "rs1410996",
       "locations": [
        {
         "offset": 1312,
         "length": 9
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AMD",
       "locations": [
        {
         "offset": 1366,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "3075",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFH",
       "locations": [
        {
         "offset": 1431,
         "length": 3
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D005128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drusen",
       "locations": [
        {
         "offset": 1473,
         "length": 6
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "3075",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFH",
       "locations": [
        {
         "offset": 1505,
         "length": 3
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       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "717",
        "type": "GeneOrGeneProduct"
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       "text": "C2",
       "locations": [
        {
         "offset": 1510,
         "length": 2
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       ]
      },
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       "id": "35",
       "infons": {
        "identifier": "629",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFB",
       "locations": [
        {
         "offset": 1514,
         "length": 3
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       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "718",
        "type": "GeneOrGeneProduct"
       },
       "text": "C3",
       "locations": [
        {
         "offset": 1523,
         "length": 2
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D008268",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AMD",
       "locations": [
        {
         "offset": 1575,
         "length": 3
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       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D005128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drusen",
       "locations": [
        {
         "offset": 1582,
         "length": 6
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "3078",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFHR1",
       "locations": [
        {
         "offset": 1622,
         "length": 5
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       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "10878",
        "type": "GeneOrGeneProduct"
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       "text": "CFHR3",
       "locations": [
        {
         "offset": 1632,
         "length": 5
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       ]
      },
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       "id": "41",
       "infons": {
        "identifier": "D008268",
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       "text": "AMD",
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         "offset": 1725,
         "length": 3
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      },
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       "id": "42",
       "infons": {
        "identifier": "D005128",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "drusen",
       "locations": [
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         "offset": 1732,
         "length": 6
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     "offset": 0,
     "text": "Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier.",
     "annotations": []
    },
    {
     "offset": 78,
     "text": "Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies.",
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       "text": "cystic fibrosis",
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     "text": "In vivo characterization of a dual adenosine A2A/A1 receptor antagonist in animal models of Parkinson's disease.",
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       "id": "0",
       "infons": {
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       "text": "adenosine A2A/A1 receptor antagonist",
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    {
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     "text": "The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.",
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       "text": "catalepsy",
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       "text": "human",
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      "novel": "No"
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  {
   "id": "21533187",
   "passages": [
    {
     "offset": 0,
     "text": "Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN11",
       "locations": [
        {
         "offset": 30,
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      },
      {
       "id": "1",
       "infons": {
        "identifier": "C562938",
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       "text": "metachondromatosis",
       "locations": [
        {
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         "length": 18
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      },
      {
       "id": "2",
       "infons": {
        "identifier": "D004687",
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       "text": "Ollier disease",
       "locations": [
        {
         "offset": 71,
         "length": 14
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D004687",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Maffucci syndrome",
       "locations": [
        {
         "offset": 89,
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       ]
      }
     ]
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    {
     "offset": 108,
     "text": "Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a \"second hit,\" that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Metachondromatosis",
       "locations": [
        {
         "offset": 108,
         "length": 18
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C562938",
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       "text": "MC",
       "locations": [
        {
         "offset": 128,
         "length": 2
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D005096",
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       "text": "exostosis",
       "locations": [
        {
         "offset": 195,
         "length": 9
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D004687",
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       "text": "enchondromatosis tumor syndrome",
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "MC",
       "locations": [
        {
         "offset": 242,
         "length": 2
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D005097",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "multiple exostosis",
       "locations": [
        {
         "offset": 279,
         "length": 18
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D004687",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "multiple enchondromatosis syndromes",
       "locations": [
        {
         "offset": 301,
         "length": 35
        }
       ]
      },
      {
       "id": "11",
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        "identifier": "2131",
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       },
       "text": "EXT1",
       "locations": [
        {
         "offset": 356,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "2132",
        "type": "GeneOrGeneProduct"
       },
       "text": "EXT2",
       "locations": [
        {
         "offset": 365,
         "length": 4
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D005097",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "multiple osteochondromas",
       "locations": [
        {
         "offset": 416,
         "length": 24
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D005097",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MO",
       "locations": [
        {
         "offset": 442,
         "length": 2
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MC",
       "locations": [
        {
         "offset": 470,
         "length": 2
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MC",
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       "text": "PTPN11",
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         "length": 6
        }
       ]
      },
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       "id": "19",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "MC",
       "locations": [
        {
         "offset": 965,
         "length": 2
        }
       ]
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       "id": "20",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
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       "text": "PTPN11",
       "locations": [
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         "offset": 1166,
         "length": 6
        }
       ]
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       "id": "21",
       "infons": {
        "identifier": "c|DEL||15K",
        "type": "SequenceVariant"
       },
       "text": "15 kb deletion",
       "locations": [
        {
         "offset": 1217,
         "length": 14
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
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       "text": "PTPN11",
       "locations": [
        {
         "offset": 1251,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "C562938",
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       "text": "MC",
       "locations": [
        {
         "offset": 1274,
         "length": 2
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1294,
         "length": 8
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN11",
       "locations": [
        {
         "offset": 1308,
         "length": 6
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
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       "text": "PTPN11",
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         "offset": 1405,
         "length": 6
        }
       ]
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       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1435,
         "length": 8
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D004687",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "enchondromatosis disorders Ollier disease",
       "locations": [
        {
         "offset": 1462,
         "length": 41
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D004687",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Maffucci syndrome",
       "locations": [
        {
         "offset": 1507,
         "length": 17
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN11",
       "locations": [
        {
         "offset": 1555,
         "length": 6
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN11",
       "locations": [
        {
         "offset": 1633,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MC",
       "locations": [
        {
         "offset": 1664,
         "length": 2
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1684,
         "length": 8
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MC",
       "locations": [
        {
         "offset": 1698,
         "length": 2
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "C562938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MC",
       "locations": [
        {
         "offset": 1748,
         "length": 2
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN11",
       "locations": [
        {
         "offset": 1861,
         "length": 6
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "5781",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPN11",
       "locations": [
        {
         "offset": 1888,
         "length": 6
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D004687",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Ollier disease",
       "locations": [
        {
         "offset": 1931,
         "length": 14
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "D004687",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Maffucci syndrome",
       "locations": [
        {
         "offset": 1949,
         "length": 17
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|DEL||15K",
      "entity2": "C562938",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "2132",
      "entity2": "D005097",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "2131",
      "entity2": "D005097",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "5781",
      "entity2": "C562938",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "23952588",
   "passages": [
    {
     "offset": 0,
     "text": "Risk factors and predictors of levodopa-induced dyskinesia among multiethnic Malaysians with Parkinson's disease.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 31,
         "length": 8
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesia",
       "locations": [
        {
         "offset": 48,
         "length": 10
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Parkinson's disease",
       "locations": [
        {
         "offset": 93,
         "length": 19
        }
       ]
      }
     ]
    },
    {
     "offset": 114,
     "text": "Chronic pulsatile levodopa therapy for Parkinson's disease (PD) leads to the development of motor fluctuations and dyskinesia. We studied the prevalence and predictors of levodopa-induced dyskinesia among multiethnic Malaysian patients with PD. METHODS: This is a cross-sectional study involving 95 patients with PD on uninterrupted levodopa therapy for at least 6 months. The instrument used was the UPDRS questionnaires. The predictors of dyskinesia were determined using multivariate logistic regression analysis. RESULTS: The mean age was 65.6 + 8.5 years. The mean onset age was 58.5 + 9.8 years. The median disease duration was 6 (7) years. Dyskinesia was present in 44% (n = 42) with median levodopa therapy of 3 years. There were 64.3% Chinese, 31% Malays, and 3.7% Indians and other ethnic groups. Eighty-one percent of patients with dyskinesia had clinical fluctuations. Patients with dyskinesia had lower onset age ( p < 0.001), longer duration of levodopa therapy ( p < 0.001), longer disease duration ( p < 0.001), higher total daily levodopa dose ( p < 0.001), and higher total UPDRS scores ( p = 0.005) than patients without dyskinesia. The three significant predictors of dyskinesia were duration of levodopa therapy, onset age, and total daily levodopa dose. CONCLUSIONS: The prevalence of levodopa-induced dyskinesia in our patients was 44%. The most significant predictors were duration of levodopa therapy, total daily levodopa dose, and onset age.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 132,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Parkinson's disease",
       "locations": [
        {
         "offset": 153,
         "length": 19
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "PD",
       "locations": [
        {
         "offset": 174,
         "length": 2
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesia",
       "locations": [
        {
         "offset": 229,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 285,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesia",
       "locations": [
        {
         "offset": 302,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 341,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "PD",
       "locations": [
        {
         "offset": 355,
         "length": 2
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 413,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 427,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
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       "text": "levodopa",
       "locations": [
        {
         "offset": 447,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "dyskinesia",
       "locations": [
        {
         "offset": 555,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Dyskinesia",
       "locations": [
        {
         "offset": 761,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D007980",
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       "text": "levodopa",
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         "offset": 812,
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        }
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      },
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       "id": "17",
       "infons": {
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       "text": "patients",
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         "offset": 943,
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D004409",
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       "text": "dyskinesia",
       "locations": [
        {
         "offset": 957,
         "length": 10
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "Patients",
       "locations": [
        {
         "offset": 995,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesia",
       "locations": [
        {
         "offset": 1009,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
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       "text": "levodopa",
       "locations": [
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         "offset": 1073,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 1161,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1237,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesia",
       "locations": [
        {
         "offset": 1254,
         "length": 10
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesia",
       "locations": [
        {
         "offset": 1302,
         "length": 10
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 1330,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 1375,
         "length": 8
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 1421,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesia",
       "locations": [
        {
         "offset": 1438,
         "length": 10
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1456,
         "length": 8
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 1523,
         "length": 8
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 1553,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D007980",
      "entity2": "D010300",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D007980",
      "entity2": "D004409",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "25305591",
   "passages": [
    {
     "offset": 0,
     "text": "VPAC2 (vasoactive intestinal peptide receptor type 2) receptor deficient mice develop exacerbated experimental autoimmune encephalomyelitis with increased Th1/Th17 and reduced Th2/Treg responses.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "22355",
        "type": "GeneOrGeneProduct"
       },
       "text": "VPAC2",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "22355",
        "type": "GeneOrGeneProduct"
       },
       "text": "vasoactive intestinal peptide receptor type 2",
       "locations": [
        {
         "offset": 7,
         "length": 45
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 73,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D004681",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "experimental autoimmune encephalomyelitis",
       "locations": [
        {
         "offset": 98,
         "length": 41
        }
       ]
      }
     ]
    },
    {
     "offset": 196,
     "text": "Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) are two structurally-related neuropeptides with widespread expression in the central and peripheral nervous systems. Although these peptides have been repeatedly shown to exert potent anti-inflammatory actions when administered in animal models of inflammatory disease, mice deficient in VIP and PACAP were recently shown to exhibit different phenotypes (ameliorated and exacerbated, respectively) in response to experimental autoimmune encephalomyelitis (EAE). Therefore, elucidating what are the specific immunoregulatory roles played by each of their receptor subtypes (VPAC1, VPAC2, and PAC1) is critical. In this study, we found that mice with a genetic deletion of VIPR2, encoding the VPAC2 receptor, exhibited exacerbated (MOG35-55)-induced EAE compared to wild type mice, characterized by enhanced clinical and histopathological features, increased proinflammatory cytokines (TNF-alpha, IL-6, IFN-gamma (Th1), and IL-17 (Th17)) and reduced anti-inflammatory cytokines (IL-10, TGFbeta, and IL-4 (Th2)) in the CNS and lymph nodes. Moreover, the abundance and proliferative index of lymph node, thymus and CNS CD4(+)CD25(+)FoxP3(+) Tregs were strikingly reduced in VPAC2-deficient mice with EAE. Finally, the in vitro suppressive activity of lymph node and splenic Tregs from VPAC2-deficient mice was impaired. Overall, our results demonstrate critical protective roles for PACAP and the VPAC2 receptor against autoimmunity, promoting the expansion and maintenance of the Treg pool. ",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "Vasoactive intestinal peptide",
       "locations": [
        {
         "offset": 196,
         "length": 29
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 227,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "11516",
        "type": "GeneOrGeneProduct"
       },
       "text": "pituitary adenylyl cyclase-activating polypeptide",
       "locations": [
        {
         "offset": 236,
         "length": 49
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "11516",
        "type": "GeneOrGeneProduct"
       },
       "text": "PACAP",
       "locations": [
        {
         "offset": 287,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory",
       "locations": [
        {
         "offset": 483,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammatory disease",
       "locations": [
        {
         "offset": 542,
         "length": 20
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mice",
       "locations": [
        {
         "offset": 564,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "22353",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 582,
         "length": 3
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     "offset": 0,
     "text": "Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study.",
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     "text": "Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed  = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed  = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.",
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       "id": "28",
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       "text": "prostate cancer",
       "locations": [
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         "offset": 1821,
         "length": 15
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       "infons": {
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       "text": "men",
       "locations": [
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         "offset": 1850,
         "length": 3
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       "id": "30",
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        "identifier": "D011471",
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       "text": "prostate cancer",
       "locations": [
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         "offset": 1869,
         "length": 15
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       "id": "31",
       "infons": {
        "identifier": "D000438",
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       "text": "alcohol",
       "locations": [
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         "offset": 1913,
         "length": 7
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       "id": "32",
       "infons": {
        "identifier": "D011471",
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       "text": "prostate cancer",
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  {
   "id": "15686794",
   "passages": [
    {
     "offset": 0,
     "text": "Acute low back pain during intravenous administration of amiodarone: a report of two cases.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D017116",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "low back pain",
       "locations": [
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         "offset": 6,
         "length": 13
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       "id": "1",
       "infons": {
        "identifier": "D000638",
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       "text": "amiodarone",
       "locations": [
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         "offset": 57,
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     ]
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    {
     "offset": 92,
     "text": "Amiodarone represents an effective antiarrhythmic drug for cardioversion of recent-onset atrial fibrillation (AF) and maintenance of sinus rhythm. We briefly describe two patients suffering from recent-onset atrial fibrillation, who experienced an acute devastating low back pain a few minutes after initiation of intravenous amiodarone loading. Notably, this side effect has not been ever reported in the medical literature. Clinicians should be aware of this reaction since prompt termination of parenteral administration leads to complete resolution.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D000638",
        "type": "ChemicalEntity"
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       "text": "Amiodarone",
       "locations": [
        {
         "offset": 92,
         "length": 10
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       ]
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       "id": "3",
       "infons": {
        "identifier": "D000889",
        "type": "ChemicalEntity"
       },
       "text": "antiarrhythmic drug",
       "locations": [
        {
         "offset": 127,
         "length": 19
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       ]
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       "id": "4",
       "infons": {
        "identifier": "D001281",
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       "text": "atrial fibrillation",
       "locations": [
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         "offset": 181,
         "length": 19
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D001281",
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       "text": "AF",
       "locations": [
        {
         "offset": 202,
         "length": 2
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 263,
         "length": 8
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001281",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atrial fibrillation",
       "locations": [
        {
         "offset": 300,
         "length": 19
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D017116",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "low back pain",
       "locations": [
        {
         "offset": 358,
         "length": 13
        }
       ]
      },
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       "id": "9",
       "infons": {
        "identifier": "D000638",
        "type": "ChemicalEntity"
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       "text": "amiodarone",
       "locations": [
        {
         "offset": 418,
         "length": 10
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       ]
      }
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   ],
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     "id": "R0",
     "infons": {
      "entity1": "D017116",
      "entity2": "D000638",
      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D000889",
      "entity2": "D001281",
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      "novel": "No"
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     "id": "R2",
     "infons": {
      "entity1": "D000638",
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      "type": "Negative_Correlation",
      "novel": "No"
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    }
   ]
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  {
   "id": "15755837",
   "passages": [
    {
     "offset": 0,
     "text": "Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1719",
        "type": "GeneOrGeneProduct"
       },
       "text": "dihydrofolate reductase",
       "locations": [
        {
         "offset": 7,
         "length": 23
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|DEL||19",
        "type": "SequenceVariant"
       },
       "text": "19-base pair deletion",
       "locations": [
        {
         "offset": 31,
         "length": 21
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D047928",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "preterm delivery",
       "locations": [
        {
         "offset": 85,
         "length": 16
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       ]
      }
     ]
    },
    {
     "offset": 103,
     "text": "BACKGROUND: Folate is critical for cell division, a major feature of in utero development. Dihydrofolate reductase (DHFR) is required to convert the folic acid used in supplements and for food fortification and the dihydrofolate produced by thymidylate synthase during DNA synthesis to the reduced folate forms used by the cell. OBJECTIVE: We aimed to determine whether a common, recently discovered deletion polymorphism in the DHFR gene is a risk factor for preterm delivery or low birth weight. DESIGN: We studied 324 pregnant women from Camden, NJ. Folate intake was computed from folate supplement intake plus the mean of two 24-h recalls completed during the course of pregnancy. Genomic DNA was extracted from the women's leukocytes and genotyped. RESULTS: Women with a deletion allele had a significantly greater risk of preterm delivery [adjusted odds ratio (AOR): 3.0; 95% CI: 1.0, 8.8; P < 0.05] than did those without a deletion allele. Women with both a DHFR deletion allele and low folate intake (<400 microg/d from diet plus supplements) had a significantly greater risk of preterm delivery (AOR: 5.5; 95% CI: 1.5, 20.4; P = 0.01) and a significantly greater risk of having an infant with a low birth weight (AOR: 8.3; 95% CI: 1.8, 38.6; P = 0.01) than did women without a deletion allele and with a folate intake >/=400 microg/d. CONCLUSIONS: The DHFR 19-base pair deletion allele may be a risk factor for preterm delivery. In the presence of low dietary folate, the allele may also be a risk factor for low birth weight. This may be a gene-environment interaction.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "D005492",
        "type": "ChemicalEntity"
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       "text": "Folate",
       "locations": [
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         "offset": 115,
         "length": 6
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       ]
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       "id": "4",
       "infons": {
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       "text": "Dihydrofolate reductase",
       "locations": [
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         "offset": 194,
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       ]
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       "id": "5",
       "infons": {
        "identifier": "1719",
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       "text": "DHFR",
       "locations": [
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         "offset": 219,
         "length": 4
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       ]
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       "id": "6",
       "infons": {
        "identifier": "D005492",
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       "text": "folic acid",
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         "offset": 252,
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       ]
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       "infons": {
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       "text": "dihydrofolate",
       "locations": [
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         "offset": 318,
         "length": 13
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       ]
      },
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       "id": "8",
       "infons": {
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       "text": "thymidylate synthase",
       "locations": [
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         "offset": 344,
         "length": 20
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       ]
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       "id": "9",
       "infons": {
        "identifier": "D005492",
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       "text": "folate",
       "locations": [
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         "offset": 401,
         "length": 6
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       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "1719",
        "type": "GeneOrGeneProduct"
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       "text": "DHFR",
       "locations": [
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         "offset": 532,
         "length": 4
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       ]
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       "id": "11",
       "infons": {
        "identifier": "D047928",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "preterm delivery",
       "locations": [
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         "offset": 563,
         "length": 16
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 633,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D005492",
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       "text": "Folate",
       "locations": [
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         "offset": 656,
         "length": 6
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       ]
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       "id": "14",
       "infons": {
        "identifier": "D005492",
        "type": "ChemicalEntity"
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       "text": "folate",
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         "offset": 688,
         "length": 6
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       ]
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       "id": "15",
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        "identifier": "9606",
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       "text": "women",
       "locations": [
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         "offset": 824,
         "length": 5
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       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "9606",
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       "text": "Women",
       "locations": [
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         "offset": 867,
         "length": 5
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      },
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       "id": "17",
       "infons": {
        "identifier": "D047928",
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       "text": "preterm delivery",
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         "offset": 932,
         "length": 16
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       "id": "18",
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       "text": "Women",
       "locations": [
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         "offset": 1052,
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       "id": "19",
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         "offset": 1070,
         "length": 4
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       ]
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       "id": "20",
       "infons": {
        "identifier": "D005492",
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       "text": "folate",
       "locations": [
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         "offset": 1099,
         "length": 6
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D047928",
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       },
       "text": "preterm delivery",
       "locations": [
        {
         "offset": 1192,
         "length": 16
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "women",
       "locations": [
        {
         "offset": 1375,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D005492",
        "type": "ChemicalEntity"
       },
       "text": "folate",
       "locations": [
        {
         "offset": 1418,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "1719",
        "type": "GeneOrGeneProduct"
       },
       "text": "DHFR",
       "locations": [
        {
         "offset": 1466,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "c|DEL||19",
        "type": "SequenceVariant"
       },
       "text": "19-base pair deletion",
       "locations": [
        {
         "offset": 1471,
         "length": 21
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D047928",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "preterm delivery",
       "locations": [
        {
         "offset": 1525,
         "length": 16
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D005492",
        "type": "ChemicalEntity"
       },
       "text": "folate",
       "locations": [
        {
         "offset": 1574,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "C010920",
      "entity2": "7298",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D005492",
      "entity2": "D047928",
      "type": "Negative_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|DEL||19",
      "entity2": "D047928",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "1719",
      "entity2": "C010920",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "1719",
      "entity2": "D005492",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "1719",
      "entity2": "D047928",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15851735",
   "passages": [
    {
     "offset": 0,
     "text": "Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D020158",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glycine encephalopathy",
       "locations": [
        {
         "offset": 5,
         "length": 22
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D020158",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NKH",
       "locations": [
        {
         "offset": 29,
         "length": 3
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "GLDC",
       "locations": [
        {
         "offset": 76,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 98,
     "text": "BACKGROUND: Classic neonatal-onset glycine encephalopathy (GE) is devastating and life threatening. Milder, later onset variants have been reported but were usually sporadic and incompletely defined. OBJECTIVE: To determine the clinical and biochemical phenotype and molecular basis of mild GE in nine children from a consanguineous Israeli Bedouin kindred. METHODS: Genomic DNA was screened for GLDC, AMT, and GCSH gene mutations. GLDC expression in lymphoblasts was studied by Northern blot and reverse transcriptase PCR analysis. RESULTS: Clinical features included hypotonia, abnormal movements, convulsions, and moderate mental retardation with relative sparing of gross motor function, activities of daily living skills, and receptive language. Aggression and irritability were prominent. CSF-to-plasma glycine ratio was mildly to moderately elevated. All nine patients were homozygous and their parents heterozygous for a novel, translationally silent GLDC exon 22 transversion c.2607C>A. Lymphoblast GLDC mRNA levels were considerably reduced. Three aberrantly spliced cDNA species were identified: exon 22 and exon 22 to 23 skipping, and insertion of an 87-base pair cryptic exon. Homozygosity for c.2607C>A was also identified in an unrelated but haplotypically identical patient with an unusually favorable outcome despite severe neonatal-onset GE. Mutation analysis enabled prenatal diagnosis of three unaffected and one affected pregnancies. CONCLUSIONS: The mutation in this kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. The 4 to 6% of normally spliced GLDC mRNA in the patients may account for their relatively favorable clinical outcome compared with patients with classic glycine encephalopathy.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D020158",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glycine encephalopathy",
       "locations": [
        {
         "offset": 133,
         "length": 22
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D020158",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GE",
       "locations": [
        {
         "offset": 157,
         "length": 2
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D020158",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GE",
       "locations": [
        {
         "offset": 389,
         "length": 2
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "GLDC",
       "locations": [
        {
         "offset": 494,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "275",
        "type": "GeneOrGeneProduct"
       },
       "text": "AMT",
       "locations": [
        {
         "offset": 500,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "2653",
        "type": "GeneOrGeneProduct"
       },
       "text": "GCSH",
       "locations": [
        {
         "offset": 509,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "GLDC",
       "locations": [
        {
         "offset": 530,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D009123",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypotonia",
       "locations": [
        {
         "offset": 667,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D009069",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "abnormal movements",
       "locations": [
        {
         "offset": 678,
         "length": 18
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D012640",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "convulsions",
       "locations": [
        {
         "offset": 698,
         "length": 11
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mental retardation",
       "locations": [
        {
         "offset": 724,
         "length": 18
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D001523",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Aggression",
       "locations": [
        {
         "offset": 849,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D001523",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "irritability",
       "locations": [
        {
         "offset": 864,
         "length": 12
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 965,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "GLDC",
       "locations": [
        {
         "offset": 1057,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs386833565",
        "type": "SequenceVariant"
       },
       "text": "c.2607C>A",
       "locations": [
        {
         "offset": 1083,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "GLDC",
       "locations": [
        {
         "offset": 1106,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs386833565",
        "type": "SequenceVariant"
       },
       "text": "c.2607C>A",
       "locations": [
        {
         "offset": 1305,
         "length": 9
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1380,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D020158",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GE",
       "locations": [
        {
         "offset": 1454,
         "length": 2
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "GLDC",
       "locations": [
        {
         "offset": 1626,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "glycine decarboxylase",
       "locations": [
        {
         "offset": 1632,
         "length": 21
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "2731",
        "type": "GeneOrGeneProduct"
       },
       "text": "GLDC",
       "locations": [
        {
         "offset": 1699,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1716,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1799,
         "length": 8
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D020158",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glycine encephalopathy",
       "locations": [
        {
         "offset": 1821,
         "length": 22
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs386833565",
      "entity2": "D020158",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D020158",
      "entity2": "2731",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18262054",
   "passages": [
    {
     "offset": 0,
     "text": "A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "657",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMPR1A",
       "locations": [
        {
         "offset": 52,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C537702",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "juvenile polyposis",
       "locations": [
        {
         "offset": 67,
         "length": 18
        }
       ]
      }
     ]
    },
    {
     "offset": 87,
     "text": "We describe a novel germline mutation of BMPR1A in a family with juvenile polyposis and colon cancer. This mutation consists of two consecutive substitutions (735-6 TG>AT) that cause two nonsense mutations (Y245X, G246X), inherited in an autosomal dominant fashion, on one parental chromosome. This mutation caused protein truncation, and represents a novel case of consecutive nonsense mutations in human disease.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "657",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMPR1A",
       "locations": [
        {
         "offset": 128,
         "length": 6
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C537702",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "juvenile polyposis",
       "locations": [
        {
         "offset": 152,
         "length": 18
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D003110",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colon cancer",
       "locations": [
        {
         "offset": 175,
         "length": 12
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "c|SUB|TG|735_736|AT",
        "type": "SequenceVariant"
       },
       "text": "735-6 TG>AT",
       "locations": [
        {
         "offset": 246,
         "length": 11
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "p|SUB|Y|245|X",
        "type": "SequenceVariant"
       },
       "text": "Y245X",
       "locations": [
        {
         "offset": 294,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "p|SUB|G|246|X",
        "type": "SequenceVariant"
       },
       "text": "G246X",
       "locations": [
        {
         "offset": 301,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 487,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|TG|735_736|AT",
      "entity2": "D003110",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|SUB|TG|735_736|AT",
      "entity2": "C537702",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "p|SUB|G|246|X",
      "entity2": "D003110",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "p|SUB|G|246|X",
      "entity2": "C537702",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "p|SUB|Y|245|X",
      "entity2": "p|SUB|G|246|X",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "p|SUB|Y|245|X",
      "entity2": "D003110",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "p|SUB|Y|245|X",
      "entity2": "C537702",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "657",
      "entity2": "D003110",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "657",
      "entity2": "C537702",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "18470323",
   "passages": [
    {
     "offset": 0,
     "text": "Anticipation in familial lattice corneal dystrophy type I with R124C mutation in the TGFBI (BIGH3) gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lattice corneal dystrophy type I",
       "locations": [
        {
         "offset": 25,
         "length": 32
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs121909210",
        "type": "SequenceVariant"
       },
       "text": "R124C",
       "locations": [
        {
         "offset": 63,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFBI",
       "locations": [
        {
         "offset": 85,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "BIGH3",
       "locations": [
        {
         "offset": 92,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 105,
     "text": "PURPOSE: To report the clinical, ophthalmic, and genetic characteristics for lattice corneal dystrophy type I (LCDI) in a Chilean family. METHODS: Six affected family members were examined clinically including visual acuity, color cornea photography, applanation tonography, and fundoscopy. Genomic DNA was extracted from peripheral leukocytes from six affected and three unaffected members of a family with lattice corneal dystrophy type I. Exon 4 of the transforming growth factor-induced gene (TGFBI) was screened for the most frequent mutation, R124C, in the proband by sequencing. We also designed a rapid polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the same mutation, amplifying exon 4 and digesting with PstI restriction enzyme. Using this strategy, we analyzed the mutation in six affected and three healthy family members. RESULTS: Three generations of family members were positively diagnosed with lattice corneal dystrophy. Six participants demonstrated LCD1 in both eyes, most of whom were symmetric. Age at onset of symptoms was variable (3-42 years old). Moreover, in this family, the age of onset of the disease decreased in succeeding generations, which could be interpreted as anticipation. Visual acuity varied from 1.0 to 0.13. Two patients, ages 69 and 44 years old, demonstrated a degree of severity \"Bad\" according to best-corrected vision and corneal commitment. The exon 4 sequence of TGFBI of the proband exhibits the heterozygous single-nucleotide mutation, C417T, leading to amino acid substitution (R124C) in the encoded TGF-induced protein. Using PCR-RFLP, we confirmed the heterozygous mutation in six affected family members and excluded it in three healthy members. CONCLUSIONS: The R124C mutation in TGFBI cosegregated with LCD type I in the investigated family. This is the first report of a molecular analysis of LCD type I in Chilean patients. The early onset affected persons in the fourth generation raises the possibility of anticipation.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lattice corneal dystrophy type I",
       "locations": [
        {
         "offset": 182,
         "length": 32
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCDI",
       "locations": [
        {
         "offset": 216,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lattice corneal dystrophy type I",
       "locations": [
        {
         "offset": 513,
         "length": 32
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "transforming growth factor-induced gene",
       "locations": [
        {
         "offset": 561,
         "length": 39
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFBI",
       "locations": [
        {
         "offset": 602,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs121909210",
        "type": "SequenceVariant"
       },
       "text": "R124C",
       "locations": [
        {
         "offset": 654,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "6690",
        "type": "GeneOrGeneProduct"
       },
       "text": "PstI",
       "locations": [
        {
         "offset": 868,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lattice corneal dystrophy",
       "locations": [
        {
         "offset": 1065,
         "length": 25
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD1",
       "locations": [
        {
         "offset": 1122,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1408,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFBI",
       "locations": [
        {
         "offset": 1566,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs121909210",
        "type": "SequenceVariant"
       },
       "text": "C417T",
       "locations": [
        {
         "offset": 1641,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs121909210",
        "type": "SequenceVariant"
       },
       "text": "R124C",
       "locations": [
        {
         "offset": 1684,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGF-induced protein",
       "locations": [
        {
         "offset": 1706,
         "length": 19
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs121909210",
        "type": "SequenceVariant"
       },
       "text": "R124C",
       "locations": [
        {
         "offset": 1872,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "7045",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGFBI",
       "locations": [
        {
         "offset": 1890,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD type I",
       "locations": [
        {
         "offset": 1914,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C537881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LCD type I",
       "locations": [
        {
         "offset": 2005,
         "length": 10
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 2027,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "7045",
      "entity2": "C537881",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs121909210",
      "entity2": "C537881",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18772193",
   "passages": [
    {
     "offset": 0,
     "text": "Novel suppressors of alpha-synuclein toxicity identified using yeast.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6622",
        "type": "GeneOrGeneProduct"
       },
       "text": "alpha-synuclein",
       "locations": [
        {
         "offset": 21,
         "length": 15
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "toxicity",
       "locations": [
        {
         "offset": 37,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "4932",
        "type": "OrganismTaxon"
       },
       "text": "yeast",
       "locations": [
        {
         "offset": 63,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 70,
     "text": "The mechanism by which the Parkinson's disease-related protein alpha-synuclein (alpha-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from alpha-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing alpha-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking and the response to stress were identified. Five of the forty genes--ENT3, IDP3, JEM1, ARG2 and HSP82--ranked highest in their ability to block alpha-syn-induced reactive oxygen species accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of alpha-syn as judged by growth defects compared with wild-type cells expressing alpha-syn, which indicates that these genes protect cells from alpha-syn. Strikingly, four of the five genes are specific for alpha-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that alpha-syn causes toxicity to cells through a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes alpha-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of alpha-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Parkinson's disease",
       "locations": [
        {
         "offset": 97,
         "length": 19
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "6622",
        "type": "GeneOrGeneProduct"
       },
       "text": "alpha-synuclein",
       "locations": [
        {
         "offset": 133,
         "length": 15
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "6622",
        "type": "GeneOrGeneProduct"
       },
       "text": "alpha-syn",
       "locations": [
        {
         "offset": 150,
         "length": 9
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D019636",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurodegeneration",
       "locations": [
        {
         "offset": 168,
         "length": 17
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6622",
        "type": "GeneOrGeneProduct"
       },
       "text": "alpha-syn",
       "locations": [
        {
         "offset": 258,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "4932",
        "type": "OrganismTaxon"
       },
       "text": "yeast",
       "locations": [
        {
         "offset": 350,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "4932",
        "type": "OrganismTaxon"
       },
       "text": "Saccharomyces cerevisiae",
       "locations": [
        {
         "offset": 356,
         "length": 24
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "6622",
        "type": "GeneOrGeneProduct"
       },
       "text": "alpha-syn",
       "locations": [
        {
         "offset": 392,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
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  {
   "id": "19101703",
   "passages": [
    {
     "offset": 0,
     "text": "Study of a Taiwanese family with oculopharyngeal muscular dystrophy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D039141",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "oculopharyngeal muscular dystrophy",
       "locations": [
        {
         "offset": 33,
         "length": 34
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       ]
      }
     ]
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    {
     "offset": 69,
     "text": "BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. OPMD is caused by a short trinucleotide repeat expansion encoding an expanded polyalanine tract in the polyadenylate binding-protein nuclear 1 (PABPN1) gene. We identified and characterized a PABPN1 mutation in a Taiwanese family with OPMD. METHODS: The phenotypic and genotypic characteristics of all subjects were evaluated in a Taiwanese OPMD family. Genetic alterations in the PABPN1 gene were identified using PCR and DNA sequencing. RESULTS: Ten subjects with OPMD (6 symptomatic and 4 asymptomatic) within the Taiwanese family carried a novel mutation in the PABPN1 gene. The normal (GCG)6(GCA)3GCG sequence was replaced by (GCG)6(GCA)(GCG)4(GCA)3GCG due to an insertion of (GCG)4GCA into the normal allele in the Taiwanese OPMD subjects. CONCLUSIONS: In contrast to a single GCG expansion in most of OPMD patients in the literature, an insertion of (GCG)4GCA in the PABPN1 gene was found in the Taiwanese OPMD subjects. The identification of this mutation appears to support the molecular mechanism of unequal cross-over of two PABPN1 alleles.",
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      {
       "id": "1",
       "infons": {
        "identifier": "D039141",
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       "text": "Oculopharyngeal muscular dystrophy",
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       "id": "2",
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        "identifier": "D039141",
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        {
         "offset": 117,
         "length": 4
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       "id": "3",
       "infons": {
        "identifier": "D030342",
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       "text": "autosomal dominant muscle disorder",
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         "length": 34
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       "id": "4",
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         "offset": 175,
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       "text": "polyadenylate binding-protein nuclear 1",
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         "offset": 278,
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       "id": "7",
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        "identifier": "8106",
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       "text": "PABPN1",
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        {
         "offset": 319,
         "length": 6
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       ]
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       "id": "8",
       "infons": {
        "identifier": "8106",
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       "text": "PABPN1",
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         "offset": 367,
         "length": 6
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      {
       "id": "9",
       "infons": {
        "identifier": "D039141",
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       "text": "OPMD",
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        {
         "offset": 410,
         "length": 4
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      },
      {
       "id": "10",
       "infons": {
        "identifier": "D039141",
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       "text": "OPMD",
       "locations": [
        {
         "offset": 516,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "8106",
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       "text": "PABPN1",
       "locations": [
        {
         "offset": 556,
         "length": 6
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       "id": "12",
       "infons": {
        "identifier": "D039141",
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        {
         "offset": 641,
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       "id": "13",
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         "offset": 843,
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       "id": "16",
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        "identifier": "D039141",
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         "offset": 906,
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       "id": "17",
       "infons": {
        "identifier": "D039141",
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       "text": "OPMD",
       "locations": [
        {
         "offset": 983,
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       ]
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       "id": "18",
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       "text": "patients",
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         "offset": 988,
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       "id": "19",
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        "identifier": "c|INS|(GCG)4GCA",
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        {
         "offset": 1019,
         "length": 22
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       ]
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       "id": "20",
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        "identifier": "8106",
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        {
         "offset": 1049,
         "length": 6
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       "id": "21",
       "infons": {
        "identifier": "D039141",
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         "offset": 1088,
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       "id": "22",
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        "identifier": "8106",
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       "text": "PABPN1",
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         "offset": 1211,
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  {
   "id": "19536134",
   "passages": [
    {
     "offset": 0,
     "text": "TAK1 is an essential regulator of BMP signalling in cartilage.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "26409",
        "type": "GeneOrGeneProduct"
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       "text": "TAK1",
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         "offset": 0,
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        {
         "offset": 34,
         "length": 3
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    {
     "offset": 63,
     "text": "TGFbeta activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1(col2) mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.",
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       "text": "TAK1",
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         "offset": 91,
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       "id": "4",
       "infons": {
        "identifier": "26409",
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       "text": "MAPKKK",
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        {
         "offset": 114,
         "length": 6
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       "id": "5",
       "infons": {
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       "text": "TAK1",
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         "offset": 288,
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       "id": "6",
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       "text": "mice",
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         "offset": 320,
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       "id": "7",
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       "text": "Tak1",
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         "offset": 356,
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       "id": "8",
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       "text": "collagen 2",
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         "offset": 375,
         "length": 10
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       "id": "9",
       "infons": {
        "identifier": "26409",
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       "id": "32",
       "infons": {
        "identifier": "D007627",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "keloid disease",
       "locations": [
        {
         "offset": 2147,
         "length": 14
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      },
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       "id": "33",
       "infons": {
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       "text": "keloid disease",
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        {
         "offset": 2253,
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   "id": "21238926",
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    {
     "offset": 0,
     "text": "Brat promotes stem cell differentiation via control of a bistable switch that restricts BMP signaling.",
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       "id": "0",
       "infons": {
        "identifier": "35197",
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       "text": "Brat",
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         "offset": 88,
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     "offset": 103,
     "text": "Drosophila ovarian germline stem cells (GSCs) are maintained by Dpp signaling and the Pumilio (Pum) and Nanos (Nos) translational repressors. Upon division, Dpp signaling is extinguished, and Nos is downregulated in one daughter cell, causing it to switch to a differentiating cystoblast (CB). However, downstream effectors of Pum-Nos remain unknown, and how CBs lose their responsiveness to Dpp is unclear. Here, we identify Brain Tumor (Brat) as a potent differentiation factor and target of Pum-Nos regulation. Brat is excluded from GSCs by Pum-Nos but functions with Pum in CBs to translationally repress distinct targets, including the Mad and dMyc mRNAs. Regulation of both targets simultaneously lowers cellular responsiveness to Dpp signaling, forcing the cell to become refractory to the self-renewal signal. Mathematical modeling elucidates bistability of cell fate in the Brat-mediated system, revealing how autoregulation of GSC number can arise from Brat coupling extracellular Dpp regulation to intracellular interpretation.",
     "annotations": [
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       "id": "2",
       "infons": {
        "identifier": "7227",
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       "text": "Drosophila",
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       "id": "3",
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       "text": "Pumilio",
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         "offset": 189,
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       "text": "Pum",
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       "id": "6",
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       "text": "Nanos",
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       "text": "Nos",
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       "id": "8",
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       "text": "Dpp",
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         "offset": 260,
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       "id": "9",
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       "text": "Nos",
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       "id": "10",
       "infons": {
        "identifier": "41094",
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       "text": "Pum",
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         "offset": 430,
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       "id": "12",
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       "text": "Pum",
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         "offset": 1066,
         "length": 4
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        "identifier": "33432",
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   ]
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  {
   "id": "21904390",
   "passages": [
    {
     "offset": 0,
     "text": "Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5080",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAX6",
       "locations": [
        {
         "offset": 27,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 88,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 98,
     "text": "PURPOSE: Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6(PAX6) gene. The PAX6 gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6 gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations. PATIENTS AND METHODS: Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6 gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. RESULTS: By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6 gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C>G (p.Ser119fsX) were identified in the patients of the AN group. A novel missense mutation c.643T>C (p.S216P) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6 gene and DKFZ p686k1684 gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid. CONCLUSION: Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6 gene.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D015783",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Aniridia",
       "locations": [
        {
         "offset": 107,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D015783",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AN",
       "locations": [
        {
         "offset": 117,
         "length": 2
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital panocular disorder",
       "locations": [
        {
         "offset": 131,
         "length": 29
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "5080",
        "type": "GeneOrGeneProduct"
       },
       "text": "paired box homeotic gene 6",
       "locations": [
        {
         "offset": 192,
         "length": 26
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "5080",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAX6",
       "locations": [
        {
         "offset": 219,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "5080",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAX6",
       "locations": [
        {
         "offset": 235,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C537775",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anterior segment malformations",
       "locations": [
        {
         "offset": 271,
         "length": 30
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "C537884",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Peters anomaly",
       "locations": [
        {
         "offset": 312,
         "length": 14
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "5080",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAX6",
       "locations": [
        {
         "offset": 343,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D015783",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AN",
       "locations": [
        {
         "offset": 443,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "coloboma of iris and choroid",
       "locations": [
        {
         "offset": 447,
         "length": 28
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "C537775",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anterior segment malformations",
       "locations": [
        {
         "offset": 480,
         "length": 30
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "PATIENTS",
       "locations": [
        {
         "offset": 512,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 573,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "5080",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAX6",
       "locations": [
        {
         "offset": 753,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 965,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D015783",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AN",
       "locations": [
        {
         "offset": 1038,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D003103",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "coloboma of iris and choroids",
       "locations": [
        {
         "offset": 1042,
         "length": 29
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "C537775",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anterior segment malformations",
       "locations": [
        {
         "offset": 1081,
         "length": 30
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C537884",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "peters anomaly",
       "locations": [
        {
         "offset": 1122,
         "length": 14
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "5080",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAX6",
       "locations": [
        {
         "offset": 1156,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|SUB|C|357-3|G",
        "type": "SequenceVariant"
       },
       "text": "c.357-3C>G",
       "locations": [
        {
         "offset": 1249,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "p|FS|S|119||",
        "type": "SequenceVariant"
       },
       "text": "p.Ser119fsX",
       "locations": [
        {
         "offset": 1261,
         "length": 11
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1297,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
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    {
     "offset": 42,
     "text": "The antioxidant enzyme paraoxonase 1 (PON1) has previously been suggested to confer protection against coronary heart disease (CHD), one of the main causes of death in the Western world. Two coding polymorphisms, 55M/L and 192Q/R, and a promoter variant, -107C/T, has been extensively studied with respect to susceptibility to CHD. In this study, we have investigated the impact of these three polymorphisms on mortality using a sample of 1932 Danish individuals aged 47-93 years, previously used in gene-longevity studies. A cross-sectional study comparing the genotype distribution of the three polymorphisms separately as well as the haplotype distribution in different age groups did not reveal any difference. However, a longitudinal follow-up study on survival in the same sample indicated that 192RR homozygotes have a poorer survival compared to QQ homozygotes (hazard rate: 1.38, P = 0.04). We hereafter used an independent sample of 541 Danish individuals from the oldest cohort and confirmed the initial findings (hazard rate: 1.38, P = 0.09). In both samples, the effect was most pronounced in women. Using self-reported data on ischemic heart disease to evaluate the impact of the PON 192Q/R polymorphism on susceptibility to CHD, we found only a nonsignificant trend of 192RR homozygosity in women being a risk factor. Our results thus indicates that PON1 192RR homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "5444",
        "type": "GeneOrGeneProduct"
       },
       "text": "paraoxonase 1",
       "locations": [
        {
         "offset": 65,
         "length": 13
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "5444",
        "type": "GeneOrGeneProduct"
       },
       "text": "PON1",
       "locations": [
        {
         "offset": 80,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D003327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "coronary heart disease",
       "locations": [
        {
         "offset": 145,
         "length": 22
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D003327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CHD",
       "locations": [
        {
         "offset": 169,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D003643",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "death",
       "locations": [
        {
         "offset": 201,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "p|SUB|M|55|L",
        "type": "SequenceVariant"
       },
       "text": "55M/L",
       "locations": [
        {
         "offset": 255,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "p|SUB|Q|192|R",
        "type": "SequenceVariant"
       },
       "text": "192Q/R",
       "locations": [
        {
         "offset": 265,
         "length": 6
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|C|-107|T",
        "type": "SequenceVariant"
       },
       "text": "-107C/T",
       "locations": [
        {
         "offset": 297,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D003327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CHD",
       "locations": [
        {
         "offset": 369,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "p|Allele|R|192",
        "type": "SequenceVariant"
       },
       "text": "192RR",
       "locations": [
        {
         "offset": 843,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1148,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D017202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic heart disease",
       "locations": [
        {
         "offset": 1183,
         "length": 22
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "5444",
        "type": "GeneOrGeneProduct"
       },
       "text": "PON",
       "locations": [
        {
         "offset": 1236,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|SUB|Q|192|R",
        "type": "SequenceVariant"
       },
       "text": "192Q/R",
       "locations": [
        {
         "offset": 1240,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D003327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CHD",
       "locations": [
        {
         "offset": 1281,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "p|Allele|R|192",
        "type": "SequenceVariant"
       },
       "text": "192RR",
       "locations": [
        {
         "offset": 1326,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1348,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "5444",
        "type": "GeneOrGeneProduct"
       },
       "text": "PON1",
       "locations": [
        {
         "offset": 1407,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "p|Allele|R|192",
        "type": "SequenceVariant"
       },
       "text": "192RR",
       "locations": [
        {
         "offset": 1412,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1473,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D003327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CHD",
       "locations": [
        {
         "offset": 1563,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D003327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CHD",
       "locations": [
        {
         "offset": 1595,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D003327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CHD",
       "locations": [
        {
         "offset": 1644,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|C|-107|T",
      "entity2": "D003327",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "5444",
      "entity2": "D003327",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "p|Allele|R|192",
      "entity2": "D003327",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D017202",
      "entity2": "5444",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D017202",
      "entity2": "p|SUB|Q|192|R",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "p|SUB|Q|192|R",
      "entity2": "D003327",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "p|SUB|M|55|L",
      "entity2": "D003327",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17273972",
   "passages": [
    {
     "offset": 0,
     "text": "Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Human",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6899",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX1",
       "locations": [
        {
         "offset": 6,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "22q11.2 deletions",
       "locations": [
        {
         "offset": 88,
         "length": 17
        }
       ]
      }
     ]
    },
    {
     "offset": 107,
     "text": "Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Deletion 22q11.2 syndrome",
       "locations": [
        {
         "offset": 107,
         "length": 25
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "DiGeorge and Shprintzen (velocardiofacial) syndromes",
       "locations": [
        {
         "offset": 245,
         "length": 52
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "6899",
        "type": "GeneOrGeneProduct"
       },
       "text": "T-box transcription factor",
       "locations": [
        {
         "offset": 334,
         "length": 26
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "6899",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX1",
       "locations": [
        {
         "offset": 366,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6899",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX1",
       "locations": [
        {
         "offset": 454,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "22q11.2 deletion syndrome",
       "locations": [
        {
         "offset": 527,
         "length": 25
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs74315522",
        "type": "SequenceVariant"
       },
       "text": "H194Q",
       "locations": [
        {
         "offset": 749,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D004062",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Shprintzen syndrome",
       "locations": [
        {
         "offset": 778,
         "length": 19
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "6899",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBX1",
       "locations": [
        {
         "offset": 988,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs74315522",
      "entity2": "D004062",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "6899",
      "entity2": "D004062",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17959715",
   "passages": [
    {
     "offset": 0,
     "text": "Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4292",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLH1",
       "locations": [
        {
         "offset": 12,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 29,
         "length": 6
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D006689",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hodgkin lymphoma",
       "locations": [
        {
         "offset": 71,
         "length": 16
        }
       ]
      }
     ]
    },
    {
     "offset": 89,
     "text": "BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D006689",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hodgkin lymphoma",
       "locations": [
        {
         "offset": 172,
         "length": 16
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancers",
       "locations": [
        {
         "offset": 248,
         "length": 7
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Cytotoxicity",
       "locations": [
        {
         "offset": 257,
         "length": 12
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4292",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLH1",
       "locations": [
        {
         "offset": 363,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cytotoxic",
       "locations": [
        {
         "offset": 427,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "4292",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLH1",
       "locations": [
        {
         "offset": 614,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs1800734",
        "type": "SequenceVariant"
       },
       "text": "rs1800734",
       "locations": [
        {
         "offset": 634,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 666,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 718,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 741,
         "length": 6
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 806,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D007938",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myeloid leukaemia",
       "locations": [
        {
         "offset": 838,
         "length": 17
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 861,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D006689",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "primary Hodgkin lymphoma",
       "locations": [
        {
         "offset": 885,
         "length": 24
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "4292",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLH1",
       "locations": [
        {
         "offset": 960,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 1137,
         "length": 6
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "4292",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLH1",
       "locations": [
        {
         "offset": 1152,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "4292",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLH1",
       "locations": [
        {
         "offset": 1338,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1369,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D015470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "acute myeloid leukaemia",
       "locations": [
        {
         "offset": 1408,
         "length": 23
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D015470",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AML",
       "locations": [
        {
         "offset": 1435,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 1459,
         "length": 13
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D006689",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hodgkin lymphoma",
       "locations": [
        {
         "offset": 1524,
         "length": 16
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1553,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D015470",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "AML",
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        {
         "offset": 1603,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D001943",
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       "text": "breast cancer",
       "locations": [
        {
         "offset": 1623,
         "length": 13
        }
       ]
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       "id": "29",
       "infons": {
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       "text": "patients",
       "locations": [
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         "offset": 1637,
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       ]
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       "id": "30",
       "infons": {
        "identifier": "4292",
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       "text": "MLH1",
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         "offset": 1667,
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       "id": "31",
       "infons": {
        "identifier": "D015470",
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       "text": "AML",
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         "offset": 1722,
         "length": 3
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       "id": "32",
       "infons": {
        "identifier": "D015470",
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       "text": "AML",
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        {
         "offset": 1757,
         "length": 3
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       ]
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       "id": "33",
       "infons": {
        "identifier": "D015470",
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       "text": "AML",
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        {
         "offset": 1894,
         "length": 3
        }
       ]
      },
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       "id": "34",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1968,
         "length": 8
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "4292",
        "type": "GeneOrGeneProduct"
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       "text": "MLH1",
       "locations": [
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         "offset": 2138,
         "length": 4
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       ]
      },
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       "id": "36",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 2188,
         "length": 6
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D006689",
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       "text": "Hodgkin lymphoma",
       "locations": [
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         "offset": 2230,
         "length": 16
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     "id": "R3",
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    }
   ]
  },
  {
   "id": "18050247",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 64,
         "length": 28
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       ]
      }
     ]
    },
    {
     "offset": 152,
     "text": "OBJECTIVE: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. METHODS: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. RESULTS: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. CONCLUSION: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.",
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       "id": "1",
       "infons": {
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       "text": "systemic lupus erythematosus",
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       "id": "2",
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       "text": "SLE",
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       "id": "7",
       "infons": {
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       "text": "SLE",
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       "id": "8",
       "infons": {
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       "text": "SLE",
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       ]
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       "text": "N673S",
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         "offset": 1029,
         "length": 5
        }
       ]
      },
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       "id": "10",
       "infons": {
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       "text": "P-selectin",
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       "id": "11",
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       "text": "SELP",
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        }
       ]
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         "offset": 1104,
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        }
       ]
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       "id": "13",
       "infons": {
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       "text": "interleukin-1 receptor-associated kinase 1",
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        }
       ]
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       "id": "14",
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       "text": "IRAK1",
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       ]
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       "id": "15",
       "infons": {
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       "text": "SLE",
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       ]
      },
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       "id": "16",
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        "identifier": "355",
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       "text": "TNFRSF6",
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       ]
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       "id": "17",
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        "identifier": "355",
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       "text": "Fas",
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         "offset": 1531,
         "length": 3
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       ]
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       "id": "18",
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       "text": "IRF5",
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         "offset": 1540,
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       ]
      },
      {
       "id": "19",
       "infons": {
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       "text": "SLE",
       "locations": [
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       ]
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       "id": "20",
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       "id": "21",
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       "text": "IRAK1",
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       "id": "22",
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       "id": "23",
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       "text": "SLE",
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   ]
  },
  {
   "id": "18541230",
   "passages": [
    {
     "offset": 0,
     "text": "Protective effects of antithrombin on puromycin aminonucleoside nephrosis in rats.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000991",
        "type": "ChemicalEntity"
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       "text": "antithrombin",
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       "id": "1",
       "infons": {
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     ]
    },
    {
     "offset": 83,
     "text": "We investigated the effects of antithrombin, a plasma inhibitor of coagulation factors, in rats with puromycin aminonucleoside-induced nephrosis, which is an experimental model of human nephrotic syndrome. Antithrombin (50 or 500 IU/kg/i.v.) was administered to rats once a day for 10 days immediately after the injection of puromycin aminonucleoside (50 mg/kg/i.v.). Treatment with antithrombin attenuated the puromycin aminonucleoside-induced hematological abnormalities. Puromycin aminonucleoside-induced renal dysfunction and hyperlipidemia were also suppressed. Histopathological examination revealed severe renal damage such as proteinaceous casts in tubuli and tubular expansion in the kidney of control rats, while an improvement of the damage was seen in antithrombin-treated rats. In addition, antithrombin treatment markedly suppressed puromycin aminonucleoside-induced apoptosis of renal tubular epithelial cells. Furthermore, puromycin aminonucleoside-induced increases in renal cytokine content were also decreased. These findings suggest that thrombin plays an important role in the pathogenesis of puromycin aminonucleoside-induced nephrotic syndrome. Treatment with antithrombin may be clinically effective in patients with nephrotic syndrome.",
     "annotations": [
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       "id": "4",
       "infons": {
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       "text": "antithrombin",
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       "text": "puromycin aminonucleoside",
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       "text": "nephrosis",
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       "id": "8",
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       "text": "human",
       "locations": [
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      },
      {
       "id": "9",
       "infons": {
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       "text": "nephrotic syndrome",
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       ]
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      {
       "id": "10",
       "infons": {
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       "text": "Antithrombin",
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       "id": "11",
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       "text": "rats",
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       "id": "12",
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       "text": "puromycin aminonucleoside",
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       "text": "puromycin aminonucleoside",
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       "text": "hematological abnormalities",
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       "text": "Puromycin aminonucleoside",
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       "text": "renal dysfunction",
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       "text": "hyperlipidemia",
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       "id": "19",
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       "text": "renal damage",
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         "length": 12
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       "text": "rats",
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       "text": "rats",
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       "text": "puromycin aminonucleoside",
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       "text": "puromycin aminonucleoside",
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       "id": "26",
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       "text": "thrombin",
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        }
       ]
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       "id": "27",
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       "text": "puromycin aminonucleoside",
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        {
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         "length": 25
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       ]
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     "offset": 0,
     "text": "Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations.",
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       "id": "0",
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     "text": "Ovarian serous carcinoma (OSC) is the most common and lethal histologic type of ovarian epithelial malignancy. Mutations of TP53 and dysfunction of the Brca1 and/or Brca2 tumor-suppressor proteins have been implicated in the molecular pathogenesis of a large fraction of OSCs, but frequent somatic mutations in other well-established tumor-suppressor genes have not been identified. Using a genome-wide screen of DNA copy number alterations in 36 primary OSCs, we identified two tumors with apparent homozygous deletions of the NF1 gene. Subsequently, 18 ovarian carcinoma-derived cell lines and 41 primary OSCs were evaluated for NF1 alterations. Markedly reduced or absent expression of Nf1 protein was observed in 6 of the 18 cell lines, and using the protein truncation test and sequencing of cDNA and genomic DNA, NF1 mutations resulting in deletion of exons and/or aberrant splicing of NF1 transcripts were detected in 5 of the 6 cell lines with loss of NF1 expression. Similarly, NF1 alterations including homozygous deletions and splicing mutations were identified in 9 (22%) of 41 primary OSCs. As expected, tumors and cell lines with NF1 defects lacked mutations in KRAS or BRAF but showed Ras pathway activation based on immunohistochemical detection of phosphorylated MAPK (primary tumors) or increased levels of GTP-bound Ras (cell lines). The TP53 tumor-suppressor gene was mutated in all OSCs with documented NF1 mutation, suggesting that the pathways regulated by these two tumor-suppressor proteins often cooperate in the development of ovarian carcinomas with serous differentiation.",
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     "offset": 0,
     "text": "Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signaling.",
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     "text": "The melanocortin system is crucial to regulation of energy homeostasis. The melanocortin receptor type 4 (MC4R) modulates insulin signaling via effects on c-Jun N-terminal kinase (JNK). The melanocortin agonist NDP-MSH dose-dependently inhibited JNK activity in HEK293 cells stably expressing the human MC4R; effects were reversed by melanocortin receptor antagonist. NDP-MSH time- and dose-dependently inhibited IRS-1(ser307) phosphorylation, effects also reversed by a specific melanocortin receptor antagonist. NDP-MSH augmented insulin-stimulated AKT phosphorylation in vitro. The melanocortin agonist melanotan II increased insulin-stimulated AKT phosphorylation in the rat hypothalamus in vivo. NDP-MSH increased insulin-stimulated glucose uptake in hypothalamic GT1-1 cells. The current study shows that the melanocortinergic system interacts with insulin signaling via novel effects on JNK activity.",
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       "text": "convulsive seizures",
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       "text": "convulsive seizures",
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       "text": "Convulsive seizures",
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       "text": "postoperative complication",
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       "text": "tranexamic acid",
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  {
   "id": "26516699",
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    {
     "offset": 0,
     "text": "Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.",
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      {
       "id": "0",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "pancreatic cancer",
       "locations": [
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         "offset": 46,
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     "text": "Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets. ",
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       "text": "PC",
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       "id": "9",
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       "text": "PC",
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         "offset": 384,
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       "id": "10",
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       "text": "PC",
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       "text": "TARBP2",
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         "offset": 1700,
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     "offset": 0,
     "text": "DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival.",
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     "text": "Hematopoietic stem cells (HSCs) maintain blood cell production life-long by their unique abilities of self-renewal and differentiation into all blood cell lineages. Growth arrest and DNA-damage-inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell cycle control, cell death and senescence, as well as in DNA-damage repair. In general, GADD45A provides cellular stability by either arresting the cell cycle progression until DNA damage is repaired or, in cases of fatal damage, by inducing apoptosis. However, the function of GADD45A in hematopoiesis remains controversial. We revealed the changes in murine HSC fate control orchestrated by the expression of GADD45A at single cell resolution. In contrast to other cellular systems, GADD45A expression did not cause a cell cycle arrest or an alteration in the decision between cell survival and apoptosis in HSCs. Strikingly, GADD45A strongly induced and accelerated the differentiation program in HSCs. Continuous tracking of individual HSCs and their progeny via time-lapse microscopy elucidated that once GADD45A was expressed, HSCs differentiate into committed progenitors within 29 hours. GADD45A-expressing HSCs failed to long-term reconstitute the blood of recipients by inducing multilineage differentiation in vivo. Importantly, g-irradiation of HSCs induced their differentiation by upregulating endogenous GADD45A. The differentiation induction by GADD45A was transmitted by activating p38 Mitogen-activated protein kinase (MAPK) signaling and allowed the generation of megakaryocytic-erythroid, myeloid, and lymphoid lineages. These data indicate that genotoxic stress-induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system.",
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    {
     "offset": 0,
     "text": "Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2- and Tr1-biased T-cell immunity.",
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       "infons": {
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     "text": "Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatin-treated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-kappaB signaling pathways without altering the levels of TNF-alpha and IL-12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10-/- mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3+CD4+LAG-3+CD49b+CD25-Foxp3- Tr1 cells, that was significantly increased without altering the Foxp3+ regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonist-induced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system. ",
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       "text": "cisplatin",
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       "id": "41",
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       "text": "Angiotensin II",
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       "infons": {
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       "id": "49",
       "infons": {
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       "locations": [
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       "id": "50",
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        "identifier": "D008113",
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       "text": "liver metastasis",
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         "offset": 1585,
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       "text": "collagen",
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       "id": "53",
       "infons": {
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       "text": "AT1a",
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       "id": "54",
       "infons": {
        "identifier": "D008113",
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       "text": "liver metastasis",
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         "offset": 1767,
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       "id": "55",
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       "text": "TGF-b1",
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        {
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       "id": "56",
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       "text": "AT1a",
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   "id": "15983230",
   "passages": [
    {
     "offset": 0,
     "text": "Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6514",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLC2A2",
       "locations": [
        {
         "offset": 21,
         "length": 6
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       "id": "1",
       "infons": {
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       "text": "GLUT2",
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       "id": "2",
       "infons": {
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       "text": "impaired glucose tolerance",
       "locations": [
        {
         "offset": 81,
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       "id": "3",
       "infons": {
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 111,
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      },
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       "id": "4",
       "infons": {
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       "text": "Diabetes",
       "locations": [
        {
         "offset": 140,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 167,
     "text": "Impaired insulin secretion is a fundamental defect in type 2 diabetes. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study. With the exception of SLC2A2, other genes were not associated with the risk of type 2 diabetes. All four SNPs of SLC2A2 predicted the conversion to diabetes, and rs5393 (AA genotype) increased the risk of type 2 diabetes in the entire study population by threefold (odds ratio 3.04, 95% CI 1.34-6.88, P = 0.008). The risk for type 2 diabetes in the AA genotype carriers was increased in the control group (5.56 [1.78-17.39], P = 0.003) but not in the intervention group. We conclude that the SNPs of SLC2A2 predict the conversion to diabetes in obese subjects with IGT.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Impaired insulin secretion",
       "locations": [
        {
         "offset": 167,
         "length": 26
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 221,
         "length": 15
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       ]
      },
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       "id": "7",
       "infons": {
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       "text": "insulin",
       "locations": [
        {
         "offset": 350,
         "length": 7
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       ]
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      {
       "id": "8",
       "infons": {
        "identifier": "6514",
        "type": "GeneOrGeneProduct"
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       "text": "SLC2A2",
       "locations": [
        {
         "offset": 369,
         "length": 6
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       ]
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       "id": "9",
       "infons": {
        "identifier": "6514",
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       "text": "GLUT2",
       "locations": [
        {
         "offset": 386,
         "length": 5
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      {
       "id": "10",
       "infons": {
        "identifier": "2645",
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       "text": "GCK",
       "locations": [
        {
         "offset": 394,
         "length": 3
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "6927",
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       "text": "TCF1",
       "locations": [
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         "offset": 399,
         "length": 4
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       ]
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       "id": "12",
       "infons": {
        "identifier": "6927",
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       "text": "HNF-1alpha",
       "locations": [
        {
         "offset": 414,
         "length": 10
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       ]
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       "id": "13",
       "infons": {
        "identifier": "3172",
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       "text": "HNF4A",
       "locations": [
        {
         "offset": 427,
         "length": 5
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       "id": "14",
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        {
         "offset": 434,
         "length": 3
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       "id": "15",
       "infons": {
        "identifier": "2740",
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       "text": "GLP1R",
       "locations": [
        {
         "offset": 443,
         "length": 5
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D018149",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "impaired glucose tolerance",
       "locations": [
        {
         "offset": 490,
         "length": 26
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       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "D018149",
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       "text": "IGT",
       "locations": [
        {
         "offset": 518,
         "length": 3
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003924",
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 526,
         "length": 15
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       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Diabetes",
       "locations": [
        {
         "offset": 573,
         "length": 8
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "6514",
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       "text": "SLC2A2",
       "locations": [
        {
         "offset": 622,
         "length": 6
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 679,
         "length": 15
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       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "6514",
        "type": "GeneOrGeneProduct"
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       "text": "SLC2A2",
       "locations": [
        {
         "offset": 713,
         "length": 6
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       ]
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      {
       "id": "23",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "diabetes",
       "locations": [
        {
         "offset": 748,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs5393",
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       "locations": [
        {
         "offset": 762,
         "length": 6
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       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D003924",
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 805,
         "length": 15
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D003924",
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 926,
         "length": 15
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "6514",
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       },
       "text": "SLC2A2",
       "locations": [
        {
         "offset": 1100,
         "length": 6
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "diabetes",
       "locations": [
        {
         "offset": 1133,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D009765",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "obese",
       "locations": [
        {
         "offset": 1145,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D018149",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IGT",
       "locations": [
        {
         "offset": 1165,
         "length": 3
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       ]
      }
     ]
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   ],
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     "id": "R0",
     "infons": {
      "entity1": "rs5393",
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      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs5393",
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      "novel": "Novel"
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    {
     "id": "R2",
     "infons": {
      "entity1": "rs5393",
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    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs5393",
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    },
    {
     "id": "R4",
     "infons": {
      "entity1": "6514",
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     "infons": {
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      "novel": "No"
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    },
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     "id": "R9",
     "infons": {
      "entity1": "3630",
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      "novel": "No"
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     "infons": {
      "entity1": "3630",
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      "novel": "No"
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     "infons": {
      "entity1": "3630",
      "entity2": "3172",
      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R12",
     "infons": {
      "entity1": "3630",
      "entity2": "6927",
      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R13",
     "infons": {
      "entity1": "3630",
      "entity2": "2645",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "16412238",
   "passages": [
    {
     "offset": 0,
     "text": "Peroxisomal proliferator activated receptor-gamma deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3).",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5468",
        "type": "GeneOrGeneProduct"
       },
       "text": "Peroxisomal proliferator activated receptor-gamma",
       "locations": [
        {
         "offset": 0,
         "length": 49
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D052496",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "familial partial lipodystrophy type 3",
       "locations": [
        {
         "offset": 88,
         "length": 37
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D052496",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FPLD3",
       "locations": [
        {
         "offset": 127,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 135,
     "text": "BACKGROUND: Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-gamma. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. METHODS: We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. RESULTS: The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. CONCLUSION: Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-gamma deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D052496",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Familial partial lipodystrophy (Dunnigan) type 3",
       "locations": [
        {
         "offset": 147,
         "length": 48
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D052496",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FPLD3",
       "locations": [
        {
         "offset": 197,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D052496",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Mendelian Inheritance in Man [MIM] 604367",
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        {
         "offset": 204,
         "length": 41
        }
       ]
      },
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       "id": "6",
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       "text": "PPARG",
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         "offset": 286,
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        }
       ]
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       "id": "7",
       "infons": {
        "identifier": "5468",
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       "text": "peroxisomal proliferator-activated receptor-gamma",
       "locations": [
        {
         "offset": 301,
         "length": 49
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D052496",
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       },
       "text": "FPLD3",
       "locations": [
        {
         "offset": 480,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D007333",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "insulin resistance",
       "locations": [
        {
         "offset": 638,
         "length": 18
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes",
       "locations": [
        {
         "offset": 658,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D015228",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertriglyceridemia",
       "locations": [
        {
         "offset": 675,
         "length": 20
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D010195",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatitis",
       "locations": [
        {
         "offset": 710,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D014280",
        "type": "ChemicalEntity"
       },
       "text": "triglycerides",
       "locations": [
        {
         "offset": 805,
         "length": 13
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D002096",
        "type": "ChemicalEntity"
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       "text": "C-peptide",
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        {
         "offset": 823,
         "length": 9
        }
       ]
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       "id": "15",
       "infons": {
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        "type": "ChemicalEntity"
       },
       "text": "high-density lipoprotein cholesterol",
       "locations": [
        {
         "offset": 847,
         "length": 36
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "5468",
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       "text": "PPARG",
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        {
         "offset": 945,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|SUB|Y|355|X",
        "type": "SequenceVariant"
       },
       "text": "Y355X",
       "locations": [
        {
         "offset": 969,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1222,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "5468",
        "type": "GeneOrGeneProduct"
       },
       "text": "PPARG",
       "locations": [
        {
         "offset": 1228,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "5468",
        "type": "GeneOrGeneProduct"
       },
       "text": "PPAR-gamma",
       "locations": [
        {
         "offset": 1273,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D052496",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FPLD3",
       "locations": [
        {
         "offset": 1465,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
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     "infons": {
      "entity1": "D002096",
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    },
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      "entity1": "D052496",
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     "id": "R2",
     "infons": {
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      "novel": "No"
     }
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     "infons": {
      "entity1": "5468",
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      "novel": "No"
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     "infons": {
      "entity1": "5468",
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "5468",
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      "type": "Association",
      "novel": "No"
     }
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      "type": "Association",
      "novel": "No"
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    },
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     "infons": {
      "entity1": "D007333",
      "entity2": "p|SUB|Y|355|X",
      "type": "Association",
      "novel": "Novel"
     }
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     "id": "R8",
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      "entity1": "p|SUB|Y|355|X",
      "entity2": "D008076",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "p|SUB|Y|355|X",
      "entity2": "D010195",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "p|SUB|Y|355|X",
      "entity2": "D015228",
      "type": "Association",
      "novel": "Novel"
     }
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    {
     "id": "R11",
     "infons": {
      "entity1": "p|SUB|Y|355|X",
      "entity2": "D003920",
      "type": "Association",
      "novel": "Novel"
     }
    },
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     "infons": {
      "entity1": "p|SUB|Y|355|X",
      "entity2": "D014280",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18270997",
   "passages": [
    {
     "offset": 0,
     "text": "Catechol-O-methyltransferase (COMT) gene variants: possible association of the Val158Met variant with opiate addiction in Hispanic women.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1312",
        "type": "GeneOrGeneProduct"
       },
       "text": "Catechol-O-methyltransferase",
       "locations": [
        {
         "offset": 0,
         "length": 28
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "1312",
        "type": "GeneOrGeneProduct"
       },
       "text": "COMT",
       "locations": [
        {
         "offset": 30,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "rs4680",
        "type": "SequenceVariant"
       },
       "text": "Val158Met",
       "locations": [
        {
         "offset": 79,
         "length": 9
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009293",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "opiate addiction",
       "locations": [
        {
         "offset": 102,
         "length": 16
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 131,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 138,
     "text": "Catechol-O-methyltransferase (COMT) catalyzes the breakdown of catechol neurotransmitters, including dopamine, which plays a prominent role in drug reward. A common single nucleotide polymorphism (SNP), G472A, codes for a Val158Met substitution and results in a fourfold down regulation of enzyme activity. We sequenced exon IV of COMT gene in search for novel polymorphisms and then genotyped four out of five identified by direct sequencing, using TaqMan assay on 266 opioid-dependent and 173 control subjects. Genotype frequencies of the G472A SNP varied significantly (P = 0.029) among the three main ethnic/cultural groups (Caucasians, Hispanics, and African Americans). Using a genotype test, we found a trend to point-wise association (P = 0.053) of the G472A SNP in Hispanic subjects with opiate addiction. Further analysis of G472A genotypes in Hispanic subjects with data stratified by gender identified a point-wise significant (P = 0.049) association of G/A and A/A genotypes with opiate addiction in women, but not men. These point-wise significant results are not significant experiment-wise (at P < 0.05) after correction for multiple testing. No significant association was found with haplotypes of the three most common SNPs. Linkage disequilibrium patterns were similar for the three ethnic/cultural groups.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "1312",
        "type": "GeneOrGeneProduct"
       },
       "text": "Catechol-O-methyltransferase",
       "locations": [
        {
         "offset": 138,
         "length": 28
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1312",
        "type": "GeneOrGeneProduct"
       },
       "text": "COMT",
       "locations": [
        {
         "offset": 168,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D002395",
        "type": "ChemicalEntity"
       },
       "text": "catechol neurotransmitters",
       "locations": [
        {
         "offset": 201,
         "length": 26
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D004298",
        "type": "ChemicalEntity"
       },
       "text": "dopamine",
       "locations": [
        {
         "offset": 239,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs4680",
        "type": "SequenceVariant"
       },
       "text": "G472A",
       "locations": [
        {
         "offset": 341,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs4680",
        "type": "SequenceVariant"
       },
       "text": "Val158Met",
       "locations": [
        {
         "offset": 360,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1312",
        "type": "GeneOrGeneProduct"
       },
       "text": "COMT",
       "locations": [
        {
         "offset": 469,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D018847",
        "type": "ChemicalEntity"
       },
       "text": "opioid",
       "locations": [
        {
         "offset": 608,
         "length": 6
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs4680",
        "type": "SequenceVariant"
       },
       "text": "G472A",
       "locations": [
        {
         "offset": 679,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs4680",
        "type": "SequenceVariant"
       },
       "text": "G472A",
       "locations": [
        {
         "offset": 899,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D009293",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "opiate addiction",
       "locations": [
        {
         "offset": 935,
         "length": 16
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs4680",
        "type": "SequenceVariant"
       },
       "text": "G472A",
       "locations": [
        {
         "offset": 973,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D009293",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "opiate addiction",
       "locations": [
        {
         "offset": 1131,
         "length": 16
        }
       ]
      },
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       "id": "18",
       "infons": {
        "identifier": "9606",
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       },
       "text": "women",
       "locations": [
        {
         "offset": 1151,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 1166,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "infons": {
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      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "1312",
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      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
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     "id": "R2",
     "infons": {
      "entity1": "1312",
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      "novel": "No"
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    },
    {
     "id": "R3",
     "infons": {
      "entity1": "1312",
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      "novel": "Novel"
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    }
   ]
  },
  {
   "id": "18487244",
   "passages": [
    {
     "offset": 0,
     "text": "Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 59,
         "length": 8
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "POLG1",
       "locations": [
        {
         "offset": 73,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 130,
     "text": "We investigated clinical and cellular phenotypes of 24 children with mutations in the catalytic (alpha) subunit of the mitochondrial DNA (mtDNA) gamma polymerase (POLG1). Twenty-one had Alpers syndrome, the commonest severe POLG1 autosomal recessive phenotype, comprising hepatoencephalopathy and often mtDNA depletion. The cellular mtDNA content reflected the genotype more closely than did clinical features. Patients with tissue depletion of mtDNA all had at least one allele with either a missense mutation in a catalytic domain or a nonsense mutation. Four out of 12 patients exhibited a progressive, mosaic pattern of mtDNA depletion in cultured fibroblasts. All these patients had mutations in a catalytic domain in both POLG1 alleles, in either the polymerase or exonuclease domain or both. The tissue mtDNA content of patients who had two linker mutations was normal, and their phenotypes the mildest. Epilepsy and/or movement disorder were major features in all 21. Previous studies have implicated replication stalling as a mechanism for mtDNA depletion. The mosaic cellular depletion that we have demonstrated in cell cultures may be a manifestation of severe replication stalling. One patient with a severe cellular and clinical phenotype was a compound heterozygote with POLG1 mutations in the polymerase and exonuclease domain intrans. This suggests that POLG1 requires both polymerase and 3'-5' exonuclease activity in the same molecule. This is consistent with current functional models for eukaryotic DNA polymerases, which alternate between polymerizing and editing modes, as determined by competition between these two active sites for the 3' end of the DNA.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "mitochondrial DNA (mtDNA) gamma polymerase",
       "locations": [
        {
         "offset": 249,
         "length": 42
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "POLG1",
       "locations": [
        {
         "offset": 293,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D002549",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Alpers syndrome",
       "locations": [
        {
         "offset": 316,
         "length": 15
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "POLG1",
       "locations": [
        {
         "offset": 354,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C563797",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "hepatoencephalopathy",
       "locations": [
        {
         "offset": 402,
         "length": 20
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "Patients",
       "locations": [
        {
         "offset": 541,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 702,
         "length": 8
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 805,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "POLG1",
       "locations": [
        {
         "offset": 858,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 957,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Epilepsy",
       "locations": [
        {
         "offset": 1041,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D009069",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "movement disorder",
       "locations": [
        {
         "offset": 1057,
         "length": 17
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1328,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "POLG1",
       "locations": [
        {
         "offset": 1415,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "5428",
        "type": "GeneOrGeneProduct"
       },
       "text": "POLG1",
       "locations": [
        {
         "offset": 1500,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "5428",
      "entity2": "C563797",
      "type": "Association",
      "novel": "Novel"
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    {
     "id": "R1",
     "infons": {
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      "novel": "Novel"
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   ]
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   "id": "19037252",
   "passages": [
    {
     "offset": 0,
     "text": "Mutations in phospholipase C epsilon 1 are not sufficient to cause diffuse mesangial sclerosis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "phospholipase C epsilon 1",
       "locations": [
        {
         "offset": 13,
         "length": 25
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C537346",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diffuse mesangial sclerosis",
       "locations": [
        {
         "offset": 67,
         "length": 27
        }
       ]
      }
     ]
    },
    {
     "offset": 96,
     "text": "Diffuse mesangial sclerosis occurs as an isolated abnormality or as a part of a syndrome. Recently, mutations in phospholipase C epsilon 1 (PLCE1) were found to cause a nonsyndromic, autosomal recessive form of this disease. Here we describe three children from one consanguineous kindred of Pakistani origin with diffuse mesangial sclerosis who presented with congenital or infantile nephrotic syndrome. Homozygous mutations in PLCE1 (also known as KIAA1516, PLCE, or NPHS3) were identified following genome-wide mapping of single-nucleotide polymorphisms. All affected children were homozygous for a four-basepair deletion in exon 3, which created a premature translational stop codon. Analysis of the asymptomatic father of two of the children revealed that he was also homozygous for the same mutation. We conclude this nonpenetrance may be due to compensatory mutations at a second locus and that mutation within PLCE1 is not always sufficient to cause diffuse mesangial sclerosis.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "C537346",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Diffuse mesangial sclerosis",
       "locations": [
        {
         "offset": 96,
         "length": 27
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "phospholipase C epsilon 1",
       "locations": [
        {
         "offset": 209,
         "length": 25
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "PLCE1",
       "locations": [
        {
         "offset": 236,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C537346",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diffuse mesangial sclerosis",
       "locations": [
        {
         "offset": 410,
         "length": 27
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C535761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital or infantile nephrotic syndrome",
       "locations": [
        {
         "offset": 457,
         "length": 42
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "PLCE1",
       "locations": [
        {
         "offset": 525,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "KIAA1516",
       "locations": [
        {
         "offset": 546,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "PLCE",
       "locations": [
        {
         "offset": 556,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "NPHS3",
       "locations": [
        {
         "offset": 565,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|DEL||4",
        "type": "SequenceVariant"
       },
       "text": "four-basepair deletion",
       "locations": [
        {
         "offset": 698,
         "length": 22
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "51196",
        "type": "GeneOrGeneProduct"
       },
       "text": "PLCE1",
       "locations": [
        {
         "offset": 1014,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "C537346",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diffuse mesangial sclerosis",
       "locations": [
        {
         "offset": 1054,
         "length": 27
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "C537346",
      "entity2": "51196",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "C537346",
      "entity2": "c|DEL||4",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19707748",
   "passages": [
    {
     "offset": 0,
     "text": "Seizures associated with levofloxacin: case presentation and literature review.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D012640",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Seizures",
       "locations": [
        {
         "offset": 0,
         "length": 8
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D064704",
        "type": "ChemicalEntity"
       },
       "text": "levofloxacin",
       "locations": [
        {
         "offset": 25,
         "length": 12
        }
       ]
      }
     ]
    },
    {
     "offset": 80,
     "text": "PURPOSE: We present a case of a patient who developed seizures shortly after initiating treatment with levofloxacin and to discuss the potential drug-drug interactions related to the inhibition of cytochrome P450 (CYP) 1A2 in this case, as well as in other cases, of levofloxacin-induced seizures. METHODS: Several biomedical databases were searched including MEDLINE, Cochrane and Ovid. The main search terms utilized were case report and levofloxacin. The search was limited to studies published in English. RESULTS: Six cases of levofloxacin-induced seizures have been reported in the literature. Drug-drug interactions related to the inhibition of CYP1A2 by levofloxacin are likely involved in the clinical outcome of these cases. CONCLUSIONS: Clinicians are exhorted to pay close attention when initiating levofloxacin therapy in patients taking medications with epileptogenic properties that are CYP1A2 substrates.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 112,
         "length": 7
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D012640",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "seizures",
       "locations": [
        {
         "offset": 134,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D064704",
        "type": "ChemicalEntity"
       },
       "text": "levofloxacin",
       "locations": [
        {
         "offset": 183,
         "length": 12
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1544",
        "type": "GeneOrGeneProduct"
       },
       "text": "cytochrome P450 (CYP) 1A2",
       "locations": [
        {
         "offset": 277,
         "length": 25
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D064704",
        "type": "ChemicalEntity"
       },
       "text": "levofloxacin",
       "locations": [
        {
         "offset": 347,
         "length": 12
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D012640",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "seizures",
       "locations": [
        {
         "offset": 368,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D064704",
        "type": "ChemicalEntity"
       },
       "text": "levofloxacin",
       "locations": [
        {
         "offset": 520,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D064704",
        "type": "ChemicalEntity"
       },
       "text": "levofloxacin",
       "locations": [
        {
         "offset": 612,
         "length": 12
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D012640",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "seizures",
       "locations": [
        {
         "offset": 633,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1544",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP1A2",
       "locations": [
        {
         "offset": 732,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D064704",
        "type": "ChemicalEntity"
       },
       "text": "levofloxacin",
       "locations": [
        {
         "offset": 742,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D064704",
        "type": "ChemicalEntity"
       },
       "text": "levofloxacin",
       "locations": [
        {
         "offset": 891,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 915,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1544",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP1A2",
       "locations": [
        {
         "offset": 982,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1544",
      "entity2": "D064704",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D012640",
      "entity2": "D064704",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "20129423",
   "passages": [
    {
     "offset": 0,
     "text": "Fatal carbamazepine induced fulminant eosinophilic (hypersensitivity) myocarditis: emphasis on anatomical and histological characteristics, mechanisms and genetics of drug hypersensitivity and differential diagnosis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D002220",
        "type": "ChemicalEntity"
       },
       "text": "carbamazepine",
       "locations": [
        {
         "offset": 6,
         "length": 13
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D006967",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypersensitivity",
       "locations": [
        {
         "offset": 52,
         "length": 16
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D009205",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocarditis",
       "locations": [
        {
         "offset": 70,
         "length": 11
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D004342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drug hypersensitivity",
       "locations": [
        {
         "offset": 167,
         "length": 21
        }
       ]
      }
     ]
    },
    {
     "offset": 217,
     "text": "The most severe adverse reactions to carbamazepine have been observed in the haemopoietic system, the liver and the cardiovascular system. A frequently fatal, although exceptionally rare side effect of carbamazepine is necrotizing eosinophilic (hypersensitivity) myocarditis. We report a case of hypersensitivity myocarditis secondary to administration of carbamazepine. Acute hypersensitivity myocarditis was not suspected clinically, and the diagnosis was made post-mortem. Histology revealed diffuse infiltration of the myocardium by eosinophils and lymphocytes with myocyte damage. Clinically, death was due to cardiogenic shock. To best of our knowledge this is the second case of fatal carbamazepine induced myocarditis reported in English literature.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D002220",
        "type": "ChemicalEntity"
       },
       "text": "carbamazepine",
       "locations": [
        {
         "offset": 254,
         "length": 13
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D002220",
        "type": "ChemicalEntity"
       },
       "text": "carbamazepine",
       "locations": [
        {
         "offset": 419,
         "length": 13
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D006967",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypersensitivity",
       "locations": [
        {
         "offset": 462,
         "length": 16
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D009205",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocarditis",
       "locations": [
        {
         "offset": 480,
         "length": 11
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D006967",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypersensitivity",
       "locations": [
        {
         "offset": 513,
         "length": 16
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D009205",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocarditis",
       "locations": [
        {
         "offset": 530,
         "length": 11
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D002220",
        "type": "ChemicalEntity"
       },
       "text": "carbamazepine",
       "locations": [
        {
         "offset": 573,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D006967",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypersensitivity",
       "locations": [
        {
         "offset": 594,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D009205",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocarditis",
       "locations": [
        {
         "offset": 611,
         "length": 11
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003643",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "death",
       "locations": [
        {
         "offset": 815,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D012770",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiogenic shock",
       "locations": [
        {
         "offset": 832,
         "length": 17
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D002220",
        "type": "ChemicalEntity"
       },
       "text": "carbamazepine",
       "locations": [
        {
         "offset": 909,
         "length": 13
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D009205",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocarditis",
       "locations": [
        {
         "offset": 931,
         "length": 11
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D002220",
      "entity2": "D006967",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D002220",
      "entity2": "D009205",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "20651814",
   "passages": [
    {
     "offset": 0,
     "text": "Lack of association between ADRA2B-4825 gene insertion/deletion polymorphism and migraine in Chinese Han population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "151",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRA2B",
       "locations": [
        {
         "offset": 28,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|INDEL|-4825||",
        "type": "SequenceVariant"
       },
       "text": "-4825 gene insertion/deletion",
       "locations": [
        {
         "offset": 34,
         "length": 29
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 81,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 117,
     "text": "OBJECTIVE: The present study aimed to estimate the association between susceptibility to migraine and the 12-nucleotide insertion/deletion (indel) polymorphism in promoter region of alpha(2B)-adrenergic receptor gene (ADRA2B). METHODS: A case-control study was carried out in Chinese Han population, including 368 cases of migraine and 517 controls. Genomic DNA was extracted from blood samples, and DNA fragments containing the site of polymorphism were amplified by PCR. Data were adjusted for sex, age, migraine history and family history, and analyzed using a logistic regression model. RESULTS: There was no association between indel polymorphism and migraine, at either the allele or the genotype level. CONCLUSION: These findings do not support a functional significance of ADRA2B indel polymorphism at position -4825 relative to the start codon in the far upstream region of the promoter in the present migraine subjects.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 206,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "c|INDEL||12",
        "type": "SequenceVariant"
       },
       "text": "12-nucleotide insertion/deletion (indel)",
       "locations": [
        {
         "offset": 223,
         "length": 40
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "151",
        "type": "GeneOrGeneProduct"
       },
       "text": "alpha(2B)-adrenergic receptor",
       "locations": [
        {
         "offset": 299,
         "length": 29
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "151",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRA2B",
       "locations": [
        {
         "offset": 335,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 440,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 623,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 773,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "151",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADRA2B",
       "locations": [
        {
         "offset": 898,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|INDEL|-4825||",
        "type": "SequenceVariant"
       },
       "text": "indel polymorphism at position -4825",
       "locations": [
        {
         "offset": 905,
         "length": 36
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008881",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "migraine",
       "locations": [
        {
         "offset": 1028,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": []
  },
  {
   "id": "21325775",
   "passages": [
    {
     "offset": 0,
     "text": "A novel apolipoprotein E mutation, ApoE Osaka (Arg158 Pro), in a dyslipidemic patient with lipoprotein glomerulopathy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apolipoprotein E",
       "locations": [
        {
         "offset": 8,
         "length": 16
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "ApoE",
       "locations": [
        {
         "offset": 35,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "p|SUB|R|158|P",
        "type": "SequenceVariant"
       },
       "text": "Arg158 Pro",
       "locations": [
        {
         "offset": 47,
         "length": 10
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D050171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyslipidemic",
       "locations": [
        {
         "offset": 65,
         "length": 12
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 78,
         "length": 7
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lipoprotein glomerulopathy",
       "locations": [
        {
         "offset": 91,
         "length": 26
        }
       ]
      }
     ]
    },
    {
     "offset": 119,
     "text": "Lipoprotein glomerulopathy (LPG) is a rare disease characterized by the presence of thrombuslike deposition in markedly dilated glomerular capillaries and is often accompanied by an increased serum apolipoprotein E (apoE) level. Several gene mutations of apoE have been reported to be associated with LPG. In the current study, we report an LPG patient with a novel apoE mutation, apoE Osaka. The patient was a 45-year-old man who was hospitalized due to nephrotic syndrome. Light and electron microscopic observations of renal biopsy clearly showed characteristic findings of LPG, including lamellate thrombi in the lumen of dilated glomerular capillaries. His apoE phenotype was apoE3/2 and he had mild dyslipidemia with a mid-band on polyacrylamide gel electrophoresis. It is intriguing that the serum apoE level was within normal limits. We determined the sequence of the apoE gene using direct sequencing of the polymerase chain reaction (PCR) products. ApoE gene analysis showed a nucleotide substitution of G to C at codon 158 of exon 4. This mutation denoted an amino acid substitution of arginine residue for the proline residue at position 158 of apoE. The result of PCR associated with restriction fragment length polymorphism analysis also suggested that this mutation is heterozygous. It is possible that apoE Osaka mutation causes a conformational change of apoE protein and affects the interaction between abnormal apoE-containing lipoproteins and the endothelial cells of glomerular capillaries. The precise mechanism of LPG related with apoE Osaka, however, remains to be elucidated.",
     "annotations": [
      {
       "id": "6",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Lipoprotein glomerulopathy",
       "locations": [
        {
         "offset": 119,
         "length": 26
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 147,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apolipoprotein E",
       "locations": [
        {
         "offset": 317,
         "length": 16
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 335,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 374,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 420,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 460,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 464,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 485,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 500,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 516,
         "length": 7
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "man",
       "locations": [
        {
         "offset": 542,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009404",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nephrotic syndrome",
       "locations": [
        {
         "offset": 574,
         "length": 18
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 696,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D013927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lamellate thrombi",
       "locations": [
        {
         "offset": 711,
         "length": 17
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 781,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE3/2",
       "locations": [
        {
         "offset": 800,
         "length": 7
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D050171",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyslipidemia",
       "locations": [
        {
         "offset": 824,
         "length": 12
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "-",
        "type": "ChemicalEntity"
       },
       "text": "polyacrylamide",
       "locations": [
        {
         "offset": 856,
         "length": 14
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 924,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 995,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "ApoE",
       "locations": [
        {
         "offset": 1078,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "c|SUB|G|CODON158|C",
        "type": "SequenceVariant"
       },
       "text": "G to C at codon 158",
       "locations": [
        {
         "offset": 1133,
         "length": 19
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "p|SUB|R|158|P",
        "type": "SequenceVariant"
       },
       "text": "arginine residue for the proline residue at position 158",
       "locations": [
        {
         "offset": 1216,
         "length": 56
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1276,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1437,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1491,
         "length": 4
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1549,
         "length": 4
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 1656,
         "length": 3
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1673,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|G|CODON158|C",
      "entity2": "C567089",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "C567089",
      "entity2": "p|SUB|R|158|P",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "C567089",
      "entity2": "348",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D050171",
      "entity2": "p|SUB|R|158|P",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "348",
      "entity2": "D050171",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "21699520",
   "passages": [
    {
     "offset": 0,
     "text": "PTCH1 gene mutations in exon 17 and loss of heterozygosity on D9S180 microsatellite in sporadic and inherited human basal cell carcinomas.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5727",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH1",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 110,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "basal cell carcinomas",
       "locations": [
        {
         "offset": 116,
         "length": 21
        }
       ]
      }
     ]
    },
    {
     "offset": 139,
     "text": "BACKGROUND: Basal cell carcinomas (BCCs) are the most frequent human cancer that results from malignant transformation of basal cells in the epidermis. Gorlin syndrome is a rare inherited autosomal dominant disease that predisposes with multiple BCCs and other birth defects. Both sporadic and inherited BCCs are associated with mutations in the tumor suppressor gene PTCH1, but there is still uncertainty on the role of its homolog PTCH2. OBJECTIVES: To search for mutations and genomic instability in sporadic and inherited BCCs. METHODS: DNA obtained from leukocytes and tumor cells was amplified by polymerase chain reaction regarding five exons of PTCH1 and PTCH2 and neighboring microsatellites. Exons were sequenced and compared with the GenBank database. RESULTS: Only D9S180, of six microsatellites, showed loss of heterozygosity in three BCCs (two sporadic and one inherited). One sporadic BCC presented the mutation g.2885G>C in exon 17 of PTCH1, which predicts the substitution p.R962T in an external domain of the protein. In addition, the leukocytes and tumor cells of one patient with Gorlin syndrome showed the mutation g.2839T>G in the same exon and gene, which predicts a p.E947stop and truncated protein. All control and tumor samples presented IVS9 + 217T in intron 9 of PTCH1. CONCLUSION: Mutations found in the PTCH1 gene and neighboring repetitive sequences may have contributed to the development of the studied BCCs.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Basal cell carcinomas",
       "locations": [
        {
         "offset": 151,
         "length": 21
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCCs",
       "locations": [
        {
         "offset": 174,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 202,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 208,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001478",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Gorlin syndrome",
       "locations": [
        {
         "offset": 291,
         "length": 15
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inherited autosomal dominant disease",
       "locations": [
        {
         "offset": 317,
         "length": 36
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCCs",
       "locations": [
        {
         "offset": 385,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "birth defects",
       "locations": [
        {
         "offset": 400,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCCs",
       "locations": [
        {
         "offset": 443,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 485,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "5727",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH1",
       "locations": [
        {
         "offset": 507,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "8643",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH2",
       "locations": [
        {
         "offset": 572,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCCs",
       "locations": [
        {
         "offset": 665,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 713,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "5727",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH1",
       "locations": [
        {
         "offset": 792,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "8643",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH2",
       "locations": [
        {
         "offset": 802,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCCs",
       "locations": [
        {
         "offset": 987,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCC",
       "locations": [
        {
         "offset": 1039,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "g|SUB|G|2885|C",
        "type": "SequenceVariant"
       },
       "text": "g.2885G>C",
       "locations": [
        {
         "offset": 1066,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "5727",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH1",
       "locations": [
        {
         "offset": 1090,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "p|SUB|R|962|T",
        "type": "SequenceVariant"
       },
       "text": "p.R962T",
       "locations": [
        {
         "offset": 1129,
         "length": 7
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1207,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1226,
         "length": 7
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D001478",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Gorlin syndrome",
       "locations": [
        {
         "offset": 1239,
         "length": 15
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "g|SUB|T|2839|G",
        "type": "SequenceVariant"
       },
       "text": "g.2839T>G",
       "locations": [
        {
         "offset": 1275,
         "length": 9
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "p|SUB|E|947|X",
        "type": "SequenceVariant"
       },
       "text": "p.E947stop",
       "locations": [
        {
         "offset": 1329,
         "length": 10
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1379,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "c|Allele|T|IVS9+217",
        "type": "SequenceVariant"
       },
       "text": "IVS9 + 217T",
       "locations": [
        {
         "offset": 1403,
         "length": 11
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "5727",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH1",
       "locations": [
        {
         "offset": 1430,
         "length": 5
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "5727",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTCH1",
       "locations": [
        {
         "offset": 1472,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D002280",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCCs",
       "locations": [
        {
         "offset": 1575,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D001478",
      "entity2": "p|SUB|E|947|X",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D001478",
      "entity2": "g|SUB|T|2839|G",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D001478",
      "entity2": "5727",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D002280",
      "entity2": "p|SUB|R|962|T",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D002280",
      "entity2": "g|SUB|G|2885|C",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D002280",
      "entity2": "5727",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
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     "offset": 0,
     "text": "Novel compound heterozygous mutation of MLYCD in a Chinese patient with malonic aciduria.",
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     "text": "A 3-year-old Chinese boy presented with prominent clinical features of malonic aciduria, including developmental delay, short stature, brain abnormalities and massive excretion of malonic acid and methylmalonic acid. Molecular characterization by DNA sequencing analysis and multiplex ligation-dependent probe amplification of the MLYCD gene revealed a heterozygous mutation (c.920T>G, p.Leu307Arg) in the patient and his father and a heterozygous deletion comprising exon 1 in the patient and his mother. The missense mutation (c.920T>G) was not found in 100 healthy controls and has not been reported previously. Our findings expand the number of reported cases and add a novel entry to the repertoire of MLYCD mutations.",
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   "id": "25218136",
   "passages": [
    {
     "offset": 0,
     "text": "Sepsis-induced changes in amino acid transporters and leucine signaling via mTOR in skeletal muscle.",
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      {
       "id": "0",
       "infons": {
        "identifier": "D018805",
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       "text": "Sepsis",
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       "id": "1",
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       "text": "amino acid transporters",
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     "text": "The present study tested the hypothesis that sepsis-induced leucine (Leu) resistance in skeletal muscle is associated with a down-regulation of amino acid transporters important in regulating Leu flux or an impairment in the formation of the Leu-sensitive mTOR-Ragulator complex. Sepsis in adult male rats decreased basal protein synthesis in gastrocnemius, associated with a reduction in mTOR activation as indicated by decreased 4E-BP1 and S6K1 phosphorylation. The ability of oral Leu to increase protein synthesis and mTOR kinase after 1 h was largely prevented in sepsis. Sepsis increased CAT1, LAT2 and SNAT2 mRNA content two- to fourfold, but only the protein content for CAT1 (20 % decrease) differed significantly. Conversely, sepsis decreased the proton-assisted amino acid transporter (PAT)-2 mRNA by 60 %, but without a coordinate change in PAT2 protein. There was no sepsis or Leu effect on the protein content for RagA-D, LAMTOR-1 and -2, raptor, Rheb or mTOR in muscle. The binding of mTOR, PRAS40 and RagC to raptor did not differ for control and septic muscle in the basal condition; however, the Leu-induced decrease in PRAS40 raptor and increase in RagC raptor seen in control muscle was absent in sepsis. The intracellular Leu concentration was increased in septic muscle, compared to basal control conditions, and oral Leu further increased the intracellular Leu concentration similarly in both control and septic rats. Hence, while alterations in select amino acid transporters are not associated with development of sepsis-induced Leu resistance, the Leu-stimulated binding of raptor with RagC and the recruitment of mTOR/raptor to the endosome-lysosomal compartment may partially explain the inability of Leu to fully activate mTOR and muscle protein synthesis.",
     "annotations": [
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       "id": "4",
       "infons": {
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       "text": "sepsis",
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       "text": "amino acid transporters",
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       "text": "Leu",
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       "text": "Leu",
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       "id": "10",
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       "text": "mTOR",
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       "id": "11",
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       "text": "Ragulator complex",
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       "text": "CAT1",
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         "offset": 695,
         "length": 4
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       "text": "proton-assisted amino acid transporter (PAT)-2",
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       "text": "PAT2",
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       "infons": {
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       "text": "sepsis",
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       "text": "Leu",
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       "id": "32",
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       "text": "raptor",
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       "id": "34",
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       "text": "mTOR",
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       "infons": {
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       "text": "RagC",
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         "length": 4
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       ]
      },
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       "id": "38",
       "infons": {
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       "text": "raptor",
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       "text": "raptor",
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       "text": "RagC",
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      {
       "id": "43",
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       "text": "raptor",
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      {
       "id": "44",
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       "text": "Leu",
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     "offset": 0,
     "text": "Star-PAP, a poly(A) polymerase, functions as a tumor suppressor in an orthotopic human breast cancer model.",
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     "text": "Star-PAP is a noncanonical poly(A) polymerase and required for the expression of a select set of mRNAs. However, the pathological role of Star-PAP in cancer largely remains unknown. In this study, we observed decreased expression of Star-PAP in breast cancer cell lines and tissues. Ectopic Star-PAP expression inhibited proliferation as well as colony-forming ability of breast cancer cells. In breast cancer patients, high levels of Star-PAP correlated with an improved prognosis. Moreover, by regulating the expression of BIK (BCL2-interacting killer), Star-PAP induced apoptosis of breast cancer cells through the mitochondrial pathway. The growth of breast cancer xenografts in NOD/SCID mice was also inhibited by the doxycycline-induced Star-PAP overexpression. Furthermore, Star-PAP sensitized breast cancer cells to chemotherapy drugs both in vitro and in vivo. In mammary epithelial cells, Star-PAP knockdown partially transformed these cells and induced them to undergo epithelial-mesenchymal transition (EMT). These findings suggested that Star-PAP possesses tumor-suppressing activity and can be a valuable target for developing new cancer therapeutic strategies.",
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   "id": "15200408",
   "passages": [
    {
     "offset": 0,
     "text": "Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
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       "id": "1",
       "infons": {
        "identifier": "11045,7380",
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       "text": "uroplakin",
       "locations": [
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       "id": "2",
       "infons": {
        "identifier": "C564042",
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       "text": "vesicoureteral reflux",
       "locations": [
        {
         "offset": 54,
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     ]
    },
    {
     "offset": 117,
     "text": "BACKGROUND: Primary vesicoureteral reflux (VUR) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. It affects about 1% of the young children and is thus one of the most common hereditary diseases. Its associated nephropathy is an important cause of end-stage renal failure in children and adults. Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis. METHODS: To begin to determine whether mutations in UP genes might play a role in human VUR, we genotyped all four UP genes in 76 patients with radiologically proven primary VUR by polymerase chain reaction (PCR) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences. RESULTS: Eighteen single nucleotide polymorphisms (SNPs) were identified, seven of which were missense, with no truncation or frame shift mutations. Since healthy relatives of the VUR probands are not reliable negative controls for VUR, we used a population of 90 race-matched, healthy individuals, unrelated to the VUR patients, as controls to perform an association study. Most of the SNPs were not found to be significantly associated with VUR. However, SNP1 of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP III affecting a C to G conversion and a Pro154Ala change, were marginally associated with VUR (both P= 0.08). Studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of UP III SNP7 in VUR (P= 0.036 adjusted for both subsets of cases vs. controls). CONCLUSION: Such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans.",
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       "infons": {
        "identifier": "C564042",
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       "text": "vesicoureteral reflux",
       "locations": [
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       "id": "4",
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       "text": "VUR",
       "locations": [
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       "text": "hereditary disorder",
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       "text": "hereditary diseases",
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       "text": "nephropathy",
       "locations": [
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         "offset": 379,
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       "id": "8",
       "infons": {
        "identifier": "D007676",
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       "text": "end-stage renal failure",
       "locations": [
        {
         "offset": 416,
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       "id": "9",
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       "text": "mouse",
       "locations": [
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         "offset": 513,
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       "id": "10",
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       "text": "uroplakin (UP) III",
       "locations": [
        {
         "offset": 519,
         "length": 18
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C564042",
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       "text": "VUR",
       "locations": [
        {
         "offset": 647,
         "length": 3
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D006869",
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       "text": "hydronephrosis",
       "locations": [
        {
         "offset": 655,
         "length": 14
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "11045,7380",
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       "text": "UP",
       "locations": [
        {
         "offset": 723,
         "length": 2
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
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       "text": "human",
       "locations": [
        {
         "offset": 753,
         "length": 5
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       ]
      },
      {
       "id": "15",
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   "id": "18000905",
   "passages": [
    {
     "offset": 0,
     "text": "Regional analysis on the occurrence of oral clefts in South America.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "oral clefts",
       "locations": [
        {
         "offset": 39,
         "length": 11
        }
       ]
      }
     ]
    },
    {
     "offset": 69,
     "text": "The aim of this work was to search for unequal birth prevalence rates (BPRs) of cleft lip +/- cleft palate (CL/P), and cleft palate only (CPO), among different geographic areas in South America, and to analyze phenotypic characteristics and associated risk factors in each identified cluster. Included were 5,128 CL/P cases, 1,745 CPO cases, and 3,712 controls (like-sexed, non-malformed liveborn infant, born immediately after a malformed one, in the same hospital), over 4,199,630 consecutive births. They were ascertained between 1967 and 2004, in 190 maternity hospitals of the ECLAMC (Estudio Colaborativo Latinoamericano de Malformaciones Congenitas) network, in 102 cities of all 10 South American countries. Non-predefined geographical areas with significantly unusual cleft BPRs were identified with Kulldorf and Nagarwalla's spatial scan statistic, employing number of cases and births, and exact location of each hospital. Expected values were cleft BPRs registered for the entire ECLAMC hospital network. Syndromic and non-syndromic clefts were considered for cluster analysis, and phenotypic characterization, while only non-syndromic for risk factor analysis. Seven clusters for CL/P, and four for CPO, with unusual BPRs were identified. CL/P cases in high BPR areas were more severe than elsewhere in the sample, similar to a previous ECLAMC report on microtia. For CL/P, high BPR clusters were associated with high altitude above sea level, Amerindian ancestry, and low socioeconomic strata; low BPR clusters showed association with African Black ancestry. Advanced maternal age, a recognized risk factor for CPO, was also associated with the only identified geographic cluster for CPO.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D002971",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cleft lip",
       "locations": [
        {
         "offset": 149,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cleft palate",
       "locations": [
        {
         "offset": 163,
         "length": 12
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D002971,D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CL/P",
       "locations": [
        {
         "offset": 177,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cleft palate",
       "locations": [
        {
         "offset": 188,
         "length": 12
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CPO",
       "locations": [
        {
         "offset": 207,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002971,D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CL/P",
       "locations": [
        {
         "offset": 382,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CPO",
       "locations": [
        {
         "offset": 400,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D002971,D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "clefts",
       "locations": [
        {
         "offset": 1114,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D002971,D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CL/P",
       "locations": [
        {
         "offset": 1262,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CPO",
       "locations": [
        {
         "offset": 1281,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D002971,D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CL/P",
       "locations": [
        {
         "offset": 1321,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D065817",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microtia",
       "locations": [
        {
         "offset": 1436,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D002971,D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CL/P",
       "locations": [
        {
         "offset": 1450,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CPO",
       "locations": [
        {
         "offset": 1694,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CPO",
       "locations": [
        {
         "offset": 1767,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": []
  },
  {
   "id": "18397285",
   "passages": [
    {
     "offset": 0,
     "text": "L1503R is a member of group I mutation and has dominant-negative effect on secretion of full-length VWF multimers: an analysis of two patients with type 2A von Willebrand disease.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs61750097",
        "type": "SequenceVariant"
       },
       "text": "L1503R",
       "locations": [
        {
         "offset": 0,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 100,
         "length": 3
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 134,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D056728",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2A von Willebrand disease",
       "locations": [
        {
         "offset": 148,
         "length": 30
        }
       ]
      }
     ]
    },
    {
     "offset": 180,
     "text": "Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF); this in turn is associated with an absence of high-molecular-weight multimers. Sequence analysis of the VWF gene from two unrelated type 2A VWD patients showed an identical, novel, heterozygous T-->G transversion at nucleotide 4508, resulting in the substitution of L1503R in the VWF A2 domain. This substitution, which was not found in 60 unrelated normal individuals, was introduced into a full-length VWF cDNA and subsequently expressed in 293T cells. Only trace amount of the mutant VWF protein was secreted but most of the same was retained in 293T cells. Co-transfection experiment of both wild-type and mutant plasmids indicated the dominant-negative mechanism of disease development; as more of mutant DNA was transfected, VWF secretion was impaired in the media, whereas more of VWF was stored in the cell lysates. Molecular dynamic simulations of structural changes induced by L1503R indicated that the mean value of all-atom root-mean-squared-deviation was shifted from those with wild type or another mutation L1503Q that has been reported to be a group II mutation, which is susceptible to ADAMTS13 proteolysis. Protein instability of L1503R may be responsible for its intracellular retention and perhaps the larger VWF multimers, containing more mutant VWF subunits, are likely to be mal-processed and retained within the cell.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D056728",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Type 2A von Willebrand disease",
       "locations": [
        {
         "offset": 180,
         "length": 30
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D014842",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VWD",
       "locations": [
        {
         "offset": 212,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "von Willebrand factor",
       "locations": [
        {
         "offset": 278,
         "length": 21
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 301,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 411,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D056728",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2A VWD",
       "locations": [
        {
         "offset": 439,
         "length": 11
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 451,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs61750097",
        "type": "SequenceVariant"
       },
       "text": "T-->G transversion at nucleotide 4508",
       "locations": [
        {
         "offset": 501,
         "length": 37
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs61750097",
        "type": "SequenceVariant"
       },
       "text": "L1503R",
       "locations": [
        {
         "offset": 573,
         "length": 6
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 587,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 711,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "CVCL_0063",
        "type": "CellLine"
       },
       "text": "293T",
       "locations": [
        {
         "offset": 750,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 794,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "CVCL_0063",
        "type": "CellLine"
       },
       "text": "293T",
       "locations": [
        {
         "offset": 856,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 1038,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 1095,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs61750097",
        "type": "SequenceVariant"
       },
       "text": "L1503R",
       "locations": [
        {
         "offset": 1194,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs61750097",
        "type": "SequenceVariant"
       },
       "text": "L1503Q",
       "locations": [
        {
         "offset": 1329,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "11093",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADAMTS13",
       "locations": [
        {
         "offset": 1410,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs61750097",
        "type": "SequenceVariant"
       },
       "text": "L1503R",
       "locations": [
        {
         "offset": 1455,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 1536,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 1574,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "11093",
      "entity2": "7450",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D056728",
      "entity2": "7450",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs61750097",
      "entity2": "D056728",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18790087",
   "passages": [
    {
     "offset": 0,
     "text": "Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "11676",
        "type": "OrganismTaxon"
       },
       "text": "HIV-1",
       "locations": [
        {
         "offset": 44,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 60,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "Delta32",
       "locations": [
        {
         "offset": 65,
         "length": 7
        }
       ]
      }
     ]
    },
    {
     "offset": 161,
     "text": "We studied the possible effects of the expansion of ancient Mediterranean civilizations during the five centuries before and after Christ on the European distribution of the mutant allele for the chemokine receptor gene CCR5 which has a 32-bp deletion (CCR5-Delta32). There is a strong evidence for the unitary origin of the CCR5-Delta32 mutation, this it is found principally in Europe and Western Asia, with generally a north-south downhill cline frequency. Homozygous carriers of this mutation show a resistance to HIV-1 infection and a slower progression towards AIDS. However, HIV has clearly emerged too recently to have been the selective force on CCR5. Our analyses showed strong negative correlations in Europe between the allele frequency and two historical parameters, i.e. the first colonization dates by the great ancient Mediterranean civilizations, and the distances from the Northern frontiers of the Roman Empire in its greatest expansion. Moreover, other studies have shown that the deletion frequencies in both German Bronze Age and Swedish Neolithic populations were similar to those found in the corresponding modern populations, and this deletion has been found in ancient DNA of around 7000 years ago, suggesting that in the past, the deletion frequency could have been relatively high in European populations. In addition, in West Nile virus pathogenesis, CCR5 plays an antimicrobial role showing that host genetic factors are highly pathogen-specific. Our results added to all these previous data suggest that the actual European allele frequency distribution might not be due to genes spreading, but to a negative selection resulting in the spread of pathogens principally during Roman expansion. Indeed, as gene flows from colonizers to European native populations were extremely low, the mutational changes might be associated with vulnerability to imported infections. To date, the nature of the parasites remains unknown; however, zoonoses could be incriminated.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "chemokine receptor",
       "locations": [
        {
         "offset": 357,
         "length": 18
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 381,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "32-bp deletion",
       "locations": [
        {
         "offset": 398,
         "length": 14
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 414,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "Delta32",
       "locations": [
        {
         "offset": 419,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 486,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "Delta32",
       "locations": [
        {
         "offset": 491,
         "length": 7
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D015658",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HIV-1 infection",
       "locations": [
        {
         "offset": 679,
         "length": 15
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D000163",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AIDS",
       "locations": [
        {
         "offset": 728,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "11676",
        "type": "OrganismTaxon"
       },
       "text": "HIV",
       "locations": [
        {
         "offset": 743,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 816,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "11082",
        "type": "OrganismTaxon"
       },
       "text": "West Nile virus",
       "locations": [
        {
         "offset": 1511,
         "length": 15
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 1541,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D007239",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "infections",
       "locations": [
        {
         "offset": 2047,
         "length": 10
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|DEL||32",
      "entity2": "D000163",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|DEL||32",
      "entity2": "D015658",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "1234",
      "entity2": "D000163",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "1234",
      "entity2": "D015658",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "20401977",
   "passages": [
    {
     "offset": 0,
     "text": "The human AHR: identification of single nucleotide polymorphisms from six ethnic populations.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 4,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "196",
        "type": "GeneOrGeneProduct"
       },
       "text": "AHR",
       "locations": [
        {
         "offset": 10,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 94,
     "text": "BACKGROUND: The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like chemicals are mediated through binding-dependent activation of the cytosolic aryl hydrocarbon receptor (AHR). The human AHR is a low-affinity receptor relative to most rodents, but some reports suggest that there may be individuals with polymorphic high-affinity receptors, thereby possibly increasing the sensitivity to dioxins in such people. METHODS: Although no polymorphisms have been reported in the ligand binding region of the AHR in the over 100 reported sequences, we sequenced 108 additional human AHR genes in an effort to further identify single single nucleotide polymorphisms (SNPs) within the open reading frames of the AHR locus. The DNA was sequenced from six ethnic populations that included Japanese, Chinese, European/Caucasian, African-American, South East Asian, and Hispanic. RESULTS: Six exonic SNPs were identified; four had been described as previously reported and two seem to be novel. Four of the SNPs identified lead to amino acid changes in the AHR protein and two of the SNPs lead to synonymous substitutions. An additional four SNPs have been reported elsewhere that were not identified in the current analysis. With these new sequences, more than 200 human AHR gene sequences have been analyzed for SNPs. CONCLUSION: The results indicate a very limited presence of polymorphisms in the core ligand binding region of the human AHR. Other regions, such as the transactivation domain, seem to be slightly more polymorphic in the human population and the impact on functionality should be further examined.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D000072317",
        "type": "ChemicalEntity"
       },
       "text": "2,3,7,8-tetrachlorodibenzo-p-dioxin",
       "locations": [
        {
         "offset": 121,
         "length": 35
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D004147",
        "type": "ChemicalEntity"
       },
       "text": "dioxin",
       "locations": [
        {
         "offset": 169,
         "length": 6
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "196",
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       },
       "text": "aryl hydrocarbon receptor",
       "locations": [
        {
         "offset": 258,
         "length": 25
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "196",
        "type": "GeneOrGeneProduct"
       },
       "text": "AHR",
       "locations": [
        {
         "offset": 285,
         "length": 3
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       ]
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       "id": "6",
       "infons": {
        "identifier": "9606",
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       "text": "human",
       "locations": [
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         "offset": 295,
         "length": 5
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       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "196",
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       "text": "AHR",
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         "offset": 301,
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       "id": "8",
       "infons": {
        "identifier": "D004147",
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       "text": "dioxins",
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         "offset": 502,
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       "id": "9",
       "infons": {
        "identifier": "196",
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         "offset": 616,
         "length": 3
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       "id": "10",
       "infons": {
        "identifier": "9606",
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       "text": "human",
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         "offset": 684,
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       "id": "11",
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        "identifier": "196",
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       "text": "AHR",
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         "offset": 690,
         "length": 3
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       "id": "12",
       "infons": {
        "identifier": "196",
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       "text": "AHR",
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         "offset": 817,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "196",
        "type": "GeneOrGeneProduct"
       },
       "text": "AHR",
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        {
         "offset": 1158,
         "length": 3
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       ]
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       "id": "14",
       "infons": {
        "identifier": "9606",
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       "text": "human",
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         "offset": 1367,
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       "id": "15",
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        "identifier": "196",
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       "text": "AHR",
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       "text": "human",
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         "offset": 1536,
         "length": 5
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       "id": "17",
       "infons": {
        "identifier": "196",
        "type": "GeneOrGeneProduct"
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       "text": "AHR",
       "locations": [
        {
         "offset": 1542,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
        {
         "offset": 1642,
         "length": 5
        }
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      }
     ]
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     "infons": {
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      "novel": "No"
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    }
   ]
  },
  {
   "id": "20588063",
   "passages": [
    {
     "offset": 0,
     "text": "Permeability, ultrastructural changes, and distribution of novel proteins in the glomerular barrier in early puromycin aminonucleoside nephrosis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D011692",
        "type": "ChemicalEntity"
       },
       "text": "puromycin aminonucleoside",
       "locations": [
        {
         "offset": 109,
         "length": 25
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D009401",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nephrosis",
       "locations": [
        {
         "offset": 135,
         "length": 9
        }
       ]
      }
     ]
    },
    {
     "offset": 146,
     "text": "BACKGROUND/AIMS: It is still unclear what happens in the glomerulus when proteinuria starts. Using puromycin aminonucleoside nephrosis (PAN) rats, we studied early ultrastructural and permeability changes in relation to the expression of the podocyte-associated molecules nephrin, a-actinin, dendrin, and plekhh2, the last two of which were only recently discovered in podocytes. METHODS: Using immune stainings, semiquantitative measurement was performed under the electron microscope. Permeability was assessed using isolated kidney perfusion with tracers. Possible effects of ACE inhibition were tested. RESULTS: By day 2, some patchy foot process effacement, but no proteinuria, appeared. The amount of nephrin was reduced in both diseased and normal areas. The other proteins showed few changes, which were limited to diseased areas. By day 4, foot process effacement was complete and proteinuria appeared in parallel with signs of size barrier damage. Nephrin decreased further, while dendrin and plekhh2 also decreased but a-actinin remained unchanged. ACE inhibition had no significant protective effect. CONCLUSIONS: PAN glomeruli already showed significant pathology by day 4, despite relatively mild proteinuria. This was preceded by altered nephrin expression, supporting its pivotal role in podocyte morphology. The novel proteins dendrin and plekhh2 were both reduced, suggesting roles in PAN, whereas a-actinin was unchanged.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D011507",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "proteinuria",
       "locations": [
        {
         "offset": 219,
         "length": 11
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D011692",
        "type": "ChemicalEntity"
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       "text": "puromycin aminonucleoside",
       "locations": [
        {
         "offset": 245,
         "length": 25
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009401",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "nephrosis",
       "locations": [
        {
         "offset": 271,
         "length": 9
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009401",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAN",
       "locations": [
        {
         "offset": 282,
         "length": 3
        }
       ]
      },
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       "id": "6",
       "infons": {
        "identifier": "10116",
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       "text": "rats",
       "locations": [
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         "offset": 287,
         "length": 4
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       ]
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       "id": "7",
       "infons": {
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       "text": "nephrin",
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         "offset": 418,
         "length": 7
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       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "81634",
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       "text": "a-actinin",
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        {
         "offset": 427,
         "length": 9
        }
       ]
      },
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       "id": "9",
       "infons": {
        "identifier": "25113",
        "type": "GeneOrGeneProduct"
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       "text": "dendrin",
       "locations": [
        {
         "offset": 438,
         "length": 7
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "313866",
        "type": "GeneOrGeneProduct"
       },
       "text": "plekhh2",
       "locations": [
        {
         "offset": 451,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "24310",
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       "text": "ACE",
       "locations": [
        {
         "offset": 725,
         "length": 3
        }
       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "D011507",
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       "text": "proteinuria",
       "locations": [
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         "offset": 816,
         "length": 11
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "64563",
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       "text": "nephrin",
       "locations": [
        {
         "offset": 853,
         "length": 7
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D011507",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "proteinuria",
       "locations": [
        {
         "offset": 1036,
         "length": 11
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "64563",
        "type": "GeneOrGeneProduct"
       },
       "text": "Nephrin",
       "locations": [
        {
         "offset": 1104,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "25113",
        "type": "GeneOrGeneProduct"
       },
       "text": "dendrin",
       "locations": [
        {
         "offset": 1137,
         "length": 7
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "313866",
        "type": "GeneOrGeneProduct"
       },
       "text": "plekhh2",
       "locations": [
        {
         "offset": 1149,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "81634",
        "type": "GeneOrGeneProduct"
       },
       "text": "a-actinin",
       "locations": [
        {
         "offset": 1176,
         "length": 9
        }
       ]
      },
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       "id": "19",
       "infons": {
        "identifier": "24310",
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       },
       "text": "ACE",
       "locations": [
        {
         "offset": 1206,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D009401",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAN",
       "locations": [
        {
         "offset": 1272,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D011507",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "proteinuria",
       "locations": [
        {
         "offset": 1357,
         "length": 11
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "64563",
        "type": "GeneOrGeneProduct"
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       "text": "nephrin",
       "locations": [
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         "offset": 1399,
         "length": 7
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "25113",
        "type": "GeneOrGeneProduct"
       },
       "text": "dendrin",
       "locations": [
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         "offset": 1490,
         "length": 7
        }
       ]
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       "id": "24",
       "infons": {
        "identifier": "313866",
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       "text": "plekhh2",
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         "offset": 1502,
         "length": 7
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       ]
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       "id": "25",
       "infons": {
        "identifier": "D009401",
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       "text": "PAN",
       "locations": [
        {
         "offset": 1549,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "81634",
        "type": "GeneOrGeneProduct"
       },
       "text": "a-actinin",
       "locations": [
        {
         "offset": 1562,
         "length": 9
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     ]
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     "infons": {
      "entity1": "D011692",
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      "type": "Positive_Correlation",
      "novel": "No"
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     "infons": {
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      "novel": "Novel"
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    {
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    }
   ]
  },
  {
   "id": "20854438",
   "passages": [
    {
     "offset": 0,
     "text": "SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "57152",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLURP1",
       "locations": [
        {
         "offset": 0,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D007645",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mal de Meleda",
       "locations": [
        {
         "offset": 60,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 75,
     "text": "BACKGROUND: Mal de Meleda (MDM) is palmoplantar erythrokeratoderma with an autosomal recessive inheritance and is caused by a mutation in the gene encoding SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1). SLURP-1 is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis. In addition, murine studies have shown that nAchR signalling is important for the regulation of T-cell function. Among the family members, patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T-cell function as well as a derangement of epidermal homeostasis. OBJECTIVES: To investigate the association of the SLURP1 gene mutation with T-cell activation in a Taiwanese family with MDM. To test that SLURP-1 is essential for T-cell activation. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated from a Taiwanese MDM family bearing the G to A substitution in nucleotide 256 in the SLURP1 gene, corresponding to a glycine to arginine substitution at amino acid 86 (G86R) in the SLURP-1 protein. PBMCs from homozygotes and wild-type controls were stimulated with anti-CD3/anti-CD28 antibodies and the level of T-cell activation was determined by the stimulation index. RESULTS: PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0 5 ug mL(-1) recombinant human SLURP-1 protein. CONCLUSIONS: Patients with MDM with the homozygous SLURP-1 G86R mutation may have an impaired T-cell activation. The presence of wild-type SLURP-1 is essential for normal T-cell activation.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D007645",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Mal de Meleda",
       "locations": [
        {
         "offset": 87,
         "length": 13
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D007645",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MDM",
       "locations": [
        {
         "offset": 102,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C563781",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "palmoplantar erythrokeratoderma",
       "locations": [
        {
         "offset": 110,
         "length": 31
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "57152",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLURP-1",
       "locations": [
        {
         "offset": 231,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "57152",
        "type": "GeneOrGeneProduct"
       },
       "text": "lymphocyte antigen 6",
       "locations": [
        {
         "offset": 240,
         "length": 20
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "57152",
        "type": "GeneOrGeneProduct"
       },
       "text": "urokinase-type plasminogen activator receptor related protein-1",
       "locations": [
        {
         "offset": 261,
         "length": 63
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "57152",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLURP-1",
       "locations": [
        {
         "offset": 327,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1137",
        "type": "GeneOrGeneProduct"
       },
       "text": "nicotinic acetylcholine receptor",
       "locations": [
        {
         "offset": 367,
         "length": 32
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "1137",
        "type": "GeneOrGeneProduct"
       },
       "text": "nAchR",
       "locations": [
        {
         "offset": 401,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "murine",
       "locations": [
        {
         "offset": 461,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "11441",
        "type": "GeneOrGeneProduct"
       },
       "text": "nAchR",
       "locations": [
        {
         "offset": 492,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 587,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "57152",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLURP1",
       "locations": [
        {
         "offset": 616,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma",
       "locations": [
        {
         "offset": 683,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D014777",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "viral infection",
       "locations": [
        {
         "offset": 696,
         "length": 15
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "57152",
        "type": "GeneOrGeneProduct"
       },
       "text": "SLURP1",
       "locations": [
        {
         "offset": 860,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
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    {
     "offset": 0,
     "text": "Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children.",
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      {
       "id": "0",
       "infons": {
        "identifier": "8660",
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       "text": "IRS2",
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       "text": "obesity",
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     "offset": 113,
     "text": "Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5' and 3' flanking regions of IRS2 ( 14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3'-UTR, and 2 in the 5'-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001-0.009) were associated with obesity-related traits (P = 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children.",
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       "infons": {
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       "text": "insulin receptor substrate 2",
       "locations": [
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       "id": "4",
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       "text": "IRS2",
       "locations": [
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       "id": "5",
       "infons": {
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       "text": "obesity",
       "locations": [
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D003920",
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       "text": "diabetes",
       "locations": [
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         "offset": 231,
         "length": 8
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       ]
      },
      {
       "id": "7",
       "infons": {
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       "text": "IRS2",
       "locations": [
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         "offset": 337,
         "length": 4
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       ]
      },
      {
       "id": "8",
       "infons": {
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       "text": "obesity",
       "locations": [
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         "offset": 639,
         "length": 7
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D003920",
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       "text": "diabetes",
       "locations": [
        {
         "offset": 651,
         "length": 8
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D009765",
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       "text": "obesity",
       "locations": [
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         "offset": 1223,
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "10510452_139",
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       "text": "SNP 10510452_139",
       "locations": [
        {
         "offset": 1266,
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       "id": "12",
       "infons": {
        "identifier": "10510452_139",
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       "text": "SNP 10510452_139",
       "locations": [
        {
         "offset": 1445,
         "length": 16
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       "id": "13",
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       "text": "diabetes",
       "locations": [
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         "offset": 1598,
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       ]
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       "id": "14",
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       "text": "glucose",
       "locations": [
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         "offset": 1723,
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       ]
      },
      {
       "id": "15",
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        "identifier": "8660",
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       "text": "IRS2",
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         "offset": 1752,
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       ]
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       "text": "glucose",
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     "offset": 0,
     "text": "Takotsubo syndrome (or apical ballooning syndrome) secondary to Zolmitriptan.",
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       "id": "0",
       "infons": {
        "identifier": "D054549",
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       "text": "Takotsubo syndrome",
       "locations": [
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      {
       "id": "1",
       "infons": {
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       "text": "apical ballooning syndrome",
       "locations": [
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       "infons": {
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       "text": "Zolmitriptan",
       "locations": [
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    {
     "offset": 78,
     "text": "Takotsubo syndrome (TS), also known as broken heart syndrome, is characterized by left ventricle apical ballooning with elevated cardiac biomarkers and electrocardiographic changes suggestive of an acute coronary syndrome (ie, ST-segment elevation, T wave inversions, and pathologic Q waves). We report a case of 54-year-old woman with medical history of mitral valve prolapse and migraines, who was admitted to the hospital for substernal chest pain and electrocardiogram demonstrated 1/2 mm ST-segment elevation in leads II, III, aVF, V5, and V6 and positive troponin I. Emergent coronary angiogram revealed normal coronary arteries with moderately reduced left ventricular ejection fraction with wall motion abnormalities consistent with TS. Detailed history obtained retrospectively revealed that the patient took zolmitriptan sparingly only when she had migraines. But before this event, she was taking zolmitriptan 2-3 times daily for several days because of a persistent migraine headache. She otherwise reported that she is quite active, rides horses, and does show jumping without any limitations in her physical activity. There was no evidence of any recent stress or status migrainosus. Extensive literature search revealed multiple cases of coronary artery vasospasm secondary to zolmitriptan, but none of the cases were associated with TS.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D054549",
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       "text": "Takotsubo syndrome",
       "locations": [
        {
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         "length": 18
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      },
      {
       "id": "4",
       "infons": {
        "identifier": "D054549",
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       "text": "TS",
       "locations": [
        {
         "offset": 98,
         "length": 2
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D054549",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "broken heart syndrome",
       "locations": [
        {
         "offset": 117,
         "length": 21
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D054058",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "acute coronary syndrome",
       "locations": [
        {
         "offset": 276,
         "length": 23
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
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       "text": "woman",
       "locations": [
        {
         "offset": 403,
         "length": 5
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D008945",
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       "text": "mitral valve prolapse",
       "locations": [
        {
         "offset": 433,
         "length": 21
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       ]
      },
      {
       "id": "9",
       "infons": {
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       "text": "migraines",
       "locations": [
        {
         "offset": 459,
         "length": 9
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D002637",
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       "text": "chest pain",
       "locations": [
        {
         "offset": 518,
         "length": 10
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       ]
      },
      {
       "id": "11",
       "infons": {
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       "text": "motion abnormalities",
       "locations": [
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         "offset": 782,
         "length": 20
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       ]
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      {
       "id": "12",
       "infons": {
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       "text": "TS",
       "locations": [
        {
         "offset": 819,
         "length": 2
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       "id": "13",
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       "text": "patient",
       "locations": [
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      {
       "id": "14",
       "infons": {
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       "text": "zolmitriptan",
       "locations": [
        {
         "offset": 896,
         "length": 12
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D008881",
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       "text": "migraines",
       "locations": [
        {
         "offset": 937,
         "length": 9
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       ]
      },
      {
       "id": "16",
       "infons": {
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       "text": "zolmitriptan",
       "locations": [
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         "length": 12
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      },
      {
       "id": "17",
       "infons": {
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       "text": "migraine headache",
       "locations": [
        {
         "offset": 1056,
         "length": 17
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9796",
        "type": "OrganismTaxon"
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       "text": "horses",
       "locations": [
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         "offset": 1130,
         "length": 6
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       ]
      },
      {
       "id": "19",
       "infons": {
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       "text": "status migrainosus",
       "locations": [
        {
         "offset": 1256,
         "length": 18
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D003329",
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       "text": "coronary artery vasospasm",
       "locations": [
        {
         "offset": 1331,
         "length": 25
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       ]
      },
      {
       "id": "21",
       "infons": {
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       "text": "zolmitriptan",
       "locations": [
        {
         "offset": 1370,
         "length": 12
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       ]
      },
      {
       "id": "22",
       "infons": {
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       "text": "TS",
       "locations": [
        {
         "offset": 1427,
         "length": 2
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     ]
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   ],
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  },
  {
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    {
     "offset": 0,
     "text": "CD25(+) Bcl6(low) T follicular helper cells provide help to maturing B cells in germinal centers of human tonsil.",
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       "text": "Bcl6",
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       "text": "human",
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     "text": "Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats.",
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     "text": "Nephrotic syndrome is often accompanied by sodium retention and generalized edema. However, the molecular basis for the decreased renal sodium excretion remains undefined. We hypothesized that epithelial Na channel (ENaC) subunit dysregulation may be responsible for the increased sodium retention. An experimental group of rats was treated with puromycin aminonucleoside (PAN; 180 mg/kg iv), whereas the control group received only vehicle. After 7 days, PAN treatment induced significant proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and extensive ascites. The protein abundance of alpha-ENaC and beta-ENaC was increased in the inner stripe of the outer medulla (ISOM) and in the inner medulla (IM) but was not altered in the cortex. gamma-ENaC abundance was increased in the cortex, ISOM, and IM. Immunoperoxidase brightfield- and laser-scanning confocal fluorescence microscopy demonstrated increased targeting of alpha-ENaC, beta-ENaC, and gamma-ENaC subunits to the apical plasma membrane in the distal convoluted tubule (DCT2), connecting tubule, and cortical and medullary collecting duct segments. Immunoelectron microscopy further revealed an increased labeling of alpha-ENaC in the apical plasma membrane of cortical collecting duct principal cells of PAN-treated rats, indicating enhanced apical targeting of alpha-ENaC subunits. In contrast, the protein abundances of Na(+)/H(+) exchanger type 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (BSC-1), and thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) were decreased. Moreover, the abundance of the alpha(1)-subunit of the Na-K-ATPase was decreased in the cortex and ISOM, but it remained unchanged in the IM. In conclusion, the increased or sustained expression of ENaC subunits combined with increased apical targeting in the DCT2, connecting tubule, and collecting duct are likely to play a role in the sodium retention associated with PAN-induced nephrotic syndrome. The decreased abundance of NHE3, BSC-1, TSC, and Na-K-ATPase may play a compensatory role to promote sodium excretion.",
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     "text": "Differential modulation by estrogen of alpha2-adrenergic and I1-imidazoline receptor-mediated hypotension in female rats.",
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     "text": "We have recently shown that estrogen negatively modulates the hypotensive effect of clonidine (mixed alpha2-/I1-receptor agonist) in female rats and implicates the cardiovascular autonomic control in this interaction. The present study investigated whether this effect of estrogen involves interaction with alpha2- and/or I1-receptors. Changes evoked by a single intraperitoneal injection of rilmenidine (600 microg/kg) or alpha-methyldopa (100 mg/kg), selective I1- and alpha2-receptor agonists, respectively, in blood pressure, hemodynamic variability, and locomotor activity were assessed in radiotelemetered sham-operated and ovariectomized (Ovx) Sprague-Dawley female rats with or without 12-wk estrogen replacement. Three time domain indexes of hemodynamic variability were employed: the standard deviation of mean arterial pressure as a measure of blood pressure variability and the standard deviation of beat-to-beat intervals (SDRR) and the root mean square of successive differences in R-wave-to-R-wave intervals as measures of heart rate variability. In sham-operated rats, rilmenidine or alpha-methyldopa elicited similar hypotension that lasted at least 5 h and was associated with reductions in standard deviation of mean arterial pressure. SDRR was reduced only by alpha-methyldopa. Ovx significantly enhanced the hypotensive response to alpha-methyldopa, in contrast to no effect on rilmenidine hypotension. The enhanced alpha-methyldopa hypotension in Ovx rats was paralleled with further reduction in SDRR and a reduced locomotor activity. Estrogen replacement (17beta-estradiol subcutaneous pellet, 14.2 microg/day, 12 wk) of Ovx rats restored the hemodynamic and locomotor effects of alpha-methyldopa to sham-operated levels. These findings suggest that estrogen downregulates alpha2- but not I1-receptor-mediated hypotension and highlight a role for the cardiac autonomic control in alpha-methyldopa-estrogen interaction.",
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     "text": "The effects of sevoflurane on lidocaine-induced convulsions.",
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     "text": "The influence of sevoflurane on lidocaine-induced convulsions was studied in cats. The convulsive threshold (mean +/- SD) was 41.4 +/- 6.5 mg. l(-1) with lidocaine infusion (6 mg.kg(-1).min(-1)), increasing significantly to 66.6 +/- 10.9 mg. l(-1) when the end-tidal concentration of sevoflurane was 0.8%. However, the threshold (61.6 +/- 8.7 mg. l(-1)) during 1.6% sevoflurane was not significant from that during 0.8% sevoflurane, indicating a celling effect. There was no significant difference in the convulsive threshold between sevoflurane and enflurane. The rise in blood pressure became less marked when higher concentrations of sevoflurane or enflurane were administered and the blood pressure at convulsions decreased significantly in 1.6% sevoflurane, and in 0.8% and 1.6% enflurane. However, there was no significant difference in the lidocaine concentrations measured when the systolic blood pressure became 70 mmHg. Apamin, a selective blocker of calcium-dependent potassium channels, was administered intracerebroventricularly in rats anesthetized with 0.8% sevoflurane to investigate the mechanism of the anticonvulsive effects. Apamin (10 ng) had a tendency to decrease the convulsive threshold (21.6 +/- 2.2 to 19.9 +/- 2.5 mg. l(-1)) but this was not statistically significant. It is suggested that sevoflurane reduces the convulsive effect of lidocaine toxicity but carries some risk due to circulatory depression.",
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     "text": "Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats.",
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        "identifier": "D014196",
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       "text": "trazodone",
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       "text": "dopamine",
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       "text": "rats",
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     "text": "RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced oral stereotypies, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.",
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    {
     "offset": 0,
     "text": "Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis.",
     "annotations": [
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       "infons": {
        "identifier": "D005947",
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       "text": "Glucose",
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       "id": "2",
       "infons": {
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       "text": "schizophrenia",
       "locations": [
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     "offset": 178,
     "text": "BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine<olanzapine<risperidone), with subjects who received clozapine and olanzapine exhibiting significant insulin resistance compared with subjects who were treated with risperidone (clozapine vs risperidone, t(33) = -4.29; P<.001; olanzapine vs risperidone, t(33) = -3.62; P = .001 [P<.001]). The homeostasis model assessment of insulin resistance also differed significantly among groups (F(33) = 4.92; P = .01) (clozapine>olanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine<olanzapine<risperidone) with significant differences between clozapine and risperidone (t(30) = -2.59; P = .02) and olanzapine and risperidone (t(30) = -2.34, P = .03). CONCLUSIONS: Both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects. Patients taking clozapine and olanzapine must be examined for insulin resistance and its consequences.",
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     "text": "A single dose of valproic acid (VPA), which is a widely used antiepileptic drug, is associated with oxidative stress in rats, as recently demonstrated by elevated levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP). To determine whether there was a temporal relationship between VPA-associated oxidative stress and hepatotoxicity, adult male Sprague-Dawley rats were treated ip with VPA (500 mg/kg) or 0.9% saline (vehicle) once daily for 2, 4, 7, 10, or 14 days. Oxidative stress was assessed by determining plasma and liver levels of 15-F(2t)-IsoP, lipid hydroperoxides (LPO), and thiobarbituric acid reactive substances (TBARs). Plasma and liver 15-F(2t)-IsoP were elevated and reached a plateau after day 2 of VPA treatment compared to control. Liver LPO levels were not elevated until day 7 of treatment (1.8-fold versus control, p < 0.05). Liver and plasma TBARs were not increased until 14 days (2-fold vs. control, p < 0.05). Liver toxicity was evaluated based on serum levels of alpha-glutathione S-transferase (alpha-GST) and by histology. Serum alpha-GST levels were significantly elevated by day 4, which corresponded to hepatotoxicity as shown by the increasing incidence of inflammation of the liver capsule, necrosis, and steatosis throughout the study. The liver levels of beta-oxidation metabolites of VPA were decreased by day 14, while the levels of 4-ene-VPA and (E)-2,4-diene-VPA were not elevated throughout the study. Overall, these findings indicate that VPA treatment results in oxidative stress, as measured by levels of 15-F(2t)-IsoP, which precedes the onset of necrosis, steatosis, and elevated levels of serum alpha-GST.",
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     "offset": 0,
     "text": "Safety of celecoxib in patients with adverse skin reactions to acetaminophen (paracetamol) and nimesulide associated or not with common non-steroidal anti-inflammatory drugs.",
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     "text": "BACKGROUND: Acetaminophen (paracetamol--P) and Nimesulide (N) are widely used analgesic-antipyretic/anti-inflammatory drugs. The rate of adverse hypersensitivity reactions to these agents is generally low. On the contrary non-steroidal anti-inflammatory drugs (NSAIDs) are commonly involved in such reactions. Celecoxib (CE) is a novel drug, with high selectivity and affinity for COX-2 enzyme. OBJECTIVE: We evaluated the tolerability of CE in a group of patients with documented history of adverse cutaneous reactions to P and N associated or not to classic NSAIDs. METHODS: We studied 9 patients with hypersensitivity to P and N with or without associated reactions to classic NSAIDs. The diagnosis of P and N-induced skin reactions was based in vivo challenge. The placebo was blindly administered at the beginning of each challenge. After three days, a cumulative dosage of 200 mg of CE in refracted doses were given. After 2-3 days, a single dose of 200 mg was administered. All patients were observed for 6 hours after each challenge, and controlled again after 24 hours to exclude delayed reactions. The challenge was considered positive if one or more of the following appeared: erythema, rush or urticaria-angioedema. RESULTS: No reaction was observed with placebo and eight patients (88.8%) tolerated CE. Only one patient developed a moderate angioedema of the lips. CONCLUSION: Only one hypersensitivity reaction to CE was documented among 9 P and N-highly NSAIDs intolerant patients. Thus, we conclude that CE is a reasonably safe alternative to be used in subjects who do not tolerate P and N.",
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     "text": "Dexrazoxane protects against myelosuppression from the DNA cleavage-enhancing drugs etoposide and daunorubicin but not doxorubicin.",
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     "text": "PURPOSE: The anthracyclines daunorubicin and doxorubicin and the epipodophyllotoxin etoposide are potent DNA cleavage-enhancing drugs that are widely used in clinical oncology; however, myelosuppression and cardiac toxicity limit their use. Dexrazoxane (ICRF-187) is recommended for protection against anthracycline-induced cardiotoxicity. EXPERIMENTAL DESIGN: Because of their widespread use, the hematologic toxicity following coadministration of dexrazoxane and these three structurally different DNA cleavage enhancers was investigated: Sensitivity of human and murine blood progenitor cells to etoposide, daunorubicin, and doxorubicin +/- dexrazoxane was determined in granulocyte-macrophage colony forming assays. Likewise, in vivo, B6D2F1 mice were treated with etoposide, daunorubicin, and doxorubicin, with or without dexrazoxane over a wide range of doses: posttreatment, a full hematologic evaluation was done. RESULTS: Nontoxic doses of dexrazoxane reduced myelosuppression and weight loss from daunorubicin and etoposide in mice and antagonized their antiproliferative effects in the colony assay; however, dexrazoxane neither reduced myelosuppression, weight loss, nor the in vitro cytotoxicity from doxorubicin. CONCLUSION: Although our findings support the observation that dexrazoxane reduces neither hematologic activity nor antitumor activity from doxorubicin clinically, the potent antagonism of daunorubicin activity raises concern; a possible interference with anticancer efficacy certainly would call for renewed attention. Our data also suggest that significant etoposide dose escalation is perhaps possible by the use of dexrazoxane. Clinical trials in patients with brain metastases combining dexrazoxane and high doses of etoposide is ongoing with the aim of improving efficacy without aggravating hematologic toxicity. If successful, this represents an exciting mechanism for pharmacologic regulation of side effects from cytotoxic chemotherapy.",
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     "text": "Microinjection of ritanserin into the CA1 region of hippocampus improves scopolamine-induced amnesia in adult male rats.",
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     "text": "The effect of ritanserin (5-HT2 antagonist) on scopolamine (muscarinic cholinergic antagonist)-induced amnesia in Morris water maze (MWM) was investigated. Rats were divided into eight groups and bilaterally cannulated into CA1 region of the hippocampus. One week later, they received repeatedly vehicles (saline, DMSO, saline+DMSO), scopolamine (2 microg/0.5 microl saline/side; 30 min before training), ritanserin (2, 4 and 8 microg/0.5 microl DMSO/side; 20 min before training) and scopolamine (2 microg/0.5 microl; 30 min before ritanserin injection)+ritanserin (4 microg/0.5 microl DMSO) through cannulae each day. Animals were tested for four consecutive days (4 trial/day) in MWM during which the position of hidden platform was unchanged. In the fifth day, the platform was elevated above the water surface in another position to evaluate the function of motor, motivational and visual systems. The results showed a significant increase in escape latencies and traveled distances to find platform in scopolamine-treated group as compared to saline group. Ritanserin-treated rats (4 microg/0.5 microl/side) showed a significant decrease in the mentioned parameters as compared to DMSO-treated group. However, scopolamine and ritanserin co-administration resulted in a significant decrease in escape latencies and traveled distances as compared to the scopolamine-treated rats. Our findings show that microinjection of ritanserin into the CA1 region of the hippocampus improves the scopolamine-induced amnesia.",
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     "offset": 0,
     "text": "Memory function and serotonin transporter promoter gene polymorphism in ecstasy (MDMA) users.",
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       "id": "0",
       "infons": {
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       "text": "serotonin transporter",
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     "text": "Although 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) has been shown to damage brain serotonin (5-HT) neurons in animals and possibly humans, little is known about the long-term consequences of MDMA-induced 5-HT neurotoxic lesions on functions in which 5-HT is involved, such as cognitive function. Because 5-HT transporters play a key element in the regulation of synaptic 5-HT transmission it may be important to control for the potential covariance effect of a polymorphism in the 5-HT transporter promoter gene region (5-HTTLPR) when studying the effects of MDMA as well as cognitive functioning. The aim of the study was to investigate the effects of moderate and heavy MDMA use on cognitive function, as well as the effects of long-term abstention from MDMA, in subjects genotyped for 5-HTTLPR. A second aim of the study was to determine whether these effects differ for females and males. Fifteen moderate MDMA users (<55 lifetime tablets), 22 heavy MDMA+ users (>55 lifetime tablets), 16 ex-MDMA+ users (last tablet > 1 year ago) and 13 controls were compared on a battery of neuropsychological tests. DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods.A significant group effect was observed only on memory function tasks (p = 0.04) but not on reaction times (p = 0.61) or attention/executive functioning (p = 0.59). Heavy and ex-MDMA+ users performed significantly poorer on memory tasks than controls. In contrast, no evidence of memory impairment was observed in moderate MDMA users. No significant effect of 5-HTTLPR or gender was observed. While the use of MDMA in quantities that may be considered \"moderate\" is not associated with impaired memory functioning, heavy use of MDMA use may lead to long lasting memory impairments. No effect of 5-HTTLPR or gender on memory function or MDMA use was observed.",
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     "offset": 0,
     "text": "Role of mangiferin on biochemical alterations and antioxidant status in isoproterenol-induced myocardial infarction in rats.",
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       "id": "0",
       "infons": {
        "identifier": "C013592",
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     "text": "The current study dealt with the protective role of mangiferin, a polyphenol from Mangifera indica Linn. (Anacardiaceae), on isoproterenol (ISPH)-induced myocardial infarction (MI) in rats through its antioxidative mechanism. Subcutaneous injection of ISPH (200 mg/kg body weight in 1 ml saline) to rats for 2 consecutive days caused myocardial damage in rat heart, which was determined by the increased activity of serum lactate dehydrogenase (LDH) and creatine phosphokinase isoenzymes (CK-MB), increased uric acid level and reduced plasma iron binding capacity. The protective role of mangiferin was analyzed by triphenyl tetrazolium chloride (TTC) test used for macroscopic enzyme mapping assay of the ischemic myocardium. The heart tissue antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase and glutathione reductase activities, non-enzymic antioxidants such as cerruloplasmin, Vitamin C, Vitamin E and glutathione levels were altered in MI rats. Upon pretreatment with mangiferin (100 mg/kg body weight suspended in 2 ml of dimethyl sulphoxide) given intraperitoneally for 28 days to MI rats protected the above-mentioned parameters to fall from the normal levels. Activities of heart tissue enzymic antioxidants and serum non-enzymic antioxidants levels rose significantly upon mangiferin administration as compared to ISPH-induced MI rats. From the present study it is concluded that mangiferin exerts a beneficial effect against ISPH-induced MI due to its antioxidant potential, which regulated the tissues defense system against cardiac damage.",
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       "text": "Cyclooxygenase inhibitors",
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       "text": "prostanoid",
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       "text": "cardiovascular adverse events",
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        }
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       "id": "10",
       "infons": {
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       "text": "cyclooxygenase inhibitors",
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       "text": "prostaglandin",
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       "id": "12",
       "infons": {
        "identifier": "C109794",
        "type": "ChemicalEntity"
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       "text": "N-terminal pro brain natriuretic peptide",
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       "id": "13",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "NT-proBNP",
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       "id": "14",
       "infons": {
        "identifier": "1401",
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       "text": "C-reactive protein",
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         "length": 18
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       "text": "patients",
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       "id": "16",
       "infons": {
        "identifier": "D002318",
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       "text": "cardiovascular toxicity",
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      "novel": "No"
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  {
   "id": "16634859",
   "passages": [
    {
     "offset": 0,
     "text": "Impact of alcohol exposure after pregnancy recognition on ultrasonographic fetal growth measures.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000431",
        "type": "ChemicalEntity"
       },
       "text": "alcohol",
       "locations": [
        {
         "offset": 10,
         "length": 7
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       ]
      }
     ]
    },
    {
     "offset": 98,
     "text": "BACKGROUND: More than 3 decades after Jones and Smith (1973) reported on the devastation caused by alcohol exposure on fetal development, the rates of heavy drinking during pregnancy remain relatively unchanged. Early identification of fetal alcohol exposure and maternal abstinence led to better infant outcomes. This study examined the utility of biometry for detecting alcohol-related fetal growth impairment. METHODS: We obtained fetal ultrasound measures from routine ultrasound examinations for 167 pregnant hazardous drinkers who were enrolled in a brief alcohol intervention study. The fetal measures for women who quit after learning of their pregnancies were compared with measures for women who continued some drinking throughout the course of their pregnancies. Because intensity of alcohol consumption is associated with poorer fetal outcomes, separate analyses were conducted for the heavy (average of >or=5 drinks per drinking day) alcohol consumers. Fetal measures from the heavy-exposed fetuses were also compared with measures from a nondrinking group that was representative of normal, uncomplicated pregnancies from our clinics. Analyses of covariance were used to determine whether there were differences between groups after controlling for influences of gestational age and drug abuse. RESULTS: Nearly half of the pregnant drinkers abstained after learning of their pregnancies. When women reportedly quit drinking early in their pregnancies, fetal growth measures were not significantly different from a non-alcohol-exposed group, regardless of prior drinking patterns. Any alcohol consumption postpregnancy recognition among the heavy drinkers resulted in reduced cerebellar growth as well as decreased cranial to body growth in comparison with women who either quit drinking or who were nondrinkers. Amphetamine abuse was predictive of larger cranial to body growth ratios. CONCLUSIONS: Alterations in fetal biometric measurements were observed among the heavy drinkers only when they continued drinking after becoming aware of their pregnancies. Although the reliance on self-reported drinking is a limitation in this study, these findings support the benefits of early abstinence and the potential for ultrasound examinations in the detection of fetal alcohol effects.",
     "annotations": [
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       "id": "1",
       "infons": {
        "identifier": "D000431",
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       "text": "alcohol",
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       "id": "2",
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       "text": "alcohol",
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       "id": "3",
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       "text": "alcohol",
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       "id": "4",
       "infons": {
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       "text": "growth impairment",
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         "offset": 492,
         "length": 17
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       ]
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       "id": "5",
       "infons": {
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       "text": "alcohol",
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         "offset": 660,
         "length": 7
        }
       ]
      },
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       "id": "6",
       "infons": {
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       "text": "women",
       "locations": [
        {
         "offset": 711,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
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       "text": "women",
       "locations": [
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         "offset": 794,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000431",
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       "text": "alcohol",
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        {
         "offset": 893,
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        }
       ]
      },
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       "id": "9",
       "infons": {
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       "text": "alcohol",
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         "offset": 1045,
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       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "D019966",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "drug abuse",
       "locations": [
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         "offset": 1395,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
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       "text": "women",
       "locations": [
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         "offset": 1505,
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       ]
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       "id": "12",
       "infons": {
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       "text": "alcohol",
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         "offset": 1630,
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       ]
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       "id": "13",
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       "text": "alcohol",
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       ]
      },
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       "id": "14",
       "infons": {
        "identifier": "D006130",
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       "text": "reduced cerebellar growth",
       "locations": [
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       ]
      },
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       "id": "15",
       "infons": {
        "identifier": "D006130",
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       "text": "decreased cranial to body growth",
       "locations": [
        {
         "offset": 1816,
         "length": 32
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       ]
      },
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       "id": "16",
       "infons": {
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       "text": "women",
       "locations": [
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         "offset": 1868,
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       ]
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       "id": "17",
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       "text": "Amphetamine",
       "locations": [
        {
         "offset": 1924,
         "length": 11
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       ]
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      {
       "id": "18",
       "infons": {
        "identifier": "D000431",
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       "text": "alcohol",
       "locations": [
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         "offset": 2378,
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  {
   "id": "16725121",
   "passages": [
    {
     "offset": 0,
     "text": "Down-regulation of norepinephrine transporter function induced by chronic administration of desipramine linking to the alteration of sensitivity of local-anesthetics-induced convulsions and the counteraction by co-administration with local anesthetics.",
     "annotations": [
      {
       "id": "0",
       "infons": {
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       "text": "norepinephrine transporter",
       "locations": [
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       ]
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       "id": "1",
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       "text": "desipramine",
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         "offset": 92,
         "length": 11
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D000777",
        "type": "ChemicalEntity"
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       "text": "anesthetics",
       "locations": [
        {
         "offset": 154,
         "length": 11
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       ]
      },
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       "id": "3",
       "infons": {
        "identifier": "D012640",
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       "text": "convulsions",
       "locations": [
        {
         "offset": 174,
         "length": 11
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       ]
      },
      {
       "id": "4",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "anesthetics",
       "locations": [
        {
         "offset": 240,
         "length": 11
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       ]
      }
     ]
    },
    {
     "offset": 253,
     "text": "Alterations of norepinephrine transporter (NET) function by chronic inhibition of NET in relation to sensitization to seizures induce by cocaine and local anesthetics were studied in mice. Daily administration of desipramine, an inhibitor of the NET, for 5 days decreased [(3)H]norepinephrine uptake in the P2 fractions of hippocampus but not cortex, striatum or amygdalae. Co-administration of lidocaine, bupivacaine or tricaine with desipramine reversed this effect. Daily treatment of cocaine increased [(3)H]norepinephrine uptake into the hippocampus. Daily administration of desipramine increased the incidence of appearance of lidocaine-induced convulsions and decreased that of cocaine-induced convulsions. Co-administration of lidocaine with desipramine reversed the changes of convulsive activity of lidocaine and cocaine induced by repeated administration of desipramine. These results suggest that down-regulation of hippocampal NET induced by chronic administration of desipramine may be relevant to desipramine-induced sensitization of lidocaine convulsions. Inhibition of Na(+) channels by local anesthetics may regulate desipramine-induced down-regulation of NET function. Repeated administration of cocaine induces up-regulation of hippocampal NET function. Desipramine-induced sensitization of lidocaine seizures may have a mechanism distinct from kindling resulting from repeated administration of cocaine.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "20538",
        "type": "GeneOrGeneProduct"
       },
       "text": "norepinephrine transporter",
       "locations": [
        {
         "offset": 268,
         "length": 26
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "20538",
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       "text": "NET",
       "locations": [
        {
         "offset": 296,
         "length": 3
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       ]
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       "id": "7",
       "infons": {
        "identifier": "20538",
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       "text": "NET",
       "locations": [
        {
         "offset": 335,
         "length": 3
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012640",
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       "text": "seizures",
       "locations": [
        {
         "offset": 371,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D003042",
        "type": "ChemicalEntity"
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       "text": "cocaine",
       "locations": [
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         "offset": 390,
         "length": 7
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000777",
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       "text": "anesthetics",
       "locations": [
        {
         "offset": 408,
         "length": 11
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "10090",
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       "text": "mice",
       "locations": [
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         "offset": 436,
         "length": 4
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       ]
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      {
       "id": "12",
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       "text": "desipramine",
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         "offset": 466,
         "length": 11
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       ]
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       "id": "13",
       "infons": {
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       "text": "NET",
       "locations": [
        {
         "offset": 499,
         "length": 3
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       ]
      },
      {
       "id": "14",
       "infons": {
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       "text": "[(3)H]norepinephrine",
       "locations": [
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         "offset": 525,
         "length": 20
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       ]
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       "id": "15",
       "infons": {
        "identifier": "D008012",
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       "text": "lidocaine",
       "locations": [
        {
         "offset": 648,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D002045",
        "type": "ChemicalEntity"
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       "text": "bupivacaine",
       "locations": [
        {
         "offset": 659,
         "length": 11
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C003636",
        "type": "ChemicalEntity"
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       "text": "tricaine",
       "locations": [
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         "offset": 674,
         "length": 8
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003891",
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       "text": "desipramine",
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         "length": 11
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       ]
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       "id": "19",
       "infons": {
        "identifier": "D003042",
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       "text": "cocaine",
       "locations": [
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         "offset": 741,
         "length": 7
        }
       ]
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       "id": "20",
       "infons": {
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       "text": "[(3)H]norepinephrine",
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         "offset": 759,
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       ]
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       "id": "21",
       "infons": {
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       "text": "desipramine",
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       "id": "22",
       "infons": {
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       "text": "lidocaine",
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       "id": "23",
       "infons": {
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       "text": "convulsions",
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       "id": "24",
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       "text": "cocaine",
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       "text": "convulsions",
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       "text": "lidocaine",
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       "text": "desipramine",
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       "infons": {
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       "text": "convulsive",
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       "text": "lidocaine",
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       "text": "cocaine",
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       ]
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       "text": "desipramine",
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       ]
      },
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       "id": "32",
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       "text": "NET",
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         "offset": 1193,
         "length": 3
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       ]
      },
      {
       "id": "33",
       "infons": {
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       "text": "desipramine",
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       ]
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      {
       "id": "34",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "desipramine",
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         "offset": 1265,
         "length": 11
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D008012",
        "type": "ChemicalEntity"
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       "text": "lidocaine",
       "locations": [
        {
         "offset": 1302,
         "length": 9
        }
       ]
      },
      {
       "id": "36",
       "infons": {
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       },
       "text": "convulsions",
       "locations": [
        {
         "offset": 1312,
         "length": 11
        }
       ]
      },
      {
       "id": "37",
       "infons": {
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        "type": "ChemicalEntity"
       },
       "text": "Na(+)",
       "locations": [
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         "offset": 1339,
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        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D000777",
        "type": "ChemicalEntity"
       },
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     "text": "Pharmacological evidence for the potential of Daucus carota in the management of cognitive dysfunctions.",
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     "text": "The present study was aimed at investigating the effects of Daucus carota seeds on cognitive functions, total serum cholesterol levels and brain cholinesterase activity in mice. The ethanolic extract of Daucus carota seeds (DCE) was administered orally in three doses (100, 200, 400 mg/kg) for seven successive days to different groups of young and aged mice. Elevated plus maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam-, scopolamine- and ageing-induced amnesia served as the interoceptive behavioral models. DCE (200, 400 mg/kg, p.o.) showed significant improvement in memory scores of young and aged mice. The extent of memory improvement evoked by DCE was 23% at the dose of 200 mg/kg and 35% at the dose of 400 mg/kg in young mice using elevated plus maze. Similarly, significant improvements in memory scores were observed using passive avoidance apparatus and aged mice. Furthermore, DCE reversed the amnesia induced by scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.). Daucus carota extract (200, 400 mg/kg, p.o.) reduced significantly the brain acetylcholinesterase activity and cholesterol levels in young and aged mice. The extent of inhibition of brain cholinesterase activity evoked by DCE at the dose of 400 mg/kg was 22% in young and 19% in aged mice. There was a remarkable reduction in total cholesterol level as well, to the extent of 23% in young and 21% in aged animals with this dose of DCE. Therefore, DCE may prove to be a useful remedy for the management of cognitive dysfunctions on account of its multifarious beneficial effects such as, memory improving property, cholesterol lowering property and anticholinesterase activity.",
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     "offset": 0,
     "text": "Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function.",
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     "text": "Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of arterial dysfunction. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension.",
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       "id": "2",
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       "text": "hypertension",
       "locations": [
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         "offset": 62,
         "length": 12
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       "text": "rat",
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     "text": "1. Dexamethasone (Dex)-induced hypertension is characterized by endothelial dysfunction associated with nitric oxide (NO) deficiency and increased superoxide (O2-) production. Atorvastatin (Ato) possesses pleiotropic properties that have been reported to improve endothelial function through increased availability of NO and reduced O2- production in various forms of hypertension. In the present study, we investigated whether 50 mg/kg per day, p.o., Ato could prevent endothelial NO synthase (eNOS) downregulation and the increase in O2- in Sprague-Dawley (SD) rats, thereby reducing blood pressure. 2. Male SD rats (n = 30) were treated with Ato (50 mg/kg per day in drinking water) or tap water for 15 days. Dexamethasone (10 microg/kg per day, s.c.) or saline was started after 4 days in Ato-treated and non-treated rats and continued for 11-13 days. Systolic blood pressure (SBP) was measured on alternate days using the tail-cuff method. Endothelial function was assessed by acetylcholine-induced vasorelaxation and phenylephrine-induced vasoconstriction in aortic segments. Vascular eNOS mRNA was assessed by semi-quantitative reverse transcription-polymerase chain reaction. 3. In rats treated with Dex alone, SBP was increased from 109 +/- 2 to 133 +/- 2 mmHg on Days 4 and Day 14, respectively (P < 0.001). In the Ato + Dex group, SBP was increased from 113 +/- 2 to 119 +/- 2 mmHg on Days 4 to 14, respectively (P < 0.001), but was significantly lower than SBP in the group treated with Dex alone (P < 0.05). Endothelial-dependent relaxation and eNOS mRNA expression were greater in the Dex + Ato group than in the Dex only group (P < 0.05 and P < 0.0001, respectively). Aortic superoxide production was lower in the Dex + Ato group compared with the group treated with Dex alone (P < 0.0001). 4. Treatment with Ato improved endothelial function, reduced superoxide production and reduced SBP in Dex-treated SD rats.",
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     "offset": 0,
     "text": "Behavioral effects of pubertal anabolic androgenic steroid exposure in male rats with low serotonin.",
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     "text": "The goal of this study was to assess the interactive effects of chronic anabolic androgenic steroid (AAS) exposure and brain serotonin (5-hydroxytryptamine, 5-HT) depletion on behavior of pubertal male rats. Serotonin was depleted beginning on postnatal day 26 with parachlorophenylalanine (PCPA 100 mg/kg, every other day); controls received saline. At puberty (P40), half the PCPA-treated rats and half the saline-treated rats began treatment with testosterone (T, 5 mg/kg, 5 days/week). Behavioral measures included locomotion, irritability, copulation, partner preference, and aggression. Animals were tested for aggression in their home cage, both with and without physical provocation (mild tail pinch). Brain levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined using HPLC. PCPA significantly and substantially depleted 5-HT and 5-HIAA in all brain regions examined. Chronic T treatment significantly decreased 5-HT and 5-HIAA in certain brain areas, but to a much lesser extent than PCPA. Chronic exposure to PCPA alone significantly decreased locomotor activity and increased irritability but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on locomotion, irritability, or sexual behavior but increased partner preference and aggression. The most striking effect of combining T+PCPA was a significant increase in attack frequency as well as a significant decrease in the latency to attack, particularly following physical provocation. Based on these data, it can be speculated that pubertal AAS users with low central 5-HT may be especially prone to exhibit aggressive behavior.",
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     "text": "In cyclophosphamide-induced cystitis in the rat, detrusor function is impaired and the expression and effects of muscarinic receptors altered. Whether or not the neuronal transmission may be affected by cystitis was presently investigated. Responses of urinary strip preparations from control and cyclophosphamide-pretreated rats to electrical field stimulation and to agonists were assessed in the absence and presence of muscarinic, adrenergic and purinergic receptor antagonists. Generally, atropine reduced contractions, but in contrast to controls, it also reduced responses to low electrical field stimulation intensity (1-5 Hz) in inflamed preparations. In both types, purinoceptor desensitization with alpha,beta-methylene adenosine-5'-triphosphate (alpha,beta-meATP) caused further reductions at low frequencies (<10 Hz). The muscarinic receptor antagonists atropine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) ('M(1)/M(3)/M(5)-selective'), methoctramine ('M(2)-selective') and pirenzepine ('M(1)-selective') antagonized the tonic component of the electrical field stimulation-evoked contractile response more potently than the phasic component. 4-DAMP inhibited the tonic contractions in controls more potently than methoctramine and pirenzepine. In inflamed preparations, the muscarinic receptor antagonism on the phasic component of the electrical field stimulation-evoked contraction was decreased and the pirenzepine and 4-DAMP antagonism on the tonic component was much less efficient than in controls. In contrast to controls, methoctramine increased -- instead of decreased -- the tonic responses at high frequencies. While contractions to carbachol and ATP were the same in inflamed and in control strips when related to a reference potassium response, isoprenaline-induced relaxations were smaller in inflamed strips. Thus, in cystitis substantial changes of the efferent functional responses occur. While postjunctional beta-adrenoceptor-mediated relaxations are reduced, effects by prejunctional inhibitory muscarinic receptors may be increased.",
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     "text": "BACKGROUND: One third of patients treated for hypertension attain adequate blood pressure (BP) control, and multidrug regimens are often required. Given the lifelong nature of hypertension, there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-hypertensive therapies. OBJECTIVE: This study investigated the efficacy and tolerability of valsartan (VAL) or hydrochlorothiazide (HCTZ)-monotherapy and higher-dose combinations in patients with essential hypertension. METHODS: The first part of this study was an 8-week, multicenter, randomized, double-blind, placebo controlled, parallel-group trial. Patients with essential hypertension (mean sitting diastolic BP [MSDBP], > or =95 mm Hg and <110 mm Hg) were randomized to 1 of 8 treatment groups: VAL 160 or 320 mg; HCTZ 12.5 or 25 mg; VAL/HCTZ 160/12.5, 320/12.5, or 320/25 mg; or placebo. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) were analyzed at the 8-week core study end point. VAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week, open-label extension. Response was defined as MSDBP <90 mm Hg or a > or =10 mm Hg decrease compared to baseline. Control was defined as MSDBP <90 mm Hg compared with baseline. Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry. RESULTS: A total of 1346 patients were randomized into the 8-week core study (734 men, 612 women; 924 white, 291 black, 23 Asian, 108 other; mean age, 52.7 years; mean weight, 92.6 kg). All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study, with each monotherapy significantly contributing to the overall effect of combination therapy (VAL and HCTZ, P < 0.001). Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo (all, P < 0.001). The mean reduction in MSSBP/MSDBP with VAL/HCTZ 320/25 mg was 24.7/16.6 mm Hg, compared with 5.9/7.0 mm Hg with placebo. The reduction in MSSBP was significantly greater with VAL/HCTZ 320/25 mg compared with VAL/HCTZ 160/12.5 mg (P < 0.002). Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy. The incidence of hypokalemia was lower with VAL/HCTZ combinations (1.8%-6.1%) than with HCTZ monotherapies (7.1%-13.3%). The majority of adverse events in the core study were of mild to moderate severity. The efficacy and tolerability of VAL/HCTZ combinations were maintained during the extension (797 patients). CONCLUSIONS: In this study population, combination therapies with VAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy, were well tolerated, and were associated with less hypokalemia than HCTZ alone.",
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     "text": "Role of xanthine oxidase in dexamethasone-induced hypertension in rats.",
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     "text": "1. Glucocorticoid-induced hypertension (GC-HT) in the rat is associated with nitric oxide-redox imbalance. 2. We studied the role of xanthine oxidase (XO), which is implicated in the production of reactive oxygen species, in dexamethasone-induced hypertension (dex-HT). 3. Thirty male Sprague-Dawley rats were divided randomly into four treatment groups: saline, dexamethasone (dex), allopurinol plus saline, and allopurinol plus dex. 4. Systolic blood pressures (SBP) and bodyweights were recorded each alternate day. Thymus weight was used as a marker of glucocorticoid activity, and serum urate to assess XO inhibition. 5. Dex increased SBP (110 +/- 2-126 +/- 3 mmHg; P < 0.001) and decreased thymus (P < 0.001) and bodyweights (P\" < 0.01). Allopurinol decreased serum urate from 76 +/- 5 to 30 +/- 3 micromol/L (P < 0.001) in saline and from 84 +/- 13 to 28 +/- 2 micromol/L in dex-treated (P < 0.01) groups. 6. Allopurinol did not prevent dex-HT. This, together with our previous findings that allopurinol failed to prevent adrenocorticotrophic hormone induced hypertension, suggests that XO activity is not a major determinant of GC-HT in the rat.",
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  {
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    {
     "offset": 0,
     "text": "Neuroprotective effects of melatonin upon the offspring cerebellar cortex in the rat model of BCNU-induced cortical dysplasia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D008550",
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       "text": "melatonin",
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     "text": "Cortical dysplasia is a malformation characterized by defects in proliferation, migration and maturation. This study was designed to evaluate the alterations in offspring rat cerebellum induced by maternal exposure to carmustine-[1,3-bis (2-chloroethyl)-1-nitrosoure] (BCNU) and to investigate the effects of exogenous melatonin upon cerebellar BCNU-induced cortical dysplasia, using histological and biochemical analyses. Pregnant Wistar rats were assigned to five groups: intact-control, saline-control, melatonin-treated, BCNU-exposed and BCNU-exposed plus melatonin. Rats were exposed to BCNU on embryonic day 15 and melatonin was given until delivery. Immuno/histochemistry and electron microscopy were carried out on the offspring cerebellum, and levels of malondialdehyde and superoxide dismutase were determined. Histopathologically, typical findings were observed in the cerebella from the control groups, but the findings consistent with early embryonic development were noted in BCNU-exposed cortical dysplasia group. There was a marked increase in the number of TUNEL positive cells and nestin positive cells in BCNU-exposed group, but a decreased immunoreactivity to glial fibrillary acidic protein, synaptophysin and transforming growth factor beta1 was observed, indicating a delayed maturation, and melatonin significantly reversed these changes. Malondialdehyde level in BCNU-exposed group was higher than those in control groups and melatonin decreased malondialdehyde levels in BCNU group (P<0.01), while there were no significant differences in the superoxide dismutase levels between these groups. These data suggest that exposure of animals to BCNU during pregnancy leads to delayed maturation of offspring cerebellum and melatonin protects the cerebellum against the effects of BCNU.",
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       "text": "Cortical dysplasia",
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       "text": "BCNU",
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       "text": "cortical dysplasia",
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       "text": "transforming growth factor beta1",
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  {
   "id": "17615423",
   "passages": [
    {
     "offset": 0,
     "text": "Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D012206",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "rhabdomyolysis",
       "locations": [
        {
         "offset": 7,
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       "id": "1",
       "infons": {
        "identifier": "D058186",
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       "text": "acute renal failure",
       "locations": [
        {
         "offset": 26,
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       "id": "2",
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       "text": "simvastatin",
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       "locations": [
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    },
    {
     "offset": 119,
     "text": "OBJECTIVE: To report a case of a severe interaction between simvastatin, amiodarone, and atazanavir resulting in rhabdomyolysis and acute renal failure. BACKGROUND: A 72-year-old white man with underlying human immunodeficiency virus, atrial fibrillation, coronary artery disease, and hyperlipidemia presented with generalized pain, fatigue, and dark orange urine for 3 days. The patient was taking 80 mg simvastatin at bedtime (initiated 27 days earlier); amiodarone at a dose of 400 mg daily for 7 days, then 200 mg daily (initiated 19 days earlier); and 400 mg atazanavir daily (initiated at least 2 years previously). Laboratory evaluation revealed 66,680 U/L creatine kinase, 93 mg/dL blood urea nitrogen, 4.6 mg/dL creatinine, 1579 U/L aspartate aminotransferase, and 738 U/L alanine aminotransferase. Simvastatin, amiodarone, and the patient's human immunodeficiency virus medications were all temporarily discontinued and the patient was given forced alkaline diuresis and started on dialysis. Nine days later the patient's creatine kinase had dropped to 1695 U/L and creatinine was 3.3 mg/dL. The patient was discharged and continued outpatient dialysis for 1 month until his renal function recovered. DISCUSSION: The risk of rhabdomyolysis is increased in the presence of concomitant drugs that inhibit simvastatin metabolism. Simvastatin is metabolized by CYP3A4. Amiodarone and atazanavir are recognized CYP3A4 inhibitors. CONCLUSIONS: Pharmacokinetic differences in statins are an important consideration for assessing the risk of potential drug interactions. In patients requiring the concurrent use of statins and CYP3A4 inhibitors, pravastatin, fluvastatin, and rosuvastatin carry the lowest risk of drug interactions; atorvastatin carries moderate risk, whereas simvastatin and lovastatin have the highest risk and should be avoided in patients taking concomitant CYP3A4 inhibitors.",
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         "offset": 179,
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     "text": "INTRODUCTION: The possible anxiogenic effects of fluoroquinolones, namely ciprofloxacin and norfloxacin, were investigated in adult Charles Foster albino rats of either sex, weighing 150-200 g. METHODS: The drugs were given orally, in doses of 50 mg/kg for five consecutive days and the experiments were performed on the fifth day. The tests included open-field exploratory behaviour, elevated plus maze and elevated zero maze, social interaction and novelty-suppressed feeding latency behaviour. RESULTS: The results indicate that ciprofloxacin- and norfloxacin-treated rats showed anxious behaviour in comparison to control rats in all the parameters studied. However, ciprofloxacin- and norfloxacin-treated rats did not differ significantly from each other in various behavioural parameters. CONCLUSION: The present experimental findings substantiate the clinically observed anxiogenic potential of ciprofloxacin and norfloxacin.",
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     "text": "Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety.",
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     "text": "BACKGROUND: Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. METHODS: In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. RESULTS: We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect. CONCLUSIONS: These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.",
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     "text": "The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model.",
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     "text": "BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates.",
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      "entity1": "D002045",
      "entity2": "4513",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "D002045",
      "entity2": "5732",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R12",
     "infons": {
      "entity1": "D002045",
      "entity2": "D010146",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R13",
     "infons": {
      "entity1": "D002045",
      "entity2": "C116926",
      "type": "Cotreatment",
      "novel": "Novel"
     }
    },
    {
     "id": "R14",
     "infons": {
      "entity1": "D002045",
      "entity2": "D008012",
      "type": "Comparison",
      "novel": "Novel"
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    }
   ]
  },
  {
   "id": "18182964",
   "passages": [
    {
     "offset": 0,
     "text": "Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003000",
        "type": "ChemicalEntity"
       },
       "text": "Clonidine",
       "locations": [
        {
         "offset": 0,
         "length": 9
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D001289",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "attention-deficit/hyperactivity disorder",
       "locations": [
        {
         "offset": 14,
         "length": 40
        }
       ]
      }
     ]
    },
    {
     "offset": 101,
     "text": "OBJECTIVE: To examine the safety and tolerability of clonidine used alone or with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: In a 16-week multicenter, double-blind trial, 122 children with ADHD were randomly assigned to clonidine (n = 31), methylphenidate (n = 29), clonidine and methylphenidate (n = 32), or placebo (n = 30). Doses were flexibly titrated up to 0.6 mg/day for clonidine and 60 mg/day for methylphenidate (both with divided dosing). Groups were compared regarding adverse events and changes from baseline to week 16 in electrocardiograms and vital signs. RESULTS: There were more incidents of bradycardia in subjects treated with clonidine compared with those not treated with clonidine (17.5% versus 3.4%; p =.02), but no other significant group differences regarding electrocardiogram and other cardiovascular outcomes. There were no suggestions of interactions between clonidine and methylphenidate regarding cardiovascular outcomes. Moderate or severe adverse events were more common in subjects on clonidine (79.4% versus 49.2%; p =.0006) but not associated with higher rates of early study withdrawal. Drowsiness was common on clonidine, but generally resolved by 6 to 8 weeks. CONCLUSIONS: Clonidine, used alone or with methylphenidate, appears safe and well tolerated in childhood ADHD. Physicians prescribing clonidine should monitor for bradycardia and advise patients about the high likelihood of initial drowsiness.",
     "annotations": [
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       "id": "2",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "clonidine",
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       ]
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       "text": "methylphenidate",
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       "infons": {
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       "text": "attention-deficit/hyperactivity disorder",
       "locations": [
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         "length": 40
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       "id": "5",
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         "length": 4
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      },
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       "id": "6",
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        "identifier": "D001289",
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         "offset": 337,
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       ]
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       "text": "methylphenidate",
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       ]
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       "infons": {
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       "text": "clonidine",
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         "offset": 414,
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       "text": "methylphenidate",
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       "text": "clonidine",
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       "infons": {
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       "text": "methylphenidate",
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       "id": "13",
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       "text": "bradycardia",
       "locations": [
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       ]
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       "id": "14",
       "infons": {
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       "infons": {
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       "text": "clonidine",
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         "offset": 841,
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       ]
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       "id": "16",
       "infons": {
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       "text": "clonidine",
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       "id": "17",
       "infons": {
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       "text": "methylphenidate",
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         "offset": 1050,
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       ]
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       "infons": {
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       "text": "clonidine",
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         "offset": 1167,
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       ]
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       "id": "19",
       "infons": {
        "identifier": "D006970",
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       },
       "text": "Drowsiness",
       "locations": [
        {
         "offset": 1272,
         "length": 10
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       ]
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       "id": "20",
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       "text": "clonidine",
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       "id": "21",
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        "identifier": "D003000",
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       "text": "Clonidine",
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       ]
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       "id": "22",
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        "identifier": "D008774",
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       "text": "methylphenidate",
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       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "D001289",
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       "text": "ADHD",
       "locations": [
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         "offset": 1453,
         "length": 4
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       ]
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       "id": "24",
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       "text": "clonidine",
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       "id": "25",
       "infons": {
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       "text": "bradycardia",
       "locations": [
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         "offset": 1511,
         "length": 11
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       "id": "26",
       "infons": {
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       "text": "patients",
       "locations": [
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         "offset": 1534,
         "length": 8
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D006970",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drowsiness",
       "locations": [
        {
         "offset": 1580,
         "length": 10
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       ]
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     ]
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   ],
   "relations": [
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     "id": "R0",
     "infons": {
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      "type": "Negative_Correlation",
      "novel": "Novel"
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    },
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     "id": "R1",
     "infons": {
      "entity1": "D006970",
      "entity2": "D003000",
      "type": "Positive_Correlation",
      "novel": "No"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D003000",
      "entity2": "D001289",
      "type": "Negative_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D003000",
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      "entity1": "D003000",
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      "type": "Positive_Correlation",
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    }
   ]
  },
  {
   "id": "18340638",
   "passages": [
    {
     "offset": 0,
     "text": "Azathioprine-induced suicidal erythrocyte death.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D001379",
        "type": "ChemicalEntity"
       },
       "text": "Azathioprine",
       "locations": [
        {
         "offset": 0,
         "length": 12
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    },
    {
     "offset": 49,
     "text": "BACKGROUND: Azathioprine is widely used as an immunosuppressive drug. The side effects of azathioprine include anemia, which has been attributed to bone marrow suppression. Alternatively, anemia could result from accelerated suicidal erythrocyte death or eryptosis, which is characterized by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. METHODS: The present experiments explored whether azathioprine influences eryptosis. According to annexin V binding, erythrocytes from patients indeed showed a significant increase of PS exposure within 1 week of treatment with azathioprine. In a second series, cytosolic Ca2+ activity (Fluo3 fluorescence), cell volume (forward scatter), and PS-exposure (annexin V binding) were determined by FACS analysis in erythrocytes from healthy volunteers. RESULTS: Exposure to azathioprine (> or =2 microg/mL) for 48 hours increased cytosolic Ca2+ activity and annexin V binding and decreased forward scatter. The effect of azathioprine on both annexin V binding and forward scatter was significantly blunted in the nominal absence of extracellular Ca2+. CONCLUSIONS: Azathioprine triggers suicidal erythrocyte death, an effect presumably contributing to azathioprine-induced anemia.",
     "annotations": [
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       "id": "1",
       "infons": {
        "identifier": "D001379",
        "type": "ChemicalEntity"
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       "text": "Azathioprine",
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       "text": "azathioprine",
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       "id": "3",
       "infons": {
        "identifier": "D000740",
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       "text": "anemia",
       "locations": [
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         "offset": 160,
         "length": 6
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D001855",
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       "text": "bone marrow suppression",
       "locations": [
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         "offset": 197,
         "length": 23
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       ]
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       "id": "5",
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       "text": "anemia",
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       "id": "6",
       "infons": {
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       "text": "phosphatidylserine",
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         "offset": 353,
         "length": 18
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       "id": "7",
       "infons": {
        "identifier": "D010718",
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       "text": "PS",
       "locations": [
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         "offset": 373,
         "length": 2
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       ]
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       "id": "8",
       "infons": {
        "identifier": "D001379",
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       "text": "azathioprine",
       "locations": [
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       ]
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       "id": "9",
       "infons": {
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       "text": "annexin V",
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       ]
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       "id": "10",
       "infons": {
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       "text": "patients",
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       "id": "11",
       "infons": {
        "identifier": "D010718",
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       "text": "PS",
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         "offset": 611,
         "length": 2
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       ]
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       "id": "12",
       "infons": {
        "identifier": "D001379",
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       "text": "azathioprine",
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       "id": "13",
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       "text": "Ca2+",
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       ]
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       "text": "Fluo3",
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       "infons": {
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       "text": "PS",
       "locations": [
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       ]
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       "id": "16",
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       "text": "annexin V",
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       ]
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       "id": "17",
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       "text": "azathioprine",
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       "id": "18",
       "infons": {
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       "text": "Ca2+",
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       ]
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       "id": "19",
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        "identifier": "308",
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       "text": "annexin V",
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         "length": 9
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       ]
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       "id": "20",
       "infons": {
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       "text": "azathioprine",
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         "offset": 1044,
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       ]
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       "id": "21",
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        "identifier": "308",
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       "text": "annexin V",
       "locations": [
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         "length": 9
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       "id": "22",
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       "text": "Ca2+",
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       "id": "23",
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       "text": "Azathioprine",
       "locations": [
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         "length": 12
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      {
       "id": "24",
       "infons": {
        "identifier": "D001379",
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       "text": "azathioprine",
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         "offset": 1275,
         "length": 12
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       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D000740",
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       },
       "text": "anemia",
       "locations": [
        {
         "offset": 1296,
         "length": 6
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       ]
      }
     ]
    }
   ],
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      "novel": "No"
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010718",
      "entity2": "308",
      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D001379",
      "entity2": "D001855",
      "type": "Positive_Correlation",
      "novel": "No"
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    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D001379",
      "entity2": "D000740",
      "type": "Positive_Correlation",
      "novel": "No"
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    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D001379",
      "entity2": "D002118",
      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D001379",
      "entity2": "308",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D001379",
      "entity2": "D010718",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18410508",
   "passages": [
    {
     "offset": 0,
     "text": "Methamphetamine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D008694",
        "type": "ChemicalEntity"
       },
       "text": "Methamphetamine",
       "locations": [
        {
         "offset": 0,
         "length": 15
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D020258",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurotoxicity",
       "locations": [
        {
         "offset": 24,
         "length": 13
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "13051",
        "type": "GeneOrGeneProduct"
       },
       "text": "fractalkine receptor",
       "locations": [
        {
         "offset": 84,
         "length": 20
        }
       ]
      }
     ]
    },
    {
     "offset": 116,
     "text": "Methamphetamine (METH) damages dopamine (DA) nerve endings by a process that has been linked to microglial activation but the signaling pathways that mediate this response have not yet been delineated. Cardona et al. [Nat. Neurosci. 9 (2006), 917] recently identified the microglial-specific fractalkine receptor (CX3CR1) as an important mediator of MPTP-induced neurodegeneration of DA neurons. Because the CNS damage caused by METH and MPTP is highly selective for the DA neuronal system in mouse models of neurotoxicity, we hypothesized that the CX3CR1 plays a role in METH-induced neurotoxicity and microglial activation. Mice in which the CX3CR1 gene has been deleted and replaced with a cDNA encoding enhanced green fluorescent protein (eGFP) were treated with METH and examined for striatal neurotoxicity. METH depleted DA, caused microglial activation, and increased body temperature in CX3CR1 knockout mice to the same extent and over the same time course seen in wild-type controls. The effects of METH in CX3CR1 knockout mice were not gender-dependent and did not extend beyond the striatum. Striatal microglia expressing eGFP constitutively show morphological changes after METH that are characteristic of activation. This response was restricted to the striatum and contrasted sharply with unresponsive eGFP-microglia in surrounding brain areas that are not damaged by METH. We conclude from these studies that CX3CR1 signaling does not modulate METH neurotoxicity or microglial activation. Furthermore, it appears that striatal-resident microglia respond to METH with an activation cascade and then return to a surveying state without undergoing apoptosis or migration.",
     "annotations": [
      {
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   "id": "18544179",
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    {
     "offset": 0,
     "text": "Omitting fentanyl reduces nausea and vomiting, without increasing pain, after sevoflurane for day surgery.",
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       "id": "0",
       "infons": {
        "identifier": "D005283",
        "type": "ChemicalEntity"
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       "text": "fentanyl",
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       ]
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       "id": "1",
       "infons": {
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       "text": "nausea",
       "locations": [
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         "offset": 26,
         "length": 6
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      {
       "id": "2",
       "infons": {
        "identifier": "D014839",
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       "text": "vomiting",
       "locations": [
        {
         "offset": 37,
         "length": 8
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      },
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       "id": "3",
       "infons": {
        "identifier": "D010146",
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       "locations": [
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         "offset": 66,
         "length": 4
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       "locations": [
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     "offset": 107,
     "text": "BACKGROUND AND OBJECTIVE: Despite advantages of induction and maintenance of anaesthesia with sevoflurane, postoperative nausea and vomiting occurs frequently. Fentanyl is a commonly used supplement that may contribute to this, although it may also improve analgesia. METHODS: This double-blind study examined the incidence and severity of postoperative nausea and vomiting and pain in the first 24 h after sevoflurane anaesthesia in 216 adult day surgery patients. Patients were randomly allocated to either receive or not receive 1 1 fentanyl, while a third group received dexamethasone in addition to fentanyl. RESULTS: Omission of fentanyl did not reduce the overall incidence of postoperative nausea and vomiting, but did reduce the incidence of vomiting and/or moderate to severe nausea prior to discharge from 20% and 17% with fentanyl and fentanyl-dexamethasone, respectively, to 5% (P = 0.013). Antiemetic requirements were reduced from 24% and 31% to 7% (P = 0.0012). Dexamethasone had no significant effect on the incidence or severity of postoperative nausea and vomiting. Combining the two fentanyl groups revealed further significant benefits from the avoidance of opioids, reducing postoperative nausea and vomiting and nausea prior to discharge from 35% and 33% to 22% and 19% (P = 0.049 and P = 0.035), respectively, while nausea in the first 24 h was decreased from 42% to 27% (P = 0.034). Pain severity and analgesic requirements were unaffected by the omission of fentanyl. Fentanyl did reduce minor intraoperative movement but had no sevoflurane-sparing effect and increased respiratory depression, hypotension and bradycardia. CONCLUSION: As fentanyl exacerbated postoperative nausea and vomiting without an improvement in postoperative pain and also had adverse cardiorespiratory effects, it appears to be an unnecessary and possibly detrimental supplement to sevoflurane in day surgery.",
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       "id": "5",
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        "identifier": "C009250",
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       "text": "sevoflurane",
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       "text": "fentanyl",
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       "text": "respiratory depression",
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  {
   "id": "18674790",
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    {
     "offset": 0,
     "text": "High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D004041",
        "type": "ChemicalEntity"
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       "text": "fat",
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       "text": "rats",
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    {
     "offset": 89,
     "text": "Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD(10) dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen led to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-alpha, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9+/-14.0 nmol/min/g heart in ND versus 400.2+/-11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-alpha2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and downregulating the JAK/STAT3 pathway.",
     "annotations": [
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       "text": "doxorubicin",
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       "text": "Adriamycin",
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       "text": "doxorubicin",
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       "id": "10",
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       "text": "cardiotoxicity",
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     "text": "Massive proteinuria and acute renal failure after oral bisphosphonate (alendronate) administration in a patient with focal segmental glomerulosclerosis.",
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     "text": "A 61-year-old Japanese man with nephrotic syndrome due to focal segmental glomerulosclerosis was initially responding well to steroid therapy. The amount of daily urinary protein decreased from 15.6 to 2.8 g. Within 14 days of the oral bisphosphonate (alendronate sodium) administration, the amount of daily urinary protein increased rapidly up to 12.8 g with acute renal failure. After discontinuing the oral alendronate, the patient underwent six cycles of hemodialysis and four cycles of LDL apheresis. Urinary volume and serum creatinine levels recovered to the normal range, with urinary protein disappearing completely within 40 days. This report demonstrates that not only intravenous, but also oral bisphosphonates can aggravate proteinuria and acute renal failure.",
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     "offset": 0,
     "text": "Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study.",
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       "id": "0",
       "infons": {
        "identifier": "D003324",
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       "id": "3",
       "infons": {
        "identifier": "D003924",
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 97,
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      }
     ]
    },
    {
     "offset": 144,
     "text": "AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different sulphonylureas. METHODS: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents.",
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   "id": "19631624",
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    {
     "offset": 0,
     "text": "Learning and memory deficits in ecstasy users and their neural correlates during a face-learning task.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "D007859,D008569",
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       "text": "Learning and memory deficits",
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     "text": "It has been consistently shown that ecstasy users display impairments in learning and memory performance. In addition, working memory processing in ecstasy users has been shown to be associated with neural alterations in hippocampal and/or cortical regions as measured by functional magnetic resonance imaging (fMRI). Using functional imaging and a face-learning task, we investigated neural correlates of encoding and recalling face-name associations in 20 recreational drug users whose predominant drug use was ecstasy and 20 controls. To address the potential confounding effects of the cannabis use of the ecstasy using group, a second analysis included 14 previously tested cannabis users (Nestor, L., Roberts, G., Garavan, H., Hester, R., 2008. Deficits in learning and memory: parahippocampal hyperactivity and frontocortical hypoactivity in cannabis users. Neuroimage 40, 1328-1339). Ecstasy users performed significantly worse in learning and memory compared to controls and cannabis users. A conjunction analysis of the encode and recall phases of the task revealed ecstasy-specific hyperactivity in bilateral frontal regions, left temporal, right parietal, bilateral temporal, and bilateral occipital brain regions. Ecstasy-specific hypoactivity was evident in the right dorsal anterior cingulated cortex (ACC) and left posterior cingulated cortex. In both ecstasy and cannabis groups brain activation was decreased in the right medial frontal gyrus, left parahippocampal gyrus, left dorsal cingulate gyrus, and left caudate. These results elucidated ecstasy-related deficits, only some of which might be attributed to cannabis use. These ecstasy-specific effects may be related to the vulnerability of isocortical and allocortical regions to the neurotoxic effects of ecstasy.",
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  {
   "id": "19692487",
   "passages": [
    {
     "offset": 0,
     "text": "Mice lacking mPGES-1 are resistant to lithium-induced polyuria.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "10090",
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       "text": "Mice",
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       "text": "lithium",
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     ]
    },
    {
     "offset": 64,
     "text": "Cyclooxygenase-2 activity is required for the development of lithium-induced polyuria. However, the involvement of a specific, terminal prostaglandin (PG) isomerase has not been evaluated. The present study was undertaken to assess lithium-induced polyuria in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1). A 2-wk administration of LiCl (4 mmol.kg(-1).day(-1) ip) in mPGES-1 +/+ mice led to a marked polyuria with hyposmotic urine. This was associated with elevated renal mPGES-1 protein expression and increased urine PGE(2) excretion. In contrast, mPGES-1 -/- mice were largely resistant to lithium-induced polyuria and a urine concentrating defect, accompanied by nearly complete blockade of high urine PGE(2) and cAMP output. Immunoblotting, immunohistochemistry, and quantitative (q) RT-PCR consistently detected a significant decrease in aquaporin-2 (AQP2) protein expression in both the renal cortex and medulla of lithium-treated +/+ mice. This decrease was significantly attenuated in the -/- mice. qRT-PCR detected similar patterns of changes in AQP2 mRNA in the medulla but not in the cortex. Similarly, the total protein abundance of the Na-K-2Cl cotransporter (NKCC2) in the medulla but not in the cortex of the +/+ mice was significantly reduced by lithium treatment. In contrast, the dowregulation of renal medullary NKCC2 expression was significantly attenuated in the -/- mice. We conclude that mPGES-1-derived PGE(2) mediates lithium-induced polyuria likely via inhibition of AQP2 and NKCC2 expression.",
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       "text": "aquaporin-2",
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       "text": "mice",
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       "text": "AQP2",
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       "id": "32",
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       "text": "Na-K-2Cl cotransporter",
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       "id": "33",
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       "text": "lithium",
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       "text": "AQP2",
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     "text": "Etodolac (E), is a non-narcotic analgesic and antiinflammatory drug. A biodegradable polymer dextran has been utilized as a carrier for synthesis of etodolac-dextran conjugates (ED) to improve its aqueous solubility and reduce gastrointestinal side effects. An activated moiety, i.e. N-acylimidazole derivative of etodolac (EAI), was condensed with the polysaccharide polymer dextran of different molecular weights (40000, 60000, 110000 and 200000). IR spectral data confirmed formation of ester bonding in the conjugates. Etodolac contents were evaluated by UV-spectrophotometric analysis. The molecular weights were determined by measuring viscosity using the Mark-Howink-Sakurada equation. In vitro hydrolysis of ED was done in aqueous buffers (pH 1.2, 7.4, 9) and in 80% (v/v) human plasma (pH 7.4). At pH 9, a higher rate of etodolac release from ED was observed as compared to aqueous buffer of pH 7.4 and 80% human plasma (pH 7.4), following first-order kinetics. In vivo investigations were performed in animals. Acute analgesic and antiinflammatory activities were ascertained using acetic acid induced writhing model (mice) and carrageenan-induced rat paw edema model, respectively. In comparison to control, E and ED1-ED4 showed highly significant analgesic and antiinflammatory activities (p <0.001). Biological evaluation suggested that conjugates (ED1-ED4) retained comparable analgesic and antiinflammatory activities with remarkably reduced ulcerogenicity as compared to their parent drug--etodolac.",
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     "text": "The antiarrhythmic effect and possible ionic mechanisms of pilocarpine on animal models.",
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     "text": "This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca(2+)](i)) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca(2+)](i) overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M(3)-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M(3)-mAChR. The mechanism may be related to the improvement of Ca(2+) handling.",
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       "text": "arrhythmic",
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       "text": "guinea pig",
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     "offset": 0,
     "text": "Nimodipine prevents memory impairment caused by nitroglycerin-induced hypotension in adult mice.",
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       "text": "Nimodipine",
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       "text": "memory impairment",
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       "text": "hypotension",
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     "text": "BACKGROUND: Hypotension and a resultant decrease in cerebral blood flow have been implicated in the development of cognitive dysfunction. We tested the hypothesis that nimodipine (NIMO) administered at the onset of nitroglycerin (NTG)-induced hypotension would preserve long-term associative memory. METHODS: The passive avoidance (PA) paradigm was used to assess memory retention. For PA training, latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock was automatically delivered. Latencies were recorded 48 h later for a testing trial. Ninety-six Swiss-Webster mice (30-35 g, 6-8 wk), were randomized into 6 groups 1) saline (control), 2) NTG immediately after learning, 3) NTG 3 h after learning, 4) NTG and NIMO, 5) vehicle, and 6) NIMO alone. The extent of hypotension and changes in brain tissue oxygenation (PbtO(2)) and in cerebral blood flow were studied in a separate group of animals. RESULTS: All groups exhibited similar training latencies (17.0 +/- 4.6 s). Mice subjected to hypotensive episodes showed a significant decrease in latency time (178 +/- 156 s) compared with those injected with saline, NTG + NIMO, or delayed NTG (580 +/- 81 s, 557 +/- 67 s, and 493 +/- 146 s, respectively). A Kruskal-Wallis 1-way analysis of variance indicated a significant difference among the 4 treatment groups (H = 15.34; P < 0.001). In a separate group of mice not subjected to behavioral studies, the same dose of NTG (n = 3) and NTG + NIMO (n = 3) caused mean arterial blood pressure to decrease from 85.9 +/- 3.8 mm Hg sem to 31.6 +/- 0.8 mm Hg sem and from 86.2 +/- 3.7 mm Hg sem to 32.6 +/- 0.2 mm Hg sem, respectively. Mean arterial blood pressure in mice treated with NIMO alone decreased from 88.1 +/- 3.8 mm Hg to 80.0 +/- 2.9 mm Hg. The intergroup difference was statistically significant (P < 0.05). PbtO(2) decreased from 51.7 +/- 4.5 mm Hg sem to 33.8 +/- 5.2 mm Hg sem in the NTG group and from 38.6 +/- 6.1 mm Hg sem to 25.4 +/- 2.0 mm Hg sem in the NTG + NIMO groups, respectively. There were no significant differences among groups. CONCLUSION: In a PA retention paradigm, the injection of NTG immediately after learning produced a significant impairment of long-term associative memory in mice, whereas delayed induced hypotension had no effect. NIMO attenuated the disruption in consolidation of long-term memory caused by NTG but did not improve latency in the absence of hypotension. The observed effect of NIMO may have been attributable to the preservation of calcium homeostasis during hypotension, because there were no differences in the PbtO(2) indices among groups.",
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  {
   "id": "20080983",
   "passages": [
    {
     "offset": 0,
     "text": "Normalizing effects of modafinil on sleep in chronic cocaine users.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C048833",
        "type": "ChemicalEntity"
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       "text": "modafinil",
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     "offset": 68,
     "text": "OBJECTIVE: The purpose of the present study was to determine the effect of morning-dosed modafinil on sleep and daytime sleepiness in chronic cocaine users. METHOD: Twenty cocaine-dependent participants were randomly assigned to receive modafinil, 400 mg (N=10), or placebo (N=10) every morning at 7:30 a.m. for 16 days in an inpatient, double-blind randomized trial. Participants underwent polysomnographic sleep recordings on days 1 to 3, 7 to 9, and 14 to 16 (first, second, and third weeks of abstinence). The Multiple Sleep Latency Test was performed at 11:30 a.m., 2:00 p.m., and 4:30 p.m. on days 2, 8, and 15. For comparison of sleep architecture variables, 12 healthy comparison participants underwent a single night of experimental polysomnography that followed 1 night of accommodation polysomnography. RESULTS: Progressive abstinence from cocaine was associated with worsening of all measured polysomnographic sleep outcomes. Compared with placebo, modafinil decreased nighttime sleep latency and increased slow-wave sleep time in cocaine-dependent participants. The effect of modafinil interacted with the abstinence week and was associated with longer total sleep time and shorter REM sleep latency in the third week of abstinence. Comparison of slow-wave sleep time, total sleep time, and sleep latency in cocaine-dependent and healthy participants revealed a normalizing effect of modafinil in cocaine-dependent participants. Modafinil was associated with increased daytime sleep latency, as measured by the Multiple Sleep Latency Test, and a nearly significant decrease in subjective daytime sleepiness. CONCLUSIONS: Morning-dosed modafinil promotes nocturnal sleep, normalizes sleep architecture, and decreases daytime sleepiness in abstinent cocaine users. These effects may be relevant in the treatment of cocaine dependence.",
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   "passages": [
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     "offset": 0,
     "text": "Studies of synergy between morphine and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain.",
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       "id": "0",
       "infons": {
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       "locations": [
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     "text": "OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002.",
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     "offset": 0,
     "text": "Coenzyme Q10 treatment ameliorates acute cisplatin nephrotoxicity in mice.",
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     "text": "Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma.",
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     "offset": 0,
     "text": "Dopamine is not essential for the development of methamphetamine-induced neurotoxicity.",
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     "text": "It is widely believed that dopamine (DA) mediates methamphetamine (METH)-induced toxicity to brain dopaminergic neurons, because drugs that interfere with DA neurotransmission decrease toxicity, whereas drugs that increase DA neurotransmission enhance toxicity. However, temperature effects of drugs that have been used to manipulate brain DA neurotransmission confound interpretation of the data. Here we show that the recently reported ability of L-dihydroxyphenylalanine to reverse the protective effect of alpha-methyl-para-tyrosine on METH-induced DA neurotoxicity is also confounded by drug effects on body temperature. Further, we show that mice genetically engineered to be deficient in brain DA develop METH neurotoxicity, as long as the thermic effects of METH are preserved. In addition, we demonstrate that mice genetically engineered to have unilateral brain DA deficits develop METH-induced dopaminergic deficits that are of comparable magnitude on both sides of the brain. Taken together, these findings demonstrate that DA is not essential for the development of METH-induced dopaminergic neurotoxicity and suggest that mechanisms independent of DA warrant more intense investigation.",
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       "text": "neurotoxicity",
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     "text": "Glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus can modulate haloperidol-induced catalepsy.",
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     "text": "The inferior colliculus (IC) is primarily involved in the processing of auditory information, but it is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Functional evidence relating the IC to motor behavior derives from experiments showing that activation of the IC by electrical stimulation or excitatory amino acid microinjection causes freezing, escape-like behavior, and immobility. However, the nature of this immobility is still unclear. The present study examined the influence of excitatory amino acid-mediated mechanisms in the IC on the catalepsy induced by the dopamine receptor blocker haloperidol administered systemically (1 or 0.5 mg/kg) in rats. Haloperidol-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, MK-801 (15 or 30 mmol/0.5 microl) and AP7 (10 or 20 nmol/0.5 microl), or of the NMDA receptor agonist N-methyl-d-aspartate (NMDA, 20 or 30 nmol/0.5 microl). The results showed that intracollicular microinjection of MK-801 and AP7 previous to systemic injections of haloperidol significantly attenuated the catalepsy, as indicated by a reduced latency to step down from a horizontal bar. Accordingly, intracollicular microinjection of NMDA increased the latency to step down the bar. These findings suggest that glutamate-mediated mechanisms in the neural circuits at the IC level influence haloperidol-induced catalepsy and participate in the regulation of motor activity.",
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     "text": "Curcumin ameliorates cognitive dysfunction and oxidative damage in phenobarbitone and carbamazepine administered rats.",
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     "text": "The antiepileptic drugs, phenobarbitone and carbamazepine are well known to cause cognitive impairment on chronic use. The increase in free radical generation has been implicated as one of the important mechanisms of cognitive impairment by antiepileptic drugs. Curcumin has shown antioxidant, anti-inflammatory and neuro-protective properties. Therefore, the present study was carried out to investigate the effect of chronic curcumin administration on phenobarbitone- and carbamazepine-induced cognitive impairment and oxidative stress in rats. Pharmacokinetic interactions of curcumin with phenobarbitone and carbamazepine were also studied. Vehicle/drugs were administered daily for 21days to male Wistar rats. Passive avoidance paradigm and elevated plus maze test were used to assess cognitive function. At the end of study period, serum phenobarbitone and carbamazepine, whole brain malondialdehyde and reduced glutathione levels were estimated. The administration of phenobarbitone and carbamazepine for 21days caused a significant impairment of learning and memory as well as an increased oxidative stress. Concomitant curcumin administration prevented the cognitive impairment and decreased the increased oxidative stress induced by these antiepileptic drugs. Curcumin co-administration did not cause any significant alteration in the serum concentrations of both phenobarbitone as well as carbamazepine. These results show that curcumin has beneficial effect in mitigating the deterioration of cognitive functions and oxidative damage in rats treated with phenobarbitone and carbamazepine without significantly altering their serum concentrations. The findings suggest that curcumin can be considered as a potential safe and effective adjuvant to phenobarbitone and carbamazepine therapy in preventing cognitive impairment associated with these drugs.",
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     "offset": 0,
     "text": "Effects of active constituents of Crocus sativus L., crocin on streptozocin-induced model of sporadic Alzheimer's disease in male rats.",
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       "id": "0",
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       "text": "constituents of Crocus sativus L.",
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       "id": "4",
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     "text": "BACKGROUND: The involvement of water-soluble carotenoids, crocins, as the main and active components of Crocus sativus L. extract in learning and memory processes has been proposed. In the present study, the effect of crocins on sporadic Alzheimer's disease induced by intracerebroventricular (icv) streptozocin (STZ) in male rats was investigated. METHODS: Male adult Wistar rats (n = 90 and 260-290 g) were divided into 1, control; 2 and 3, crocins (15 and 30 mg/kg); 4, STZ; 5 and 6, STZ + crocins (15 and 30 mg/kg) groups. In Alzheimer's disease groups, rats were injected with STZ-icv bilaterally (3 mg/kg) in first day and 3 days later, a similar STZ-icv application was repeated. In STZ + crocin animal groups, crocin was applied in doses of 15 and 30 mg/kg, i.p., one day pre-surgery and continued for three weeks. Prescription of crocin in each dose was repeated once for two days. However, the learning and memory performance was assessed using passive avoidance paradigm, and for spatial cognition evaluation, Y-maze task was used. RESULTS: It was found out that crocin (30 mg/kg)-treated STZ-injected rats show higher correct choices and lower errors in Y-maze than vehicle-treated STZ-injected rats. In addition, crocin in the mentioned dose could significantly attenuated learning and memory impairment in treated STZ-injected group in passive avoidance test. CONCLUSION: Therefore, these results demonstrate the effectiveness of crocin (30 mg/kg) in antagonizing the cognitive deficits caused by STZ-icv in rats and its potential in the treatment of neurodegenerative diseases such as Alzheimer's disease.",
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    {
     "offset": 0,
     "text": "The role of nitric oxide in convulsions induced by lindane in rats.",
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     "text": "Lindane is an organochloride pesticide and scabicide. It evokes convulsions mainly trough the blockage of GABA(A) receptors. Nitric oxide (NO), gaseous neurotransmitter, has contradictor role in epileptogenesis due to opposite effects of L-arginine, precursor of NO syntheses (NOS), and L-NAME (NOS inhibitor) observed in different epilepsy models. The aim of the current study was to determine the effects of NO on the behavioral and EEG characteristics of lindane-induced epilepsy in male Wistar albino rats. The administration of L-arginine (600, 800 and 1000 mg/kg, i.p.) in dose-dependent manner significantly increased convulsion incidence and severity and shortened latency time to first convulsion elicited by lower lindane dose (4 mg/kg, i.p.). On the contrary, pretreatment with L-NAME (500, 700 and 900 mg/kg, i.p.) decreased convulsion incidence and severity and prolonged latency time to convulsion following injection with a convulsive dose of lindane (8 mg/kg, i.p.). EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving l-arginine prior to lindane and decrease of this number in rats pretreated with L-NAME. These results support the conclusion that NO plays a role of endogenous convulsant in rat model of lindane seizures.",
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       "text": "NO",
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       "id": "17",
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     "offset": 0,
     "text": "Crocin improves lipid dysregulation in subacute diazinon exposure through ERK1/2 pathway in rat liver.",
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       "id": "0",
       "infons": {
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     "text": "INTRODUCTION: Diazinon Yis one of the most broadly used organophosphorus insecticides in agriculture. It has been shown that exposure to diazinon may interfere with lipid metabolism. Moreover, the hypolipidemic effect of crocin has been established. Earlier studies revealed the major role of Extracellular signal-regulated kinase (ERK) pathways in low-density lipoprotein receptor (LDLr) expression. The aim of this study was to evaluate changes in the regulation of lipid metabolism, ERK and LDLr expression in the liver of rats exposed to subacute diazinon. Furthermore ameliorating effect of crocin on diazinon induced disturbed cholesterol homeostasis was studied. METHODS: 24 Rats were divided into 4 groups and received following treatments for 4 weeks; Corn oil (control), diazinon (15mg/kg per day, orally) and crocin (12.5 and 25mg/kg per day, intraperitoneally) in combination with diazinon (15 mg/kg). The levels of cholesterol, triglyceride and LDL in blood of rats were analyzed. Moreover mRNA levels of LDLr and ERK1/2 as well as protein levels of total and activated forms of ERK1/2 in rat liver were evaluated by Western blotting and quantitative real time polymerase chain reaction analysis. RESULTS: Our data showed that subacute exposure to diazinon significantly increased concentrations of cholesterol, triglyceride and LDL. Moreover diazinon decreased ERK1/2 protein phosphorylation and LDLr transcript. Crocin reduced inhibition of ERK activation and diazinon-induced hyperlipemia and increased levels of LDLr transcript. CONCLUSIONS: Crocin may be considered as a novel protective agent in diazinon-induced hyperlipemia through modulating of ERK pathway and increase of LDLr expression.",
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     "infons": {
      "entity1": "C058121",
      "entity2": "D012844",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "25706",
      "entity2": "C058121",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "24341598",
   "passages": [
    {
     "offset": 0,
     "text": "Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast-induced nephropathy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D012965",
        "type": "ChemicalEntity"
       },
       "text": "sodium chloride",
       "locations": [
        {
         "offset": 34,
         "length": 15
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D004110",
        "type": "ChemicalEntity"
       },
       "text": "diltiazem",
       "locations": [
        {
         "offset": 55,
         "length": 9
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D003287",
        "type": "ChemicalEntity"
       },
       "text": "contrast",
       "locations": [
        {
         "offset": 82,
         "length": 8
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nephropathy",
       "locations": [
        {
         "offset": 99,
         "length": 11
        }
       ]
      }
     ]
    },
    {
     "offset": 112,
     "text": "INTRODUCTION AND OBJECTIVE: Contrast-induced nephropathy (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D003287",
        "type": "ChemicalEntity"
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       "text": "Contrast",
       "locations": [
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         "offset": 140,
         "length": 8
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       "id": "5",
       "infons": {
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       "text": "nephropathy",
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         "offset": 157,
         "length": 11
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      },
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       "id": "6",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "CIN",
       "locations": [
        {
         "offset": 170,
         "length": 3
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       ]
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       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 230,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012965",
        "type": "ChemicalEntity"
       },
       "text": "sodium chloride",
       "locations": [
        {
         "offset": 327,
         "length": 15
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D017693",
        "type": "ChemicalEntity"
       },
       "text": "sodium bicarbonate",
       "locations": [
        {
         "offset": 348,
         "length": 18
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D012965",
        "type": "ChemicalEntity"
       },
       "text": "sodium chloride",
       "locations": [
        {
         "offset": 389,
         "length": 15
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D004110",
        "type": "ChemicalEntity"
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       "text": "diltiazem",
       "locations": [
        {
         "offset": 419,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "calcium",
       "locations": [
        {
         "offset": 432,
         "length": 7
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CIN",
       "locations": [
        {
         "offset": 471,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 518,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D003287",
        "type": "ChemicalEntity"
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       "text": "contrast",
       "locations": [
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         "offset": 571,
         "length": 8
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       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "D003404",
        "type": "ChemicalEntity"
       },
       "text": "creatinine",
       "locations": [
        {
         "offset": 641,
         "length": 10
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "Patients",
       "locations": [
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         "offset": 686,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 748,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 777,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D012965",
        "type": "ChemicalEntity"
       },
       "text": "sodium chloride",
       "locations": [
        {
         "offset": 812,
         "length": 15
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D005947",
        "type": "ChemicalEntity"
       },
       "text": "dextrose",
       "locations": [
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         "offset": 885,
         "length": 8
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       ]
      },
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       "id": "22",
       "infons": {
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       "text": "sodium bicarbonate",
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       ]
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       "id": "23",
       "infons": {
        "identifier": "D012965",
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       "text": "sodium chloride",
       "locations": [
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         "offset": 966,
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       "id": "24",
       "infons": {
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       "text": "contrast",
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         "offset": 1003,
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       ]
      },
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       "id": "25",
       "infons": {
        "identifier": "D004110",
        "type": "ChemicalEntity"
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       "text": "diltiazem",
       "locations": [
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         "offset": 1075,
         "length": 9
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       ]
      },
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       "id": "26",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "contrast",
       "locations": [
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         "offset": 1127,
         "length": 8
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       ]
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       "id": "27",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 1158,
         "length": 8
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D001806",
        "type": "ChemicalEntity"
       },
       "text": "blood urea nitrogen",
       "locations": [
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         "offset": 1175,
         "length": 19
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D001806",
        "type": "ChemicalEntity"
       },
       "text": "BUN",
       "locations": [
        {
         "offset": 1196,
         "length": 3
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D003404",
        "type": "ChemicalEntity"
       },
       "text": "creatinine",
       "locations": [
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         "offset": 1205,
         "length": 10
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       ]
      },
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       "id": "31",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "contrast",
       "locations": [
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         "offset": 1307,
         "length": 8
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       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D003404",
        "type": "ChemicalEntity"
       },
       "text": "creatinine",
       "locations": [
        {
         "offset": 1345,
         "length": 10
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
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         "offset": 1429,
         "length": 8
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1464,
         "length": 8
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D058186",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "acute renal failure",
       "locations": [
        {
         "offset": 1483,
         "length": 19
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D058186",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ARF",
       "locations": [
        {
         "offset": 1504,
         "length": 3
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D003287",
        "type": "ChemicalEntity"
       },
       "text": "contrast",
       "locations": [
        {
         "offset": 1533,
         "length": 8
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1587,
         "length": 8
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "D058186",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ARF",
       "locations": [
        {
         "offset": 1610,
         "length": 3
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "D012965",
        "type": "ChemicalEntity"
       },
       "text": "sodium chloride",
       "locations": [
        {
         "offset": 1833,
         "length": 15
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "D017693",
        "type": "ChemicalEntity"
       },
       "text": "sodium bicarbonate",
       "locations": [
        {
         "offset": 1850,
         "length": 18
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "D012965",
        "type": "ChemicalEntity"
       },
       "text": "sodium chloride",
       "locations": [
        {
         "offset": 1882,
         "length": 15
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "D004110",
        "type": "ChemicalEntity"
       },
       "text": "diltiazem",
       "locations": [
        {
         "offset": 1903,
         "length": 9
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CIN",
       "locations": [
        {
         "offset": 1942,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D058186",
      "entity2": "D003287",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D017693",
      "entity2": "D007674",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D017693",
      "entity2": "D004110",
      "type": "Comparison",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D003287",
      "entity2": "D007674",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D004110",
      "entity2": "D002118",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D004110",
      "entity2": "D007674",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D004110",
      "entity2": "D003287",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "24535067",
   "passages": [
    {
     "offset": 0,
     "text": "Prevention of etomidate-induced myoclonus: which is superior: Fentanyl, midazolam, or a combination? A Retrospective comparative study.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D005045",
        "type": "ChemicalEntity"
       },
       "text": "etomidate",
       "locations": [
        {
         "offset": 14,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D009207",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myoclonus",
       "locations": [
        {
         "offset": 32,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D005283",
        "type": "ChemicalEntity"
       },
       "text": "Fentanyl",
       "locations": [
        {
         "offset": 62,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D008874",
        "type": "ChemicalEntity"
       },
       "text": "midazolam",
       "locations": [
        {
         "offset": 72,
         "length": 9
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       ]
      }
     ]
    },
    {
     "offset": 136,
     "text": "BACKGROUND: In this retrospective comparative study, we aimed to compare the effectiveness of fentanyl, midazolam, and a combination of fentanyl and midazolam to prevent etomidate-induced myoclonus. MATERIAL AND METHODS: This study was performed based on anesthesia records. Depending on the drugs that would be given before the induction of anesthesia with etomidate, the patients were separated into 4 groups: no pretreatment (Group NP), fentanyl 1 ug.kg-1 (Group F), midazolam 0.03 mg.kg-1 (Group M), and midazolam 0.015 mg.kg-1 + fentanyl 0.5 ug.kg-1 (Group FM). Patients who received the same anesthetic procedure were selected: 2 minutes after intravenous injections of the pretreatment drugs, anesthesia is induced with 0.3 mg.kg-1 etomidate injected intravenously over a period of 20-30 seconds. Myoclonic movements are evaluated, which were observed and graded according to clinical severity during the 2 minutes after etomidate injection. The severity of pain due to etomidate injection, mean arterial pressure, heart rate, and adverse effects were also evaluated. RESULTS: Study results showed that myoclonus incidence was 85%, 40%, 70%, and 25% in Group NP, Group F, Group M, and Group FM, respectively, and were significantly lower in Group F and Group FM. CONCLUSIONS: We conclude that pretreatment with fentanyl or combination of fentanyl and midazolam was effective in preventing etomidate-induced myoclonus.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D005283",
        "type": "ChemicalEntity"
       },
       "text": "fentanyl",
       "locations": [
        {
         "offset": 230,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008874",
        "type": "ChemicalEntity"
       },
       "text": "midazolam",
       "locations": [
        {
         "offset": 240,
         "length": 9
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D005283",
        "type": "ChemicalEntity"
       },
       "text": "fentanyl",
       "locations": [
        {
         "offset": 272,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008874",
        "type": "ChemicalEntity"
       },
       "text": "midazolam",
       "locations": [
        {
         "offset": 285,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D005045",
        "type": "ChemicalEntity"
       },
       "text": "etomidate",
       "locations": [
        {
         "offset": 306,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D009207",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myoclonus",
       "locations": [
        {
         "offset": 324,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D005045",
        "type": "ChemicalEntity"
       },
       "text": "etomidate",
       "locations": [
        {
         "offset": 494,
         "length": 9
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 509,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D005283",
        "type": "ChemicalEntity"
       },
       "text": "fentanyl",
       "locations": [
        {
         "offset": 576,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008874",
        "type": "ChemicalEntity"
       },
       "text": "midazolam",
       "locations": [
        {
         "offset": 606,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008874",
        "type": "ChemicalEntity"
       },
       "text": "midazolam",
       "locations": [
        {
         "offset": 644,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D005283",
        "type": "ChemicalEntity"
       },
       "text": "fentanyl",
       "locations": [
        {
         "offset": 670,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Patients",
       "locations": [
        {
         "offset": 703,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D005045",
        "type": "ChemicalEntity"
       },
       "text": "etomidate",
       "locations": [
        {
         "offset": 875,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009069",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Myoclonic movements",
       "locations": [
        {
         "offset": 940,
         "length": 19
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D005045",
        "type": "ChemicalEntity"
       },
       "text": "etomidate",
       "locations": [
        {
         "offset": 1064,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D010146",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pain",
       "locations": [
        {
         "offset": 1101,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D005045",
        "type": "ChemicalEntity"
       },
       "text": "etomidate",
       "locations": [
        {
         "offset": 1113,
         "length": 9
        }
       ]
      },
      {
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     "text": "Testosterone ameliorates streptozotocin-induced memory impairment in male rats.",
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     "text": "AIM: To study the effects of testosterone on streptozotocin (STZ)-induced memory impairment in male rats. METHODS: Adult male Wistar rats were intracerebroventricularly (icv) infused with STZ (750 ug) on d 1 and d 3, and a passive avoidance task was assessed 2 weeks after the first injection of STZ. Castration surgery was performed in another group of rats, and the passive avoidance task was assessed 4 weeks after the operation. Testosterone (1 mg.kg(-1).d(-1), sc), the androgen receptor antagonist flutamide (10 mg.kg(-1).d(-1), ip), the estrogen receptor antagonist tamoxifen (1 mg.kg(-1).d(-1), ip) or the aromatase inhibitor letrozole (4 mg.kg(-1).d(-1), ip) were administered for 6 d after the first injection of STZ. RESULTS: STZ administration and castration markedly decreased both STL1 (the short memory) and STL2 (the long memory) in passive avoidance tests. Testosterone replacement almost restored the STL1 and STL2 in castrated rats, and significantly prolonged the STL1 and STL2 in STZ-treated rats. Administration of flutamide, letrozole or tamoxifen significantly impaired the memory in intact rats, and significantly attenuated the testosterone replacement in improving STZ- and castration-induced memory impairment. CONCLUSION: Testosterone administration ameliorates STZ- and castration-induced memory impairment in male Wistar rats.",
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     "text": "A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions.",
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