{
 "source": "PubTator",
 "date": "2021-11-30",
 "key": "BioC.key",
 "documents": [
  {
   "id": "15485686",
   "passages": [
    {
     "offset": 0,
     "text": "A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6331",
        "type": "GeneOrGeneProduct"
       },
       "text": "SCN5A",
       "locations": [
        {
         "offset": 8,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "long QT syndrome",
       "locations": [
        {
         "offset": 56,
         "length": 16
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D013610",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tachycardia",
       "locations": [
        {
         "offset": 97,
         "length": 11
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D001919",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bradycardia",
       "locations": [
        {
         "offset": 109,
         "length": 11
        }
       ]
      }
     ]
    },
    {
     "offset": 122,
     "text": "OBJECTIVE: Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth. METHODS: Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia. RESULTS: A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Na(v)1.5 cardiac sodium channel, with a G-->A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation. CONCLUSIONS: These findings suggest that the Na(v)1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "long QT syndrome",
       "locations": [
        {
         "offset": 144,
         "length": 16
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LQTS",
       "locations": [
        {
         "offset": 162,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 292,
         "length": 7
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001919",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bradycardia",
       "locations": [
        {
         "offset": 311,
         "length": 11
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D054537",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atrioventricular block",
       "locations": [
        {
         "offset": 328,
         "length": 22
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D017180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ventricular tachycardia",
       "locations": [
        {
         "offset": 355,
         "length": 23
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D054537",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atrioventricular block",
       "locations": [
        {
         "offset": 482,
         "length": 22
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D008012",
        "type": "ChemicalEntity"
       },
       "text": "lidocaine",
       "locations": [
        {
         "offset": 555,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D008801",
        "type": "ChemicalEntity"
       },
       "text": "mexiletine",
       "locations": [
        {
         "offset": 592,
         "length": 10
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D017180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ventricular tachycardia",
       "locations": [
        {
         "offset": 630,
         "length": 23
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LQTS",
       "locations": [
        {
         "offset": 685,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "6331",
        "type": "GeneOrGeneProduct"
       },
       "text": "Na(v)1.5",
       "locations": [
        {
         "offset": 767,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D012964",
        "type": "ChemicalEntity"
       },
       "text": "sodium",
       "locations": [
        {
         "offset": 784,
         "length": 6
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|SUB|G|CODON1763|A",
        "type": "SequenceVariant"
       },
       "text": "G-->A substitution at codon 1763",
       "locations": [
        {
         "offset": 807,
         "length": 32
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|SUB|V||M",
        "type": "SequenceVariant"
       },
       "text": "valine (GTG) to a methionine (ATG)",
       "locations": [
        {
         "offset": 857,
         "length": 34
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "CVCL_2737",
        "type": "CellLine"
       },
       "text": "tsA201",
       "locations": [
        {
         "offset": 1018,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D013779",
        "type": "ChemicalEntity"
       },
       "text": "tetrodotoxin",
       "locations": [
        {
         "offset": 1092,
         "length": 12
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D008012",
        "type": "ChemicalEntity"
       },
       "text": "lidocaine",
       "locations": [
        {
         "offset": 1119,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "p|SUB|V|1764|M",
        "type": "SequenceVariant"
       },
       "text": "V1764M",
       "locations": [
        {
         "offset": 1366,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "p|SUB|I|1762|A",
        "type": "SequenceVariant"
       },
       "text": "I1762A",
       "locations": [
        {
         "offset": 1408,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "6331",
        "type": "GeneOrGeneProduct"
       },
       "text": "Na(v)1.5",
       "locations": [
        {
         "offset": 1557,
         "length": 8
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "p|SUB|V|1763|M",
        "type": "SequenceVariant"
       },
       "text": "V1763M",
       "locations": [
        {
         "offset": 1566,
         "length": 6
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D008133",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LQTS",
       "locations": [
        {
         "offset": 1731,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D001145",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "arrhythmias",
       "locations": [
        {
         "offset": 1760,
         "length": 11
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D008012",
        "type": "ChemicalEntity"
       },
       "text": "lidocaine",
       "locations": [
        {
         "offset": 1790,
         "length": 9
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D008801",
        "type": "ChemicalEntity"
       },
       "text": "mexiletine",
       "locations": [
        {
         "offset": 1804,
         "length": 10
        }
       ]
      }
     ]
    }
   ],
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     "infons": {
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      "novel": "Novel"
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      "entity1": "D001145",
      "entity2": "D008012",
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      "novel": "No"
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     "id": "R13",
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      "entity1": "D008133",
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      "novel": "No"
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   "id": "16046395",
   "passages": [
    {
     "offset": 0,
     "text": "Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 32,
         "length": 5
        }
       ]
      },
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       "id": "1",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
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       "text": "mu opioid receptor",
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         "offset": 38,
         "length": 18
        }
       ]
      },
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       "id": "2",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 58,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
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       "text": "A118G",
       "locations": [
        {
         "offset": 83,
         "length": 5
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       ]
      }
     ]
    },
    {
     "offset": 90,
     "text": "As a primary target for opioid drugs and peptides, the mu opioid receptor (OPRM1) plays a key role in pain perception and addiction. Genetic variants of OPRM1 have been implicated in predisposition to drug addiction, in particular the single nucleotide polymorphism A118G, leading to an N40D substitution, with an allele frequency of 10-32%, and uncertain functions. We have measured allele-specific mRNA expression of OPRM1 in human autopsy brain tissues, using A118G as a marker. In 8 heterozygous samples measured, the A118 mRNA allele was 1.5-2.5-fold more abundant than the G118 allele. Transfection into Chinese hamster ovary cells of a cDNA representing only the coding region of OPRM1, carrying adenosine, guanosine, cytidine, and thymidine in position 118, resulted in 1.5-fold lower mRNA levels only for OPRM1-G118, and more than 10-fold lower OPRM1 protein levels, measured by Western blotting and receptor binding assay. After transfection and inhibition of transcription with actinomycin D, analysis of mRNA turnover failed to reveal differences in mRNA stability between A118 and G118 alleles, indicating a defect in transcription or mRNA maturation. These results indicate that OPRM1-G118 is a functional variant with deleterious effects on both mRNA and protein yield. Clarifying the functional relevance of polymorphisms associated with susceptibility to a complex disorder such as drug addiction provides a foundation for clinical association studies.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
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       "text": "mu opioid receptor",
       "locations": [
        {
         "offset": 145,
         "length": 18
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 165,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D010146",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pain",
       "locations": [
        {
         "offset": 192,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 243,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D019966",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "drug addiction",
       "locations": [
        {
         "offset": 291,
         "length": 14
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "A118G",
       "locations": [
        {
         "offset": 356,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
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       "text": "N40D",
       "locations": [
        {
         "offset": 377,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "4988",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 509,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 518,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "A118G",
       "locations": [
        {
         "offset": 553,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "A118",
       "locations": [
        {
         "offset": 612,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "G118",
       "locations": [
        {
         "offset": 669,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "10029",
        "type": "OrganismTaxon"
       },
       "text": "Chinese hamster",
       "locations": [
        {
         "offset": 700,
         "length": 15
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "100770962",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 777,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "adenosine, guanosine, cytidine, and thymidine in position 118",
       "locations": [
        {
         "offset": 793,
         "length": 61
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "100770962",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 904,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "G118",
       "locations": [
        {
         "offset": 910,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "100770962",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 944,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D003609",
        "type": "ChemicalEntity"
       },
       "text": "actinomycin D",
       "locations": [
        {
         "offset": 1079,
         "length": 13
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "A118",
       "locations": [
        {
         "offset": 1175,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs1799971",
        "type": "SequenceVariant"
       },
       "text": "G118",
       "locations": [
        {
         "offset": 1184,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "100770962",
        "type": "GeneOrGeneProduct"
       },
       "text": "OPRM1",
       "locations": [
        {
         "offset": 1283,
         "length": 5
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs1799971",
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       },
       "text": "G118",
       "locations": [
        {
         "offset": 1289,
         "length": 4
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D019966",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "drug addiction",
       "locations": [
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         "offset": 1489,
         "length": 14
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       ]
      }
     ]
    }
   ],
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      "novel": "No"
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     "text": "Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer.",
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       "text": "carbonyl reductase 3",
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       "text": "NQO1",
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       "infons": {
        "identifier": "D006333",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "congestive heart failure",
       "locations": [
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         "length": 24
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     "text": "BACKGROUND: Exposure to anthracyclines as part of cancer therapy has been associated with the development of congestive heart failure (CHF). The potential role of genetic risk factors in anthracycline-related CHF remains to be defined. Thus, in this study, the authors examined whether common polymorphisms in candidate genes involved in the pharmacodynamics of anthracyclines (in particular, the nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and the carbonyl reductase 3 gene CBR3) had an impact on the risk of anthracycline-related CHF. METHODS: A nested case-control study was conducted within a cohort of 1979 patients enrolled in the Childhood Cancer Survivor Study who received treatment with anthracyclines and had available DNA. Thirty patients with CHF (cases) and 115 matched controls were genotyped for polymorphisms in NQO1 (NQO1*2) and CBR3 (the CBR3 valine [V] to methionine [M] substitution at position 244 [V244M]). Enzyme activity assays with recombinant CBR3 isoforms (CBR3 V244 and CBR3 M244) and the anthracycline substrate doxorubicin were used to investigate the functional impact of the CBR3 V244M polymorphism. RESULTS: Multivariate analyses adjusted for sex and primary disease recurrence were used to test for associations between the candidate genetic polymorphisms (NQO1*2 and CBR3 V244M) and the risk of CHF. Analyses indicated no association between the NQO1*2 polymorphism and the risk of anthracycline-related CHF (odds ratio [OR], 1.04; P=.97). There was a trend toward an association between the CBR3 V244M polymorphism and the risk of CHF (OR, 8.16; P=.056 for G/G vs A/A; OR, 5.44; P=.092 for G/A vs A/A). In line, recombinant CBR3 V244 (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit of time than CBR3 M244 (A allele; CBR3 V244 [8.26+/-3.57 nmol/hour.mg] vs CBR3 M244 [3.22+/-0.67 nmol/hour.mg]; P=.01). CONCLUSIONS: The functional CBR3 V244M polymorphism may have an impact on the risk of anthracycline-related CHF among childhood cancer survivors by modulating the intracardiac formation of cardiotoxic anthracycline alcohol metabolites. Larger confirmatory case-control studies are warranted.",
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     "id": "R12",
     "infons": {
      "entity1": "874",
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      "novel": "Novel"
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     "id": "R13",
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      "entity1": "874",
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      "novel": "Novel"
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     "id": "R14",
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      "type": "Association",
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    }
   ]
  },
  {
   "id": "1848636",
   "passages": [
    {
     "offset": 0,
     "text": "Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003647",
        "type": "ChemicalEntity"
       },
       "text": "Debrisoquine",
       "locations": [
        {
         "offset": 0,
         "length": 12
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "154",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-2 receptor",
       "locations": [
        {
         "offset": 52,
         "length": 15
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D008790",
        "type": "ChemicalEntity"
       },
       "text": "metoprolol",
       "locations": [
        {
         "offset": 88,
         "length": 10
        }
       ]
      }
     ]
    },
    {
     "offset": 120,
     "text": "The metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D008790",
        "type": "ChemicalEntity"
       },
       "text": "metoprolol",
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       "id": "4",
       "infons": {
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       "text": "debrisoquine",
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       ]
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       "id": "5",
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       "text": "sparteine",
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         "offset": 227,
         "length": 9
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       ]
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       "id": "6",
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       "text": "beta-1 adrenoceptor",
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       ]
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       "id": "7",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "metoprolol",
       "locations": [
        {
         "offset": 442,
         "length": 10
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       ]
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       "id": "8",
       "infons": {
        "identifier": "154",
        "type": "GeneOrGeneProduct"
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       "text": "beta-2 adrenoceptor",
       "locations": [
        {
         "offset": 511,
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       "id": "9",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "metoprolol",
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       ]
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       "id": "10",
       "infons": {
        "identifier": "D008790",
        "type": "ChemicalEntity"
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       "text": "metoprolol",
       "locations": [
        {
         "offset": 603,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D013726",
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       "text": "terbutaline",
       "locations": [
        {
         "offset": 617,
         "length": 11
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D007008",
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       "text": "hypokalemia",
       "locations": [
        {
         "offset": 637,
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        }
       ]
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      {
       "id": "13",
       "infons": {
        "identifier": "D008790",
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       "text": "metoprolol",
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        }
       ]
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       "id": "14",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "metoprolol",
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         "offset": 838,
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      {
       "id": "15",
       "infons": {
        "identifier": "D013726",
        "type": "ChemicalEntity"
       },
       "text": "terbutaline",
       "locations": [
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         "offset": 944,
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        }
       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "D008790",
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       "text": "metoprolol",
       "locations": [
        {
         "offset": 1059,
         "length": 10
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       ]
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       "id": "17",
       "infons": {
        "identifier": "D013726",
        "type": "ChemicalEntity"
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       "text": "terbutaline",
       "locations": [
        {
         "offset": 1149,
         "length": 11
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D011188",
        "type": "ChemicalEntity"
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       "text": "potassium",
       "locations": [
        {
         "offset": 1227,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D013726",
        "type": "ChemicalEntity"
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       "text": "terbutaline",
       "locations": [
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         "offset": 1238,
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        }
       ]
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       "id": "20",
       "infons": {
        "identifier": "D008790",
        "type": "ChemicalEntity"
       },
       "text": "metoprolol",
       "locations": [
        {
         "offset": 1251,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C029504",
        "type": "ChemicalEntity"
       },
       "text": "alpha-hydroxymetoprolol",
       "locations": [
        {
         "offset": 1294,
         "length": 23
        }
       ]
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       "id": "22",
       "infons": {
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       "text": "metoprolol",
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       "id": "23",
       "infons": {
        "identifier": "D008790",
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       "text": "metoprolol",
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       "id": "24",
       "infons": {
        "identifier": "D013726",
        "type": "ChemicalEntity"
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       "text": "terbutaline",
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        }
       ]
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       "id": "25",
       "infons": {
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        "type": "ChemicalEntity"
       },
       "text": "metoprolol",
       "locations": [
        {
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         "length": 10
        }
       ]
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       "id": "26",
       "infons": {
        "identifier": "C029504",
        "type": "ChemicalEntity"
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       "text": "alpha-hydroxymetoprolol",
       "locations": [
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         "offset": 1523,
         "length": 23
        }
       ]
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       "id": "27",
       "infons": {
        "identifier": "D008790",
        "type": "ChemicalEntity"
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       "text": "metoprolol",
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         "length": 10
        }
       ]
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       "id": "28",
       "infons": {
        "identifier": "D008790",
        "type": "ChemicalEntity"
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       "text": "metoprolol",
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      "novel": "No"
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      "entity1": "D008790",
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      "novel": "No"
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      "type": "Negative_Correlation",
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    }
   ]
  },
  {
   "id": "19394258",
   "passages": [
    {
     "offset": 0,
     "text": "The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "DGUOK",
       "locations": [
        {
         "offset": 18,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C580039",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hepatocerebral mitochondrial DNA depletion syndrome",
       "locations": [
        {
         "offset": 49,
         "length": 51
        }
       ]
      }
     ]
    },
    {
     "offset": 102,
     "text": "Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "C580039",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Deoxyguanosine kinase (dGK) deficiency",
       "locations": [
        {
         "offset": 102,
         "length": 38
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C580039",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mitochondrial DNA depletion",
       "locations": [
        {
         "offset": 164,
         "length": 27
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "DGUOK",
       "locations": [
        {
         "offset": 297,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "DGUOK",
       "locations": [
        {
         "offset": 368,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 374,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "DGUOK",
       "locations": [
        {
         "offset": 393,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|C|444-62|A",
        "type": "SequenceVariant"
       },
       "text": "c.444-62C>A",
       "locations": [
        {
         "offset": 420,
         "length": 11
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 457,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D028361",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "respiratory chain deficiencies",
       "locations": [
        {
         "offset": 527,
         "length": 30
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C580039",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mitochondrial DNA depletion",
       "locations": [
        {
         "offset": 562,
         "length": 27
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "DGUOK",
       "locations": [
        {
         "offset": 629,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 635,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "-",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "subtentorial abnormal myelination",
       "locations": [
        {
         "offset": 687,
         "length": 33
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "moderate hyperintensity",
       "locations": [
        {
         "offset": 725,
         "length": 23
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 781,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "dGK",
       "locations": [
        {
         "offset": 1116,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003853",
        "type": "ChemicalEntity"
       },
       "text": "deoxyribonucleosides",
       "locations": [
        {
         "offset": 1179,
         "length": 20
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "DGUOK",
       "locations": [
        {
         "offset": 1406,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "DGUOK",
       "locations": [
        {
         "offset": 1450,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "1716",
        "type": "GeneOrGeneProduct"
       },
       "text": "dGK",
       "locations": [
        {
         "offset": 1530,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
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      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
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      "novel": "Novel"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|SUB|C|444-62|A",
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      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|SUB|C|444-62|A",
      "entity2": "D028361",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19565319",
   "passages": [
    {
     "offset": 0,
     "text": "Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "135",
        "type": "GeneOrGeneProduct"
       },
       "text": "Adenosine A(2A) receptor",
       "locations": [
        {
         "offset": 0,
         "length": 24
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "135",
        "type": "GeneOrGeneProduct"
       },
       "text": "ADORA2A",
       "locations": [
        {
         "offset": 31,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001321",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autistic symptoms",
       "locations": [
        {
         "offset": 62,
         "length": 17
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D001008",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anxiety",
       "locations": [
        {
         "offset": 84,
         "length": 7
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000067877",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autism spectrum disorder",
       "locations": [
        {
         "offset": 95,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 121,
     "text": "Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A(2A) receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A(2A) receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D000067877",
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  {
   "id": "20648600",
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    {
     "offset": 0,
     "text": "High frequency of lamivudine resistance mutations in Brazilian patients co-infected with HIV and hepatitis B.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
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       "text": "lamivudine",
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       ]
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       "id": "1",
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       "text": "patients",
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       "id": "2",
       "infons": {
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       "text": "co-infected with HIV and hepatitis B",
       "locations": [
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         "offset": 72,
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    },
    {
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     "text": "This study analyzed the genotype distribution and frequency of lamivudine (LAM) and tenofovir (TDF) resistance mutations in a group of patients co-infected with HIV and hepatitis B virus (HBV). A cross-sectional study of 847 patients with HIV was conducted. Patients provided blood samples for HBsAg detection. The load of HBV was determined using an \"in-house\" real-time polymerase chain reaction. HBV genotypes/subgenotypes, antiviral resistance, basal core promoter (BCP), and precore mutations were detected by DNA sequencing. Twenty-eight patients with co-infection were identified. The distribution of HBV genotypes among these patients was A (n = 9; 50%), D (n = 4; 22.2%), G (n = 3; 16.7%), and F (n = 2; 11.1%). Eighteen patients were treated with LAM and six patients were treated with LAM plus TDF. The length of exposure to LAM and TDF varied from 4 to 216 months. LAM resistance substitutions (rtL180M + rtM204V) were detected in 10 (50%) of the 20 patients with viremia. This pattern and an accompanying rtV173L mutation was found in four patients. Three patients with the triple polymerase substitution pattern (rtV173L + rtL180M + rtM204V) had associated changes in the envelope gene (sE164D + sI195M). Mutations in the BCP region (A1762T, G1764A) and in the precore region (G1896A, G1899A) were also found. No putative TDF resistance substitution was detected. The data suggest that prolonged LAM use is associated with the emergence of particular changes in the HBV genome, including substitutions that may elicit a vaccine escape phenotype. No putative TDF resistance change was detected after prolonged use of TDF.",
     "annotations": [
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       "id": "3",
       "infons": {
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       "text": "lamivudine",
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       "id": "4",
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       "text": "LAM",
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         "length": 3
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       "id": "5",
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       "text": "tenofovir",
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         "length": 9
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       "text": "TDF",
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       "text": "patients",
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         "length": 8
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      },
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       "id": "8",
       "infons": {
        "identifier": "D006509,D015658",
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       "text": "co-infected with HIV and hepatitis B virus",
       "locations": [
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         "offset": 254,
         "length": 42
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       ]
      },
      {
       "id": "9",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "HBV",
       "locations": [
        {
         "offset": 298,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
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       "text": "patients",
       "locations": [
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       ]
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       "id": "11",
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       "text": "HIV",
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       "id": "12",
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       "text": "Patients",
       "locations": [
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         "offset": 368,
         "length": 8
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       ]
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       "id": "13",
       "infons": {
        "identifier": "D006514",
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       "text": "HBsAg",
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         "length": 5
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       "id": "14",
       "infons": {
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       "text": "HBV",
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       "id": "15",
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       "text": "HBV",
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       "id": "16",
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       "text": "patients",
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       "text": "infection",
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       "id": "19",
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       "text": "HBV",
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       "id": "20",
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       "text": "patients",
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       "id": "21",
       "infons": {
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       "text": "patients",
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       "id": "22",
       "infons": {
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         "offset": 867,
         "length": 3
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       "id": "23",
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       "id": "24",
       "infons": {
        "identifier": "D019259",
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       "text": "LAM",
       "locations": [
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         "offset": 906,
         "length": 3
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      },
      {
       "id": "25",
       "infons": {
        "identifier": "D000068698",
        "type": "ChemicalEntity"
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       "text": "TDF",
       "locations": [
        {
         "offset": 915,
         "length": 3
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
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       "text": "LAM",
       "locations": [
        {
         "offset": 946,
         "length": 3
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D000068698",
        "type": "ChemicalEntity"
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       "text": "TDF",
       "locations": [
        {
         "offset": 954,
         "length": 3
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D019259",
        "type": "ChemicalEntity"
       },
       "text": "LAM",
       "locations": [
        {
         "offset": 987,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "p|SUB|L|180|M",
        "type": "SequenceVariant"
       },
       "text": "L180M",
       "locations": [
        {
         "offset": 1019,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "p|SUB|M|204|V",
        "type": "SequenceVariant"
       },
       "text": "M204V",
       "locations": [
        {
         "offset": 1029,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1072,
         "length": 8
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D014766",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "viremia",
       "locations": [
        {
         "offset": 1086,
         "length": 7
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "p|SUB|V|173|L",
        "type": "SequenceVariant"
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       "text": "V173L",
       "locations": [
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         "offset": 1130,
         "length": 5
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       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 1163,
         "length": 8
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       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1179,
         "length": 8
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       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "944565",
        "type": "GeneOrGeneProduct"
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       "text": "polymerase",
       "locations": [
        {
         "offset": 1204,
         "length": 10
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       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "p|SUB|V|173|L",
        "type": "SequenceVariant"
       },
       "text": "V173L",
       "locations": [
        {
         "offset": 1239,
         "length": 5
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       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "p|SUB|L|180|M",
        "type": "SequenceVariant"
       },
       "text": "L180M",
       "locations": [
        {
         "offset": 1249,
         "length": 5
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       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "p|SUB|M|204|V",
        "type": "SequenceVariant"
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       "text": "M204V",
       "locations": [
        {
         "offset": 1259,
         "length": 5
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       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "944569",
        "type": "GeneOrGeneProduct"
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       "text": "envelope",
       "locations": [
        {
         "offset": 1296,
         "length": 8
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "p|SUB|E|164|D",
        "type": "SequenceVariant"
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       "text": "E164D",
       "locations": [
        {
         "offset": 1312,
         "length": 5
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       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "p|SUB|I|195|M",
        "type": "SequenceVariant"
       },
       "text": "I195M",
       "locations": [
        {
         "offset": 1321,
         "length": 5
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       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "g|SUB|A|1762|T",
        "type": "SequenceVariant"
       },
       "text": "A1762T",
       "locations": [
        {
         "offset": 1358,
         "length": 6
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "g|SUB|G|1764|A",
        "type": "SequenceVariant"
       },
       "text": "G1764A",
       "locations": [
        {
         "offset": 1366,
         "length": 6
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       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "944568",
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     "text": "Identification of a novel FBN1 gene mutation in a Chinese family with Marfan syndrome.",
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     "text": "PURPOSE: To identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with Marfan syndrome (MFS). METHODS: Patients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of six individuals in the family and 170 healthy Chinese individuals. All of the 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction and followed by direct sequencing. The mutation identified in the proband was screened in the other family members and the 170 healthy Chinese individuals by direct sequencing. Protein conservation analysis was performed in six species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in DeepView v4.0.1 to predict the functional consequences of the mutation. RESULTS: A novel heterozygous c.3703T>C change in exon 29 of FBN1 was detected in the proband, which resulted in the substitution of serine by proline at codon 1235 (p.S1235P). This mutation was also present in two family members but absent in the other, unaffected family members and the 170 healthy Chinese individuals. The mutant residue located in the calcium binding epidermal growth factor-like#15 domain is highly conserved among mammalian species and could probably induce conformation change of the domain. CONCLUSIONS: We indentified a novel p.S1235P mutation in FBN1, which is the causative mutation for MFS in this family. Our result expands the mutation spectrum of FBN1 and contributes to the study of the molecular pathogenesis of Marfan syndrome.",
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     "offset": 0,
     "text": "Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene.",
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    {
     "offset": 140,
     "text": "Eighty unrelated individuals with Duchenne muscular dystrophy (DMD)or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al. at the 5 ' end of the gene.",
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     "text": "BACKGROUND: Chronic alcohol consumption leads to a loss of white adipose tissue (WAT) but the underlying mechanisms for this lipodystrophy are not fully elucidated. This study tested the hypothesis that the reduction in WAT mass in chronic alcohol-fed mice is associated with a decreased protein synthesis specifically related to impaired function of mammalian target of rapamycin (mTOR). METHODS: Adult male mice were provided an alcohol-containing liquid diet for 24 weeks or an isonitrogenous isocaloric control diet. In vivo protein synthesis was determined at this time and thereafter epididymal WAT (eWAT) was excised for analysis of signal transduction pathways central to controling protein synthesis and degradation. RESULTS: While chronic alcohol feeding decreased whole-body and eWAT mass, this was associated with a discordant increase in protein synthesis in eWAT. This increase was not associated with a change in mTOR, 4E-BP1, Akt, or PRAS40 phosphorylation. Instead, a selective increase in phosphorylation of S6K1 and its downstream substrates, S6 and eIF4B was detected in alcohol-fed mice. Alcohol also increased eEF2K phosphorylation and decreased eEF2 phosphorylation consistent with increased translation elongation. Alcohol increased Atg12-5, LC3B-I and -II, and ULK1 S555 phosphorylation, suggesting increased autophagy, while markers of apoptosis (cleaved caspase-3 and -9, and PARP) were unchanged. Lipolytic enzymes (ATGL and HSL phosphorylation) were increased and lipogenic regulators (PPARgamma and C/EBPalpha) were decreased in eWAT by alcohol. Although alcohol increased TNF-alpha, IL-6, and IL-1beta mRNA, no change in key components of the NLRP3 inflammasome (NLRP3, ACS, and cleaved caspase-1) was detected suggesting alcohol did not increase pyroptosis. Plasma insulin did not differ between groups. CONCLUSIONS: These results demonstrate that the alcohol-induced decrease in whole-body fat mass resulted in part from activation of autophagy in eWAT as protein synthesis was increased and mediated by the specific increase in the activity of S6K1.",
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     "text": "A healthy 17-year-old male received standard intermittent doses of pethidine via a patient-controlled analgesia (PCA) pump for management of postoperative pain control. Twenty-three h postoperatively he developed a brief self-limited seizure. Both plasma pethidine and norpethidine were elevated in the range associated with clinical manifestations of central nervous system excitation. No other risk factors for CNS toxicity were identified. This method allowed frequent self-dosing of pethidine at short time intervals and rapid accumulation of pethidine and norpethidine. The routine use of pethidine via PCA even for a brief postoperative analgesia should be reconsidered.",
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     "text": "Recovery of tacrolimus-associated brachial neuritis after conversion to everolimus in a pediatric renal transplant recipient--case report and review of the literature.",
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     "text": "TAC has been shown to be a potent immunosuppressive agent for solid organ transplantation in pediatrics. Neurotoxicity is a potentially serious toxic effect. It is characterized by encephalopathy, headaches, seizures, or neurological deficits. Here, we describe an eight-and-a-half-yr-old male renal transplant recipient with right BN. MRI demonstrated hyperintense T2 signals in the cervical cord and right brachial plexus roots indicative of both myelitis and right brachial plexitis. Symptoms persisted for three months despite TAC dose reduction, administration of IVIG and four doses of methylprednisolone pulse therapy. Improvement and eventually full recovery only occurred after TAC was completely discontinued and successfully replaced by everolimus.",
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    {
     "offset": 0,
     "text": "MOL1 is required for cambium homeostasis in Arabidopsis.",
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     "text": "Plants maintain pools of pluripotent stem cells which allow them to constantly produce new tissues and organs. Stem cell homeostasis in shoot and root tips depends on negative regulation by ligand-receptor pairs of the CLE peptide and leucine-rich repeat receptor-like kinase (LRR-RLK) families. However, regulation of the cambium, the stem cell niche required for lateral growth of shoots and roots, is poorly characterized. Here we show that the LRR-RLK MOL1 is necessary for cambium homeostasis in Arabidopsis thaliana. By employing promoter reporter lines, we reveal that MOL1 is active in a domain that is distinct from the domain of the positively acting CLE41/PXY signaling module. In particular, we show that MOL1 acts in an opposing manner to the CLE41/PXY module and that changing the domain or level of MOL1 expression both result in disturbed cambium organization. Underlining discrete roles of MOL1 and PXY, both LRR-RLKs are not able to replace each other when their expression domains are interchanged. Furthermore, MOL1 but not PXY is able to rescue CLV1 deficiency in the shoot apical meristem. By identifying genes mis-expressed in mol1 mutants, we demonstrate that MOL1 represses genes associated with stress-related ethylene and jasmonic acid hormone signaling pathways which have known roles in coordinating lateral growth of the Arabidopsis stem. Our findings provide evidence that common regulatory mechanisms in different plant stem cell niches are adapted to specific niche anatomies and emphasize the importance of a complex spatial organization of intercellular signaling cascades for a strictly bidirectional tissue production.",
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       "text": "patients",
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       "infons": {
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       "text": "cone and cone rod dystrophy",
       "locations": [
        {
         "offset": 74,
         "length": 27
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    {
     "offset": 103,
     "text": "Background: Heterozygous mutations in GUCA1A (MIM # 600364) have been identified to cause autosomal dominantly inherited cone dystrophy, cone rod dystrophy and macular dystrophy. However, the role of GUCA1B gene mutations in inherited retinal disease has been controversial. We therefore performed a mutation analysis of the GUCA1B gene in a clinically well characterized group of patients of European and North-American geographical origin with autosomal dominantly inherited cone dystrophy and cone rod dystrophy. Material and Methods: Twenty-four unrelated patients diagnosed with cone dystrophy or cone rod dystrophy according to standard diagnostic criteria and a family history consistent with an autosomal dominant mode of inheritance were included in the study. Mutation analysis of all coding exons of the GUCA1B gene was performed by polymerase chain reaction amplification of genomic DNA and subsequent DNA sequencing. Results: Three different sequence variants, c.-17T>C, c.171T>C, c.465G>T were identified. The sequence variant c.465G>T encodes a conservative amino acid substitution, p.Glu155Asp, located in EF-hand 4, the calcium binding site of GCAP2 protein. All sequence variants were previously reported in healthy subjects. Conclusion: The absence of clearly pathogenic mutations in the selected patient group suggests that the GUCA1B gene is a minor cause for retinal degenerations in Europeans or North-Americans.",
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       "id": "3",
       "infons": {
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       "infons": {
        "identifier": "D012162",
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     "offset": 0,
     "text": "Cardioprotective effect of tincture of Crataegus on isoproterenol-induced myocardial infarction in rats.",
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       "infons": {
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       "text": "tincture of Crataegus",
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     "text": "Tincture of Crataegus (TCR), an alcoholic extract of the berries of hawthorn (Crataegus oxycantha), is used in herbal and homeopathic medicine. The present study was done to investigate the protective effect of TCR on experimentally induced myocardial infarction in rats. Pretreatment of TCR, at a dose of 0.5 mL/100 g bodyweight per day, orally for 30 days, prevented the increase in lipid peroxidation and activity of marker enzymes observed in isoproterenol-induced rats (85 mg kg(-1) s. c. for 2 days at an interval of 24 h). TCR prevented the isoproterenol-induced decrease in antioxidant enzymes in the heart and increased the rate of ADP-stimulated oxygen uptake and respiratory coupling ratio. TCR protected against pathological changes induced by isoproterenol in rat heart. The results show that pretreatment with TCR may be useful in preventing the damage induced by isoproterenol in rat heart.",
     "annotations": [
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       "id": "4",
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       "text": "alcoholic extract of the berries of hawthorn",
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  {
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    {
     "offset": 0,
     "text": "A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension.",
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     "text": "We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS.",
     "annotations": [
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       "text": "Gitelman syndrome",
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     "text": "Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "infons": {
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         "length": 4
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         "offset": 76,
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       "id": "6",
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        "identifier": "54901",
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       "text": "CDKAL1",
       "locations": [
        {
         "offset": 82,
         "length": 6
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       ]
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       "id": "7",
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         "length": 15
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     ]
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     "text": "According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.",
     "annotations": [
      {
       "id": "9",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2 diabetes mellitus",
       "locations": [
        {
         "offset": 281,
         "length": 24
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003924",
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       },
       "text": "T2DM",
       "locations": [
        {
         "offset": 307,
         "length": 4
        }
       ]
      },
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       "id": "11",
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         "length": 7
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       ]
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        "type": "GeneOrGeneProduct"
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       "text": "HHEX",
       "locations": [
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         "offset": 414,
         "length": 4
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       ]
      },
      {
       "id": "13",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "CDKN2A/B",
       "locations": [
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         "length": 8
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       "infons": {
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       "locations": [
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         "offset": 430,
         "length": 7
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       ]
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       "text": "FTO",
       "locations": [
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         "offset": 439,
         "length": 3
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       ]
      },
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        "type": "GeneOrGeneProduct"
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       "locations": [
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         "offset": 444,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "54901",
        "type": "GeneOrGeneProduct"
       },
       "text": "CDKAL1",
       "locations": [
        {
         "offset": 450,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "3784",
        "type": "GeneOrGeneProduct"
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       "text": "KCNQ1",
       "locations": [
        {
         "offset": 461,
         "length": 5
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       ]
      },
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       "id": "19",
       "infons": {
        "identifier": "D003924",
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       "text": "T2DM",
       "locations": [
        {
         "offset": 483,
         "length": 4
        }
       ]
      },
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       "id": "20",
       "infons": {
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       "text": "patients",
       "locations": [
        {
         "offset": 586,
         "length": 8
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D003924",
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       "text": "T2DM",
       "locations": [
        {
         "offset": 600,
         "length": 4
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       ]
      },
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       "id": "22",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "diabetic",
       "locations": [
        {
         "offset": 617,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs13266634",
        "type": "SequenceVariant"
       },
       "text": "rs13266634",
       "locations": [
        {
         "offset": 649,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs1111875",
        "type": "SequenceVariant"
       },
       "text": "rs1111875",
       "locations": [
        {
         "offset": 661,
         "length": 9
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs10811661",
        "type": "SequenceVariant"
       },
       "text": "rs10811661",
       "locations": [
        {
         "offset": 672,
         "length": 10
        }
       ]
      },
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       "infons": {
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       "text": "rs4402960",
       "locations": [
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         "offset": 684,
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       "text": "rs8050136",
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       "text": "rs734312",
       "locations": [
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         "offset": 706,
         "length": 8
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       "id": "29",
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       "text": "rs7754840",
       "locations": [
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         "offset": 716,
         "length": 9
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       "text": "rs2237892",
       "locations": [
        {
         "offset": 730,
         "length": 9
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       ]
      },
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       "id": "31",
       "infons": {
        "identifier": "D005947",
        "type": "ChemicalEntity"
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       "text": "glucose",
       "locations": [
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         "offset": 805,
         "length": 7
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       ]
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       "id": "32",
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        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 820,
         "length": 8
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       ]
      },
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       "id": "33",
       "infons": {
        "identifier": "54901",
        "type": "GeneOrGeneProduct"
       },
       "text": "CDKAL1",
       "locations": [
        {
         "offset": 895,
         "length": 6
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "rs7754840",
        "type": "SequenceVariant"
       },
       "text": "rs7754840",
       "locations": [
        {
         "offset": 903,
         "length": 9
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       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "rs1111875",
        "type": "SequenceVariant"
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       "text": "rs1111875",
       "locations": [
        {
         "offset": 994,
         "length": 9
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       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "3087",
        "type": "GeneOrGeneProduct"
       },
       "text": "HHEX",
       "locations": [
        {
         "offset": 1057,
         "length": 4
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     "text": "Serotonin 6 receptor gene is associated with methamphetamine-induced psychosis in a Japanese population.",
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     "text": "BACKGROUND: Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and d-amphetamine-induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by d-amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. METHOD: Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. RESULTS: rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype-wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively. CONCLUSION: HTR6 may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population.",
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     "text": "Reciprocal effects of NNK and SLURP-1 on oncogene expression in target epithelial cells.",
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     "text": "AIMS: To elucidate how the nicotinic acetylcholine receptors expressed on bronchial and oral epithelial cells targeted by the tobacco nitrosamine (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) facilitate carcinogenic transformation. MAIN METHODS: Since NNK-dependent transformation can be abolished by the nicotinergic secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1 (SLURP-1), we compared effects of NNK and recombinant (r)SLURP-1 on the expression of genes related to tumorigenesis in human immortalized bronchial and oral epithelial cell lines BEP2D and Het-1A, respectively. KEY FINDINGS: NNK stimulated expression of oncogenic genes, including MYB and PIK3CA in BEP2D, ETS1, NRAS and SRC in Het-1A, and AKT1, KIT and RB1 in both cell types, which could be abolished in the presence of rSLURP-1. Other cancer-related genes whose upregulation by NNK was abolishable by rSLURP-1 were the growth factors EGF in BEP2D cells and HGF in Het-1A cells, and the transcription factors CDKN2A and STAT3 (Het-1A only). NNK also upregulated the anti-apoptotic BCL2 (Het-1A) and downregulated the pro-apoptotic TNF (Het-1A), BAX and CASP8 (BEP2D), all of which could be abolished, in part, by rSLURP-1. NNK decreased expression of the CTNNB1 gene encoding the intercellular adhesion molecule beta-catenin (BEP2D), as well as tumor suppressors CDKN3 and FOXD3 in BEP2D cells and SERPINB5 in Het-1A cells. These pro-oncogenic effects of NNK were abolished by rSLURP-1 that also upregulated RUNX3. SIGNIFICANCE: The obtained results identified target genes for both NNK and SLURP-1 and shed light on the molecular mechanism of their reciprocal effects on tumorigenic transformation of bronchial and oral epithelial cells.",
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     "infons": {
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      "entity1": "3694",
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      "entity1": "3866",
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     }
    },
    {
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      "novel": "Novel"
     }
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     "infons": {
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      "novel": "No"
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     "infons": {
      "entity1": "D000431",
      "entity2": "4501",
      "type": "Positive_Correlation",
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     }
    },
    {
     "id": "R27",
     "infons": {
      "entity1": "D000431",
      "entity2": "4680",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R28",
     "infons": {
      "entity1": "D000431",
      "entity2": "79923",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R29",
     "infons": {
      "entity1": "D000431",
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      "type": "Positive_Correlation",
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    },
    {
     "id": "R30",
     "infons": {
      "entity1": "D000431",
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    }
   ]
  },
  {
   "id": "21684788",
   "passages": [
    {
     "offset": 0,
     "text": "Large contiguous gene deletions in Sjogren-Larsson syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Sjogren-Larsson syndrome",
       "locations": [
        {
         "offset": 35,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 61,
     "text": "Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Sjogren-Larsson syndrome",
       "locations": [
        {
         "offset": 61,
         "length": 24
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SLS",
       "locations": [
        {
         "offset": 87,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal recessive disorder",
       "locations": [
        {
         "offset": 98,
         "length": 28
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D007057",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ichthyosis",
       "locations": [
        {
         "offset": 144,
         "length": 10
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mental retardation",
       "locations": [
        {
         "offset": 156,
         "length": 18
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009128",
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       },
       "text": "spasticity",
       "locations": [
        {
         "offset": 176,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "224",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALDH3A2",
       "locations": [
        {
         "offset": 208,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "224",
        "type": "GeneOrGeneProduct"
       },
       "text": "fatty aldehyde dehydrogenase",
       "locations": [
        {
         "offset": 225,
         "length": 28
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "C001634",
        "type": "ChemicalEntity"
       },
       "text": "fatty aldehyde",
       "locations": [
        {
         "offset": 297,
         "length": 14
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D005227",
        "type": "ChemicalEntity"
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       "text": "fatty acid",
       "locations": [
        {
         "offset": 315,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SLS",
       "locations": [
        {
         "offset": 374,
         "length": 3
        }
       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 378,
         "length": 8
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SLS",
       "locations": [
        {
         "offset": 516,
         "length": 3
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       ]
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       "id": "14",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
        {
         "offset": 520,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "224",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALDH3A2",
       "locations": [
        {
         "offset": 595,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SLS",
       "locations": [
        {
         "offset": 750,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|DEL||352K",
        "type": "SequenceVariant"
       },
       "text": "352-kb deletion",
       "locations": [
        {
         "offset": 782,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "223,224",
        "type": "GeneOrGeneProduct"
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       "text": "ALDH3A2 and 4",
       "locations": [
        {
         "offset": 808,
         "length": 13
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "218",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALDH3A1",
       "locations": [
        {
         "offset": 849,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D003316",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "corneal disease",
       "locations": [
        {
         "offset": 928,
         "length": 15
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SLS",
       "locations": [
        {
         "offset": 975,
         "length": 3
        }
       ]
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      {
       "id": "22",
       "infons": {
        "identifier": "9606",
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       "text": "patient",
       "locations": [
        {
         "offset": 1084,
         "length": 7
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       ]
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      {
       "id": "23",
       "infons": {
        "identifier": "c|DEL||1.44M",
        "type": "SequenceVariant"
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       "text": "1.44-Mb contiguous gene deletion",
       "locations": [
        {
         "offset": 1126,
         "length": 32
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "c|SUB|C|407|T",
        "type": "SequenceVariant"
       },
       "text": "c.407C>T",
       "locations": [
        {
         "offset": 1184,
         "length": 8
        }
       ]
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       "id": "25",
       "infons": {
        "identifier": "p|SUB|P|136|L",
        "type": "SequenceVariant"
       },
       "text": "P136L",
       "locations": [
        {
         "offset": 1194,
         "length": 5
        }
       ]
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      {
       "id": "26",
       "infons": {
        "identifier": "224",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALDH3A2",
       "locations": [
        {
         "offset": 1204,
         "length": 7
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLS",
       "locations": [
        {
         "offset": 1311,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1410,
         "length": 8
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       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D016111",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLS",
       "locations": [
        {
         "offset": 1424,
         "length": 3
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       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D008661",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "inborn errors of metabolism",
       "locations": [
        {
         "offset": 1438,
         "length": 27
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      "novel": "No"
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      "entity1": "224",
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      "novel": "No"
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   ]
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  {
   "id": "26937641",
   "passages": [
    {
     "offset": 0,
     "text": "Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells.",
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      {
       "id": "0",
       "infons": {
        "identifier": "20208,20210,6288",
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       "text": "Serum Amyloid A",
       "locations": [
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    {
     "offset": 104,
     "text": "Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IkappaB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-kappaB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-kappaB- and JNK-dependent manner. Blockade of NF-kappaB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-kappaB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs. ",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "20208,20210,6288",
        "type": "GeneOrGeneProduct"
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       "text": "Serum amyloid A",
       "locations": [
        {
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       "id": "2",
       "infons": {
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       "text": "SAA",
       "locations": [
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         "offset": 121,
         "length": 3
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       "id": "3",
       "infons": {
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       "text": "liver injury and fibrogenesis",
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       "infons": {
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       "text": "Serum amyloid A",
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       "text": "IkappaB kinase",
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       "text": "c-Jun N-terminal kinase",
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       "text": "JNK",
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         "offset": 520,
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       "text": "Akt",
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         "offset": 528,
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        "identifier": "4790,81736",
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       "text": "NF-kappaB",
       "locations": [
        {
         "offset": 545,
         "length": 9
        }
       ]
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       "id": "12",
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       "text": "human",
       "locations": [
        {
         "offset": 596,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
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        "identifier": "10116",
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       "text": "rat",
       "locations": [
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         "offset": 606,
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       ]
      },
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       "id": "14",
       "infons": {
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       "text": "Serum amyloid A",
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      "novel": "Novel"
     }
    },
    {
     "id": "R83",
     "infons": {
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      "novel": "Novel"
     }
    },
    {
     "id": "R84",
     "infons": {
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      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R85",
     "infons": {
      "entity1": "20210",
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      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R86",
     "infons": {
      "entity1": "20210",
      "entity2": "207",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R87",
     "infons": {
      "entity1": "20208",
      "entity2": "9641",
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      "novel": "Novel"
     }
    },
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     "id": "R88",
     "infons": {
      "entity1": "20208",
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     }
    },
    {
     "id": "R89",
     "infons": {
      "entity1": "20208",
      "entity2": "5594",
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     }
    },
    {
     "id": "R90",
     "infons": {
      "entity1": "20208",
      "entity2": "116590",
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      "novel": "Novel"
     }
    },
    {
     "id": "R91",
     "infons": {
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     }
    },
    {
     "id": "R92",
     "infons": {
      "entity1": "20208",
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     }
    },
    {
     "id": "R93",
     "infons": {
      "entity1": "20208",
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     }
    },
    {
     "id": "R94",
     "infons": {
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      "novel": "Novel"
     }
    },
    {
     "id": "R95",
     "infons": {
      "entity1": "20208",
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     }
    },
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      "entity1": "20208",
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     }
    },
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     "id": "R97",
     "infons": {
      "entity1": "20208",
      "entity2": "5599",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R98",
     "infons": {
      "entity1": "20208",
      "entity2": "116554",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R99",
     "infons": {
      "entity1": "20208",
      "entity2": "81687",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R100",
     "infons": {
      "entity1": "20208",
      "entity2": "4318",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R101",
     "infons": {
      "entity1": "20208",
      "entity2": "81780",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R102",
     "infons": {
      "entity1": "20208",
      "entity2": "6352",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R103",
     "infons": {
      "entity1": "20208",
      "entity2": "6347",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R104",
     "infons": {
      "entity1": "20208",
      "entity2": "24770",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R105",
     "infons": {
      "entity1": "20208",
      "entity2": "24185",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R106",
     "infons": {
      "entity1": "20208",
      "entity2": "207",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15464247",
   "passages": [
    {
     "offset": 0,
     "text": "Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "interleukin 12B",
       "locations": [
        {
         "offset": 13,
         "length": 15
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL12B",
       "locations": [
        {
         "offset": 30,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D006526",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hepatitis C virus infection",
       "locations": [
        {
         "offset": 102,
         "length": 27
        }
       ]
      }
     ]
    },
    {
     "offset": 131,
     "text": "BACKGROUND/AIMS: Interleukin-12 (IL-12) governs the Th1-type immune response, affecting the spontaneous and treatment-induced recovery from HCV-infection. We investigated whether the IL12B polymorphisms within the promoter region (4 bp insertion/deletion) and the 3'-UTR (1188-A/C), which have been reported to influence IL-12 synthesis, are associated with the outcome of HCV infection. METHODS: We analyzed 186 individuals with spontaneous HCV clearance, 501 chronically HCV infected patients, and 217 healthy controls. IL12B 3'-UTR and promoter genotyping was performed by Taqman-based assays with allele-specific oligonucleotide probes and PCR-based allele-specific DNA-amplification, respectively. RESULTS: The proportion of IL12B promoter and 3'-UTR genotypes did not differ significantly between the different cohorts. However, HCV genotype 1-infected patients with high baseline viremia carrying the IL12B 3'-UTR 1188-C-allele showed significantly higher sustained virologic response (SVR) rates (25.3% vs. 46% vs. 54.5% for A/A, A/C and C/C) due to reduced relapse rates (24.2% vs. 12% vs. zero % for A/A, A/C and C/C). CONCLUSIONS: IL12B 3'-UTR 1188-C-allele carriers appear to be capable of responding more efficiently to antiviral combination therapy as a consequence of a reduced relapse rate. No association of IL12B polymorphisms and self-limited HCV infection could be demonstrated.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "Interleukin-12",
       "locations": [
        {
         "offset": 148,
         "length": 14
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-12",
       "locations": [
        {
         "offset": 164,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D006526",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCV-infection",
       "locations": [
        {
         "offset": 271,
         "length": 13
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL12B",
       "locations": [
        {
         "offset": 314,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "c|INDEL||4",
        "type": "SequenceVariant"
       },
       "text": "4 bp insertion/deletion",
       "locations": [
        {
         "offset": 362,
         "length": 23
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|A|1188|C",
        "type": "SequenceVariant"
       },
       "text": "1188-A/C",
       "locations": [
        {
         "offset": 403,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-12",
       "locations": [
        {
         "offset": 452,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D006526",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCV infection",
       "locations": [
        {
         "offset": 504,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "11103",
        "type": "OrganismTaxon"
       },
       "text": "HCV",
       "locations": [
        {
         "offset": 573,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D006526",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCV infected",
       "locations": [
        {
         "offset": 604,
         "length": 12
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 617,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL12B",
       "locations": [
        {
         "offset": 653,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D009841",
        "type": "ChemicalEntity"
       },
       "text": "oligonucleotide",
       "locations": [
        {
         "offset": 748,
         "length": 15
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL12B",
       "locations": [
        {
         "offset": 861,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D006526",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCV genotype 1-infected",
       "locations": [
        {
         "offset": 966,
         "length": 23
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 990,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D014766",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "viremia",
       "locations": [
        {
         "offset": 1018,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL12B",
       "locations": [
        {
         "offset": 1039,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|Allele|C|1188",
        "type": "SequenceVariant"
       },
       "text": "1188-C",
       "locations": [
        {
         "offset": 1052,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL12B",
       "locations": [
        {
         "offset": 1273,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|Allele|C|1188",
        "type": "SequenceVariant"
       },
       "text": "1188-C",
       "locations": [
        {
         "offset": 1286,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "3593",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL12B",
       "locations": [
        {
         "offset": 1456,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D006526",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HCV infection",
       "locations": [
        {
         "offset": 1493,
         "length": 13
        }
       ]
      }
     ]
    }
   ],
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     "id": "R0",
     "infons": {
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      "entity2": "c|Allele|C|1188",
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      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D014766",
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      "type": "Association",
      "novel": "Novel"
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    }
   ]
  },
  {
   "id": "15824163",
   "passages": [
    {
     "offset": 0,
     "text": "No Evidence for BRAF as a melanoma/nevus susceptibility gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 16,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma",
       "locations": [
        {
         "offset": 26,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D009506",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nevus",
       "locations": [
        {
         "offset": 35,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 62,
     "text": "Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 83,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma tumors",
       "locations": [
        {
         "offset": 117,
         "length": 15
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009506",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nevi",
       "locations": [
        {
         "offset": 144,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 173,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma",
       "locations": [
        {
         "offset": 240,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 291,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sporadic melanoma",
       "locations": [
        {
         "offset": 334,
         "length": 17
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 355,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 399,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D009506",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nevus",
       "locations": [
        {
         "offset": 465,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma",
       "locations": [
        {
         "offset": 471,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "familial melanoma",
       "locations": [
        {
         "offset": 708,
         "length": 17
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 736,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 860,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs1639679",
        "type": "SequenceVariant"
       },
       "text": "rs1639679",
       "locations": [
        {
         "offset": 892,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma",
       "locations": [
        {
         "offset": 934,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1019,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma",
       "locations": [
        {
         "offset": 1040,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1394,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1484,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D008545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "melanoma",
       "locations": [
        {
         "offset": 1539,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1702,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D009506",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nevi",
       "locations": [
        {
         "offset": 1759,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D008545",
      "entity2": "673",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "26900322",
   "passages": [
    {
     "offset": 0,
     "text": "CFI-rs7356506 polymorphisms associated with Vogt-Koyanagi-Harada syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 0,
         "length": 3
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs7356506",
        "type": "SequenceVariant"
       },
       "text": "rs7356506",
       "locations": [
        {
         "offset": 4,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Vogt-Koyanagi-Harada syndrome",
       "locations": [
        {
         "offset": 44,
         "length": 29
        }
       ]
      }
     ]
    },
    {
     "offset": 75,
     "text": "PURPOSE: Complement factor I (CFI) plays an important role in complement activation pathways and is known to affect the development of uveitis. The present study was performed to investigate the existence of an association between CFI genetic polymorphisms and Vogt-Koyanagi-Harada (VKH) syndrome. METHODS: A total of 100 patients diagnosed with VKH syndrome and 300 healthy controls were recruited for the study. Two milliliters of peripheral blood were collected in a sterile anticoagulative tube. CFI-rs7356506 polymorphisms were genotyped using Sequenom MassARRAY technology. Allele and genotype frequencies were compared between patients and controls using a X(2) test. The analyses were stratified for recurrent status, complicated cataract status, and steroid-sensitive status. RESULTS: No significant association was found between CFI-rs7356506 polymorphisms and VKH syndrome. However, patients with recurrent VKH syndrome had lower frequencies of the G allele and GG homozygosity in CFI-rs7356506 when compared to the controls (p=0.016, odds ratio [OR]=0.429, 95% confidence interval [CI]=0.212-0.871; p=0.014, OR=0.364, 95% CI=0.158-0.837, respectively). Furthermore, there were significant decreases in the frequencies of the G allele and GG homozygosity in CFI-rs7356506 in patients with VKH syndrome with complicated cataract compared to the controls (p<0.001, OR=0.357, 95% CI=0.197-0.648; p<0.001, OR=0.273, 95% CI=0.135-0.551, respectively). Nevertheless, no significant association with patients with VKH syndrome in steroid-sensitive statuses was detected for CFI-rs7356506 polymorphisms. CONCLUSIONS: Our results indicate that CFI polymorphisms are not significantly associated with VKH syndrome; nevertheless, we identified a trend for the association of CFI-7356506 with VKH syndrome that depends on the recurrent status and the complicated cataract status but not on the steroid-sensitive status.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "Complement factor I",
       "locations": [
        {
         "offset": 84,
         "length": 19
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 105,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D014605",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "uveitis",
       "locations": [
        {
         "offset": 210,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 306,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Vogt-Koyanagi-Harada (VKH) syndrome",
       "locations": [
        {
         "offset": 336,
         "length": 35
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 397,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VKH syndrome",
       "locations": [
        {
         "offset": 421,
         "length": 12
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 575,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs7356506",
        "type": "SequenceVariant"
       },
       "text": "rs7356506",
       "locations": [
        {
         "offset": 579,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 709,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D002386",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cataract",
       "locations": [
        {
         "offset": 813,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D013256",
        "type": "ChemicalEntity"
       },
       "text": "steroid",
       "locations": [
        {
         "offset": 834,
         "length": 7
        }
       ]
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       "id": "15",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
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       "text": "CFI",
       "locations": [
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         "offset": 914,
         "length": 3
        }
       ]
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      {
       "id": "16",
       "infons": {
        "identifier": "rs7356506",
        "type": "SequenceVariant"
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         "offset": 918,
         "length": 9
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       ]
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      {
       "id": "17",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "VKH syndrome",
       "locations": [
        {
         "offset": 946,
         "length": 12
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 969,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "VKH syndrome",
       "locations": [
        {
         "offset": 993,
         "length": 12
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
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       "text": "CFI",
       "locations": [
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         "offset": 1067,
         "length": 3
        }
       ]
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       "id": "21",
       "infons": {
        "identifier": "rs7356506",
        "type": "SequenceVariant"
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         "offset": 1071,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 1344,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs7356506",
        "type": "SequenceVariant"
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       "text": "rs7356506",
       "locations": [
        {
         "offset": 1348,
         "length": 9
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1361,
         "length": 8
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VKH syndrome",
       "locations": [
        {
         "offset": 1375,
         "length": 12
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D002386",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cataract",
       "locations": [
        {
         "offset": 1405,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1579,
         "length": 8
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VKH syndrome",
       "locations": [
        {
         "offset": 1593,
         "length": 12
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D013256",
        "type": "ChemicalEntity"
       },
       "text": "steroid",
       "locations": [
        {
         "offset": 1609,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 1653,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "rs7356506",
        "type": "SequenceVariant"
       },
       "text": "rs7356506",
       "locations": [
        {
         "offset": 1657,
         "length": 9
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 1721,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VKH syndrome",
       "locations": [
        {
         "offset": 1777,
         "length": 12
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "3426",
        "type": "GeneOrGeneProduct"
       },
       "text": "CFI",
       "locations": [
        {
         "offset": 1850,
         "length": 3
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "rs7356506",
        "type": "SequenceVariant"
       },
       "text": "7356506",
       "locations": [
        {
         "offset": 1854,
         "length": 7
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D014607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VKH syndrome",
       "locations": [
        {
         "offset": 1867,
         "length": 12
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D002386",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cataract",
       "locations": [
        {
         "offset": 1937,
         "length": 8
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D013256",
        "type": "ChemicalEntity"
       },
       "text": "steroid",
       "locations": [
        {
         "offset": 1968,
         "length": 7
        }
       ]
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     ]
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   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "rs7356506",
      "entity2": "D002386",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs7356506",
      "entity2": "D014607",
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    },
    {
     "id": "R2",
     "infons": {
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     "infons": {
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    }
   ]
  },
  {
   "id": "16840830",
   "passages": [
    {
     "offset": 0,
     "text": "Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 27,
         "length": 4
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "D018761",
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       "text": "multiple endocrine neoplasia-1",
       "locations": [
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         "offset": 54,
         "length": 30
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     ]
    },
    {
     "offset": 86,
     "text": "Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Multiple endocrine neoplasia type 1",
       "locations": [
        {
         "offset": 86,
         "length": 35
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D018761",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 123,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C535650,D010911",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "enteropancreatic endocrine and pituitary adenomas",
       "locations": [
        {
         "offset": 162,
         "length": 49
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 248,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 287,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 320,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 379,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D049950",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "primary hyperparathyroidism",
       "locations": [
        {
         "offset": 391,
         "length": 27
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D049950",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PHPT",
       "locations": [
        {
         "offset": 420,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D015175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prolactinoma",
       "locations": [
        {
         "offset": 433,
         "length": 12
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D049950",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PHPT",
       "locations": [
        {
         "offset": 467,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 488,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "woman",
       "locations": [
        {
         "offset": 533,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 580,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D010146",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pain",
       "locations": [
        {
         "offset": 629,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D003967",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diarrhea",
       "locations": [
        {
         "offset": 645,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D007516",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic islet cell tumor",
       "locations": [
        {
         "offset": 742,
         "length": 27
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D015175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prolactinoma",
       "locations": [
        {
         "offset": 807,
         "length": 12
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 846,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 945,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "p|SUB|K|557|E",
        "type": "SequenceVariant"
       },
       "text": "A to G transition at codon 557 (AAG-->GAG)",
       "locations": [
        {
         "offset": 1003,
         "length": 42
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 1060,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "p|SUB|K||E",
        "type": "SequenceVariant"
       },
       "text": "lysine by glutamic acid",
       "locations": [
        {
         "offset": 1098,
         "length": 23
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1141,
         "length": 7
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "p|SUB|D|418|Y",
        "type": "SequenceVariant"
       },
       "text": "mutation at codon 418 of exon 9 (GAC-->TAT)",
       "locations": [
        {
         "offset": 1192,
         "length": 43
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "p|SUB|D||Y",
        "type": "SequenceVariant"
       },
       "text": "aspartic acid by tyrosine",
       "locations": [
        {
         "offset": 1270,
         "length": 25
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 1365,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D018761",
      "entity2": "p|SUB|D||Y",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D018761",
      "entity2": "p|SUB|D|418|Y",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D018761",
      "entity2": "p|SUB|K||E",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D018761",
      "entity2": "p|SUB|K|557|E",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "4221",
      "entity2": "D018761",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15668505",
   "passages": [
    {
     "offset": 0,
     "text": "Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "675",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA2",
       "locations": [
        {
         "offset": 7,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D001943,D010051",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast and ovarian cancer",
       "locations": [
        {
         "offset": 42,
         "length": 25
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 76,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 101,
     "text": "The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "rs144848",
        "type": "SequenceVariant"
       },
       "text": "N372H",
       "locations": [
        {
         "offset": 177,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "675",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA2",
       "locations": [
        {
         "offset": 190,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D001943,D010051",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast and ovarian cancer",
       "locations": [
        {
         "offset": 280,
         "length": 25
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 343,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs144848",
        "type": "SequenceVariant"
       },
       "text": "N372H",
       "locations": [
        {
         "offset": 381,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "g|SUB|G|203|A",
        "type": "SequenceVariant"
       },
       "text": "203G > A",
       "locations": [
        {
         "offset": 453,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "675",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA2",
       "locations": [
        {
         "offset": 470,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001943,D010051",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast or ovarian cancer",
       "locations": [
        {
         "offset": 488,
         "length": 24
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 521,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 569,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 586,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "675",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA2",
       "locations": [
        {
         "offset": 646,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 875,
         "length": 13
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 903,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D010051",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ovarian cancer",
       "locations": [
        {
         "offset": 965,
         "length": 14
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs144848",
        "type": "SequenceVariant"
       },
       "text": "N372H",
       "locations": [
        {
         "offset": 1017,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "g|Allele|A|203",
        "type": "SequenceVariant"
       },
       "text": "203A",
       "locations": [
        {
         "offset": 1107,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs144848",
        "type": "SequenceVariant"
       },
       "text": "N372H",
       "locations": [
        {
         "offset": 1322,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 1351,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 1447,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 1457,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs144848",
        "type": "SequenceVariant"
       },
       "text": "N372H",
       "locations": [
        {
         "offset": 1538,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs144848",
      "entity2": "D010051",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs144848",
      "entity2": "D001943",
      "type": "Positive_Correlation",
      "novel": "No"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "672",
      "entity2": "D010051",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "672",
      "entity2": "D001943",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D010051",
      "entity2": "g|Allele|A|203",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "675",
      "entity2": "D010051",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "675",
      "entity2": "D001943",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "26847345",
   "passages": [
    {
     "offset": 0,
     "text": "Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "Transgelin",
       "locations": [
        {
         "offset": 0,
         "length": 10
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colorectal cancer",
       "locations": [
        {
         "offset": 45,
         "length": 17
        }
       ]
      }
     ]
    },
    {
     "offset": 135,
     "text": "BACKGROUND: Transgelin is an actin-binding protein that promotes motility in normal cells. Although the role of transgelin in cancer is controversial, a number of studies have shown that elevated levels correlate with aggressive tumor behavior, advanced stage, and poor prognosis. Here we sought to determine the role of transgelin more directly by determining whether experimental manipulation of transgelin levels in colorectal cancer (CRC) cells led to changes in metastatic potential in vivo. METHODS: Isogenic CRC cell lines that differ in transgelin expression were characterized using in vitro assays of growth and invasiveness and a mouse tail vein assay of experimental metastasis. Downstream effects of transgelin overexpression were investigated by gene expression profiling and quantitative PCR. RESULTS: Stable overexpression of transgelin in RKO cells, which have low endogenous levels, led to increased invasiveness, growth at low density, and growth in soft agar. Overexpression also led to an increase in the number and size of lung metastases in the mouse tail vein injection model. Similarly, attenuation of transgelin expression in HCT116 cells, which have high endogenous levels, decreased metastases in the same model. Investigation of mRNA expression patterns showed that transgelin overexpression altered the levels of approximately 250 other transcripts, with over-representation of genes that affect function of actin or other cytoskeletal proteins. Changes included increases in HOOK1, SDCCAG8, ENAH/Mena, and TNS1 and decreases in EMB, BCL11B, and PTPRD. CONCLUSIONS: Increases or decreases in transgelin levels have reciprocal effects on tumor cell behavior, with higher expression promoting metastasis. Chronic overexpression influences steady-state levels of mRNAs for metastasis-related genes.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "Transgelin",
       "locations": [
        {
         "offset": 147,
         "length": 10
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "21345,6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "actin-binding protein",
       "locations": [
        {
         "offset": 164,
         "length": 21
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 247,
         "length": 10
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 261,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 364,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 456,
         "length": 10
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 533,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colorectal cancer",
       "locations": [
        {
         "offset": 554,
         "length": 17
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CRC",
       "locations": [
        {
         "offset": 573,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CRC",
       "locations": [
        {
         "offset": 650,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 680,
         "length": 10
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 776,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 848,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 977,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "CVCL_0504",
        "type": "CellLine"
       },
       "text": "RKO",
       "locations": [
        {
         "offset": 991,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung metastases",
       "locations": [
        {
         "offset": 1180,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 1203,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 1262,
         "length": 10
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "CVCL_0291",
        "type": "CellLine"
       },
       "text": "HCT116",
       "locations": [
        {
         "offset": 1287,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D009362",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "metastases",
       "locations": [
        {
         "offset": 1346,
         "length": 10
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 1430,
         "length": 10
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "60",
        "type": "GeneOrGeneProduct"
       },
       "text": "actin",
       "locations": [
        {
         "offset": 1573,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "51361,55740,7145",
        "type": "GeneOrGeneProduct"
       },
       "text": "cytoskeletal proteins",
       "locations": [
        {
         "offset": 1588,
         "length": 21
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "51361",
        "type": "GeneOrGeneProduct"
       },
       "text": "HOOK1",
       "locations": [
        {
         "offset": 1641,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "10806",
        "type": "GeneOrGeneProduct"
       },
       "text": "SDCCAG8",
       "locations": [
        {
         "offset": 1648,
         "length": 7
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "55740",
        "type": "GeneOrGeneProduct"
       },
       "text": "ENAH",
       "locations": [
        {
         "offset": 1657,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "55740",
        "type": "GeneOrGeneProduct"
       },
       "text": "Mena",
       "locations": [
        {
         "offset": 1662,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "7145",
        "type": "GeneOrGeneProduct"
       },
       "text": "TNS1",
       "locations": [
        {
         "offset": 1672,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "133418",
        "type": "GeneOrGeneProduct"
       },
       "text": "EMB",
       "locations": [
        {
         "offset": 1694,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "64919",
        "type": "GeneOrGeneProduct"
       },
       "text": "BCL11B",
       "locations": [
        {
         "offset": 1699,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "5789",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTPRD",
       "locations": [
        {
         "offset": 1711,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "6876",
        "type": "GeneOrGeneProduct"
       },
       "text": "transgelin",
       "locations": [
        {
         "offset": 1757,
         "length": 10
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1802,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "6876",
      "entity2": "D009369",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "6876",
      "entity2": "5789",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "6876",
      "entity2": "64919",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "6876",
      "entity2": "133418",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "6876",
      "entity2": "10806",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "6876",
      "entity2": "7145",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "6876",
      "entity2": "55740",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "6876",
      "entity2": "51361",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "6876",
      "entity2": "60",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "6876",
      "entity2": "D008175",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "6876",
      "entity2": "D015179",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15818664",
   "passages": [
    {
     "offset": 0,
     "text": "Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sporadic chondrocalcinosis",
       "locations": [
        {
         "offset": 15,
         "length": 26
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|SUB|G|-4|A",
        "type": "SequenceVariant"
       },
       "text": "-4-basepair G-to-A",
       "locations": [
        {
         "offset": 49,
         "length": 18
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 112,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 154,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D043564",
        "type": "ChemicalEntity"
       },
       "text": "inorganic pyrophosphate",
       "locations": [
        {
         "offset": 206,
         "length": 23
        }
       ]
      }
     ]
    },
    {
     "offset": 231,
     "text": "OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 263,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D043564",
        "type": "ChemicalEntity"
       },
       "text": "inorganic pyrophosphate",
       "locations": [
        {
         "offset": 336,
         "length": 23
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D043564",
        "type": "ChemicalEntity"
       },
       "text": "PPi",
       "locations": [
        {
         "offset": 361,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal-dominant familial chondrocalcinosis",
       "locations": [
        {
         "offset": 391,
         "length": 45
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 480,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chondrocalcinosis",
       "locations": [
        {
         "offset": 523,
         "length": 17
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 551,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chondrocalcinosis",
       "locations": [
        {
         "offset": 633,
         "length": 17
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 658,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chondrocalcinosis",
       "locations": [
        {
         "offset": 688,
         "length": 17
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pseudogout",
       "locations": [
        {
         "offset": 709,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 941,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "CVCL_M020",
        "type": "CellLine"
       },
       "text": "CH-8",
       "locations": [
        {
         "offset": 960,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Sporadic chondrocalcinosis",
       "locations": [
        {
         "offset": 998,
         "length": 26
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|SUB|G||A",
        "type": "SequenceVariant"
       },
       "text": "G-to-A",
       "locations": [
        {
         "offset": 1047,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 1072,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "familial and sporadic chondrocalcinosis",
       "locations": [
        {
         "offset": 1331,
         "length": 39
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "c|SUB|C|14|T",
        "type": "SequenceVariant"
       },
       "text": "+14 bp C-to-T",
       "locations": [
        {
         "offset": 1372,
         "length": 13
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|DEL||GAG",
        "type": "SequenceVariant"
       },
       "text": "GAG deletion",
       "locations": [
        {
         "offset": 1401,
         "length": 12
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "familial chondrocalcinosis",
       "locations": [
        {
         "offset": 1449,
         "length": 26
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "c|SUB|T|143|C",
        "type": "SequenceVariant"
       },
       "text": "143-bp T-to-C",
       "locations": [
        {
         "offset": 1484,
         "length": 13
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 1531,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 1550,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 1634,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 1653,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D043564",
        "type": "ChemicalEntity"
       },
       "text": "PPi",
       "locations": [
        {
         "offset": 1707,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "CVCL_M020",
        "type": "CellLine"
       },
       "text": "CH-8",
       "locations": [
        {
         "offset": 1714,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 1750,
         "length": 4
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D043564",
        "type": "ChemicalEntity"
       },
       "text": "PPi",
       "locations": [
        {
         "offset": 1820,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D006984",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertrophy",
       "locations": [
        {
         "offset": 1844,
         "length": 11
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "1300",
        "type": "GeneOrGeneProduct"
       },
       "text": "type X collagen",
       "locations": [
        {
         "offset": 1864,
         "length": 15
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sporadic chondrocalcinosis",
       "locations": [
        {
         "offset": 1905,
         "length": 26
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "c|SUB|G|-4|A",
        "type": "SequenceVariant"
       },
       "text": "-4-bp G-to-A",
       "locations": [
        {
         "offset": 1962,
         "length": 12
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 1975,
         "length": 4
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 2030,
         "length": 4
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "D043564",
        "type": "ChemicalEntity"
       },
       "text": "PPi",
       "locations": [
        {
         "offset": 2053,
         "length": 3
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "56172",
        "type": "GeneOrGeneProduct"
       },
       "text": "ANKH",
       "locations": [
        {
         "offset": 2088,
         "length": 4
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "D002805",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chondrocalcinosis",
       "locations": [
        {
         "offset": 2129,
         "length": 17
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "D043564",
        "type": "ChemicalEntity"
       },
       "text": "PPi",
       "locations": [
        {
         "offset": 2205,
         "length": 3
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "D006984",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertrophy",
       "locations": [
        {
         "offset": 2225,
         "length": 11
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|SUB|G|-4|A",
      "entity2": "D006984",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|SUB|G|-4|A",
      "entity2": "D043564",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D002805",
      "entity2": "c|SUB|G|-4|A",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D002805",
      "entity2": "D043564",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D002805",
      "entity2": "c|DEL||GAG",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D002805",
      "entity2": "c|SUB|C|14|T",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D002805",
      "entity2": "c|SUB|G||A",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "56172",
      "entity2": "D006984",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "56172",
      "entity2": "D043564",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "56172",
      "entity2": "D002805",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "22729903",
   "passages": [
    {
     "offset": 0,
     "text": "Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6775",
        "type": "GeneOrGeneProduct"
       },
       "text": "STAT4",
       "locations": [
        {
         "offset": 16,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 61,
         "length": 28
        }
       ]
      }
     ]
    },
    {
     "offset": 116,
     "text": "The STAT4 has been found to be a susceptible gene in the development of systemic lupus erythematosus (SLE) in various populations. There are evident population differences in the context of clinical manifestations of SLE, therefore we investigated the prevalence of the STAT4 G > C (rs7582694) polymorphism in patients with SLE (n = 253) and controls (n = 521) in a sample of the Polish population. We found that patients with the STAT4 C/G and CC genotypes exhibited a 1.583-fold increased risk of SLE incidence (95 % CI = 1.168-2.145, p = 0.003), with OR for the C/C versus C/G and G/G genotypes was 1.967 (95 % CI = 1.152-3.358, p = 0.0119). The OR for the STAT4 C allele frequency showed a 1.539-fold increased risk of SLE (95 % CI = 1.209-1.959, p = 0.0004). We also observed an increased frequency of STAT4 C/C and C/G genotypes in SLE patients with renal symptoms OR = 2.259 (1.365-3.738, p = 0.0014), (p (corr) = 0.0238) and in SLE patients with neurologic manifestations OR = 2.867 (1.467-5.604, p = 0.0016), (p (corr) = 0.0272). Moreover, we found a contribution of STAT4 C/C and C/G genotypes to the presence of the anti-snRNP Ab OR = 3.237 (1.667-6.288, p = 0.0003), (p (corr) = 0.0051) and the presence of the anti-Scl-70 Ab OR = 2.665 (1.380-5.147, p = 0.0028), (p (corr) = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "6775",
        "type": "GeneOrGeneProduct"
       },
       "text": "STAT4",
       "locations": [
        {
         "offset": 120,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 188,
         "length": 28
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 218,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 333,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "6775",
        "type": "GeneOrGeneProduct"
       },
       "text": "STAT4",
       "locations": [
        {
         "offset": 386,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs7582694",
        "type": "SequenceVariant"
       },
       "text": "G > C",
       "locations": [
        {
         "offset": 392,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs7582694",
        "type": "SequenceVariant"
       },
       "text": "rs7582694",
       "locations": [
        {
         "offset": 399,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 426,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 440,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 529,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "6775",
        "type": "GeneOrGeneProduct"
       },
       "text": "STAT4",
       "locations": [
        {
         "offset": 547,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 615,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "6775",
        "type": "GeneOrGeneProduct"
       },
       "text": "STAT4",
       "locations": [
        {
         "offset": 776,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 839,
         "length": 3
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     "offset": 0,
     "text": "Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection.",
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       "id": "0",
       "infons": {
        "identifier": "16878,3976",
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       "text": "Leukemia inhibitory factor",
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    {
     "offset": 91,
     "text": "BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-b (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-b). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1b, IL-4, IL-5, IL-6, IL-12(p40), IFN-g, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1b, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-g. Silencing of retinoic acid-inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection.",
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     "text": "Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide.",
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       "infons": {
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     "text": "OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.",
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         "offset": 829,
         "length": 14
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D014890",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Wegener's granulomatosis",
       "locations": [
        {
         "offset": 872,
         "length": 24
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
       },
       "text": "cyclophosphamide",
       "locations": [
        {
         "offset": 959,
         "length": 16
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D001749",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bladder cancer",
       "locations": [
        {
         "offset": 1066,
         "length": 14
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
       },
       "text": "cyclophosphamide",
       "locations": [
        {
         "offset": 1117,
         "length": 16
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D001749",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bladder cancer",
       "locations": [
        {
         "offset": 1325,
         "length": 14
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D014890",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Wegener's granulomatosis",
       "locations": [
        {
         "offset": 1394,
         "length": 24
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D001749",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bladder cancer",
       "locations": [
        {
         "offset": 1437,
         "length": 14
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D014890",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Wegener's granulomatosis",
       "locations": [
        {
         "offset": 1532,
         "length": 24
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D003520",
        "type": "ChemicalEntity"
       },
       "text": "cyclophosphamide",
       "locations": [
        {
         "offset": 1628,
         "length": 16
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D001749",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bladder cancer",
       "locations": [
        {
         "offset": 1661,
         "length": 14
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D014890",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Wegener's granulomatosis",
       "locations": [
        {
         "offset": 1784,
         "length": 24
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D003520",
      "entity2": "D014890",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D003520",
      "entity2": "D001749",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18257781",
   "passages": [
    {
     "offset": 0,
     "text": "Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5310",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD1",
       "locations": [
        {
         "offset": 20,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "5311",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD2",
       "locations": [
        {
         "offset": 49,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D007690",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant polycystic kidney disease",
       "locations": [
        {
         "offset": 87,
         "length": 44
        }
       ]
      }
     ]
    },
    {
     "offset": 133,
     "text": "BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D007690",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Autosomal dominant polycystic kidney disease",
       "locations": [
        {
         "offset": 145,
         "length": 44
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D007690",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ADPKD",
       "locations": [
        {
         "offset": 191,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "5310",
        "type": "GeneOrGeneProduct"
       },
       "text": "polycystins 1",
       "locations": [
        {
         "offset": 231,
         "length": 13
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "5310",
        "type": "GeneOrGeneProduct"
       },
       "text": "PC1",
       "locations": [
        {
         "offset": 246,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "5311",
        "type": "GeneOrGeneProduct"
       },
       "text": "PC2",
       "locations": [
        {
         "offset": 258,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "renal diseases",
       "locations": [
        {
         "offset": 302,
         "length": 14
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D007690",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ADPKD",
       "locations": [
        {
         "offset": 391,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 397,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 516,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs75762896",
        "type": "SequenceVariant"
       },
       "text": "c.1445T > G",
       "locations": [
        {
         "offset": 559,
         "length": 11
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs75762896",
        "type": "SequenceVariant"
       },
       "text": "phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482",
       "locations": [
        {
         "offset": 646,
         "length": 70
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs75762896",
        "type": "SequenceVariant"
       },
       "text": "p.F482C",
       "locations": [
        {
         "offset": 718,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "5311",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD2",
       "locations": [
        {
         "offset": 734,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "5310",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD1",
       "locations": [
        {
         "offset": 758,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|DEL|IVS21-2|AG",
        "type": "SequenceVariant"
       },
       "text": "IVS21-2delAG",
       "locations": [
        {
         "offset": 783,
         "length": 12
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "5311",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD2",
       "locations": [
        {
         "offset": 818,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "5310",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD1",
       "locations": [
        {
         "offset": 952,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "5311",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD2",
       "locations": [
        {
         "offset": 988,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1065,
         "length": 7
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1121,
         "length": 7
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "18764",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD2",
       "locations": [
        {
         "offset": 1380,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 1385,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "rs75762896",
        "type": "SequenceVariant"
       },
       "text": "p.F482C",
       "locations": [
        {
         "offset": 1535,
         "length": 7
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "5311",
        "type": "GeneOrGeneProduct"
       },
       "text": "polycystin-2",
       "locations": [
        {
         "offset": 1595,
         "length": 12
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1687,
         "length": 7
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D007690",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ADPKD",
       "locations": [
        {
         "offset": 1700,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "5310",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD1",
       "locations": [
        {
         "offset": 1740,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "5311",
        "type": "GeneOrGeneProduct"
       },
       "text": "PKD2",
       "locations": [
        {
         "offset": 1780,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|DEL|IVS21-2|AG",
      "entity2": "D007690",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D007690",
      "entity2": "5311",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D007690",
      "entity2": "5310",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs75762896",
      "entity2": "D007690",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "20534762",
   "passages": [
    {
     "offset": 0,
     "text": "Two novel mutations of the TSH-beta subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "7252",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSH-beta",
       "locations": [
        {
         "offset": 27,
         "length": 8
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D003409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital central hypothyroidism",
       "locations": [
        {
         "offset": 60,
         "length": 33
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "7252",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSH",
       "locations": [
        {
         "offset": 119,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 134,
     "text": "CONTEXT: Patients with TSH-beta subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. OBJECTIVE: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-beta subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. RESULTS: Patient 1 had a homozygous G to A nucleotide change at the 5' donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-beta subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. CONCLUSIONS: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Patients",
       "locations": [
        {
         "offset": 143,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "7252",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSH-beta",
       "locations": [
        {
         "offset": 157,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D003409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital hypothyroidism",
       "locations": [
        {
         "offset": 186,
         "length": 25
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "7252",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSH",
       "locations": [
        {
         "offset": 226,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "7252",
        "type": "GeneOrGeneProduct"
       },
       "text": "TSH-beta",
       "locations": [
        {
         "offset": 395,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 430,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D003409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital central hypothyroidism",
       "locations": [
        {
         "offset": 444,
         "length": 33
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000740",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anemia",
       "locations": [
        {
         "offset": 515,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Patient",
       "locations": [
        {
         "offset": 532,
         "length": 7
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|SUB|G||A",
        "type": "SequenceVariant"
       },
       "text": "G to A",
       "locations": [
        {
         "offset": 559,
         "length": 6
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 978,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|DEL|313|T",
        "type": "SequenceVariant"
       },
       "text": "313delT",
       "locations": [
        {
         "offset": 1066,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "p|FS|C|105|V|114",
        "type": "SequenceVariant"
       },
       "text": "C105Vfs114X",
       "locations": [
        {
         "offset": 1075,
         "length": 11
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|SUB|G|323|A",
        "type": "SequenceVariant"
       },
       "text": "G for A at cDNA nucleotide position 323",
       "locations": [
        {
         "offset": 1153,
         "length": 39
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|SUB|C|88|Y",
        "type": "SequenceVariant"
       },
       "text": "C88Y",
       "locations": [
        {
         "offset": 1209,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "122876",
        "type": "GeneOrGeneProduct"
       },
       "text": "glycoprotein hormone-beta subunits",
       "locations": [
        {
         "offset": 1299,
         "length": 34
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "p|SUB|C|88|Y",
        "type": "SequenceVariant"
       },
       "text": "C88Y",
       "locations": [
        {
         "offset": 1383,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "p|SUB|C|88|Y",
        "type": "SequenceVariant"
       },
       "text": "C88Y",
       "locations": [
        {
         "offset": 1519,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D007037",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "TSH deficiency",
       "locations": [
        {
         "offset": 1580,
         "length": 14
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "C566321",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "isolated pituitary deficiency",
       "locations": [
        {
         "offset": 1656,
         "length": 29
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D007037",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "central hypothyroidism",
       "locations": [
        {
         "offset": 1760,
         "length": 22
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D000740",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anemia",
       "locations": [
        {
         "offset": 1833,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D003409",
      "entity2": "7252",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D003409",
      "entity2": "p|SUB|C|88|Y",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D003409",
      "entity2": "c|SUB|G|323|A",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D003409",
      "entity2": "p|FS|C|105|V|114",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D003409",
      "entity2": "c|DEL|313|T",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D003409",
      "entity2": "c|SUB|G||A",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "7252",
      "entity2": "D000740",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "D000740",
      "entity2": "p|SUB|C|88|Y",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "D000740",
      "entity2": "c|SUB|G|323|A",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "D000740",
      "entity2": "p|FS|C|105|V|114",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "D000740",
      "entity2": "c|DEL|313|T",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "D000740",
      "entity2": "c|SUB|G||A",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16970763",
   "passages": [
    {
     "offset": 0,
     "text": "Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4693",
        "type": "GeneOrGeneProduct"
       },
       "text": "NDP",
       "locations": [
        {
         "offset": 17,
         "length": 3
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie disease",
       "locations": [
        {
         "offset": 43,
         "length": 14
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D000080345",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "familial exudative vitreoretinopathy",
       "locations": [
        {
         "offset": 59,
         "length": 36
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D012178",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "retinopathy of prematurity",
       "locations": [
        {
         "offset": 100,
         "length": 26
        }
       ]
      }
     ]
    },
    {
     "offset": 128,
     "text": "BACKGROUND: To examine the contribution of mutations within the Norrie disease (NDP) gene to the clinically similar retinal diseases Norrie disease, X-linked familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity (ROP). METHODS: A dataset comprising 13 Norrie-FEVR, one Coat's disease, 31 ROP patients and 90 ex-premature babies of <32 weeks' gestation underwent an ophthalmologic examination and were screened for mutations within the NDP gene by direct DNA sequencing, denaturing high-performance liquid chromatography or gel electrophoresis. Controls were only screened using denaturing high-performance liquid chromatography and gel electrophoresis. Confirmation of mutations identified was obtained by DNA sequencing. RESULTS: Evidence for two novel mutations in the NDP gene was presented: Leu103Val in one FEVR patient and His43Arg in monozygotic twin Norrie disease patients. Furthermore, a previously described 14-bp deletion located in the 5' unstranslated region of the NDP gene was detected in three cases of regressed ROP. A second heterozygotic 14-bp deletion was detected in an unaffected ex-premature girl. Only two of the 13 Norrie-FEVR index cases had the full features of Norrie disease with deafness and mental retardation. CONCLUSION: Two novel mutations within the coding region of the NDP gene were found, one associated with a severe disease phenotypes of Norrie disease and the other with FEVR. A deletion within the non-coding region was associated with only mild-regressed ROP, despite the presence of low birthweight, prematurity and exposure to oxygen. In full-term children with retinal detachment only 15% appear to have the full features of Norrie disease and this is important for counselling parents on the possible long-term outcome.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie disease",
       "locations": [
        {
         "offset": 192,
         "length": 14
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4693",
        "type": "GeneOrGeneProduct"
       },
       "text": "NDP",
       "locations": [
        {
         "offset": 208,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "retinal diseases Norrie disease",
       "locations": [
        {
         "offset": 244,
         "length": 31
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D000080345",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked familial exudative vitreoretinopathy",
       "locations": [
        {
         "offset": 277,
         "length": 45
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000080345",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FEVR",
       "locations": [
        {
         "offset": 324,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D058456",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Coat's disease",
       "locations": [
        {
         "offset": 331,
         "length": 14
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D012178",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "retinopathy of prematurity",
       "locations": [
        {
         "offset": 350,
         "length": 26
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D012178",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ROP",
       "locations": [
        {
         "offset": 378,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie-FEVR",
       "locations": [
        {
         "offset": 417,
         "length": 11
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D058456",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Coat's disease",
       "locations": [
        {
         "offset": 434,
         "length": 14
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D012178",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ROP",
       "locations": [
        {
         "offset": 453,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 457,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "4693",
        "type": "GeneOrGeneProduct"
       },
       "text": "NDP",
       "locations": [
        {
         "offset": 600,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "4693",
        "type": "GeneOrGeneProduct"
       },
       "text": "NDP",
       "locations": [
        {
         "offset": 936,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|SUB|L|103|V",
        "type": "SequenceVariant"
       },
       "text": "Leu103Val",
       "locations": [
        {
         "offset": 960,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D000080345",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FEVR",
       "locations": [
        {
         "offset": 977,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 982,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "p|SUB|H|43|R",
        "type": "SequenceVariant"
       },
       "text": "His43Arg",
       "locations": [
        {
         "offset": 994,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie disease",
       "locations": [
        {
         "offset": 1023,
         "length": 14
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1038,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "c|DEL||14",
        "type": "SequenceVariant"
       },
       "text": "14-bp deletion",
       "locations": [
        {
         "offset": 1084,
         "length": 14
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "4693",
        "type": "GeneOrGeneProduct"
       },
       "text": "NDP",
       "locations": [
        {
         "offset": 1145,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D012178",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ROP",
       "locations": [
        {
         "offset": 1195,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "c|DEL||14",
        "type": "SequenceVariant"
       },
       "text": "14-bp deletion",
       "locations": [
        {
         "offset": 1223,
         "length": 14
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie-FEVR",
       "locations": [
        {
         "offset": 1306,
         "length": 11
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie disease",
       "locations": [
        {
         "offset": 1355,
         "length": 14
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 1375,
         "length": 8
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mental retardation",
       "locations": [
        {
         "offset": 1388,
         "length": 18
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "4693",
        "type": "GeneOrGeneProduct"
       },
       "text": "NDP",
       "locations": [
        {
         "offset": 1472,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie disease",
       "locations": [
        {
         "offset": 1544,
         "length": 14
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D000080345",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FEVR",
       "locations": [
        {
         "offset": 1578,
         "length": 4
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D012178",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ROP",
       "locations": [
        {
         "offset": 1664,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D007235",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "prematurity",
       "locations": [
        {
         "offset": 1710,
         "length": 11
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D010100",
        "type": "ChemicalEntity"
       },
       "text": "oxygen",
       "locations": [
        {
         "offset": 1738,
         "length": 6
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D012163",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "retinal detachment",
       "locations": [
        {
         "offset": 1773,
         "length": 18
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "C537849",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Norrie disease",
       "locations": [
        {
         "offset": 1837,
         "length": 14
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|DEL||14",
      "entity2": "D012178",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "p|SUB|H|43|R",
      "entity2": "C537849",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "p|SUB|L|103|V",
      "entity2": "D000080345",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "4693",
      "entity2": "D012178",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "4693",
      "entity2": "D000080345",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "4693",
      "entity2": "C537849",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19207031",
   "passages": [
    {
     "offset": 0,
     "text": "Growth hormone dose in growth hormone-deficient adults is not associated with IGF-1 gene polymorphisms.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "2688",
        "type": "GeneOrGeneProduct"
       },
       "text": "Growth hormone",
       "locations": [
        {
         "offset": 0,
         "length": 14
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D004393",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "growth hormone-deficient",
       "locations": [
        {
         "offset": 23,
         "length": 24
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "3479",
        "type": "GeneOrGeneProduct"
       },
       "text": "IGF-1",
       "locations": [
        {
         "offset": 78,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 104,
     "text": "AIMS: Several SNPs and a microsatellite cytosine-adenine repeat promoter polymorphism of the IGF-1 gene have been reported to be associated with circulating IGF-1 serum concentrations. Variance in IGF-1 concentrations due to genetic variations may affect different response to growth hormone (GH) treatment, resulting in different individually required GH-doses in GH-deficient patients. The aim of this study was to test if the IGF-1 gene polymorphisms are associated with the GH-dose of GH-deficient adults. MATERIALS & METHODS: A total of nine tagging SNPs, five additionally selected SNPs and a cytosine-adenine repeat polymorphism were determined in 133 German adult patients (66 men, 67 women; mean age 45.4 years +/- 13.1 standard deviation; majority Caucasian) with GH-deficiency (GHD) of different origin, derived from the prospective Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. Patients received GH-treatment for 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH-dose after 1 year of treatment, IGF-1 concentrations, IGF-1-standard deviation score (SDS), the IGF-1:GH ratio and anthropometric data were analyzed by genotype. RESULTS: Except for rs1019731, which showed a significant difference of IGF-1-SDS by genotypes (p = 0.02), all polymorphisms showed no associations with the GH-doses, IGF-1 concentrations, IGF-1-SDS and IGF-1:GH ratio after adjusting for the confounding variables gender, age and BMI. CONCLUSION: IGF-1 gene polymorphisms were not associated with the responsiveness to exogenous GH in GHD. Therefore, genetic variations of the IGF-1 gene seem not to be major influencing factors of the GH-IGF-axis causing variable response to exogenous GH-treatment.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "3479",
        "type": "GeneOrGeneProduct"
       },
       "text": "IGF-1",
       "locations": [
        {
         "offset": 197,
         "length": 5
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "3479",
        "type": "GeneOrGeneProduct"
       },
       "text": "IGF-1",
       "locations": [
        {
         "offset": 261,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "3479",
        "type": "GeneOrGeneProduct"
       },
       "text": "IGF-1",
       "locations": [
        {
         "offset": 301,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2688",
        "type": "GeneOrGeneProduct"
       },
       "text": "growth hormone",
       "locations": [
        {
         "offset": 381,
         "length": 14
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2688",
        "type": "GeneOrGeneProduct"
       },
       "text": "GH",
       "locations": [
        {
         "offset": 397,
         "length": 2
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "2688",
        "type": "GeneOrGeneProduct"
       },
       "text": "GH",
       "locations": [
        {
         "offset": 457,
         "length": 2
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D004393",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GH-deficient",
       "locations": [
        {
         "offset": 469,
         "length": 12
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 482,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "3479",
        "type": "GeneOrGeneProduct"
       },
       "text": "IGF-1",
       "locations": [
        {
         "offset": 533,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "2688",
        "type": "GeneOrGeneProduct"
       },
       "text": "GH",
       "locations": [
        {
         "offset": 582,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D004393",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GH-deficient",
       "locations": [
        {
         "offset": 593,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 776,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 789,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 797,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D004393",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GH-deficiency",
       "locations": [
        {
         "offset": 878,
         "length": 13
        }
       ]
      },
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     "offset": 0,
     "text": "Mutation analysis of FOXF2 in patients with disorders of sex development (DSD) in combination with cleft palate.",
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       "infons": {
        "identifier": "2295",
        "type": "GeneOrGeneProduct"
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     "text": "In contrast to disorders of sexual differentiation caused by lack of androgen production or inhibited androgen action, defects affecting development of the bipotent genital anlagen have rarely been investigated in humans. We have previously documented that the transcription factor FOXF2 is highly expressed in human foreskin. Moreover, Foxf2 knockout mice present with cleft palate in combination with hypoplasia of the genital tubercle. We hypothesized that humans with disorders of sex development (DSD) in combination with cleft palate could have mutations in the FOXF2 gene. Eighteen children with DSD and cleft palate were identified in the L beck DSD database (about 1,500 entries). Genomic DNA sequence analysis of the FOXF2 gene was performed and compared with 10 normal female and 10 normal male controls, respectively. Two heterozygous DNA sequence variations were solely present in one single patient each but in none of the 20 normal controls: a duplication of GCC (c.97GCC[9]+[10]) resulting in an extra alanine within exon 1 and a 25*G>A substitution in the 3'-untranslated region. Two patients carried a c.262G>A sequence variation predicting for an Ala88Thr exchange which was also detected in 2 normal controls. Two silent mutations, c.1272C>T (Ser424Ser) and c.1284T>C (Tyr428Tyr), respectively, occurred in the coding region of exon 2, again in both patients and normal controls. In conclusion, the majority of the detected sequence alterations were polymorphisms without obvious functional relevance. However, it cannot be excluded that the 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development.",
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     "text": "Ehlers-Danlos syndrome, vascular type (vEDS) (MIM #130050) is an autosomal dominant disorder caused by type III procollagen gene (COL3A1) mutations. Most COL3A1 mutations are detected by using total RNA from patient-derived fibroblasts, which requires an invasive skin biopsy. High-resolution melting curve analysis (hrMCA) has recently been developed as a post-PCR mutation scanning method which enables simple, rapid, cost-effective, and highly sensitive mutation screening of large genes. We established a hrMCA method to screen for COL3A1 mutations using genomic DNA. PCR primers pairs for COL3A1 (52 amplicons) were designed to cover all coding regions of the 52 exons, including the splicing sites. We used 15 DNA samples (8 validation samples and 7 samples of clinically suspected vEDS patients) in this study. The eight known COL3A1 mutations in validation samples were all successfully detected by the hrMCA. In addition, we identified five novel COL3A1 mutations, including one deletion (c.2187delA) and one nonsense mutation (c.2992C>T) that could not be determined by the conventional total RNA method. Furthermore, we established a small amplicon genotyping (SAG) method for detecting three high frequency coding-region SNPs (rs1800255:G>A, rs1801184:T>C, and rs2271683:A>G) in COL3A1 to differentiate mutations before sequencing. The use of hrMCA in combination with SAG from genomic DNA enables rapid detection of COL3A1 mutations with high efficiency and specificity. A better understanding of the genotype-phenotype correlation in COL3A1 using this method will lead to improve in diagnosis and treatment.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D004535",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Ehlers-Danlos syndrome, vascular type",
       "locations": [
        {
         "offset": 183,
         "length": 37
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D004535",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "vEDS",
       "locations": [
        {
         "offset": 222,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D004535",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MIM #130050",
       "locations": [
        {
         "offset": 229,
         "length": 11
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant disorder",
       "locations": [
        {
         "offset": 248,
         "length": 27
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1281",
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       "text": "type III procollagen",
       "locations": [
        {
         "offset": 286,
         "length": 20
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1281",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL3A1",
       "locations": [
        {
         "offset": 313,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1281",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL3A1",
       "locations": [
        {
         "offset": 337,
         "length": 6
        }
       ]
      },
      {
       "id": "8",
       "infons": {
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       },
       "text": "patient",
       "locations": [
        {
         "offset": 391,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1281",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL3A1",
       "locations": [
        {
         "offset": 719,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "1281",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL3A1",
       "locations": [
        {
         "offset": 777,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D004535",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "vEDS",
       "locations": [
        {
         "offset": 971,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 976,
         "length": 8
        }
       ]
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       "id": "13",
       "infons": {
        "identifier": "1281",
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       "text": "COL3A1",
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        }
       ]
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       "id": "14",
       "infons": {
        "identifier": "1281",
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       "text": "COL3A1",
       "locations": [
        {
         "offset": 1139,
         "length": 6
        }
       ]
      },
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       "id": "15",
       "infons": {
        "identifier": "c|DEL|2187|A",
        "type": "SequenceVariant"
       },
       "text": "c.2187delA",
       "locations": [
        {
         "offset": 1181,
         "length": 10
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|SUB|C|2992|T",
        "type": "SequenceVariant"
       },
       "text": "c.2992C>T",
       "locations": [
        {
         "offset": 1220,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs1800255",
        "type": "SequenceVariant"
       },
       "text": "rs1800255",
       "locations": [
        {
         "offset": 1422,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs1800255",
        "type": "SequenceVariant"
       },
       "text": "G>A",
       "locations": [
        {
         "offset": 1432,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs1801184",
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       "text": "rs1801184",
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        {
         "offset": 1437,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs1801184",
        "type": "SequenceVariant"
       },
       "text": "T>C",
       "locations": [
        {
         "offset": 1447,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs2271683",
        "type": "SequenceVariant"
       },
       "text": "rs2271683",
       "locations": [
        {
         "offset": 1456,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs2271683",
        "type": "SequenceVariant"
       },
       "text": "A>G",
       "locations": [
        {
         "offset": 1466,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "1281",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL3A1",
       "locations": [
        {
         "offset": 1474,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "1281",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL3A1",
       "locations": [
        {
         "offset": 1612,
         "length": 6
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "1281",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL3A1",
       "locations": [
        {
         "offset": 1731,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
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     "id": "R0",
     "infons": {
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      "novel": "No"
     }
    },
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    },
    {
     "id": "R2",
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      "entity1": "D004535",
      "entity2": "rs1801184",
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      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D004535",
      "entity2": "rs1800255",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D004535",
      "entity2": "c|SUB|C|2992|T",
      "type": "Positive_Correlation",
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     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D004535",
      "entity2": "c|DEL|2187|A",
      "type": "Positive_Correlation",
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     }
    }
   ]
  },
  {
   "id": "23069675",
   "passages": [
    {
     "offset": 0,
     "text": "Critical role of neuronal pentraxin 1 in mitochondria-mediated hypoxic-ischemic neuronal injury.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "neuronal pentraxin 1",
       "locations": [
        {
         "offset": 17,
         "length": 20
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D020925",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypoxic-ischemic neuronal injury",
       "locations": [
        {
         "offset": 63,
         "length": 32
        }
       ]
      }
     ]
    },
    {
     "offset": 97,
     "text": "Developing brain is highly susceptible to hypoxic-ischemic (HI) injury leading to severe neurological disabilities in surviving infants and children. Previously, we have reported induction of neuronal pentraxin 1 (NP1), a novel neuronal protein of long-pentraxin family, following HI neuronal injury. Here, we investigated how this specific signal is propagated to cause the HI neuronal death. We used wild-type (WT) and NP1 knockout (NP1-KO) mouse hippocampal cultures, modeled in vitro following exposure to oxygen glucose deprivation (OGD), and in vivo neonatal (P9-10) mouse model of HI brain injury. Our results show induction of NP1 in primary hippocampal neurons following OGD exposure (4-8 h) and in the ipsilateral hippocampal CA1 and CA3 regions at 24-48 h post-HI compared to the contralateral side. We also found increased PTEN activity concurrent with OGD time-dependent (4-8 h) dephosphorylation of Akt (Ser473) and GSK-3b (Ser9). OGD also caused a time-dependent decrease in the phosphorylation of Bad (Ser136), and Bax protein levels. Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential (D (m)). This NP1 induction preceded the increased mitochondrial release of cytochrome C (Cyt C) into the cytosol, activation of caspase-3 and OGD time-dependent cell death in WT primary hippocampal neurons. In contrast, in NP1-KO neurons there was no translocation of Bad and Bax from cytosol to the mitochondria, and no evidence of D (m) loss, increased Cyt C release and caspase-3 activation following OGD; which resulted in significantly reduced neuronal death. Our results indicate a regulatory role of NP1 in Bad/Bax-dependent mitochondrial release of Cyt C and caspase-3 activation. Together our findings demonstrate a novel mechanism by which NP1 regulates mitochondria-driven hippocampal cell death; suggesting NP1 as a potential therapeutic target against HI brain injury in neonates.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D020925",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypoxic-ischemic (HI) injury",
       "locations": [
        {
         "offset": 139,
         "length": 28
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009461",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neurological disabilities",
       "locations": [
        {
         "offset": 186,
         "length": 25
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "266777",
        "type": "GeneOrGeneProduct"
       },
       "text": "neuronal pentraxin 1",
       "locations": [
        {
         "offset": 289,
         "length": 20
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "266777",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 311,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D020925",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HI neuronal injury",
       "locations": [
        {
         "offset": 378,
         "length": 18
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D020925",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HI neuronal death",
       "locations": [
        {
         "offset": 472,
         "length": 17
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 518,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 532,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 540,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D010100",
        "type": "ChemicalEntity"
       },
       "text": "oxygen",
       "locations": [
        {
         "offset": 607,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D005947",
        "type": "ChemicalEntity"
       },
       "text": "glucose",
       "locations": [
        {
         "offset": 614,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 670,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D020925",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HI brain injury",
       "locations": [
        {
         "offset": 685,
         "length": 15
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 732,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "12346",
        "type": "GeneOrGeneProduct"
       },
       "text": "CA1",
       "locations": [
        {
         "offset": 833,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "12350",
        "type": "GeneOrGeneProduct"
       },
       "text": "CA3",
       "locations": [
        {
         "offset": 841,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "19211",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTEN",
       "locations": [
        {
         "offset": 932,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "11651",
        "type": "GeneOrGeneProduct"
       },
       "text": "Akt",
       "locations": [
        {
         "offset": 1010,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "p|AellelS|473",
        "type": "SequenceVariant"
       },
       "text": "Ser473",
       "locations": [
        {
         "offset": 1015,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "56637",
        "type": "GeneOrGeneProduct"
       },
       "text": "GSK-3b",
       "locations": [
        {
         "offset": 1027,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "p|AellelS|9",
        "type": "SequenceVariant"
       },
       "text": "Ser9",
       "locations": [
        {
         "offset": 1035,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "12015",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bad",
       "locations": [
        {
         "offset": 1110,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "p|AellelS|136",
        "type": "SequenceVariant"
       },
       "text": "Ser136",
       "locations": [
        {
         "offset": 1115,
         "length": 6
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "12028",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bax",
       "locations": [
        {
         "offset": 1128,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "12015",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bad",
       "locations": [
        {
         "offset": 1265,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "12028",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bax",
       "locations": [
        {
         "offset": 1273,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "13063",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cyt C",
       "locations": [
        {
         "offset": 1361,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "12367",
        "type": "GeneOrGeneProduct"
       },
       "text": "caspase-3",
       "locations": [
        {
         "offset": 1411,
         "length": 9
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 1422,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "12015",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bad",
       "locations": [
        {
         "offset": 1462,
         "length": 3
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "12028",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bax",
       "locations": [
        {
         "offset": 1470,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 1521,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "12015",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bad",
       "locations": [
        {
         "offset": 1530,
         "length": 3
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "12028",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bax",
       "locations": [
        {
         "offset": 1538,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 1665,
         "length": 3
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "13063",
        "type": "GeneOrGeneProduct"
       },
       "text": "cytochrome C",
       "locations": [
        {
         "offset": 1727,
         "length": 12
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "13063",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cyt C",
       "locations": [
        {
         "offset": 1741,
         "length": 5
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "12367",
        "type": "GeneOrGeneProduct"
       },
       "text": "caspase-3",
       "locations": [
        {
         "offset": 1780,
         "length": 9
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "18164",
        "type": "GeneOrGeneProduct"
       },
       "text": "NP1",
       "locations": [
        {
         "offset": 1875,
         "length": 3
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "12015",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bad",
       "locations": [
        {
         "offset": 1920,
         "length": 3
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "12028",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bax",
       "locations": [
        {
         "offset": 1928,
         "length": 3
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "13063",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cyt C",
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     "offset": 0,
     "text": "Interleukin 6 (IL-6) and Tumor Necrosis Factor alpha (TNF-alpha) Single Nucleotide Polymorphisms (SNPs), Inflammation and Metabolism in Gestational Diabetes Mellitus in Inner Mongolia.",
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       "text": "Tumor Necrosis Factor alpha",
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       "id": "3",
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       "id": "4",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Inflammation",
       "locations": [
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         "offset": 105,
         "length": 12
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       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D016640",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Gestational Diabetes Mellitus",
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     "offset": 185,
     "text": "BACKGROUND Gestational diabetes mellitus (GDM) is common all over the world. GDM women are with inflammatory and metabolisms abnormalities. However, few studies have focused on the association of IL-65-72C/G and TNF-alpha -857C/T single nucleotide polymorphisms (SNPs), inflammatory biomarkers, and metabolic indexes in women with GDM, especially in the Inner Mongolia population. The aim of this study was to investigate the associations of IL-65-72C/G and TNF-alpha -857C/T SNPs, and inflammation and metabolic biomarkers in women with GDM pregnancies. MATERIAL AND METHODS Blood samples and placentas from 140 women with GDM and 140 women with healthy pregnancies were collected. Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) and MassARRAY-IPLEX were performed to analyze IL-65-72C/G and TNF-alpha -857C/T SNPs. Enzyme linked immunosorbent assay (ELISA) was performed to analyze inflammatory biomarkers and adipokines. RESULTS Distribution frequency of TNF-alpha -857CT (OR=3.316, 95% CI=1.092-8.304, p=0.025) in women with GDM pregnancies were obviously higher than that in women with healthy pregnancies. Women with GDM were of older maternal age, had higher BMI, were more nulliparous, and had T2DM and GDM history, compared to women with healthy pregnancies (p   <0.05). Inflammatory biomarkers in serum (hs-CRP, IL-6, IL-8, IL-6/IL-10 ratio) and placental (NF-kappaB, IL-6, IL-8, IL-6/IL-10 ratio, IL-1b, TNF-alpha) were significantly different (p   <0.05) between women with GDM and women with healthy pregnancies. Differences were found for serum FBG, FINS, HOMA-IR, and HOMA-beta, and placental IRS-1, IRS-2, leptin, adiponectin, visfatin, RBP-4, chemerin, nesfatin-1, FATP-4, EL, LPL, FABP-1, FABP-3, FABP-4, and FABP-5. CONCLUSIONS TNF-alpha -857C/T SNP, hs-CRP, IL-6, IL-8, and IL-6/IL-10 were associated with GDM in women from Inner Mongolia, as was serious inflammation and disordered lipid and glucose metabolisms.",
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       "text": "Gestational diabetes mellitus",
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  {
   "id": "15459975",
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    {
     "offset": 0,
     "text": "Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis.",
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       "id": "0",
       "infons": {
        "identifier": "54434",
        "type": "GeneOrGeneProduct"
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       "text": "SSH1",
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     "text": "Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, the genetic basis and pathogenesis of this disorder have not been elucidated yet. In this study, we performed a genome-wide linkage analysis in three Chinese affected families and localized the gene in an 8.0 cM interval defined by D12S330 and D12S354 on chromosome 12. Upon screening 30 candidate genes, we identified a missense mutation, p.Ser63Asn in SSH1 in one family, a frameshift mutation, p.Ser19CysfsX24 in an alternative variant (isoform f) of SSH1 in another family, and a frameshift mutation, p.Pro27ProfsX54 in the same alternative variant in one non-familial case with DSAP. SSH1 encodes a phosphatase that plays a pivotal role in actin dynamics. Our data suggested that cytoskeleton disorganization in epidermal cells is likely associated with the pathogenesis of DSAP.",
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       "id": "2",
       "infons": {
        "identifier": "D017499",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Disseminated superficial actinic porokeratosis",
       "locations": [
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         "offset": 108,
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       "id": "3",
       "infons": {
        "identifier": "D017499",
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       "text": "DSAP",
       "locations": [
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         "offset": 156,
         "length": 4
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      {
       "id": "4",
       "infons": {
        "identifier": "D007642",
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       "text": "keratinization disorder",
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       "text": "keratotic lesions",
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       "id": "7",
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       "id": "8",
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         "offset": 748,
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         "offset": 791,
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       "id": "10",
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         "offset": 848,
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       "id": "11",
       "infons": {
        "identifier": "p|FS|P|63|P|54",
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       "id": "13",
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         "offset": 1173,
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  {
   "id": "16330669",
   "passages": [
    {
     "offset": 0,
     "text": "Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D016403",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "primary cutaneous large B-cell lymphoma",
       "locations": [
        {
         "offset": 126,
         "length": 39
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       ]
      }
     ]
    },
    {
     "offset": 167,
     "text": "PURPOSE: To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL). PATIENTS AND METHODS: Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation. RESULTS: The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma. CONCLUSION: Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.",
     "annotations": [
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       "id": "1",
       "infons": {
        "identifier": "D016403",
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       "text": "primary cutaneous large B-cell lymphoma",
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         "offset": 237,
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       "id": "2",
       "infons": {
        "identifier": "D016403",
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       "text": "PCLBCL",
       "locations": [
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         "offset": 278,
         "length": 6
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       "id": "3",
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       "text": "PATIENTS",
       "locations": [
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         "offset": 287,
         "length": 8
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       "id": "4",
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         "offset": 335,
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       "id": "5",
       "infons": {
        "identifier": "D016403",
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       "text": "PCLBCL",
       "locations": [
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         "offset": 351,
         "length": 6
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       ]
      },
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       "id": "6",
       "infons": {
        "identifier": "D008224",
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       "text": "primary cutaneous follicle center lymphoma",
       "locations": [
        {
         "offset": 379,
         "length": 42
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       "id": "7",
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       "text": "PCFCL",
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        {
         "offset": 423,
         "length": 5
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         "length": 6
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        "identifier": "D009369",
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       "text": "Cancer",
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        {
         "offset": 541,
         "length": 6
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        "identifier": "D008224",
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         "length": 8
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       "text": "PCLBCL",
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       "text": "BCL-2",
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        "identifier": "D016403",
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       "text": "PCLBCL",
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         "offset": 1286,
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       "text": "CDKN2A",
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       "id": "24",
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        "identifier": "D016403",
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       "text": "PCLBCL",
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       "infons": {
        "identifier": "D016403",
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         "offset": 1569,
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       "text": "lymphoma",
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         "offset": 1684,
         "length": 8
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       ]
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       "text": "CDKN2A",
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         "offset": 1915,
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       ]
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        "identifier": "D016403",
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         "offset": 2032,
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    }
   ]
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  {
   "id": "19208385",
   "passages": [
    {
     "offset": 0,
     "text": "Osteogenesis imperfecta type III with intracranial hemorrhage and brachydactyly associated with mutations in exon 49 of COL1A2.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C536044",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Osteogenesis imperfecta type III",
       "locations": [
        {
         "offset": 0,
         "length": 32
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       ]
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       "id": "1",
       "infons": {
        "identifier": "D020300",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "intracranial hemorrhage",
       "locations": [
        {
         "offset": 38,
         "length": 23
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       ]
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       "id": "2",
       "infons": {
        "identifier": "D059327",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "brachydactyly",
       "locations": [
        {
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         "length": 13
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       ]
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         "offset": 120,
         "length": 6
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     ]
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    {
     "offset": 128,
     "text": "Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by fractures with minimal trauma. Intracranial hemorrhage has been reported in a small number of OI patients. Here we describe three patients, a boy (aged 15 years) and two girls (aged 17 and 7 years) with OI type III who suffered intracranial hemorrhage and in addition had brachydactyly and nail hypoplasia. In all of these patients, OI was caused by glycine mutations affecting exon 49 of the COL1A2 gene, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen type I alpha 2 chain. These observations suggest that mutations in this region of the collagen type I alpha 2 chain carry a high risk of abnormal limb development and intracranial bleeding.",
     "annotations": [
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       "id": "4",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Osteogenesis imperfecta",
       "locations": [
        {
         "offset": 128,
         "length": 23
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       ]
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       "id": "5",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "OI",
       "locations": [
        {
         "offset": 153,
         "length": 2
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001847",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "bone disorder",
       "locations": [
        {
         "offset": 172,
         "length": 13
        }
       ]
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      {
       "id": "7",
       "infons": {
        "identifier": "D050723",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "fractures",
       "locations": [
        {
         "offset": 203,
         "length": 9
        }
       ]
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       "id": "8",
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        "identifier": "D014947",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "trauma",
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        {
         "offset": 226,
         "length": 6
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D020300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Intracranial hemorrhage",
       "locations": [
        {
         "offset": 234,
         "length": 23
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "OI",
       "locations": [
        {
         "offset": 297,
         "length": 2
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 300,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 333,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "C536044",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "OI type III",
       "locations": [
        {
         "offset": 406,
         "length": 11
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D020300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intracranial hemorrhage",
       "locations": [
        {
         "offset": 431,
         "length": 23
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D059327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "brachydactyly",
       "locations": [
        {
         "offset": 475,
         "length": 13
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D009260",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nail hypoplasia",
       "locations": [
        {
         "offset": 493,
         "length": 15
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 526,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D010013",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "OI",
       "locations": [
        {
         "offset": 536,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "1278",
        "type": "GeneOrGeneProduct"
       },
       "text": "COL1A2",
       "locations": [
        {
         "offset": 596,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "1278",
        "type": "GeneOrGeneProduct"
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       "text": "collagen type I alpha 2",
       "locations": [
        {
         "offset": 692,
         "length": 23
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "1278",
        "type": "GeneOrGeneProduct"
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       "text": "collagen type I alpha 2",
       "locations": [
        {
         "offset": 787,
         "length": 23
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D009140",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "abnormal limb development",
       "locations": [
        {
         "offset": 838,
         "length": 25
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D020300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intracranial bleeding",
       "locations": [
        {
         "offset": 868,
         "length": 21
        }
       ]
      }
     ]
    }
   ],
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     "infons": {
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      "novel": "Novel"
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    },
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    },
    {
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    },
    {
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     "infons": {
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      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "19681452",
   "passages": [
    {
     "offset": 0,
     "text": "Bilateral haemorrhagic infarction of the globus pallidus after cocaine and alcohol intoxication.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D002543,D020520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "haemorrhagic infarction of the globus pallidus",
       "locations": [
        {
         "offset": 10,
         "length": 46
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D003042",
        "type": "ChemicalEntity"
       },
       "text": "cocaine",
       "locations": [
        {
         "offset": 63,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D000431",
        "type": "ChemicalEntity"
       },
       "text": "alcohol",
       "locations": [
        {
         "offset": 75,
         "length": 7
        }
       ]
      }
     ]
    },
    {
     "offset": 97,
     "text": "Cocaine is a risk factor for both ischemic and haemorrhagic stroke. We present the case of a 31-year-old man with bilateral ischemia of the globus pallidus after excessive alcohol and intranasal cocaine use. Drug-related globus pallidus infarctions are most often associated with heroin. Bilateral basal ganglia infarcts after the use of cocaine, without concurrent heroin use, have never been reported. In our patient, transient cardiac arrhythmia or respiratory dysfunction related to cocaine and/or ethanol use were the most likely causes of cerebral hypoperfusion.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D003042",
        "type": "ChemicalEntity"
       },
       "text": "Cocaine",
       "locations": [
        {
         "offset": 97,
         "length": 7
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D002544,D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemic and haemorrhagic stroke",
       "locations": [
        {
         "offset": 131,
         "length": 32
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "man",
       "locations": [
        {
         "offset": 202,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002545",
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       },
       "text": "ischemia of the globus pallidus",
       "locations": [
        {
         "offset": 221,
         "length": 31
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D000431",
        "type": "ChemicalEntity"
       },
       "text": "alcohol",
       "locations": [
        {
         "offset": 269,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D003042",
        "type": "ChemicalEntity"
       },
       "text": "cocaine",
       "locations": [
        {
         "offset": 292,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D020520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "globus pallidus infarctions",
       "locations": [
        {
         "offset": 318,
         "length": 27
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003932",
        "type": "ChemicalEntity"
       },
       "text": "heroin",
       "locations": [
        {
         "offset": 377,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D020520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "basal ganglia infarcts",
       "locations": [
        {
         "offset": 395,
         "length": 22
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003042",
        "type": "ChemicalEntity"
       },
       "text": "cocaine",
       "locations": [
        {
         "offset": 435,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003932",
        "type": "ChemicalEntity"
       },
       "text": "heroin",
       "locations": [
        {
         "offset": 463,
         "length": 6
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       ]
      },
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       "id": "14",
       "infons": {
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       },
       "text": "patient",
       "locations": [
        {
         "offset": 508,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D001145",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiac arrhythmia",
       "locations": [
        {
         "offset": 527,
         "length": 18
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D012131",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "respiratory dysfunction",
       "locations": [
        {
         "offset": 549,
         "length": 23
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D003042",
        "type": "ChemicalEntity"
       },
       "text": "cocaine",
       "locations": [
        {
         "offset": 584,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D000431",
        "type": "ChemicalEntity"
       },
       "text": "ethanol",
       "locations": [
        {
         "offset": 599,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D002545",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cerebral hypoperfusion",
       "locations": [
        {
         "offset": 642,
         "length": 22
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "D000431",
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      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
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     "infons": {
      "entity1": "D000431",
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     "infons": {
      "entity1": "D000431",
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      "novel": "No"
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     "infons": {
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      "novel": "No"
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      "entity1": "D003042",
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      "entity1": "D003042",
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      "entity1": "D003042",
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      "type": "Positive_Correlation",
      "novel": "Novel"
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    {
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     "infons": {
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  {
   "id": "20709368",
   "passages": [
    {
     "offset": 0,
     "text": "The fibrinogen gamma 10034C>T polymorphism is not associated with Peripheral Arterial Disease.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "fibrinogen gamma",
       "locations": [
        {
         "offset": 4,
         "length": 16
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs2066865",
        "type": "SequenceVariant"
       },
       "text": "10034C>T",
       "locations": [
        {
         "offset": 21,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Peripheral Arterial Disease",
       "locations": [
        {
         "offset": 66,
         "length": 27
        }
       ]
      }
     ]
    },
    {
     "offset": 95,
     "text": "Conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the fibrin clot. Fibrinogen consists of three pairs of non-identical polypeptide chains, encoded by different genes (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]). A functional single nucleotide polymorphism (SNP) in the 3' untranslated region of the FGG gene (FGG 10034C>T, rs2066865) has been associated with deep venous thrombosis and myocardial infarction. Aim of the present study was to analyze the role of this polymorphism in peripheral arterial disease (PAD). The study was designed as case-control study including 891 patients with documented PAD and 777 control subjects. FGG genotypes were determined by exonuclease (TaqMan) assays. FGG genotype frequencies were not significantly different between PAD patients (CC: 57.3%, CT: 36.7%, TT: 5.8%) and control subjects (CC: 60.9%, CT: 33.5%, TT 5.6%; p=0.35). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, the FGG 10034 T variant was not significantly associated with the presence of PAD (Odds ratio 1.07, 95% confidence interval 0.84 - 1.37; p = 0.60). The FGG 10034C>T polymorphism was furthermore not associated with age at onset of PAD. We conclude that the thrombophilic FGG 10034 T gene variant does not contribute to the genetic susceptibility to PAD.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "2243,2244,2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "fibrinogen",
       "locations": [
        {
         "offset": 109,
         "length": 10
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2243,2244,2266",
        "type": "GeneOrGeneProduct"
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       "text": "fibrin",
       "locations": [
        {
         "offset": 123,
         "length": 6
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "2243,2244,2266",
        "type": "GeneOrGeneProduct"
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       "text": "fibrin",
       "locations": [
        {
         "offset": 204,
         "length": 6
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2243,2244,2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "Fibrinogen",
       "locations": [
        {
         "offset": 217,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2243",
        "type": "GeneOrGeneProduct"
       },
       "text": "fibrinogen alpha",
       "locations": [
        {
         "offset": 317,
         "length": 16
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "2243",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGA",
       "locations": [
        {
         "offset": 335,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2244",
        "type": "GeneOrGeneProduct"
       },
       "text": "fibrinogen beta",
       "locations": [
        {
         "offset": 341,
         "length": 15
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2244",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGB",
       "locations": [
        {
         "offset": 358,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "fibrinogen gamma",
       "locations": [
        {
         "offset": 367,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 385,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 479,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 489,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs2066865",
        "type": "SequenceVariant"
       },
       "text": "10034C>T",
       "locations": [
        {
         "offset": 493,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs2066865",
        "type": "SequenceVariant"
       },
       "text": "rs2066865",
       "locations": [
        {
         "offset": 503,
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       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D020246",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deep venous thrombosis",
       "locations": [
        {
         "offset": 539,
         "length": 22
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D009203",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocardial infarction",
       "locations": [
        {
         "offset": 566,
         "length": 21
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "peripheral arterial disease",
       "locations": [
        {
         "offset": 662,
         "length": 27
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAD",
       "locations": [
        {
         "offset": 691,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 756,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAD",
       "locations": [
        {
         "offset": 781,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 811,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 873,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAD",
       "locations": [
        {
         "offset": 939,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 943,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes",
       "locations": [
        {
         "offset": 1123,
         "length": 8
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1142,
         "length": 12
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D006937",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypercholesterolemia",
       "locations": [
        {
         "offset": 1159,
         "length": 20
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 1185,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "rs2066865",
        "type": "SequenceVariant"
       },
       "text": "10034 T",
       "locations": [
        {
         "offset": 1189,
         "length": 7
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAD",
       "locations": [
        {
         "offset": 1259,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 1333,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "rs2066865",
        "type": "SequenceVariant"
       },
       "text": "10034C>T",
       "locations": [
        {
         "offset": 1337,
         "length": 8
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAD",
       "locations": [
        {
         "offset": 1411,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "2266",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGG",
       "locations": [
        {
         "offset": 1451,
         "length": 3
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "rs2066865",
        "type": "SequenceVariant"
       },
       "text": "10034 T",
       "locations": [
        {
         "offset": 1455,
         "length": 7
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D058729",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAD",
       "locations": [
        {
         "offset": 1529,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
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    {
     "id": "R0",
     "infons": {
      "entity1": "rs2066865",
      "entity2": "D009203",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs2066865",
      "entity2": "D020246",
      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "2266",
      "entity2": "D009203",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "2266",
      "entity2": "D020246",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "21879313",
   "passages": [
    {
     "offset": 0,
     "text": "Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs8099917",
        "type": "SequenceVariant"
       },
       "text": "rs8099917",
       "locations": [
        {
         "offset": 9,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "282617",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL28B",
       "locations": [
        {
         "offset": 28,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "11103",
        "type": "OrganismTaxon"
       },
       "text": "hepatitis C virus",
       "locations": [
        {
         "offset": 108,
         "length": 17
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "338",
        "type": "GeneOrGeneProduct"
       },
       "text": "apolipoprotein B-100",
       "locations": [
        {
         "offset": 152,
         "length": 20
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D019698",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic hepatitis C",
       "locations": [
        {
         "offset": 190,
         "length": 19
        }
       ]
      }
     ]
    },
    {
     "offset": 211,
     "text": "The life cycle of the hepatitis C virus (HCV) is closely related to host lipoprotein metabolism. Serum levels of lipid are associated with the response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, while single nucleotide polymorphisms (SNPs) around the human interleukin 28B (IL28B) gene locus and amino acid substitutions in the core region of the HCV have been reported to affect the efficacy of PEG-IFN/RBV therapy in chronic hepatitis with HCV genotype 1b infection. The aim of this study was to elucidate the relationship between serum lipid and factors that are able to predict the efficacy of PEG-IFN/RB therapy, with specific focus on apolipoprotein B-100 (apoB-100) in 148 subjects with chronic HCV G1b infection. Our results demonstrated that both the aa 70 substitution in the core region of the HCV and the rs8099917 SNP located proximal to the IL28B were independent factors in determining serum apoB-100 and low-density lipoprotein (LDL) cholesterol levels. A significant association was noted between higher levels of apoB-100 (P = 1.1 10(-3)) and LDL cholesterol (P = 0.02) and the subjects having Arg70. A significant association was also observed between subjects carrying the rs8099917 TT responder genotype and higher levels of apoB-100 (P = 6.4 10(-3)) and LDL cholesterol (P = 4.2 10(-3)). Our results suggest that apoB-100 and LDL cholesterol are markers of impaired cellular lipoprotein pathways and/or host endogenous interferon response to HCV in chronic HCV infection. In particular, serum apoB-100 concentration might be an informative marker for judging changes in HCV-associated intracellular lipoprotein metabolism in patients carrying the rs8099917 responder genotype.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "11103",
        "type": "OrganismTaxon"
       },
       "text": "hepatitis C virus",
       "locations": [
        {
         "offset": 233,
         "length": 17
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "11103",
        "type": "OrganismTaxon"
       },
       "text": "HCV",
       "locations": [
        {
         "offset": 252,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008055",
        "type": "ChemicalEntity"
       },
       "text": "lipid",
       "locations": [
        {
         "offset": 324,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "3439",
        "type": "GeneOrGeneProduct"
       },
       "text": "pegylated interferon",
       "locations": [
        {
         "offset": 366,
         "length": 20
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D012254",
        "type": "ChemicalEntity"
       },
       "text": "ribavirin",
       "locations": [
        {
         "offset": 392,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3439",
        "type": "GeneOrGeneProduct"
       },
       "text": "PEG-IFN",
       "locations": [
        {
         "offset": 403,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D012254",
        "type": "ChemicalEntity"
       },
       "text": "RBV",
       "locations": [
        {
         "offset": 411,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 481,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "282617",
        "type": "GeneOrGeneProduct"
       },
       "text": "interleukin 28B",
       "locations": [
        {
         "offset": 487,
         "length": 15
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "282617",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL28B",
       "locations": [
        {
         "offset": 504,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
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       },
       "text": "MT1-MMP",
       "locations": [
        {
         "offset": 1529,
         "length": 7
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
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    },
    {
     "id": "R1",
     "infons": {
      "entity1": "55361",
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      "novel": "No"
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    },
    {
     "id": "R2",
     "infons": {
      "entity1": "55361",
      "entity2": "D008055",
      "type": "Association",
      "novel": "No"
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    },
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    },
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    },
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     "id": "R9",
     "infons": {
      "entity1": "55300",
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      "type": "Negative_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R10",
     "infons": {
      "entity1": "55300",
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      "novel": "No"
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     "id": "R11",
     "infons": {
      "entity1": "55300",
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      "type": "Association",
      "novel": "No"
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    {
     "id": "R12",
     "infons": {
      "entity1": "55300",
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      "type": "Association",
      "novel": "Novel"
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    {
     "id": "R13",
     "infons": {
      "entity1": "55300",
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    {
     "id": "R14",
     "infons": {
      "entity1": "55300",
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      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "27993978",
   "passages": [
    {
     "offset": 0,
     "text": "CenpH regulates meiotic G2/M transition by modulating the APC/CCdh1-cyclin B1 pathway in oocytes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "26886",
        "type": "GeneOrGeneProduct"
       },
       "text": "CenpH",
       "locations": [
        {
         "offset": 0,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "56371",
        "type": "GeneOrGeneProduct"
       },
       "text": "APC/CCdh1",
       "locations": [
        {
         "offset": 58,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "268697",
        "type": "GeneOrGeneProduct"
       },
       "text": "cyclin B1",
       "locations": [
        {
         "offset": 68,
         "length": 9
        }
       ]
      }
     ]
    },
    {
     "offset": 98,
     "text": "Meiotic resumption (G2/M transition) and progression through meiosis I (MI) are two key stages for producing fertilization-competent eggs. Here, we report that CenpH, a component of the kinetochore inner plate, is responsible for G2/M transition in meiotic mouse oocytes. Depletion of CenpH by morpholino injection decreased cyclin B1 levels, resulting in attenuation of maturation-promoting factor (MPF) activation, and severely compromised meiotic resumption. CenpH protects cyclin B1 from destruction by competing with the action of APC/C(Cdh1) Impaired G2/M transition after CenpH depletion could be rescued by expression of exogenous cyclin B1. Unexpectedly, blocking CenpH did not affect spindle organization and meiotic cell cycle progression after germinal vesicle breakdown. Our findings reveal a novel role of CenpH in regulating meiotic G2/M transition by acting via the APC/C(Cdh1)-cyclin B1 pathway.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "26886",
        "type": "GeneOrGeneProduct"
       },
       "text": "CenpH",
       "locations": [
        {
         "offset": 258,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 355,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "26886",
        "type": "GeneOrGeneProduct"
       },
       "text": "CenpH",
       "locations": [
        {
         "offset": 383,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D060172",
        "type": "ChemicalEntity"
       },
       "text": "morpholino",
       "locations": [
        {
         "offset": 392,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "268697",
        "type": "GeneOrGeneProduct"
       },
       "text": "cyclin B1",
       "locations": [
        {
         "offset": 423,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "268697",
        "type": "GeneOrGeneProduct"
       },
       "text": "maturation-promoting factor",
       "locations": [
        {
         "offset": 469,
         "length": 27
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "268697",
        "type": "GeneOrGeneProduct"
       },
       "text": "MPF",
       "locations": [
        {
         "offset": 498,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "26886",
        "type": "GeneOrGeneProduct"
       },
       "text": "CenpH",
       "locations": [
        {
         "offset": 560,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "268697",
        "type": "GeneOrGeneProduct"
       },
       "text": "cyclin B1",
       "locations": [
        {
         "offset": 575,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "56371",
        "type": "GeneOrGeneProduct"
       },
       "text": "APC/C",
       "locations": [
        {
         "offset": 634,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "56371",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cdh1",
       "locations": [
        {
         "offset": 640,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "26886",
        "type": "GeneOrGeneProduct"
       },
       "text": "CenpH",
       "locations": [
        {
         "offset": 677,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "268697",
        "type": "GeneOrGeneProduct"
       },
       "text": "cyclin B1",
       "locations": [
        {
         "offset": 737,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "26886",
        "type": "GeneOrGeneProduct"
       },
       "text": "CenpH",
       "locations": [
        {
         "offset": 771,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "26886",
        "type": "GeneOrGeneProduct"
       },
       "text": "CenpH",
       "locations": [
        {
         "offset": 918,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "56371",
        "type": "GeneOrGeneProduct"
       },
       "text": "APC/C",
       "locations": [
        {
         "offset": 980,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "56371",
        "type": "GeneOrGeneProduct"
       },
       "text": "Cdh1",
       "locations": [
        {
         "offset": 986,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "268697",
        "type": "GeneOrGeneProduct"
       },
       "text": "cyclin B1",
       "locations": [
        {
         "offset": 992,
         "length": 9
        }
       ]
      }
     ]
    }
   ],
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     "infons": {
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     "infons": {
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      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "26886",
      "entity2": "56371",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "26886",
      "entity2": "D060172",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "26886",
      "entity2": "268697",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15111599",
   "passages": [
    {
     "offset": 0,
     "text": "CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1411",
        "type": "GeneOrGeneProduct"
       },
       "text": "CRYBA3/A1",
       "locations": [
        {
         "offset": 0,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C565137",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant congenital nuclear cataract",
       "locations": [
        {
         "offset": 55,
         "length": 46
        }
       ]
      }
     ]
    },
    {
     "offset": 122,
     "text": "PURPOSE: To identify the genetic defect leading to the congenital nuclear cataract affecting a large five-generation Swiss family. METHODS: Family history and clinical data were recorded. The phenotype was documented by both slit lamp and Scheimpflug photography. One cortical lens was evaluated by electron microscopy after cataract extraction. Lenticular phenotyping and genotyping were performed independently with short tandem repeat polymorphism. Linkage analysis was performed, and candidate genes were PCR amplified and screened for mutations on both strands using direct sequencing. RESULTS: Affected individuals had a congenital nuclear lactescent cataract in both eyes. Linkage was observed on chromosome 17 for DNA marker D17S1857 (lod score: 3.44 at theta = 0). Direct sequencing of CRYBA3/A1, which maps to the vicinity, revealed an in-frame 3-bp deletion in exon 4 (279delGAG). This mutation involved a deletion of glycine-91, cosegregated in all affected individuals, and was not observed in unaffected individuals or in 250 normal control subjects from the same ethnic background. Electron microscopy showed that cortical lens fiber morphology was normal. CONCLUSIONS: The DeltaG91 mutation in CRYBA3/A1 is associated with an autosomal dominant congenital nuclear lactescent cataract. A splice mutation (IVS3+1G/A) in this gene has been reported in a zonular cataract with sutural opacities. These results indicate phenotypic heterogeneity related to mutations in this gene.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "genetic defect",
       "locations": [
        {
         "offset": 147,
         "length": 14
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C565137",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital nuclear cataract",
       "locations": [
        {
         "offset": 177,
         "length": 27
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D002386",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cataract",
       "locations": [
        {
         "offset": 447,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C565137",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital nuclear lactescent cataract",
       "locations": [
        {
         "offset": 749,
         "length": 38
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1411",
        "type": "GeneOrGeneProduct"
       },
       "text": "CRYBA3/A1",
       "locations": [
        {
         "offset": 917,
         "length": 9
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "c|DEL||3",
        "type": "SequenceVariant"
       },
       "text": "3-bp deletion",
       "locations": [
        {
         "offset": 977,
         "length": 13
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|DEL|279|GAG",
        "type": "SequenceVariant"
       },
       "text": "279delGAG",
       "locations": [
        {
         "offset": 1002,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "p|DEL|91|G",
        "type": "SequenceVariant"
       },
       "text": "deletion of glycine-91",
       "locations": [
        {
         "offset": 1039,
         "length": 22
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "p|DEL|91|G",
        "type": "SequenceVariant"
       },
       "text": "DeltaG91",
       "locations": [
        {
         "offset": 1311,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1411",
        "type": "GeneOrGeneProduct"
       },
       "text": "CRYBA3/A1",
       "locations": [
        {
         "offset": 1332,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C565137",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant congenital nuclear lactescent cataract",
       "locations": [
        {
         "offset": 1364,
         "length": 57
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|SUB|G|IVS3+1|A",
        "type": "SequenceVariant"
       },
       "text": "IVS3+1G/A",
       "locations": [
        {
         "offset": 1442,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "C535342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "zonular cataract",
       "locations": [
        {
         "offset": 1489,
         "length": 16
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "p|DEL|91|G",
      "entity2": "C565137",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|DEL|279|GAG",
      "entity2": "C565137",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|DEL||3",
      "entity2": "C565137",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|SUB|G|IVS3+1|A",
      "entity2": "C535342",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "C535342",
      "entity2": "1411",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "1411",
      "entity2": "C565137",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "15820770",
   "passages": [
    {
     "offset": 0,
     "text": "Vitamin D-binding protein gene polymorphism association with IA-2 autoantibodies in type 1 diabetes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "Vitamin D-binding protein",
       "locations": [
        {
         "offset": 0,
         "length": 25
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "5798",
        "type": "GeneOrGeneProduct"
       },
       "text": "IA-2",
       "locations": [
        {
         "offset": 61,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 84,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 101,
     "text": "BACKGROUND: Vitamin D-binding protein (DBP) is the main systemic transporter of 1.25(OH)2D3 and is essential for its cellular endocytosis. There are two known polymorphisms in exon 11 of the DBP gene resulting in amino acid variants: GAT-->GAG substitution replaces aspartic acid by glutamic acid in codon 416; and ACG-->AAG substitution in codon 420 leads to an exchange of threonine for lysine. These DBP variants lead to differences in the affinity for 1.25(OH)2D3. Correlations between DBP alleles and type 1 diabetes have been described in different populations. Therefore, we investigated the polymorphism in codon 416 of the DBP gene for an association with autoimmune markers of type 1 diabetes. DESIGN AND METHODS: The present analysis was a case control study. 110 patients, 68 controls, and 115 first-degree relatives were genotyped for the DBP polymorphism in codon 416. DNA typing of DBP locus was performed by the PCR-restriction fragment length polymorphism method (RFLP). RESULTS: The frequencies of the Asp/Glu and Glu/Glu were significantly increased in diabetic subjects with detectable IA-2 antibodies (P < 0.01). On the contrary, the DBP Glu-containing genotype was not accompanied by differences in the prevalence of GAD65 antibodies. These finding supports a role of the vitamin D endocrine system in the autoimmune process of type 1 diabetes.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "Vitamin D-binding protein",
       "locations": [
        {
         "offset": 113,
         "length": 25
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 140,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D002117",
        "type": "ChemicalEntity"
       },
       "text": "1.25(OH)2D3",
       "locations": [
        {
         "offset": 181,
         "length": 11
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 292,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "p|SUB|D|416|E",
        "type": "SequenceVariant"
       },
       "text": "GAT-->GAG substitution replaces aspartic acid by glutamic acid in codon 416",
       "locations": [
        {
         "offset": 335,
         "length": 75
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "p|SUB|T|420|K",
        "type": "SequenceVariant"
       },
       "text": "ACG-->AAG substitution in codon 420",
       "locations": [
        {
         "offset": 416,
         "length": 35
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "p|SUB|T||K",
        "type": "SequenceVariant"
       },
       "text": "threonine for lysine",
       "locations": [
        {
         "offset": 476,
         "length": 20
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 504,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D002117",
        "type": "ChemicalEntity"
       },
       "text": "1.25(OH)2D3",
       "locations": [
        {
         "offset": 557,
         "length": 11
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 591,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 607,
         "length": 15
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 733,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 788,
         "length": 15
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 876,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 953,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 998,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetic",
       "locations": [
        {
         "offset": 1173,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "5798",
        "type": "GeneOrGeneProduct"
       },
       "text": "IA-2",
       "locations": [
        {
         "offset": 1207,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "2638",
        "type": "GeneOrGeneProduct"
       },
       "text": "DBP",
       "locations": [
        {
         "offset": 1256,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "2572",
        "type": "GeneOrGeneProduct"
       },
       "text": "GAD65",
       "locations": [
        {
         "offset": 1340,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D014807",
        "type": "ChemicalEntity"
       },
       "text": "vitamin D",
       "locations": [
        {
         "offset": 1395,
         "length": 9
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D003922",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 1 diabetes",
       "locations": [
        {
         "offset": 1451,
         "length": 15
        }
       ]
      }
     ]
    }
   ],
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     "id": "R0",
     "infons": {
      "entity1": "p|SUB|T||K",
      "entity2": "D002117",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "p|SUB|T|420|K",
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      "type": "Association",
      "novel": "No"
     }
    },
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      "entity1": "p|SUB|D|416|E",
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      "novel": "No"
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     "infons": {
      "entity1": "5798",
      "entity2": "D003922",
      "type": "Association",
      "novel": "No"
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    {
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     "infons": {
      "entity1": "2638",
      "entity2": "D002117",
      "type": "Association",
      "novel": "No"
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     "infons": {
      "entity1": "2638",
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      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R8",
     "infons": {
      "entity1": "2638",
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      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "16186368",
   "passages": [
    {
     "offset": 0,
     "text": "Characterization of Bietti crystalline dystrophy patients with CYP4V2 mutations.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C535440",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Bietti crystalline dystrophy",
       "locations": [
        {
         "offset": 20,
         "length": 28
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 49,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "285440",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP4V2",
       "locations": [
        {
         "offset": 63,
         "length": 6
        }
       ]
      }
     ]
    },
    {
     "offset": 81,
     "text": "PURPOSE: Mutations of the CYP4V2 gene, a novel family member of the cytochrome P450 genes on chromosome 4q35, have recently been identified in patients with Bietti crystalline dystrophy (BCD). The aim of this study was to investigate the spectrum of mutations in this gene in BCD patients from Singapore, and to characterize their phenotype. METHODS: Nine patients with BCD from six families were recruited into the study. The 11 exons of the CYP4V2 gene were amplified from genomic DNA of patients by polymerase chain reaction and then sequenced. Detailed characterization of the patients' phenotype was performed with fundal photography, visual field testing, fundal fluorescein angiography, and electroretinography (ERG). RESULTS: Three pathogenic mutations were identified; two mutations, S482X and K386T, were novel and found in three patients. The third mutation, a previously identified 15-bp deletion that included the 3' splice site for exon 7, was found in all nine patients, with six patients carrying the deletion in the homozygous state. Haplotype analysis in patients and controls indicated a founder effect for this deletion mutation in exon 7. Clinical heterogeneity was present in the patients. Compound heterozygotes for the deletion in exon 7 seemed to have more severe disease compared to patients homozygous for the deletion. There was good correlation between clinical stage of disease and ERG changes, but age did not correlate with disease severity. CONCLUSIONS: This study identified novel mutations in the CYP4V2 gene as a cause of BCD. A high carrier frequency for the 15-bp deletion in exon 7 may exist in the Singapore population. Phenotype characterization showed clinical heterogeneity, and age did not correlate with disease severity.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "285440",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP4V2",
       "locations": [
        {
         "offset": 107,
         "length": 6
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "285440",
        "type": "GeneOrGeneProduct"
       },
       "text": "cytochrome P450",
       "locations": [
        {
         "offset": 149,
         "length": 15
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 224,
         "length": 8
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C535440",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Bietti crystalline dystrophy",
       "locations": [
        {
         "offset": 238,
         "length": 28
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "C535440",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCD",
       "locations": [
        {
         "offset": 268,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "C535440",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCD",
       "locations": [
        {
         "offset": 357,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 361,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 437,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C535440",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCD",
       "locations": [
        {
         "offset": 451,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "285440",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP4V2",
       "locations": [
        {
         "offset": 524,
         "length": 6
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 571,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 662,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs146494374",
        "type": "SequenceVariant"
       },
       "text": "S482X",
       "locations": [
        {
         "offset": 874,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs199476200",
        "type": "SequenceVariant"
       },
       "text": "K386T",
       "locations": [
        {
         "offset": 884,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 921,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|DEL||15",
        "type": "SequenceVariant"
       },
       "text": "15-bp deletion",
       "locations": [
        {
         "offset": 975,
         "length": 14
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1057,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1076,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1154,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1283,
         "length": 8
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1390,
         "length": 8
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "285440",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP4V2",
       "locations": [
        {
         "offset": 1613,
         "length": 6
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "C535440",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BCD",
       "locations": [
        {
         "offset": 1639,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "c|DEL||15",
        "type": "SequenceVariant"
       },
       "text": "15-bp deletion",
       "locations": [
        {
         "offset": 1677,
         "length": 14
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "c|DEL||15",
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     "infons": {
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     "id": "R3",
     "infons": {
      "entity1": "C535440",
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      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17511042",
   "passages": [
    {
     "offset": 0,
     "text": "An extremely rare case of delusional parasitosis in a chronic hepatitis C patient during pegylated interferon alpha-2b and ribavirin treatment.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D063726",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "delusional parasitosis",
       "locations": [
        {
         "offset": 26,
         "length": 22
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      },
      {
       "id": "1",
       "infons": {
        "identifier": "D019698",
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       "text": "chronic hepatitis C",
       "locations": [
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         "offset": 54,
         "length": 19
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       ]
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       "id": "2",
       "infons": {
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       "text": "patient",
       "locations": [
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         "offset": 74,
         "length": 7
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       "id": "3",
       "infons": {
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       "text": "pegylated interferon alpha-2b",
       "locations": [
        {
         "offset": 89,
         "length": 29
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       ]
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       "id": "4",
       "infons": {
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       "text": "ribavirin",
       "locations": [
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         "offset": 123,
         "length": 9
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       ]
      }
     ]
    },
    {
     "offset": 144,
     "text": "During treatment of chronic hepatitis C patients with interferon and ribavirin, a lot of side effects are described. Twenty-three percent to 44% of patients develop depression. A minority of patients evolve to psychosis. To the best of our knowledge, no cases of psychogenic parasitosis occurring during interferon therapy have been described in the literature. We present a 49-year-old woman who developed a delusional parasitosis during treatment with pegylated interferon alpha-2b weekly and ribavirin. She complained of seeing parasites and the larvae of fleas in her stools. This could not be confirmed by any technical examination. All the complaints disappeared after stopping pegylated interferon alpha-2b and reappeared after restarting it. She had a complete sustained viral response.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D019698",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "chronic hepatitis C",
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       "text": "patients",
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       "id": "7",
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       "text": "interferon",
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         "offset": 198,
         "length": 10
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       ]
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       "id": "8",
       "infons": {
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       "text": "ribavirin",
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         "offset": 213,
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       "id": "9",
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       "text": "patients",
       "locations": [
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         "offset": 292,
         "length": 8
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003866",
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       "text": "depression",
       "locations": [
        {
         "offset": 309,
         "length": 10
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
        {
         "offset": 335,
         "length": 8
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D011605",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psychosis",
       "locations": [
        {
         "offset": 354,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D063726",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psychogenic parasitosis",
       "locations": [
        {
         "offset": 407,
         "length": 23
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "3440",
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       "text": "interferon",
       "locations": [
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         "offset": 448,
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       ]
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      {
       "id": "15",
       "infons": {
        "identifier": "9606",
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       "text": "woman",
       "locations": [
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         "offset": 531,
         "length": 5
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D063726",
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       "text": "delusional parasitosis",
       "locations": [
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       ]
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      {
       "id": "17",
       "infons": {
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       "text": "pegylated interferon alpha-2b",
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       "text": "ribavirin",
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       "text": "pegylated interferon alpha-2b",
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      "novel": "No"
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    },
    {
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      "type": "Negative_Correlation",
      "novel": "No"
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    },
    {
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     "infons": {
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      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R5",
     "infons": {
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      "type": "Cotreatment",
      "novel": "No"
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    },
    {
     "id": "R6",
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      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "26110643",
   "passages": [
    {
     "offset": 0,
     "text": "Protein-Trap Insertional Mutagenesis Uncovers New Genes Involved in Zebrafish Skin Development, Including a Neuregulin 2a-Based ErbB Signaling Pathway Required during Median Fin Fold Morphogenesis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "436725",
        "type": "GeneOrGeneProduct"
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       "text": "Trap",
       "locations": [
        {
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     "offset": 0,
     "text": "Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients.",
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     "text": "Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit (CHRNG) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1, CHRNB1, CHRND, and rapsyn (RAPSN) genes. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA, was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.",
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       },
       "text": "fetal akinesia",
       "locations": [
        {
         "offset": 844,
         "length": 14
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "1146",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHRNG",
       "locations": [
        {
         "offset": 867,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "1134",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHRNA1",
       "locations": [
        {
         "offset": 904,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "1140",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHRNB1",
       "locations": [
        {
         "offset": 912,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "1144",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHRND",
       "locations": [
        {
         "offset": 920,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "5913",
        "type": "GeneOrGeneProduct"
       },
       "text": "rapsyn",
       "locations": [
        {
         "offset": 931,
         "length": 6
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "5913",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAPSN",
       "locations": [
        {
         "offset": 939,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "1134",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHRNA1",
       "locations": [
        {
         "offset": 956,
         "length": 6
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "1140",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHRNB1",
       "locations": [
        {
         "offset": 964,
         "length": 6
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "1144",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHRND",
       "locations": [
        {
         "offset": 975,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "5913",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAPSN",
       "locations": [
        {
         "offset": 1023,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "c|DEL|1177_1178|AA",
        "type": "SequenceVariant"
       },
       "text": "c.1177-1178delAA",
       "locations": [
        {
         "offset": 1050,
         "length": 16
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "C536647",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fetal akinesia sequence",
       "locations": [
        {
         "offset": 1136,
         "length": 23
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "5913",
        "type": "GeneOrGeneProduct"
       },
       "text": "RAPSN",
       "locations": [
        {
         "offset": 1173,
         "length": 5
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D020294",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital myasthenia",
       "locations": [
        {
         "offset": 1211,
         "length": 21
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "5913",
        "type": "GeneOrGeneProduct"
       },
       "text": "rapsyn",
       "locations": [
        {
         "offset": 1321,
         "length": 6
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D020294",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital myasthenia",
       "locations": [
        {
         "offset": 1347,
         "length": 21
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "C536647",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fetal akinesia",
       "locations": [
        {
         "offset": 1422,
         "length": 14
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|DEL|1177_1178|AA",
      "entity2": "C536647",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "5913",
      "entity2": "D020294",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "5913",
      "entity2": "C536647",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "1146",
      "entity2": "C537377",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "19353688",
   "passages": [
    {
     "offset": 0,
     "text": "Pure monosomy and pure trisomy of 13q21.2-31.1 consequent to a familial insertional translocation: exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1).",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5101",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCDH9",
       "locations": [
        {
         "offset": 112,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C563790",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal dominant auditory neuropathy",
       "locations": [
        {
         "offset": 146,
         "length": 38
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C563790",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AUNA1",
       "locations": [
        {
         "offset": 186,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 194,
     "text": "Insertional translocations (IT) are rare structural rearrangements. Offspring of IT balanced carriers are at high risk to have either pure partial trisomy or monosomy for the inserted segment as manifested by \"pure\" phenotypes. We describe an IT between chromosomes 3 and 13 segregating in a three-generation pedigree. Short tandem repeat (STR) segregation analysis and array-comparative genomic hybridization were used to define the IT as a 25.1 Mb segment spanning 13q21.2-q31.1. The phenotype of pure monosomy included deafness, duodenal stenosis, developmental and growth delay, vertebral anomalies, and facial dysmorphisms; the trisomy was manifested by only minor dysmorphisms. As the AUNA1 deafness locus on 13q14-21 overlaps the IT in the PCDH9 (protocadherin-9) gene region, PCDH9 was investigated as a candidate gene for deafness in both families. Genotyping of STRs and single nucleotide polymorphisms defined the AUNA1 breakpoint as 35 kb 5' to PCDH9, with a 2.4 Mb area of overlap with the IT. DNA sequencing of coding regions in the AUNA1 family and in the retained homologue chromosome in the monosomic patient revealed no mutations. We conclude that AUNA1 deafness does not share a common etiology with deafness associated with monosomy 13q21.2-q31.3; deafness may result from monosomy of PCHD9 or another gene in the IT, as has been demonstrated in contiguous gene deletion syndromes. Precise characterization of the breakpoints of the translocated region is useful to identify which genes may be contributing to the phenotype, either through haploinsufficiency or extra dosage effects, in order to define genotype-phenotype correlations.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 716,
         "length": 8
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C535720",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "duodenal stenosis",
       "locations": [
        {
         "offset": 726,
         "length": 17
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D002658",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "developmental and growth delay",
       "locations": [
        {
         "offset": 745,
         "length": 30
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "C535781",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "vertebral anomalies",
       "locations": [
        {
         "offset": 777,
         "length": 19
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D019465",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "facial dysmorphisms",
       "locations": [
        {
         "offset": 802,
         "length": 19
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D019465",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dysmorphisms",
       "locations": [
        {
         "offset": 864,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "C563790",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AUNA1",
       "locations": [
        {
         "offset": 885,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 891,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "5101",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCDH9",
       "locations": [
        {
         "offset": 941,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "5101",
        "type": "GeneOrGeneProduct"
       },
       "text": "protocadherin-9",
       "locations": [
        {
         "offset": 948,
         "length": 15
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "5101",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCDH9",
       "locations": [
        {
         "offset": 978,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 1025,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "C563790",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AUNA1",
       "locations": [
        {
         "offset": 1119,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "5101",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCDH9",
       "locations": [
        {
         "offset": 1151,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C563790",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AUNA1",
       "locations": [
        {
         "offset": 1241,
         "length": 5
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1312,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "C563790",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "AUNA1",
       "locations": [
        {
         "offset": 1360,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 1366,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 1413,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D003638",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deafness",
       "locations": [
        {
         "offset": 1462,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "5101",
        "type": "GeneOrGeneProduct"
       },
       "text": "PCHD9",
       "locations": [
        {
         "offset": 1499,
         "length": 5
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "C563790",
      "entity2": "5101",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D003638",
      "entity2": "5101",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "21126715",
   "passages": [
    {
     "offset": 0,
     "text": "A Taiwanese boy with congenital generalized lipodystrophy caused by homozygous Ile262fs mutation in the BSCL2 gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D052497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital generalized lipodystrophy",
       "locations": [
        {
         "offset": 21,
         "length": 36
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "p|FS|I|262||",
        "type": "SequenceVariant"
       },
       "text": "Ile262fs",
       "locations": [
        {
         "offset": 79,
         "length": 8
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "26580",
        "type": "GeneOrGeneProduct"
       },
       "text": "BSCL2",
       "locations": [
        {
         "offset": 104,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 116,
     "text": "Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by a near-complete absence of adipose tissue from birth or early infancy. Mutations in the BSCL2 gene are known to result in CGL2, a more severe phenotype than CGL1, with earlier onset, more extensive fat loss and biochemical changes, more severe intellectual impairment, and more severe cardiomyopathy. We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia. Absence of mechanical adipose tissue in the orbits and scalp was revealed by head magnetic resonance imaging. Hepatomegaly was noticed, and histological examination of a liver biopsy specimen suggested severe hepatic steatosis and periportal necrosis. However, echocardiography indicated no sign of cardiomyopathy and he showed no distinct intellectual impairment that interfered with daily life. About 1 year later, abdominal computed tomography revealed enlargement of kidneys. He had a homozygous insertion of a nucleotide, 783insG (Ile262fs mutation), in exon 7 of the BSCL2 gene. We reviewed the genotype of CGL cases from Japan, India, China and Taiwan, and found that BSCL2 is a major causative gene for CGL in Asian.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D052497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Congenital generalized lipodystrophy",
       "locations": [
        {
         "offset": 116,
         "length": 36
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D052497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CGL",
       "locations": [
        {
         "offset": 154,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal recessive disease",
       "locations": [
        {
         "offset": 169,
         "length": 27
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "26580",
        "type": "GeneOrGeneProduct"
       },
       "text": "BSCL2",
       "locations": [
        {
         "offset": 310,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D052497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CGL2",
       "locations": [
        {
         "offset": 344,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D052497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CGL1",
       "locations": [
        {
         "offset": 379,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intellectual impairment",
       "locations": [
        {
         "offset": 466,
         "length": 23
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D009202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiomyopathy",
       "locations": [
        {
         "offset": 507,
         "length": 14
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D014973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "eruptive xanthomas",
       "locations": [
        {
         "offset": 653,
         "length": 18
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D015228",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertriglyceridemia",
       "locations": [
        {
         "offset": 685,
         "length": 20
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D006529",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hepatomegaly",
       "locations": [
        {
         "offset": 817,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D005234",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hepatic steatosis",
       "locations": [
        {
         "offset": 916,
         "length": 17
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D009336",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "necrosis",
       "locations": [
        {
         "offset": 949,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D009202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiomyopathy",
       "locations": [
        {
         "offset": 1006,
         "length": 14
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D008607",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intellectual impairment",
       "locations": [
        {
         "offset": 1047,
         "length": 23
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "enlargement of kidneys",
       "locations": [
        {
         "offset": 1163,
         "length": 22
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|INS|783|G",
        "type": "SequenceVariant"
       },
       "text": "783insG",
       "locations": [
        {
         "offset": 1234,
         "length": 7
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "p|FS|I|262||",
        "type": "SequenceVariant"
       },
       "text": "Ile262fs",
       "locations": [
        {
         "offset": 1243,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "26580",
        "type": "GeneOrGeneProduct"
       },
       "text": "BSCL2",
       "locations": [
        {
         "offset": 1280,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D052497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CGL",
       "locations": [
        {
         "offset": 1320,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "26580",
        "type": "GeneOrGeneProduct"
       },
       "text": "BSCL2",
       "locations": [
        {
         "offset": 1382,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D052497",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CGL",
       "locations": [
        {
         "offset": 1418,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D007674",
      "entity2": "c|INS|783|G",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D007674",
      "entity2": "26580",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D007674",
      "entity2": "p|FS|I|262||",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "26580",
      "entity2": "D008607",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "26580",
      "entity2": "D009202",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D052497",
      "entity2": "26580",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D052497",
      "entity2": "p|FS|I|262||",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "28068934",
   "passages": [
    {
     "offset": 0,
     "text": "Concordance between PIK3CA mutations in endoscopic biopsy and surgically resected specimens of esophageal squamous cell carcinoma.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 20,
         "length": 6
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D000077277",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "esophageal squamous cell carcinoma",
       "locations": [
        {
         "offset": 95,
         "length": 34
        }
       ]
      }
     ]
    },
    {
     "offset": 131,
     "text": "BACKGROUND: PIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC). We aimed to clarify the concordance between PIK3CA mutations detected in endoscopic biopsy specimens and corresponding surgically resected specimens. METHODS: We examined five hotspot mutations in the PIK3CA gene (E542K, E545K, E546K, H1047R, and H1047L) in formalin-fixed and paraffin-embedded tissue sections of paired endoscopic biopsy and surgically resected specimens from 181 patients undergoing curative resection for ESCC between 2000 and 2011 using a Luminex technology-based multiplex gene mutation detection kit. RESULTS: Mutation analyses were successfully performed for both endoscopic biopsy and surgically resected specimens in all the cases. A PIK3CA mutation was detected in either type of specimen in 13 cases (7.2%, 95% confidence interval: 3.9-12.0). The overall concordance rate, positive predictive value, and negative predictive value were 98.3% (178/181), 90.9% (10/11), and 98.8% (168/170), respectively. Among patients with a PIK3CA mutation detected in both types of specimens, the concordance between PIK3CA mutation genotypes was 100%. There were three cases with a discordant mutation status between the types of specimens (PIK3CA mutation in surgically resected specimen and wild-type in biopsy specimen in two cases, and the opposite pattern in one case), suggesting possible intratumoral heterogeneity in the PIK3CA mutation status. CONCLUSIONS: The PIK3CA mutation status was highly concordant between endoscopic biopsy and surgically resected specimens from the same patient, suggesting that endoscopic biopsy specimens can be clinically used to detect PIK3CA mutations in patients with ESCC.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 143,
         "length": 6
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D000077277",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "esophageal squamous cell carcinoma",
       "locations": [
        {
         "offset": 213,
         "length": 34
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000077277",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ESCC",
       "locations": [
        {
         "offset": 249,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 300,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 457,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs121913273",
        "type": "SequenceVariant"
       },
       "text": "E542K",
       "locations": [
        {
         "offset": 470,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs104886003",
        "type": "SequenceVariant"
       },
       "text": "E545K",
       "locations": [
        {
         "offset": 477,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "p|SUB|E|546|K",
        "type": "SequenceVariant"
       },
       "text": "E546K",
       "locations": [
        {
         "offset": 484,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs121913279",
        "type": "SequenceVariant"
       },
       "text": "H1047R",
       "locations": [
        {
         "offset": 491,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs121913279",
        "type": "SequenceVariant"
       },
       "text": "H1047L",
       "locations": [
        {
         "offset": 503,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D005557",
        "type": "ChemicalEntity"
       },
       "text": "formalin",
       "locations": [
        {
         "offset": 514,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D010232",
        "type": "ChemicalEntity"
       },
       "text": "paraffin",
       "locations": [
        {
         "offset": 533,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 638,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000077277",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ESCC",
       "locations": [
        {
         "offset": 681,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 916,
         "length": 6
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1192,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 1208,
         "length": 6
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 1285,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 1410,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 1598,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 1639,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1758,
         "length": 7
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "5290",
        "type": "GeneOrGeneProduct"
       },
       "text": "PIK3CA",
       "locations": [
        {
         "offset": 1844,
         "length": 6
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1864,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D000077277",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ESCC",
       "locations": [
        {
         "offset": 1878,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "p|SUB|E|546|K",
      "entity2": "D000077277",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs104886003",
      "entity2": "D000077277",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs121913273",
      "entity2": "D000077277",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs121913279",
      "entity2": "D000077277",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "5290",
      "entity2": "D000077277",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "16252083",
   "passages": [
    {
     "offset": 0,
     "text": "Polymorphisms of the DNA mismatch repair gene HMSH2 in breast cancer occurence and progression.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "mismatch repair",
       "locations": [
        {
         "offset": 25,
         "length": 15
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "HMSH2",
       "locations": [
        {
         "offset": 46,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 55,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 96,
     "text": "The response of the cell to DNA damage and its ability to maintain genomic stability by DNA repair are crucial in preventing cancer initiation and progression. Therefore, polymorphism of DNA repair genes may affect the process of carcinogenesis. The importance of genetic variability of the components of mismatch repair (MMR) genes is well documented in colorectal cancer, but little is known about its role in breast cancer. hMSH2 is one of the crucial proteins of MMR. We performed a case-control study to test the association between two polymorphisms in the hMSH2 gene: an A --> G transition at 127 position producing an Asn --> Ser substitution at codon 127 (the Asn127Ser polymorphism) and a G --> A transition at 1032 position resulting in a Gly --> Asp change at codon 322 (the Gly322Asp polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 age-matched women (controls) by restriction fragment length polymorphism and allele-specific PCR. We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom-Richardson grading. A strong association between breast cancer occurrence and the Gly/Gly phenotype of the Gly322Asp polymorphism (odds ratio 8.39; 95% confidence interval 1.44-48.8) was found. Therefore, MMR may play a role in the breast carcinogenesis and the Gly322Asp polymorphism of the hMSH2 gene may be considered as a potential marker in breast cancer.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer initiation",
       "locations": [
        {
         "offset": 221,
         "length": 17
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D063646",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "carcinogenesis",
       "locations": [
        {
         "offset": 326,
         "length": 14
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "mismatch repair",
       "locations": [
        {
         "offset": 401,
         "length": 15
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMR",
       "locations": [
        {
         "offset": 418,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D015179",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "colorectal cancer",
       "locations": [
        {
         "offset": 451,
         "length": 17
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 508,
         "length": 13
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "hMSH2",
       "locations": [
        {
         "offset": 523,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMR",
       "locations": [
        {
         "offset": 563,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "hMSH2",
       "locations": [
        {
         "offset": 659,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs17217772",
        "type": "SequenceVariant"
       },
       "text": "A --> G transition at 127 position",
       "locations": [
        {
         "offset": 674,
         "length": 34
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs17217772",
        "type": "SequenceVariant"
       },
       "text": "Asn --> Ser substitution at codon 127",
       "locations": [
        {
         "offset": 722,
         "length": 37
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs17217772",
        "type": "SequenceVariant"
       },
       "text": "Asn127Ser",
       "locations": [
        {
         "offset": 765,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs4987188",
        "type": "SequenceVariant"
       },
       "text": "G --> A transition at 1032 position",
       "locations": [
        {
         "offset": 795,
         "length": 35
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs4987188",
        "type": "SequenceVariant"
       },
       "text": "Gly --> Asp change at codon 322",
       "locations": [
        {
         "offset": 846,
         "length": 31
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs4987188",
        "type": "SequenceVariant"
       },
       "text": "Gly322Asp",
       "locations": [
        {
         "offset": 883,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 911,
         "length": 13
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 934,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 1028,
         "length": 13
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1042,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1071,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 1226,
         "length": 13
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1282,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 1352,
         "length": 13
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs4987188",
        "type": "SequenceVariant"
       },
       "text": "Gly322Asp",
       "locations": [
        {
         "offset": 1410,
         "length": 9
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMR",
       "locations": [
        {
         "offset": 1508,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast carcinogenesis",
       "locations": [
        {
         "offset": 1535,
         "length": 21
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "rs4987188",
        "type": "SequenceVariant"
       },
       "text": "Gly322Asp",
       "locations": [
        {
         "offset": 1565,
         "length": 9
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
       },
       "text": "hMSH2",
       "locations": [
        {
         "offset": 1595,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 1649,
         "length": 13
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D001943",
      "entity2": "rs4987188",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs17217772",
      "entity2": "D001943",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs17217772",
      "entity2": "D009369",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "4436",
      "entity2": "D015179",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "4436",
      "entity2": "D001943",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "4436",
      "entity2": "D009369",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16820346",
   "passages": [
    {
     "offset": 0,
     "text": "Atorvastatin prevented and reversed dexamethasone-induced hypertension in the rat.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "Atorvastatin",
       "locations": [
        {
         "offset": 0,
         "length": 12
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dexamethasone",
       "locations": [
        {
         "offset": 36,
         "length": 13
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D006973",
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       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 58,
         "length": 12
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rat",
       "locations": [
        {
         "offset": 78,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 83,
     "text": "To assess the antioxidant effects of atorvastatin (atorva) on dexamethasone (dex)-induced hypertension, 60 male Sprague-Dawley rats were treated with atorva 30 mg/kg/day or tap water for 15 days. Dex increased systolic blood pressure (SBP) from 109 +/- 1.8 to 135 +/- 0.6 mmHg and plasma superoxide (5711 +/- 284.9 saline, 7931 +/- 392.8 U/ml dex, P < 0.001). In this prevention study, SBP in the atorva + dex group was increased from 115 +/- 0.4 to 124 +/- 1.5 mmHg, but this was significantly lower than in the dex-only group (P' < 0.05). Atorva reversed dex-induced hypertension (129 +/- 0.6 mmHg, vs. 135 +/- 0.6 mmHg P' < 0.05) and decreased plasma superoxide (7931 +/- 392.8 dex, 1187 +/- 441.2 atorva + dex, P < 0.0001). Plasma nitrate/nitrite (NOx) was decreased in dex-treated rats compared to saline-treated rats (11.2 +/- 1.08 microm, 15.3 +/- 1.17 microm, respectively, P < 0.05). Atorva affected neither plasma NOx nor thymus weight. Thus, atorvastatin prevented and reversed dexamethasone-induced hypertension in the rat.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D000975",
        "type": "ChemicalEntity"
       },
       "text": "antioxidant",
       "locations": [
        {
         "offset": 97,
         "length": 11
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "atorvastatin",
       "locations": [
        {
         "offset": 120,
         "length": 12
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "atorva",
       "locations": [
        {
         "offset": 134,
         "length": 6
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dexamethasone",
       "locations": [
        {
         "offset": 145,
         "length": 13
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dex",
       "locations": [
        {
         "offset": 160,
         "length": 3
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 173,
         "length": 12
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 210,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "atorva",
       "locations": [
        {
         "offset": 233,
         "length": 6
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "Dex",
       "locations": [
        {
         "offset": 279,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D013481",
        "type": "ChemicalEntity"
       },
       "text": "superoxide",
       "locations": [
        {
         "offset": 371,
         "length": 10
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dex",
       "locations": [
        {
         "offset": 426,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "atorva",
       "locations": [
        {
         "offset": 480,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
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       "text": "dex",
       "locations": [
        {
         "offset": 489,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
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       "text": "dex",
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        {
         "offset": 596,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "Atorva",
       "locations": [
        {
         "offset": 624,
         "length": 6
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dex",
       "locations": [
        {
         "offset": 640,
         "length": 3
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 652,
         "length": 12
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D013481",
        "type": "ChemicalEntity"
       },
       "text": "superoxide",
       "locations": [
        {
         "offset": 737,
         "length": 10
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
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       "text": "dex",
       "locations": [
        {
         "offset": 764,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "atorva",
       "locations": [
        {
         "offset": 784,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dex",
       "locations": [
        {
         "offset": 793,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D009566",
        "type": "ChemicalEntity"
       },
       "text": "nitrate",
       "locations": [
        {
         "offset": 818,
         "length": 7
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D009573",
        "type": "ChemicalEntity"
       },
       "text": "nitrite",
       "locations": [
        {
         "offset": 826,
         "length": 7
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D009589",
        "type": "ChemicalEntity"
       },
       "text": "NOx",
       "locations": [
        {
         "offset": 835,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dex",
       "locations": [
        {
         "offset": 857,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 869,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 901,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "Atorva",
       "locations": [
        {
         "offset": 976,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D009589",
        "type": "ChemicalEntity"
       },
       "text": "NOx",
       "locations": [
        {
         "offset": 1007,
         "length": 3
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D000069059",
        "type": "ChemicalEntity"
       },
       "text": "atorvastatin",
       "locations": [
        {
         "offset": 1036,
         "length": 12
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D003907",
        "type": "ChemicalEntity"
       },
       "text": "dexamethasone",
       "locations": [
        {
         "offset": 1072,
         "length": 13
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 1094,
         "length": 12
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rat",
       "locations": [
        {
         "offset": 1114,
         "length": 3
        }
       ]
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    },
    {
     "id": "R1",
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    },
    {
     "id": "R3",
     "infons": {
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      "type": "Positive_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D003907",
      "entity2": "D006973",
      "type": "Positive_Correlation",
      "novel": "No"
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    },
    {
     "id": "R5",
     "infons": {
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      "type": "Negative_Correlation",
      "novel": "Novel"
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    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D000069059",
      "entity2": "D003907",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17003923",
   "passages": [
    {
     "offset": 0,
     "text": "Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D054556",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "venous and arterial thromboembolism",
       "locations": [
        {
         "offset": 63,
         "length": 35
        }
       ]
      }
     ]
    },
    {
     "offset": 155,
     "text": "Evolvement and progression of cardiovascular diseases affecting the venous and arterial system are influenced by a multitude of environmental and hereditary factors. Many of these hereditary factors consist of defined gene polymorphisms, such as single nucleotide polymorphisms (SNPs) or insertion-deletion polymorphisms, which directly or indirectly affect the hemostatic system. The frequencies of individual hemostatic gene polymorphisms in different normal populations are well defined. However, descriptions of patterns of genetic variability of a larger extent of different factors of hereditary hypercoagulability in single populations are scarce. The aim of this study was i) to give a detailed description of the frequencies of factors of hereditary thrombophilia and their combinations in a German population (n = 282) and ii) to compare their distributions with those reported for other regions. Variants of coagulation factors [factor V 1691G>A (factor V Leiden), factor V 4070A>G (factor V HR2 haplotype), factor VII Arg353Gln, factor XIII Val34Leu, beta-fibrinogen -455G>A, prothrombin 20210G>A], coagulation inhibitors [tissue factor pathway inhibitor 536C>T, thrombomodulin 127G>A], fibrinolytic factors [angiotensin converting enzyme intron 16 insertion/deletion, factor VII-activating protease 1601G>A (FSAP Marburg I), plasminogen activator inhibitor 1-675 insertion/deletion (5G/4G), tissue plasminogen activator intron h deletion/insertion], and other factors implicated in influencing susceptibility to thromboembolic diseases [apolipoprotein E2/E3/E4, glycoprotein Ia 807C>T, methylenetetrahydrofolate reductase 677C>T] were included. The distribution of glycoprotein Ia 807C>T deviated significantly from the Hardy-Weinberg equilibrium, and a comparison with previously published data indicates marked region and ethnicity dependent differences in the genotype distributions of some other factors.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D002318",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cardiovascular diseases",
       "locations": [
        {
         "offset": 185,
         "length": 23
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D019851",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hereditary hypercoagulability",
       "locations": [
        {
         "offset": 746,
         "length": 29
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C540694",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hereditary thrombophilia",
       "locations": [
        {
         "offset": 903,
         "length": 24
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "factor V",
       "locations": [
        {
         "offset": 1095,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "c|SUB|G|1691|A",
        "type": "SequenceVariant"
       },
       "text": "1691G>A",
       "locations": [
        {
         "offset": 1104,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "factor V Leiden",
       "locations": [
        {
         "offset": 1113,
         "length": 15
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "factor V",
       "locations": [
        {
         "offset": 1131,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|A|4070|G",
        "type": "SequenceVariant"
       },
       "text": "4070A>G",
       "locations": [
        {
         "offset": 1140,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "factor V",
       "locations": [
        {
         "offset": 1149,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2155",
        "type": "GeneOrGeneProduct"
       },
       "text": "factor VII",
       "locations": [
        {
         "offset": 1174,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "p|SUB|R|353|Q",
        "type": "SequenceVariant"
       },
       "text": "Arg353Gln",
       "locations": [
        {
         "offset": 1185,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "2162",
        "type": "GeneOrGeneProduct"
       },
       "text": "factor XIII",
       "locations": [
        {
         "offset": 1196,
         "length": 11
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "p|SUB|V|34|L",
        "type": "SequenceVariant"
       },
       "text": "Val34Leu",
       "locations": [
        {
         "offset": 1208,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "2244",
        "type": "GeneOrGeneProduct"
       },
       "text": "beta-fibrinogen",
       "locations": [
        {
         "offset": 1218,
         "length": 15
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "c|SUB|G|-455|A",
        "type": "SequenceVariant"
       },
       "text": "-455G>A",
       "locations": [
        {
         "offset": 1234,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "2147",
        "type": "GeneOrGeneProduct"
       },
       "text": "prothrombin",
       "locations": [
        {
         "offset": 1243,
         "length": 11
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|SUB|G|20210|A",
        "type": "SequenceVariant"
       },
       "text": "20210G>A",
       "locations": [
        {
         "offset": 1255,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "7035",
        "type": "GeneOrGeneProduct"
       },
       "text": "tissue factor pathway inhibitor",
       "locations": [
        {
         "offset": 1290,
         "length": 31
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|SUB|C|536|T",
        "type": "SequenceVariant"
       },
       "text": "536C>T",
       "locations": [
        {
         "offset": 1322,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "7056",
        "type": "GeneOrGeneProduct"
       },
       "text": "thrombomodulin",
       "locations": [
        {
         "offset": 1330,
         "length": 14
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|SUB|G|127|A",
        "type": "SequenceVariant"
       },
       "text": "127G>A",
       "locations": [
        {
         "offset": 1345,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "1636",
        "type": "GeneOrGeneProduct"
       },
       "text": "angiotensin converting enzyme",
       "locations": [
        {
         "offset": 1376,
         "length": 29
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "3026",
        "type": "GeneOrGeneProduct"
       },
       "text": "factor VII-activating protease",
       "locations": [
        {
         "offset": 1436,
         "length": 30
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "c|SUB|G|1601|A",
        "type": "SequenceVariant"
       },
       "text": "1601G>A",
       "locations": [
        {
         "offset": 1467,
         "length": 7
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "3026",
        "type": "GeneOrGeneProduct"
       },
       "text": "FSAP",
       "locations": [
        {
         "offset": 1476,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "5054",
        "type": "GeneOrGeneProduct"
       },
       "text": "plasminogen activator inhibitor 1",
       "locations": [
        {
         "offset": 1493,
         "length": 33
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "c|INDEL|675|",
        "type": "SequenceVariant"
       },
       "text": "675 insertion/deletion",
       "locations": [
        {
         "offset": 1527,
         "length": 22
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "5327",
        "type": "GeneOrGeneProduct"
       },
       "text": "tissue plasminogen activator",
       "locations": [
        {
         "offset": 1559,
         "length": 28
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D013923",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "thromboembolic diseases",
       "locations": [
        {
         "offset": 1680,
         "length": 23
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "22915",
        "type": "GeneOrGeneProduct"
       },
       "text": "apolipoprotein E2/E3/E4, glycoprotein Ia",
       "locations": [
        {
         "offset": 1705,
         "length": 40
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "c|SUB|C|807|T",
        "type": "SequenceVariant"
       },
       "text": "807C>T",
       "locations": [
        {
         "offset": 1746,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "4524",
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     "offset": 0,
     "text": "rTMS of supplementary motor area modulates therapy-induced dyskinesias in Parkinson disease.",
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     "text": "The neural mechanisms and circuitry involved in levodopa-induced dyskinesia are unclear. Using repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in a group of patients with advanced Parkinson disease, the authors investigated whether modulation of SMA excitability may result in a modification of a dyskinetic state induced by continuous apomorphine infusion. rTMS at 1 Hz was observed to markedly reduce drug-induced dyskinesias, whereas 5-Hz rTMS induced a slight but not significant increase.",
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     "offset": 0,
     "text": "Angiotensin converting enzyme gene polymorphism in Turkish asthmatic patients.",
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     "text": "Asthma is a chronic inflammatory disease of the airways. Several candidate genes have been identified with a potential role in the pathogenesis of asthma, including the angiotensin converting enzyme (ACE) gene. We aimed to investigate the frequency of an ACE gene polymorphism in Turkish asthmatic patients and to determine its impact on clinical parameters and disease severity. Ninety-seven asthmatic patients (M/F 25/72, mean age 39 +/- 13 years) and 96 healthy subjects (M/F 26/70, mean age 38 +/- 12 years) were included. At baseline, all participants completed a questionnaire on demographics, symptoms, triggering factors, severity of asthma, and the presence of atopism. Blood samples were obtained from all patients and genomic DNA was isolated. The frequency of the ACE genotypes (I = insertion and D = deletion) among asthmatics and controls were compared: asthmatics showed a 40.2% prevalence of the DD genotype (n = 39), ID was 45.4% (n = 44), and II was 14.4% (n = 14.4). In the control subjects, the frequency of DD was 18.8% (n = 18), ID was 50% (n = 48) and II was 31.3% (n = 30). The DD ACE genotype was significantly more frequent in asthmatics compared with controls (p < 0.001). Asthmatics with the ID ACE genotype showed a higher frequency of drug allergies, although this was not statistically significant (p = 0.08). Asthmatics with the DD genotype appeared to have a higher incidence of asthmatic episode exacerbations due to viral infections, but again this was not statistically significant (p = 0.08). Patients with mild or moderate-severe asthma had similar frequencies of these mutations. We found a higher frequency of the ACE DD gene mutation in Turkish asthmatic patients compared with non-asthmatics, suggesting that this ACE gene polymorphism may be a risk factor for asthma but does not increase the severity of the disease.",
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    {
     "offset": 0,
     "text": "The impact of PPARa activation on whole genome gene expression in human precision cut liver slices.",
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       "id": "0",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "PPARa",
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     "offset": 100,
     "text": "BACKGROUND: Studies in mice have shown that PPARa is an important regulator of lipid metabolism in liver and key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARa in human liver. METHODS: Here we set out to study the function of PPARa in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARa agonist Wy14643. RESULTS: Quantitative PCR indicated that PPARa is well expressed in human liver and human liver slices and that the classical PPARa targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARa activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARa activation (q value < 0.05). Many genes induced by PPARa activation were involved in lipid metabolism (ACSL5, AGPAT9, FADS1, SLC27A4), xenobiotic metabolism (POR, ABCC2, CYP3A5) or the unfolded protein response, whereas most of the downregulated genes were involved in immune-related pathways. Among the most highly repressed genes upon PPARa activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon g-induced genes (e.g. IFITM1, IFIT1, IFIT2, IFIT3) and numerous other immune-related genes (e.g. TLR3, NOS2, and LCN2). Comparative analysis of gene regulation by Wy14643 between human liver slices and primary human hepatocytes showed that down-regulation of gene expression by PPARa is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARa activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARa were identified that were commonly induced by PPARa activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L. CONCLUSION: Our paper demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARa in human liver. Our data underscore the major role of PPARa in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARa in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease.",
     "annotations": [
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       "text": "human",
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     "offset": 0,
     "text": "Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen.",
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      {
       "id": "0",
       "infons": {
        "identifier": "D007545",
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       "text": "isoproterenol",
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     "text": "We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart.",
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       "text": "LV hypertrophy",
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   "id": "16849419",
   "passages": [
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     "offset": 0,
     "text": "Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria.",
     "annotations": [
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       "id": "0",
       "infons": {
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       "text": "SLC34A3",
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      {
       "id": "1",
       "infons": {
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       "text": "hereditary hypophosphatemic rickets with hypercalciuria",
       "locations": [
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    },
    {
     "offset": 102,
     "text": "CONTEXT: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia and rickets/osteomalacia with increased serum 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] resulting in hypercalciuria. OBJECTIVE: Our objective was to determine whether mutations in the SLC34A3 gene, which encodes sodium-phosphate cotransporter type IIc, are responsible for the occurrence of HHRH. DESIGN AND SETTING: Mutation analysis of exons and adjacent introns in the SLC34A3 gene was conducted at an academic research laboratory and medical center. PATIENTS OR OTHER PARTICIPANTS: Members of two unrelated families with HHRH participated in the study. RESULTS: Two affected siblings in one family were homozygous for a 101-bp deletion in intron 9. Haplotype analysis of the SLC34A3 locus in the family showed that the two deletions are on different haplotypes. An unrelated individual with HHRH was a compound heterozygote for an 85-bp deletion in intron 10 and a G-to-A substitution at the last nucleotide in exon 7. The intron 9 deletion (and likely the other two mutations) identified in this study causes aberrant RNA splicing. Sequence analysis of the deleted regions revealed the presence of direct repeats of homologous sequences. CONCLUSION: HHRH is caused by biallelic mutations in the SLC34A3 gene. Haplotype analysis suggests that the two intron 9 deletions arose independently. The identification of three independent deletions in introns 9 and 10 suggests that the SLC34A3 gene may be susceptible to unequal crossing over because of sequence misalignment during meiosis.",
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       "id": "2",
       "infons": {
        "identifier": "C562793",
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       "text": "Hereditary hypophosphatemic rickets with hypercalciuria",
       "locations": [
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         "offset": 111,
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       "id": "3",
       "infons": {
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       "text": "HHRH",
       "locations": [
        {
         "offset": 168,
         "length": 4
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       "id": "4",
       "infons": {
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       "text": "metabolic disorder",
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         "offset": 184,
         "length": 18
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       "id": "5",
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       "locations": [
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         "length": 16
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       "text": "rickets",
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         "offset": 242,
         "length": 7
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       "id": "7",
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       "text": "osteomalacia",
       "locations": [
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         "offset": 250,
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       "text": "sodium-phosphate cotransporter type IIc",
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       "id": "13",
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       "id": "16",
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     "text": "Vitamin D receptor expression is associated with PIK3CA and KRAS mutations in colorectal cancer.",
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     "text": "Vitamin D is associated with decreased risks of various cancers, including colon cancer. The vitamin D receptor (VDR) is a transcription factor, which plays an important role in cellular differentiation and inhibition of proliferation. A link between VDR and the RAS-mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been suggested. However, the prognostic role of VDR expression or its relationship with PIK3CA or KRAS mutation remains uncertain. Among 619 colorectal cancers in two prospective cohort studies, 233 (38%) tumors showed VDR overexpression by immunohistochemistry. We analyzed for PIK3CA and KRAS mutations and LINE-1 methylation by Pyrosequencing, microsatellite instability (MSI), and DNA methylation (epigenetic changes) in eight CpG island methylator phenotype (CIMP)-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by MethyLight (real-time PCR). VDR overexpression was significantly associated with KRAS mutation (odds ratio, 1.55; 95% confidence interval, 1.11-2.16) and PIK3CA mutation (odds ratio, 2.17; 95% confidence interval, 1.36-3.47), both of which persisted in multivariate logistic regression analysis. VDR was not independently associated with body mass index, family history of colorectal cancer, tumor location (colon versus rectum), stage, tumor grade, signet ring cells, CIMP, MSI, LINE-1 hypomethylation, BRAF, p53, p21, beta-catenin, or cyclooxygenase-2. VDR expression was not significantly related with patient survival, prognosis, or clinical outcome. In conclusion, VDR overexpression in colorectal cancer is independently associated with PIK3CA and KRAS mutations. Our data support potential interactions between the VDR, RAS-MAPK and PI3K-AKT pathways, and possible influence by KRAS or PIK3CA mutation on therapy or chemoprevention targeting VDR.",
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     "text": "Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice.",
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     "text": "Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and D-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (.OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, .OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model control. Compared with the model group, CMCS and 1,10-phenanthroline significantly improved serum ALT/AST, attenuated hepatic inflammation and improved peroxidative injury in liver, decreased MMP-2/9 activities in liver tissue, improved integration of scaffold structure, and decreased protein expression of VCAM-1 and ICAM-1. CMCS could protect LSECs from injury and maintain the microvasculature integration in acute injured liver of mice induced by LPS/D-GalN. Its action mechanism was associated with the down-regulation of MMP-2/9 activities and inhibition of peroxidation in injured liver.",
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  {
   "id": "28684635",
   "passages": [
    {
     "offset": 0,
     "text": "A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003924",
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       "text": "Type 2 Diabetes",
       "locations": [
        {
         "offset": 2,
         "length": 15
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    {
     "offset": 110,
     "text": "Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic b-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent b-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion.",
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       "id": "2",
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        {
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       "text": "type 2 diabetes",
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       "text": "adenylate cyclase 5",
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       "text": "Adenylate cyclase 5",
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       "text": "cyclic AMP",
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       "text": "insulin",
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       "text": "type 2 diabetes",
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       ]
      },
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       "id": "11",
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        "identifier": "111",
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       "text": "ADCY5",
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       "text": "human",
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         "length": 5
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         "length": 6
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       "text": "type 2 diabetes",
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         "offset": 1307,
         "length": 15
        }
       ]
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       "id": "28",
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        "type": "GeneOrGeneProduct"
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       "text": "ADCY5",
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         "offset": 1381,
         "length": 5
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       ]
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       "text": "impaired insulin secretion",
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        {
         "offset": 1402,
         "length": 26
        }
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  {
   "id": "21750150",
   "passages": [
    {
     "offset": 0,
     "text": "Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1602",
        "type": "GeneOrGeneProduct"
       },
       "text": "DACH1",
       "locations": [
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         "offset": 26,
         "length": 5
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       ]
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      {
       "id": "1",
       "infons": {
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       "text": "tumor",
       "locations": [
        {
         "offset": 42,
         "length": 5
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D005910",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "glioma",
       "locations": [
        {
         "offset": 71,
         "length": 6
        }
       ]
      }
     ]
    },
    {
     "offset": 85,
     "text": "Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumor",
       "locations": [
        {
         "offset": 118,
         "length": 5
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D009369",
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       "text": "tumorigenesis",
       "locations": [
        {
         "offset": 156,
         "length": 13
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       ]
      },
      {
       "id": "5",
       "infons": {
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       "text": "glioblastoma",
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         "length": 12
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       ]
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       "id": "6",
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       "text": "DACH1",
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       "id": "7",
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       "text": "glioma",
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         "length": 6
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       ]
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       "id": "8",
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       "text": "DACH1",
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         "length": 5
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       ]
      },
      {
       "id": "9",
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       "text": "U87TR-Da",
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        {
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         "length": 8
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       ]
      },
      {
       "id": "10",
       "infons": {
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       "text": "glioma",
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        {
         "offset": 527,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
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       "text": "DACH1",
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         "offset": 547,
         "length": 5
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       ]
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      {
       "id": "12",
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       "text": "doxycycline",
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      {
       "id": "13",
       "infons": {
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       "text": "tumors",
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         "offset": 700,
         "length": 6
        }
       ]
      },
      {
       "id": "14",
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        "identifier": "10090",
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       "text": "mice",
       "locations": [
        {
         "offset": 710,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "CVCL_0022",
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       "text": "U87TR-Da",
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       ]
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      {
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       "text": "DACH1",
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         "offset": 750,
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       ]
      },
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       "text": "U87",
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        {
         "offset": 768,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "1602",
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       "text": "DACH1",
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         "offset": 772,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "1602",
        "type": "GeneOrGeneProduct"
       },
       "text": "DACH1",
       "locations": [
        {
         "offset": 799,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "CVCL_0022",
        "type": "CellLine"
       },
       "text": "U87TR-Da",
       "locations": [
        {
         "offset": 819,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "CVCL_0022",
        "type": "CellLine"
       },
       "text": "U87",
       "locations": [
        {
         "offset": 835,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "1602",
        "type": "GeneOrGeneProduct"
       },
       "text": "DACH1",
       "locations": [
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         "offset": 839,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "CVCL_0022",
        "type": "CellLine"
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       "text": "U87",
       "locations": [
        {
         "offset": 851,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
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        "identifier": "1602",
        "type": "GeneOrGeneProduct"
       },
       "text": "DACH1",
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         "offset": 855,
         "length": 5
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       ]
      },
      {
       "id": "25",
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       "text": "CD133",
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         "offset": 891,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
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        "type": "GeneOrGeneProduct"
       },
       "text": "Nestin",
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     "text": "Systemic sclerosis (SSc) is a connective tissue disorder characterized by early generalized microangiopathy with disturbed angiogenesis. Endoglin gene (ENG) encodes a transmembrane glycoprotein which acts as an accessory receptor for the transforming growth factor-beta (TGF-beta) superfamily, and is crucial for maintaining vascular integrity. A 6-base insertion in intron 7 (6bINS) of ENG has been reported to be associated with microvascular disturbance. OBJECTIVES: Our objective was to investigate the relationship between 6bINS and the vascular complication pulmonary arterial hypertension (PAH) in SSc in a French Caucasian population. METHODS: Two hundred eighty SSc cases containing 29/280 having PAH diagnosed by catheterism were compared with 140 patients with osteoarthritis. Genotyping was performed by polymerase-chain-reaction-based fluorescence and direct sequencing of genomic DNA. RESULTS: The polymorphism was in Hardy-Weinberg equilibrium. We observed a significant lower frequency of 6bINS allele in SSc patients with associated PAH compared with controls [10.3 vs 23.9%, P = 0.01; odds ratio (OR) 0.37, 95% confidence interval (CI) 0.15-0.89], and a trend in comparison with SSc patients without PAH (10.3 vs 20.3%, P = 0.05; OR: 0.45, 95% CI: 0.19-1.08). Genotypes carrying allele 6bINS were also less frequent in SSc patients with PAH than in controls (20.7 vs 42.9%, P = 0.02). CONCLUSIONS: Thus the frequency of 6bINS differs between SSc patients with or without PAH, suggesting the implication of ENG in this devastating vascular complication of SSc.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Systemic sclerosis",
       "locations": [
        {
         "offset": 114,
         "length": 18
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 134,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D057049",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microangiopathy",
       "locations": [
        {
         "offset": 206,
         "length": 15
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "2022",
        "type": "GeneOrGeneProduct"
       },
       "text": "Endoglin",
       "locations": [
        {
         "offset": 251,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2022",
        "type": "GeneOrGeneProduct"
       },
       "text": "ENG",
       "locations": [
        {
         "offset": 266,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "351",
        "type": "GeneOrGeneProduct"
       },
       "text": "glycoprotein",
       "locations": [
        {
         "offset": 295,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "7040",
        "type": "GeneOrGeneProduct"
       },
       "text": "transforming growth factor-beta",
       "locations": [
        {
         "offset": 352,
         "length": 31
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "7040",
        "type": "GeneOrGeneProduct"
       },
       "text": "TGF-beta",
       "locations": [
        {
         "offset": 385,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|INS||6",
        "type": "SequenceVariant"
       },
       "text": "6-base insertion",
       "locations": [
        {
         "offset": 461,
         "length": 16
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|INS||6",
        "type": "SequenceVariant"
       },
       "text": "6bINS",
       "locations": [
        {
         "offset": 491,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "2022",
        "type": "GeneOrGeneProduct"
       },
       "text": "ENG",
       "locations": [
        {
         "offset": 501,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|INS||6",
        "type": "SequenceVariant"
       },
       "text": "6bINS",
       "locations": [
        {
         "offset": 642,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D014652",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "vascular complication",
       "locations": [
        {
         "offset": 656,
         "length": 21
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pulmonary arterial hypertension",
       "locations": [
        {
         "offset": 678,
         "length": 31
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 711,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 719,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 785,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 820,
         "length": 3
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 872,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D010003",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "osteoarthritis",
       "locations": [
        {
         "offset": 886,
         "length": 14
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|INS||6",
        "type": "SequenceVariant"
       },
       "text": "6bINS",
       "locations": [
        {
         "offset": 1119,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 1135,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1139,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 1164,
         "length": 3
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 1311,
         "length": 3
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1315,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 1332,
         "length": 3
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "c|INS||6",
        "type": "SequenceVariant"
       },
       "text": "6bINS",
       "locations": [
        {
         "offset": 1418,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 1451,
         "length": 3
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1455,
         "length": 8
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 1469,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "c|INS||6",
        "type": "SequenceVariant"
       },
       "text": "6bINS",
       "locations": [
        {
         "offset": 1552,
         "length": 5
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 1574,
         "length": 3
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1578,
         "length": 8
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D000081029",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 1603,
         "length": 3
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "2022",
        "type": "GeneOrGeneProduct"
       },
       "text": "ENG",
       "locations": [
        {
         "offset": 1638,
         "length": 3
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "D014652",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "vascular complication",
       "locations": [
        {
         "offset": 1662,
         "length": 21
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "D012595",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SSc",
       "locations": [
        {
         "offset": 1687,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D000081029",
      "entity2": "2022",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|INS||6",
      "entity2": "D000081029",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|INS||6",
      "entity2": "D012595",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "c|INS||6",
      "entity2": "D014652",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "2022",
      "entity2": "7040",
      "type": "Bind",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "2022",
      "entity2": "D012595",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "2022",
      "entity2": "D014652",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17491223",
   "passages": [
    {
     "offset": 0,
     "text": "Assessment of a new non-invasive index of cardiac performance for detection of dobutamine-induced myocardial ischemia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D004280",
        "type": "ChemicalEntity"
       },
       "text": "dobutamine",
       "locations": [
        {
         "offset": 79,
         "length": 10
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D017202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocardial ischemia",
       "locations": [
        {
         "offset": 98,
         "length": 19
        }
       ]
      }
     ]
    },
    {
     "offset": 119,
     "text": "BACKGROUND: Electrocardiography has a very low sensitivity in detecting dobutamine-induced myocardial ischemia. OBJECTIVES: To assess the added diagnostic value of a new cardiac performance index (dP/dtejc) measurement, based on brachial artery flow changes, as compared to standard 12-lead ECG, for detecting dobutamine-induced myocardial ischemia, using Tc99m-Sestamibi single-photon emission computed tomography as the gold standard of comparison to assess the presence or absence of ischemia. METHODS: The study group comprised 40 patients undergoing Sestamibi-SPECT/dobutamine stress test. Simultaneous measurements of ECG and brachial artery dP/dtejc were performed at each dobutamine level. In 19 of the 40 patients perfusion defects compatible with ischemia were detected on SPECT. The increase in dP/dtejc during infusion of dobutamine in this group was severely impaired as compared to the non-ischemic group. dP/dtejc outcome was combined with the ECG results, giving an ECG-enhanced value, and compared to ECG alone. RESULTS: The sensitivity improved dramatically from 16% to 79%, positive predictive value increased from 60% to 68% and negative predictive value from 54% to 78%, and specificity decreased from 90% to 67%. CONCLUSIONS: If ECG alone is used for specificity, the combination with dP/dtejc improved the sensitivity of the test and could be a cost-savings alternative to cardiac imaging or perfusion studies to detect myocardial ischemia, especially in patients unable to exercise.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D004280",
        "type": "ChemicalEntity"
       },
       "text": "dobutamine",
       "locations": [
        {
         "offset": 191,
         "length": 10
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D017202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocardial ischemia",
       "locations": [
        {
         "offset": 210,
         "length": 19
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D004280",
        "type": "ChemicalEntity"
       },
       "text": "dobutamine",
       "locations": [
        {
         "offset": 429,
         "length": 10
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D017202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocardial ischemia",
       "locations": [
        {
         "offset": 448,
         "length": 19
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemia",
       "locations": [
        {
         "offset": 606,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 654,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D004280",
        "type": "ChemicalEntity"
       },
       "text": "dobutamine",
       "locations": [
        {
         "offset": 690,
         "length": 10
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D004280",
        "type": "ChemicalEntity"
       },
       "text": "dobutamine",
       "locations": [
        {
         "offset": 799,
         "length": 10
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 833,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D007511",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ischemia",
       "locations": [
        {
         "offset": 876,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D004280",
        "type": "ChemicalEntity"
       },
       "text": "dobutamine",
       "locations": [
        {
         "offset": 953,
         "length": 10
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D017202",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "myocardial ischemia",
       "locations": [
        {
         "offset": 1562,
         "length": 19
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1597,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D004280",
      "entity2": "D007511",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D004280",
      "entity2": "D017202",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "18507837",
   "passages": [
    {
     "offset": 0,
     "text": "Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 76,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 140,
     "text": "INTRODUCTION: Somatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division. METHODS: We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency    > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis. RESULTS: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding. CONCLUSION: It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D001943",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "breast cancer",
       "locations": [
        {
         "offset": 208,
         "length": 13
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "595",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCND1",
       "locations": [
        {
         "offset": 537,
         "length": 5
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "894",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCND2",
       "locations": [
        {
         "offset": 544,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "896",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCND3",
       "locations": [
        {
         "offset": 551,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "898",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCNE1",
       "locations": [
        {
         "offset": 558,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1017",
        "type": "GeneOrGeneProduct"
       },
       "text": "CDK2 [p33]",
       "locations": [
        {
         "offset": 565,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1019",
        "type": "GeneOrGeneProduct"
       },
       "text": "CDK4",
       "locations": [
        {
         "offset": 577,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "1021",
        "type": "GeneOrGeneProduct"
       },
       "text": "CDK6",
       "locations": [
        {
         "offset": 583,
         "length": 4
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     "offset": 0,
     "text": "Upregulation of centrosomal protein 55 is associated with unfavorable prognosis and tumor invasion in epithelial ovarian carcinoma.",
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       "text": "centrosomal protein 55",
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     "text": "Centrosomal protein 55 (CEP55) is a cell cycle regulator implicated in development of certain cancers. However, characteristics of CEP55 expression and its clinical/prognostic significance are unclear in human epithelial ovarian carcinoma (EOC). Therefore, we investigated the expression and clinicopathological significance of CEP55 in patients with EOC and its role in regulating invasion and metastasis of ovarian cell lines. CEP55 mRNA and protein expression levels were detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC). Potential associations of CEP55 expression scores with clinical parameters and patient survival were evaluated. CEP55 function was investigated further using RNA interference, wound healing assay, transwell assay, immunofluorescence analysis, qRT-PCR, and Western blotting. CEP55 was significantly upregulated in ovarian cancer cell lines and lesions compared with normal cells and adjacent noncancerous ovarian tissues. In the 213 EOC samples, CEP55 protein levels were positively correlated with clinical stage (P < 0.001), lymph node metastasis (P < 0.001), intraperitoneal metastasis (P < 0.001), tumor recurrence (P < 0.001), differentiation grade (P < 0.001), residual tumor size (P < 0.001), ascites see tumor cells (P = 0.020), and serum CA153 level (P < 0.001). Moreover, patients with aberrant CEP55 protein expression showed tendencies to receive neoadjuvant chemotherapy (P < 0.001) and cytoreductive surgery (P = 0.020). By contrast, no significant correlation was detected between the protein levels and patient age, histological type, or serum CA125, CA199, CA724, NSE, CEA, and b-HCG levels. Patients with high CEP55 protein expression had shorter overall survival and disease-free survival compared with those with low CEP55 expression. Multivariate analysis implicated CEP55 as an independent prognostic indicator for EOC patients. Additionally, downregulation of CEP55 in ovarian cancer cells remarkably inhibited cellular motility and invasion. Aberrant CEP55 expression may predict unfavorable clinical outcomes in EOC patients and play an important role in regulating invasion in ovarian cancer cells. Thus, CEP55 may serve as a prognostic marker and therapeutic target for EOC.",
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     "text": "Fragile X syndrome is one of the most common causes of mental retardation in males, and patients with fragile X syndrome occasionally develop autism. It is usually caused by an expansion of the trinucleotide repeat in the 5'-untranslated region of the FMR1 gene, but in a small number of patients deletions and point mutations have been identified. We screened all 17 exons of the FMR1 gene for mutations in 90 autistic or mentally retarded children using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. No mutations were found in 76 male patients. However, one female patient was heterozygous for a normal allele and a mutant allele with an A to C substitution at nucleotide 879 in exon 9. This mutation was not found in 50 controls. Reverse transcription-PCR revealed that a large proportion of the mutant transcripts were spliced aberrantly, causing premature termination of the protein synthesis. Although uncommon, point mutations in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients.",
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     "offset": 0,
     "text": "Pheochromocytoma unmasked by amisulpride and tiapride.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "D010673",
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       "locations": [
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    {
     "offset": 55,
     "text": "OBJECTIVE: To describe the unmasking of pheochromocytoma in a patient treated with amisulpride and tiapride. CASE SUMMARY: A 42-year-old white man developed acute hypertension with severe headache and vomiting 2 hours after the first doses of amisulpride 100 mg and tiapride 100 mg. Both drugs were immediately discontinued, and the patient recovered after subsequent nicardipine and verapamil treatment. Abdominal ultrasound showed an adrenal mass, and postoperative histologic examination confirmed the diagnosis of pheochromocytoma. DISCUSSION: Drug-induced symptoms of pheochromocytoma are often associated with the use of substituted benzamide drugs, but the underlying mechanism is unknown. In our case, use of the Naranjo probability scale indicated a possible relationship between the hypertensive crisis and amisulpride and tiapride therapy. CONCLUSIONS: As of March 24, 2005, this is the first reported case of amisulpride- and tiapride-induced hypertensive crisis in a patient with pheochromocytoma. Physicians and other healthcare professionals should be aware of this potential adverse effect of tiapride and amisulpride.",
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   "passages": [
    {
     "offset": 0,
     "text": "Phenylephrine but not ephedrine reduces frontal lobe oxygenation following anesthesia-induced hypotension.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D010656",
        "type": "ChemicalEntity"
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       "text": "Phenylephrine",
       "locations": [
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       "id": "1",
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       "id": "2",
       "infons": {
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       "text": "hypotension",
       "locations": [
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         "offset": 94,
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    },
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     "offset": 107,
     "text": "BACKGROUND: Vasopressor agents are used to correct anesthesia-induced hypotension. We describe the effect of phenylephrine and ephedrine on frontal lobe oxygenation (S(c)O(2)) following anesthesia-induced hypotension. METHODS: Following induction of anesthesia by fentanyl (0.15 mg kg(-1)) and propofol (2.0 mg kg(-1)), 13 patients received phenylephrine (0.1 mg iv) and 12 patients received ephedrine (10 mg iv) to restore mean arterial pressure (MAP). Heart rate (HR), MAP, stroke volume (SV), cardiac output (CO), and frontal lobe oxygenation (S(c)O(2)) were registered. RESULTS: Induction of anesthesia was followed by a decrease in MAP, HR, SV, and CO concomitant with an elevation in S(c)O(2). After administration of phenylephrine, MAP increased (51 +/- 12 to 81 +/- 13 mmHg; P < 0.001; mean +/- SD). However, a 14% (from 70 +/- 8% to 60 +/- 7%) reduction in S(c)O(2) (P < 0.05) followed with no change in CO (3.7 +/- 1.1 to 3.4 +/- 0.9 l min(-1)). The administration of ephedrine led to a similar increase in MAP (53 +/- 9 to 79 +/- 8 mmHg; P < 0.001), restored CO (3.2 +/- 1.2 to 5.0 +/- 1.3 l min(-1)), and preserved S(c)O(2). CONCLUSIONS: The utilization of phenylephrine to correct hypotension induced by anesthesia has a negative impact on S(c)O(2) while ephedrine maintains frontal lobe oxygenation potentially related to an increase in CO.",
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       "id": "5",
       "infons": {
        "identifier": "D004809",
        "type": "ChemicalEntity"
       },
       "text": "ephedrine",
       "locations": [
        {
         "offset": 234,
         "length": 9
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D007022",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypotension",
       "locations": [
        {
         "offset": 312,
         "length": 11
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D005283",
        "type": "ChemicalEntity"
       },
       "text": "fentanyl",
       "locations": [
        {
         "offset": 371,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D015742",
        "type": "ChemicalEntity"
       },
       "text": "propofol",
       "locations": [
        {
         "offset": 401,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 430,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D010656",
        "type": "ChemicalEntity"
       },
       "text": "phenylephrine",
       "locations": [
        {
         "offset": 448,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 481,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D004809",
        "type": "ChemicalEntity"
       },
       "text": "ephedrine",
       "locations": [
        {
         "offset": 499,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 583,
         "length": 6
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D010656",
        "type": "ChemicalEntity"
       },
       "text": "phenylephrine",
       "locations": [
        {
         "offset": 831,
         "length": 13
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D004809",
        "type": "ChemicalEntity"
       },
       "text": "ephedrine",
       "locations": [
        {
         "offset": 1085,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D010656",
        "type": "ChemicalEntity"
       },
       "text": "phenylephrine",
       "locations": [
        {
         "offset": 1276,
         "length": 13
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D007022",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypotension",
       "locations": [
        {
         "offset": 1301,
         "length": 11
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D004809",
        "type": "ChemicalEntity"
       },
       "text": "ephedrine",
       "locations": [
        {
         "offset": 1375,
         "length": 9
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D004809",
      "entity2": "D007022",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D007022",
      "entity2": "D015742",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D007022",
      "entity2": "D005283",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D010656",
      "entity2": "D004809",
      "type": "Comparison",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D010656",
      "entity2": "D007022",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17935240",
   "passages": [
    {
     "offset": 0,
     "text": "Somatic and gonadal mosaicism in X-linked retinitis pigmentosa.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked retinitis pigmentosa",
       "locations": [
        {
         "offset": 33,
         "length": 29
        }
       ]
      }
     ]
    },
    {
     "offset": 64,
     "text": "The g.ORF15 + 652-653delAG mutation in the RPGR gene is the most frequent mutation in X-linked retinitis pigmentosa (XLRP). The objective of this study was to investigate the possibility of mosaicism in an XLRP family. Eight subjects in the RP family were recruited. Blood samples were collected for DNA extraction. Haplotype analysis and mutational screening on the RPGR gene were performed. Additionally, samples of hair follicles and buccal cells from the mother of the proband were acquired for DNA extraction and molecular analysis. Phenotype was characterized with routine ophthalmic examination, Goldmann perimetry, electroretinography, and color fundus photography. A g.ORF15 + 652-653delAG mutation was identified in second- and third-generation patients/carriers. A first-generation female, who was considered to be an obligate carrier, demonstrated a normal phenotype as well as a normal genotype in lymphocytic DNA, indicating the gonadal mosaicism; however, a heterozygous AG-deletion at nucleotide 652 and 653 was identified in the genomic DNA of hair follicles, hair shaft, and buccal cells, indicating that the mutation is somatic. In conclusion, we reported on a family in which an asymptomatic woman with somatic-gonadal mosaicism for a RPGR gene mutation transmitted the mutation to an asymptomatic daughter and to a son with XLRP. Gonadal mosaicism may be responsible for a proportion of multiplex or simplex RP families, in which more than 50% of all cases of RP are found. (c) 2007 Wiley-Liss, Inc.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "g|DEL|ORF15+652_653|AG",
        "type": "SequenceVariant"
       },
       "text": "g.ORF15 + 652-653delAG",
       "locations": [
        {
         "offset": 68,
         "length": 22
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "6103",
        "type": "GeneOrGeneProduct"
       },
       "text": "RPGR",
       "locations": [
        {
         "offset": 107,
         "length": 4
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked retinitis pigmentosa",
       "locations": [
        {
         "offset": 150,
         "length": 29
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLRP",
       "locations": [
        {
         "offset": 181,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLRP",
       "locations": [
        {
         "offset": 270,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RP",
       "locations": [
        {
         "offset": 305,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6103",
        "type": "GeneOrGeneProduct"
       },
       "text": "RPGR",
       "locations": [
        {
         "offset": 431,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "g|DEL|ORF15+652_653|AG",
        "type": "SequenceVariant"
       },
       "text": "g.ORF15 + 652-653delAG",
       "locations": [
        {
         "offset": 740,
         "length": 22
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 819,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "g|DEL|652_653|AG",
        "type": "SequenceVariant"
       },
       "text": "AG-deletion at nucleotide 652 and 653",
       "locations": [
        {
         "offset": 1050,
         "length": 37
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "woman",
       "locations": [
        {
         "offset": 1276,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "6103",
        "type": "GeneOrGeneProduct"
       },
       "text": "RPGR",
       "locations": [
        {
         "offset": 1319,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XLRP",
       "locations": [
        {
         "offset": 1409,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RP",
       "locations": [
        {
         "offset": 1493,
         "length": 2
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D012174",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RP",
       "locations": [
        {
         "offset": 1545,
         "length": 2
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "g|DEL|652_653|AG",
      "entity2": "D012174",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "6103",
      "entity2": "D012174",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "g|DEL|ORF15+652_653|AG",
      "entity2": "D012174",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "18441470",
   "passages": [
    {
     "offset": 0,
     "text": "Complete atrioventricular block secondary to lithium therapy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D054537",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Complete atrioventricular block",
       "locations": [
        {
         "offset": 0,
         "length": 31
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008094",
        "type": "ChemicalEntity"
       },
       "text": "lithium",
       "locations": [
        {
         "offset": 45,
         "length": 7
        }
       ]
      }
     ]
    },
    {
     "offset": 62,
     "text": "Sinus node dysfunction has been reported most frequently among the adverse cardiovascular effects of lithium. In the present case, complete atrioventricular (AV) block with syncopal attacks developed secondary to lithium therapy, necessitating permanent pacemaker implantation. Serum lithium levels remained under or within the therapeutic range during the syncopal attacks. Lithium should be used with extreme caution, especially in patients with mild disturbance of AV conduction.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D012804",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Sinus node dysfunction",
       "locations": [
        {
         "offset": 62,
         "length": 22
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D018376",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "adverse cardiovascular effects",
       "locations": [
        {
         "offset": 129,
         "length": 30
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008094",
        "type": "ChemicalEntity"
       },
       "text": "lithium",
       "locations": [
        {
         "offset": 163,
         "length": 7
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D054537",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "complete atrioventricular (AV) block",
       "locations": [
        {
         "offset": 193,
         "length": 36
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D013575",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "syncopal attacks",
       "locations": [
        {
         "offset": 235,
         "length": 16
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D008094",
        "type": "ChemicalEntity"
       },
       "text": "lithium",
       "locations": [
        {
         "offset": 275,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D008094",
        "type": "ChemicalEntity"
       },
       "text": "lithium",
       "locations": [
        {
         "offset": 346,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D013575",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "syncopal attacks",
       "locations": [
        {
         "offset": 419,
         "length": 16
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D008094",
        "type": "ChemicalEntity"
       },
       "text": "Lithium",
       "locations": [
        {
         "offset": 437,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 496,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D013575",
      "entity2": "D008094",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D054537",
      "entity2": "D008094",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D008094",
      "entity2": "D012804",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D008094",
      "entity2": "D018376",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "15036754",
   "passages": [
    {
     "offset": 0,
     "text": "Organophosphate-induced convulsions and prevention of neuropathological damages.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D010755",
        "type": "ChemicalEntity"
       },
       "text": "Organophosphate",
       "locations": [
        {
         "offset": 0,
         "length": 15
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D012640",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "convulsions",
       "locations": [
        {
         "offset": 24,
         "length": 11
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D004194",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "neuropathological damages",
       "locations": [
        {
         "offset": 54,
         "length": 25
        }
       ]
      }
     ]
    },
    {
     "offset": 81,
     "text": "Such organophosphorus (OP) compounds as diisopropylfluorophosphate (DFP), sarin and soman are potent inhibitors of acetylcholinesterases (AChEs) and butyrylcholinesterases (BChEs). The acute toxicity of OPs is the result of their irreversible binding with AChEs in the central nervous system (CNS), which elevates acetylcholine (ACh) levels. The protective action of subcutaneously (SC) administered antidotes or their combinations in DFP (2.0 mg/kg BW) intoxication was studied in 9-10-weeks-old Han-Wistar male rats. The rats received AChE reactivator pralidoxime-2-chloride (2PAM) (30.0 mg/kg BW), anticonvulsant diazepam (2.0 mg/kg BW), A(1)-adenosine receptor agonist N(6)-cyclopentyl adenosine (CPA) (2.0 mg/kg BW), NMDA-receptor antagonist dizocilpine maleate (+-MK801 hydrogen maleate) (2.0 mg/kg BW) or their combinations with cholinolytic drug atropine sulfate (50.0 mg/kg BW) immediately or 30 min after the single SC injection of DFP. The control rats received atropine sulfate, but also saline and olive oil instead of other antidotes and DFP, respectively. All rats were terminated either 24 h or 3 weeks after the DFP injection. The rats treated with DFP-atropine showed severe typical OP-induced toxicity signs. When CPA, diazepam or 2PAM was given immediately after DFP-atropine, these treatments prevented, delayed or shortened the occurrence of serious signs of poisoning. Atropine-MK801 did not offer any additional protection against DFP toxicity. In conclusion, CPA, diazepam and 2PAM in combination with atropine prevented the occurrence of serious signs of poisoning and thus reduced the toxicity of DFP in rat.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D010755",
        "type": "ChemicalEntity"
       },
       "text": "organophosphorus",
       "locations": [
        {
         "offset": 86,
         "length": 16
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D010755",
        "type": "ChemicalEntity"
       },
       "text": "OP",
       "locations": [
        {
         "offset": 104,
         "length": 2
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D007531",
        "type": "ChemicalEntity"
       },
       "text": "diisopropylfluorophosphate",
       "locations": [
        {
         "offset": 121,
         "length": 26
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D007531",
        "type": "ChemicalEntity"
       },
       "text": "DFP",
       "locations": [
        {
         "offset": 149,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D012524",
        "type": "ChemicalEntity"
       },
       "text": "sarin",
       "locations": [
        {
         "offset": 155,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D012999",
        "type": "ChemicalEntity"
       },
       "text": "soman",
       "locations": [
        {
         "offset": 165,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "83817",
        "type": "GeneOrGeneProduct"
       },
       "text": "acetylcholinesterases",
       "locations": [
        {
         "offset": 196,
         "length": 21
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "83817",
        "type": "GeneOrGeneProduct"
       },
       "text": "AChEs",
       "locations": [
        {
         "offset": 219,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "65036",
        "type": "GeneOrGeneProduct"
       },
       "text": "butyrylcholinesterases",
       "locations": [
        {
         "offset": 230,
         "length": 22
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "65036",
        "type": "GeneOrGeneProduct"
       },
       "text": "BChEs",
       "locations": [
        {
         "offset": 254,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "toxicity",
       "locations": [
        {
         "offset": 272,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D010755",
        "type": "ChemicalEntity"
       },
       "text": "OPs",
       "locations": [
        {
         "offset": 284,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "83817",
        "type": "GeneOrGeneProduct"
       },
       "text": "AChEs",
       "locations": [
        {
         "offset": 337,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D000109",
        "type": "ChemicalEntity"
       },
       "text": "acetylcholine",
       "locations": [
        {
         "offset": 395,
         "length": 13
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D000109",
        "type": "ChemicalEntity"
       },
       "text": "ACh",
       "locations": [
        {
         "offset": 410,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D007531",
        "type": "ChemicalEntity"
       },
       "text": "DFP",
       "locations": [
        {
         "offset": 516,
         "length": 3
        }
       ]
      },
      {
       "id": "19",
       "infons": {
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       "text": "neurotoxic",
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       "id": "25",
       "infons": {
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       "text": "spinal cord ischemia",
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       "id": "26",
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  {
   "id": "15987266",
   "passages": [
    {
     "offset": 0,
     "text": "Growth-associated protein 43 expression in hippocampal molecular layer of chronic epileptic rats treated with cycloheximide.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "29423",
        "type": "GeneOrGeneProduct"
       },
       "text": "Growth-associated protein 43",
       "locations": [
        {
         "offset": 0,
         "length": 28
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D004827",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "epileptic",
       "locations": [
        {
         "offset": 82,
         "length": 9
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       ]
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      {
       "id": "2",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
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       "text": "rats",
       "locations": [
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         "offset": 92,
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       "id": "3",
       "infons": {
        "identifier": "D003513",
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       "text": "cycloheximide",
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         "offset": 110,
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    {
     "offset": 125,
     "text": "PURPOSE: GAP43 has been thought to be linked with mossy fiber sprouting (MFS) in various experimental models of epilepsy. To investigate how GAP43 expression (GAP43-ir) correlates with MFS, we assessed the intensity (densitometry) and extension (width) of GAP43-ir in the inner molecular layer of the dentate gyrus (IML) of rats subject to status epilepticus induced by pilocarpine (Pilo), previously injected or not with cycloheximide (CHX), which has been shown to inhibit MFS. METHODS: CHX was injected before the Pilo injection in adult Wistar rats. The Pilo group was injected with the same drugs, except for CHX. Animals were killed between 30 and 60 days later, and brain sections were processed for GAP43 immunohistochemistry. RESULTS: Densitometry showed no significant difference regarding GAP43-ir in the IML between Pilo, CHX+Pilo, and control groups. However, the results of the width of the GAP43-ir band in the IML showed that CHX+Pilo and control animals had a significantly larger band (p = 0.03) as compared with that in the Pilo group. CONCLUSIONS: Our current finding that animals in the CHX+Pilo group have a GAP43-ir band in the IML, similar to that of controls, reinforces prior data on the blockade of MFS in these animals. The change in GAP43-ir present in Pilo-treated animals was a thinning of the band to a very narrow layer just above the granule cell layer that is likely to be associated with the loss of hilar cell projections that express GAP-43.",
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       "id": "4",
       "infons": {
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       "text": "GAP43",
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         "offset": 134,
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       "text": "epilepsy",
       "locations": [
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         "offset": 237,
         "length": 8
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       "id": "6",
       "infons": {
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       "text": "GAP43",
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         "offset": 266,
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       "text": "GAP43",
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         "offset": 284,
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       "id": "8",
       "infons": {
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       "text": "GAP43",
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         "offset": 381,
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       "id": "9",
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        "identifier": "10116",
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       "text": "rats",
       "locations": [
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         "offset": 449,
         "length": 4
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       ]
      },
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       "id": "10",
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       "text": "status epilepticus",
       "locations": [
        {
         "offset": 465,
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       "id": "11",
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       "text": "pilocarpine",
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       "id": "12",
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       "text": "Pilo",
       "locations": [
        {
         "offset": 508,
         "length": 4
        }
       ]
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       "id": "13",
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        "identifier": "D003513",
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       "text": "cycloheximide",
       "locations": [
        {
         "offset": 547,
         "length": 13
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       "id": "14",
       "infons": {
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       "text": "CHX",
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         "offset": 562,
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       "id": "15",
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       "text": "CHX",
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       "id": "16",
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       "text": "Pilo",
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       "text": "rats",
       "locations": [
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       "id": "20",
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       "text": "GAP43",
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       "id": "21",
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       "text": "GAP43",
       "locations": [
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         "offset": 925,
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       "id": "22",
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       "text": "Pilo",
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       "id": "25",
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       "text": "GAP43",
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       "id": "26",
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       "text": "CHX",
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        {
         "offset": 1067,
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       "id": "27",
       "infons": {
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       "text": "Pilo",
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       "text": "Pilo",
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         "offset": 1168,
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       "id": "29",
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        "identifier": "D003513",
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       "text": "CHX",
       "locations": [
        {
         "offset": 1233,
         "length": 3
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       "id": "30",
       "infons": {
        "identifier": "D010862",
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       "text": "Pilo",
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        {
         "offset": 1237,
         "length": 4
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       ]
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       "id": "31",
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        "identifier": "29423",
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       "text": "GAP43",
       "locations": [
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         "offset": 1255,
         "length": 5
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       "id": "32",
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        "identifier": "29423",
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       "text": "GAP43",
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        {
         "offset": 1387,
         "length": 5
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       "id": "33",
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        "identifier": "D010862",
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       "text": "Pilo",
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         "offset": 1407,
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       "id": "34",
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        "identifier": "29423",
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       "text": "GAP-43",
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        {
         "offset": 1597,
         "length": 6
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   "id": "16428827",
   "passages": [
    {
     "offset": 0,
     "text": "Daidzein activates choline acetyltransferase from MC-IXC cells and improves drug-induced amnesia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C004742",
        "type": "ChemicalEntity"
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       "text": "Daidzein",
       "locations": [
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       "id": "1",
       "infons": {
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       "text": "choline acetyltransferase",
       "locations": [
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         "offset": 19,
         "length": 25
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "CVCL_1398",
        "type": "CellLine"
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       "text": "MC-IXC",
       "locations": [
        {
         "offset": 50,
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       "id": "3",
       "infons": {
        "identifier": "D000647",
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       "text": "amnesia",
       "locations": [
        {
         "offset": 89,
         "length": 7
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       ]
      }
     ]
    },
    {
     "offset": 98,
     "text": "The choline acetyltransferase (ChAT) activator, which enhances cholinergic transmission via an augmentation of the enzymatic production of acetylcholine (ACh), is an important factor in the treatment of Alzheimer's disease (AD). Methanolic extracts from Pueraria thunbergiana exhibited an activation effect (46%) on ChAT in vitro. Via the sequential isolation of Pueraria thunbergiana, the active component was ultimately identified as daidzein (4',7-dihydroxy-isoflavone). In order to investigate the effects of daidzein from Pueraria thunbergiana on scopolamine-induced impairments of learning and memory, we conducted a series of in vivo tests. Administration of daidzein (4.5 mg/kg body weight) to mice was shown significantly to reverse scopolamine-induced amnesia, according to the results of a Y-maze test. Injections of scopolamine into mice resulted in impaired performance on Y-maze tests (a 37% decreases in alternation behavior). By way of contrast, mice treated with daidzein prior to the scopolamine injections were noticeably protected from this performance impairment (an approximately 12%-21% decrease in alternation behavior). These results indicate that daidzein might play a role in acetylcholine biosynthesis as a ChAT activator, and that it also ameliorates scopolamine-induced amnesia.",
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       "id": "4",
       "infons": {
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       "text": "choline acetyltransferase",
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         "offset": 129,
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       "text": "acetylcholine",
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       "text": "ACh",
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       "text": "Alzheimer's disease",
       "locations": [
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         "length": 19
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       ]
      },
      {
       "id": "9",
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       "id": "12",
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       "text": "daidzein",
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       "infons": {
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       "text": "daidzein",
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       ]
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       "id": "15",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "scopolamine",
       "locations": [
        {
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     "text": "Methamphetamine (MA)-induced dopaminergic neurotoxicity is believed to be associated with the increased formation of free radicals. This study examined the effect of alpha-tocopherol (alpha-TC), a scavenger of reactive oxygen species, and deferoxamine (DFO), an iron chelator, on the MA-induced neurotoxicity. Male rats were treated with MA (10 mg/kg, every 2 h for four injections). The rat received either alpha-TC (20 mg/kg) intraperitoneally for 3 days and 30 min prior to MA administration or DFO (50 mg/kg) subcutaneously 30 min before MA administration. The concentrations of dopamine (DA), serotonin and their metabolites decreased significantly after MA administration, which was inhibited by the alpha-TC and DFO pretreatment. alpha-TC and DFO attenuated the MA-induced hyperthermia as well as the alterations in the locomotor activity. The level of lipid peroxidation was higher and the reduced glutathione concentration was lower in the MA-treated rats. These changes were significantly attenuated by alpha-TC and DFO. This suggests that alpha-TC and DFO ameliorate the MA-induced neuronal damage by decreasing the level of oxidative stress.",
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     "offset": 0,
     "text": "Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease.",
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       "id": "0",
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       "text": "Patients",
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       "text": "nephropathy",
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       "text": "patients",
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       "text": "chronic kidney disease",
       "locations": [
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     "text": "BACKGROUND: No direct comparisons exist of the renal tolerability of the low-osmolality contrast medium iopamidol with that of the iso-osmolality contrast medium iodixanol in high-risk patients. METHODS AND RESULTS: The present study is a multicenter, randomized, double-blind comparison of iopamidol and iodixanol in patients with chronic kidney disease (estimated glomerular filtration rate, 20 to 59 mL/min) who underwent cardiac angiography or percutaneous coronary interventions. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2 to 5 days after receiving medications. The primary outcome was a postdose SCr increase > or = 0.5 mg/dL (44.2 micromol/L) over baseline. Secondary outcomes were a postdose SCr increase > or = 25%, a postdose estimated glomerular filtration rate decrease of > or = 25%, and the mean peak change in SCr. In 414 patients, contrast volume, presence of diabetes mellitus, use of N-acetylcysteine, mean baseline SCr, and estimated glomerular filtration rate were comparable in the 2 groups. SCr increases > or = 0.5 mg/dL occurred in 4.4% (9 of 204 patients) after iopamidol and 6.7% (14 of 210 patients) after iodixanol (P=0.39), whereas rates of SCr increases > or = 25% were 9.8% and 12.4%, respectively (P=0.44). In patients with diabetes, SCr increases > or = 0.5 mg/dL were 5.1% (4 of 78 patients) with iopamidol and 13.0% (12 of 92 patients) with iodixanol (P=0.11), whereas SCr increases > or = 25% were 10.3% and 15.2%, respectively (P=0.37). Mean post-SCr increases were significantly less with iopamidol (all patients: 0.07 versus 0.12 mg/dL, 6.2 versus 10.6 micromol/L, P=0.03; patients with diabetes: 0.07 versus 0.16 mg/dL, 6.2 versus 14.1 micromol/L, P=0.01). CONCLUSIONS: The rate of contrast-induced nephropathy, defined by multiple end points, is not statistically different after the intraarterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus. Any true difference between the agents is small and not likely to be clinically significant.",
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     "text": "Estrogen prevents cholesteryl ester accumulation in macrophages induced by the HIV protease inhibitor ritonavir.",
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     "text": "Individuals with HIV can now live long lives with drug therapy that often includes protease inhibitors such as ritonavir. Many patients, however, develop negative long-term side effects such as premature atherosclerosis. We have previously demonstrated that ritonavir treatment increases atherosclerotic lesion formation in male mice to a greater extent than in female mice. Furthermore, peripheral blood monocytes isolated from ritonavir-treated females had less cholesteryl ester accumulation. In the present study, we have investigated the molecular mechanisms by which female hormones influence cholesterol metabolism in macrophages in response to the HIV protease inhibitor ritonavir. We have utilized the human monocyte cell line, THP-1 as a model to address this question. Briefly, cells were differentiated for 72 h with 100 nM PMA to obtain a macrophage-like phenotype in the presence or absence of 1 nM 17beta-estradiol (E2), 100 nM progesterone or vehicle (0.01% ethanol). Cells were then treated with 30 ng/ml ritonavir or vehicle in the presence of aggregated LDL for 24 h. Cell extracts were harvested, and lipid or total RNA was isolated. E2 decreased the accumulation of cholesteryl esters in macrophages following ritonavir treatment. Ritonavir increased the expression of the scavenger receptor, CD36 mRNA, responsible for the uptake of LDL. Additionally, ritonavir treatment selectively increased the relative levels of PPARgamma mRNA, a transcription factor responsible for the regulation of CD36 mRNA expression. Treatment with E2, however, failed to prevent these increases at the mRNA level. E2 did, however, significantly suppress CD36 protein levels as measured by fluorescent immunocytochemistry. This data suggests that E2 modifies the expression of CD36 at the level of protein expression in monocyte-derived macrophages resulting in reduced cholesteryl ester accumulation following ritonavir treatment.",
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     "offset": 0,
     "text": "Clinical comparison of cardiorespiratory effects during unilateral and conventional spinal anaesthesia.",
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    {
     "offset": 104,
     "text": "BACKGROUND: Spinal anaesthesia is widely employed in clinical practice but has the main drawback of post-spinal block hypotension. Efforts must therefore continue to be made to obviate this setback OBJECTIVE: To evaluate the cardiovascular and respiratory changes during unilateral and conventional spinal anaesthesia. METHODS: With ethical approval, we studied 74 American Society of Anesthesiologists (ASA), physical status class 1 and 2 patients scheduled for elective unilateral lower limb surgery. Patients were randomly allocated into one of two groups: lateral and conventional spinal anaesthesia groups. In the lateral position with operative side down, patients recived 10 mg (2mls) of 0.5% hyperbaric bupivacaine through a 25-gauge spinal needle. Patients in the unilateral group were maintained in the lateral position for 15 minutes following spinal injection while those in the conventional group were turned supine immediately after injection. Blood pressure, heart rate, respiratory rate and oxygen saturation were monitored over 1 hour. RESULTS: Three patients (8.1%) in the unilateral group and 5 (13.5%) in the conventional group developed hypotension, P= 0.71. Four (10.8%) patients in the conventional group and 1 (2.7%) in the unilateral group, P= 0.17 required epinephrine infusion to treat hypotension. Patients in the conventional group had statistically significant greater fall in the systolic blood pressures at 15, 30 and 45 minutes when compared to the baseline (P= 0.003, 0.001 and 0.004). The mean respiratory rate and oxygen saturations in the two groups were similar. CONCLUSION: Compared to conventional spinal anaesthesia, unilateral spinal anaesthesia was associated with fewer cardiovascular perturbations. Also, the type of spinal block instituted affected neither the respiratory rate nor the arterial oxygen saturation.",
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     "offset": 0,
     "text": "Acute effects of N-(2-propylpentanoyl)urea on hippocampal amino acid neurotransmitters in pilocarpine-induced seizure in rats.",
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     "text": "The present study aimed to investigate the anticonvulsant activity as well as the effects on the level of hippocampal amino acid neurotransmitters (glutamate, aspartate, glycine and GABA) of N-(2-propylpentanoyl)urea (VPU) in comparison to its parent compound, valproic acid (VPA). VPU was more potent than VPA, exhibiting the median effective dose (ED(50)) of 49 mg/kg in protecting rats against pilocarpine-induced seizure whereas the corresponding value for VPA was 322 mg/kg. In vivo microdialysis demonstrated that an intraperitoneal administration of pilocarpine induced a pronounced increment of hippocampal glutamate and aspartate whereas no significant change was observed on the level of glycine and GABA. Pretreatment with either VPU (50 and 100 mg/kg) or VPA (300 and 600 mg/kg) completely abolished pilocarpine-evoked increases in extracellular glutamate and aspartate. In addition, a statistically significant reduction was also observed on the level of GABA and glycine but less than a drastic reduction of glutamate and aspartate level. Based on the finding that VPU and VPA could protect the animals against pilocarpine-induced seizure it is suggested that the reduction of inhibitory amino acid neurotransmitters was comparatively minor and offset by a pronounced reduction of glutamate and aspartate. Therefore, like VPA, the finding that VPU could drastically reduce pilocarpine-induced increases in glutamate and aspartate should account, at least partly, for its anticonvulsant activity observed in pilocarpine-induced seizure in experimental animals. Some other mechanism than those being reported herein should be further investigated.",
     "annotations": [
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       "id": "4",
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        "type": "ChemicalEntity"
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       "text": "glutamate",
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       "text": "glycine",
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     "text": "Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine.",
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     "text": "OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors.",
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    {
     "offset": 0,
     "text": "Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy).",
     "annotations": [
      {
       "id": "0",
       "infons": {
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     "text": "RATIONALE: Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present ecstasy users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/nicotine (AN), cannabis/alcohol/nicotine (CAN), non-ecstasy polydrug (PD)), and two ecstasy polydrug groups (present (MDMA) and past users (EX-MDMA). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the MDMA and EX-MDMA groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past ecstasy users showed few signs of recovery. Compared with present ecstasy users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of impaired memory and clinically significant levels of depression, impulsiveness, and sleep disturbance, the prognosis for the current generation of ecstasy users is a major cause for concern.",
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     "offset": 0,
     "text": "A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients.",
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       "locations": [
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     "text": "OBJECTIVE: Dexmedetomidine and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and propofol. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with dexmedetomidine or propofol. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 dexmedetomidine and 237 propofol) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe hypotension (mean arterial pressure < 60 mm Hg) and bradycardia (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe hypotension or bradycardia in either the unmatched or matched cohorts. CONCLUSIONS: Severe hypotension and bradycardia occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or propofol. Providers should similarly consider the likelihood of hypotension or bradycardia before starting either sedative.",
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     "id": "R4",
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  {
   "id": "24739405",
   "passages": [
    {
     "offset": 0,
     "text": "Effects of dehydroepiandrosterone in amphetamine-induced schizophrenia models in mice.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003687",
        "type": "ChemicalEntity"
       },
       "text": "dehydroepiandrosterone",
       "locations": [
        {
         "offset": 11,
         "length": 22
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D000661",
        "type": "ChemicalEntity"
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       "text": "amphetamine",
       "locations": [
        {
         "offset": 37,
         "length": 11
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenia",
       "locations": [
        {
         "offset": 57,
         "length": 13
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
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       "text": "mice",
       "locations": [
        {
         "offset": 81,
         "length": 4
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       ]
      }
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    {
     "offset": 87,
     "text": "OBJECTIVE: To examine the effects of dehydroepiandrosterone (DHEA) on animal models of schizophrenia. METHODS: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: amphetamine-free (control), amphetamine, 50, and 100 mg/kg DHEA. The DHEA was administered intraperitoneally (ip) for 5 days. Amphetamine (3 mg/kg ip) induced hyper locomotion, apomorphine (1.5 mg/kg subcutaneously [sc]) induced climbing, and haloperidol (1.5 mg/kg sc) induced catalepsy tests were used as animal models of schizophrenia. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for hyper locomotion, and one-way ANOVA for climbing and catalepsy tests. RESULTS: In the amphetamine-induced locomotion test, there were significant increases in all movements compared with the amphetamine-free group. Both DHEA 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the amphetamine-induced locomotion group. There was a significant difference between groups in the haloperidol-induced catalepsy test (p<0.05). There was no significant difference between groups in terms of total climbing time in the apomorphine-induced climbing test (p>0.05). CONCLUSION: We observed that DHEA reduced locomotor activity and increased catalepsy at both doses, while it had no effect on climbing behavior. We suggest that DHEA displays typical neuroleptic-like effects, and may be used in the treatment of schizophrenia.",
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       "infons": {
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       "text": "dehydroepiandrosterone",
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         "offset": 148,
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       "text": "schizophrenia",
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       "text": "mice",
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       "text": "amphetamine",
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       "text": "Amphetamine",
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       "text": "hyper locomotion",
       "locations": [
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       "text": "apomorphine",
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       "text": "haloperidol",
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       "text": "catalepsy",
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       "text": "schizophrenia",
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       "text": "hyper locomotion",
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       "text": "haloperidol",
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       "text": "apomorphine",
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       "text": "DHEA",
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       "infons": {
        "identifier": "D012559",
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       "text": "schizophrenia",
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   "id": "24840785",
   "passages": [
    {
     "offset": 0,
     "text": "Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000157",
        "type": "ChemicalEntity"
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       "text": "Aconitine",
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       "text": "arrhythmia",
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       ]
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       "text": "p38 MAPK",
       "locations": [
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       ]
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       "id": "4",
       "infons": {
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       "text": "rats",
       "locations": [
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         "offset": 111,
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       ]
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     ]
    },
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     "offset": 117,
     "text": "Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D000157",
        "type": "ChemicalEntity"
       },
       "text": "Aconitine",
       "locations": [
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         "offset": 117,
         "length": 9
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "-",
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       "text": "diterpenoid alkaloid",
       "locations": [
        {
         "offset": 148,
         "length": 20
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       ]
      },
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       "text": "Na(+)",
       "locations": [
        {
         "offset": 275,
         "length": 5
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       ]
      },
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       "id": "8",
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       "text": "cardiotoxicity",
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       ]
      },
      {
       "id": "9",
       "infons": {
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       "text": "aconitine",
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         "offset": 334,
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       ]
      },
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       "id": "10",
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       "text": "Ca(2+)",
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        }
       ]
      },
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       "id": "11",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "aconitine",
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         "length": 9
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       ]
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       "id": "12",
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       "text": "poisoning",
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         "length": 9
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       ]
      },
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       "id": "13",
       "infons": {
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       "text": "Ca(2+)",
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       ]
      },
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       "id": "14",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "aconitine",
       "locations": [
        {
         "offset": 503,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D011041",
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       "text": "poisoning",
       "locations": [
        {
         "offset": 513,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "Ca(2+)",
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        }
       ]
      },
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       "id": "17",
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       "text": "rat",
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         "offset": 619,
         "length": 3
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       ]
      },
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       "id": "18",
       "infons": {
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       "text": "arrhythmia",
       "locations": [
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         "length": 10
        }
       ]
      },
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       "text": "rats",
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       ]
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       "id": "20",
       "infons": {
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       "text": "aconitine",
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         "length": 9
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       ]
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       "id": "21",
       "infons": {
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       "text": "myocardial injury",
       "locations": [
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         "offset": 738,
         "length": 17
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D064420",
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       },
       "text": "cytotoxicity",
       "locations": [
        {
         "offset": 770,
         "length": 12
        }
       ]
      },
      {
       "id": "23",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "rat",
       "locations": [
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         "offset": 801,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
       "infons": {
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        "type": "GeneOrGeneProduct"
       },
       "text": "lactate dehydrogenase",
       "locations": [
        {
         "offset": 855,
         "length": 21
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 957,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D000157",
        "type": "ChemicalEntity"
       },
       "text": "aconitine",
       "locations": [
        {
         "offset": 987,
         "length": 9
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D009202",
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       },
       "text": "myocardial injury",
       "locations": [
        {
         "offset": 1009,
         "length": 17
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "-",
        "type": "ChemicalEntity"
       },
       "text": "dUTP",
       "locations": [
        {
         "offset": 1254,
         "length": 4
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       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D001710",
        "type": "ChemicalEntity"
       },
       "text": "biotin",
       "locations": [
        {
         "offset": 1259,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D000157",
        "type": "ChemicalEntity"
       },
       "text": "aconitine",
       "locations": [
        {
         "offset": 1315,
         "length": 9
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca(2+)",
       "locations": [
        {
         "offset": 1391,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D000157",
        "type": "ChemicalEntity"
       },
       "text": "aconitine",
       "locations": [
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         "offset": 1434,
         "length": 9
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       ]
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      {
       "id": "33",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "Ca(2+)",
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         "length": 6
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       ]
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       "id": "34",
       "infons": {
        "identifier": "D002118",
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       "text": "Ca(2+)",
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         "length": 5
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       ]
      },
      {
       "id": "36",
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       "text": "MAPK",
       "locations": [
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         "offset": 1755,
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