{
 "source": "PubTator",
 "date": "2021-11-30",
 "key": "BioC.key",
 "documents": [
  {
   "id": "14510914",
   "passages": [
    {
     "offset": 0,
     "text": "Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Congenital hypothyroidism",
       "locations": [
        {
         "offset": 0,
         "length": 25
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "6528",
        "type": "GeneOrGeneProduct"
       },
       "text": "sodium/iodide symporter",
       "locations": [
        {
         "offset": 55,
         "length": 23
        }
       ]
      }
     ]
    },
    {
     "offset": 88,
     "text": "OBJECTIVE: Iodide transport defect (ITD) is a rare disorder characterised by an inability of the thyroid to maintain an iodide gradient across the basolateral membrane of thyroid follicular cells, that often results in congenital hypothyroidism. When present the defect is also found in the salivary glands and gastric mucosa and it has been shown to arise from abnormalities of the sodium/iodide symporter (NIS). PATIENT: We describe a woman with hypothyroidism identified at the 3rd month of life. The diagnosis of ITD was suspected because of nodular goitre, and little if any iodide uptake by the thyroid and salivary glands. Treatment with iodide partially corrected the hypothyroidism; however, long-term substitution therapy with L-thyroxine was started. MEASUREMENTS: Thyroid radioiodide uptake was only 1.4% and 0.3% at 1 and 24 h after the administration of recombinant human TSH. The saliva to plasma I- ratio was 1.1 indicating that the inability of the thyroid gland to concentrate I- was also present in the salivary glands. RESULTS: Analysis of the patient's NIS gene revealed a 15 nucleotide (nt) deletion of the coding sequence (nt 1314 through nt 1328) and the insertion of 15 nt duplicating the first 15 nt of the adjacent intron. The patient was homozygous for this insertion/deletion, while both consanguineous parents were heterozygous. This deletion predicts the production of a protein lacking the five terminal amino acids of exon XI (439-443) which are located in the 6th intracellular loop. COS-7 cells transfected with a vector expressing the mutant del-(439-443) NIS failed to concentrate iodide, suggesting that the mutation was the direct cause of the ITD in this patient. CONCLUSION: In conclusion we describe the first Italian case of congenital hypothyroidism due to a new deletion in the NIS gene.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "C564766",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Iodide transport defect",
       "locations": [
        {
         "offset": 99,
         "length": 23
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "C564766",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ITD",
       "locations": [
        {
         "offset": 124,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D050033",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inability of the thyroid",
       "locations": [
        {
         "offset": 168,
         "length": 24
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D007454",
        "type": "ChemicalEntity"
       },
       "text": "iodide",
       "locations": [
        {
         "offset": 208,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D003409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital hypothyroidism",
       "locations": [
        {
         "offset": 307,
         "length": 25
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6528",
        "type": "GeneOrGeneProduct"
       },
       "text": "sodium/iodide symporter",
       "locations": [
        {
         "offset": 471,
         "length": 23
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "6528",
        "type": "GeneOrGeneProduct"
       },
       "text": "NIS",
       "locations": [
        {
         "offset": 496,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "PATIENT",
       "locations": [
        {
         "offset": 502,
         "length": 7
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "woman",
       "locations": [
        {
         "offset": 525,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D007037",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypothyroidism",
       "locations": [
        {
         "offset": 536,
         "length": 14
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C564766",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ITD",
       "locations": [
        {
         "offset": 605,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D020518",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nodular goitre",
       "locations": [
        {
         "offset": 634,
         "length": 14
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D007454",
        "type": "ChemicalEntity"
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       "text": "iodide",
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       "text": "iodide",
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         "length": 6
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       ]
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      {
       "id": "16",
       "infons": {
        "identifier": "D007037",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypothyroidism",
       "locations": [
        {
         "offset": 764,
         "length": 14
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D013974",
        "type": "ChemicalEntity"
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       "text": "L-thyroxine",
       "locations": [
        {
         "offset": 825,
         "length": 11
        }
       ]
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       "id": "18",
       "infons": {
        "identifier": "D007454",
        "type": "ChemicalEntity"
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       "text": "radioiodide",
       "locations": [
        {
         "offset": 872,
         "length": 11
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "human",
       "locations": [
        {
         "offset": 968,
         "length": 5
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       ]
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       "id": "20",
       "infons": {
        "identifier": "7200",
        "type": "GeneOrGeneProduct"
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       "text": "TSH",
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        {
         "offset": 974,
         "length": 3
        }
       ]
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       "id": "21",
       "infons": {
        "identifier": "D007454",
        "type": "ChemicalEntity"
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       "text": "I-",
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        {
         "offset": 1000,
         "length": 2
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D007454",
        "type": "ChemicalEntity"
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       "text": "I-",
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         "offset": 1083,
         "length": 2
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1152,
         "length": 7
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "6528",
        "type": "GeneOrGeneProduct"
       },
       "text": "NIS",
       "locations": [
        {
         "offset": 1162,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "c|DEL|1314_1328|",
        "type": "SequenceVariant"
       },
       "text": "deletion of the coding sequence (nt 1314 through nt 1328)",
       "locations": [
        {
         "offset": 1201,
         "length": 57
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "c|DUP||15",
        "type": "SequenceVariant"
       },
       "text": "insertion of 15 nt duplicating the first 15",
       "locations": [
        {
         "offset": 1267,
         "length": 43
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1342,
         "length": 7
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "p|DEL|439_443|",
        "type": "SequenceVariant"
       },
       "text": "lacking the five terminal amino acids of exon XI (439-443)",
       "locations": [
        {
         "offset": 1498,
         "length": 58
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "CVCL_0224",
        "type": "CellLine"
       },
       "text": "COS-7",
       "locations": [
        {
         "offset": 1606,
         "length": 5
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "p|DEL|439_443|",
        "type": "SequenceVariant"
       },
       "text": "del-(439-443)",
       "locations": [
        {
         "offset": 1666,
         "length": 13
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "6528",
        "type": "GeneOrGeneProduct"
       },
       "text": "NIS",
       "locations": [
        {
         "offset": 1680,
         "length": 3
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D007454",
        "type": "ChemicalEntity"
       },
       "text": "iodide",
       "locations": [
        {
         "offset": 1706,
         "length": 6
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "C564766",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ITD",
       "locations": [
        {
         "offset": 1771,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1783,
         "length": 7
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D003409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital hypothyroidism",
       "locations": [
        {
         "offset": 1856,
         "length": 25
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "6528",
        "type": "GeneOrGeneProduct"
       },
       "text": "NIS",
       "locations": [
        {
         "offset": 1911,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
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      "entity1": "c|DEL|1314_1328|",
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      "novel": "Novel"
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    {
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      "type": "Association",
      "novel": "No"
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     "id": "R2",
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     "id": "R4",
     "infons": {
      "entity1": "C564766",
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      "type": "Association",
      "novel": "No"
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     "id": "R5",
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    {
     "offset": 0,
     "text": "Pallidal stimulation: an alternative to pallidotomy?",
     "annotations": []
    },
    {
     "offset": 53,
     "text": "A resurgence of interest in the surgical treatment of Parkinson's disease (PD) came with the rediscovery of posteroventral pallidotomy by Laitinen in 1985. Laitinen's procedure improved most symptoms in drug-resistant PD, which engendered wide interest in the neurosurgical community. Another lesioning procedure, ventrolateral thalamotomy, has become a powerful alternative to stimulate the nucleus ventralis intermedius, producing high long-term success rates and low morbidity rates. Pallidal stimulation has not met with the same success. According to the literature pallidotomy improves the \"on\" symptoms of PD, such as dyskinesias, as well as the \"off\" symptoms, such as rigidity, bradykinesia, and on-off fluctuations. Pallidal stimulation improves bradykinesia and rigidity to a minor extent; however, its strength seems to be in improving levodopa-induced dyskinesias. Stimulation often produces an improvement in the hyper- or dyskinetic upper limbs, but increases the \"freezing\" phenomenon in the lower limbs at the same time. Considering the small increase in the patient's independence, the high costs of bilateral implants, and the difficulty most patients experience in handling the devices, the question arises as to whether bilateral pallidal stimulation is a real alternative to pallidotomy.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Parkinson's disease",
       "locations": [
        {
         "offset": 107,
         "length": 19
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 128,
         "length": 2
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PD",
       "locations": [
        {
         "offset": 271,
         "length": 2
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D010300",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "PD",
       "locations": [
        {
         "offset": 666,
         "length": 2
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesias",
       "locations": [
        {
         "offset": 678,
         "length": 11
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009127",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "rigidity",
       "locations": [
        {
         "offset": 730,
         "length": 8
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D018476",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bradykinesia",
       "locations": [
        {
         "offset": 740,
         "length": 12
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D018476",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bradykinesia",
       "locations": [
        {
         "offset": 809,
         "length": 12
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009127",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "rigidity",
       "locations": [
        {
         "offset": 826,
         "length": 8
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D007980",
        "type": "ChemicalEntity"
       },
       "text": "levodopa",
       "locations": [
        {
         "offset": 901,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D004409",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dyskinesias",
       "locations": [
        {
         "offset": 918,
         "length": 11
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D004409,D006948",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyper- or dyskinetic",
       "locations": [
        {
         "offset": 980,
         "length": 20
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1129,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1215,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
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     "id": "R0",
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      "novel": "No"
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   ]
  },
  {
   "id": "16152606",
   "passages": [
    {
     "offset": 0,
     "text": "Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "c|DEL|657|5",
        "type": "SequenceVariant"
       },
       "text": "657del5",
       "locations": [
        {
         "offset": 30,
         "length": 7
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4683",
        "type": "GeneOrGeneProduct"
       },
       "text": "NBS1",
       "locations": [
        {
         "offset": 45,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 91,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D008223",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sporadic lymphoid malignancies",
       "locations": [
        {
         "offset": 105,
         "length": 30
        }
       ]
      }
     ]
    },
    {
     "offset": 137,
     "text": "Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency = 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Nijmegen breakage syndrome",
       "locations": [
        {
         "offset": 137,
         "length": 26
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D049932",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NBS",
       "locations": [
        {
         "offset": 165,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
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     "offset": 0,
     "text": "Segregation of a M404V mutation of the p62/sequestosome 1 (p62/SQSTM1) gene with polyostotic Paget's disease of bone in an Italian family.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs771966860",
        "type": "SequenceVariant"
       },
       "text": "M404V",
       "locations": [
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         "offset": 17,
         "length": 5
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       ]
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       "id": "1",
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         "length": 3
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       ]
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       "id": "2",
       "infons": {
        "identifier": "8878",
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       "text": "sequestosome 1",
       "locations": [
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         "offset": 43,
         "length": 14
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     "text": "Mutations of the p62/Sequestosome 1 gene (p62/SQSTM1) account for both sporadic and familial forms of Paget's disease of bone (PDB). We originally described a methionine-->valine substitution at codon 404 (M404V) of exon 8, in the ubiquitin protein-binding domain of p62/SQSTM1 gene in an Italian PDB patient. The collection of data from the patient's pedigree provided evidence for a familial form of PDB. Extension of the genetic analysis to other relatives in this family demonstrated segregation of the M404V mutation with the polyostotic PDB phenotype and provided the identification of six asymptomatic gene carriers. DNA for mutational analysis of the exon 8 coding sequence was obtained from 22 subjects, 4 PDB patients and 18 clinically unaffected members. Of the five clinically ascertained affected members of the family, four possessed the M404V mutation and exhibited the polyostotic form of PDB, except one patient with a single X-ray-assessed skeletal localization and one with a polyostotic disease who had died several years before the DNA analysis. By both reconstitution and mutational analysis of the pedigree, six unaffected subjects were shown to bear the M404V mutation, representing potential asymptomatic gene carriers whose circulating levels of alkaline phosphatase were recently assessed as still within the normal range. Taken together, these results support a genotype-phenotype correlation between the M404V mutation in the p62/SQSTM1 gene and a polyostotic form of PDB in this family. The high penetrance of the PDB trait in this family together with the study of the asymptomatic gene carriers will allow us to confirm the proposed genotype-phenotype correlation and to evaluate the potential use of mutational analysis of the p62/SQSTM1 gene in the early detection of relatives at risk for PDB.",
     "annotations": [
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       "id": "6",
       "infons": {
        "identifier": "8878",
        "type": "GeneOrGeneProduct"
       },
       "text": "p62",
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         "offset": 156,
         "length": 3
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       ]
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       "id": "7",
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       "text": "Sequestosome 1",
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         "offset": 160,
         "length": 14
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       ]
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       "id": "8",
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         "offset": 181,
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       ]
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       "id": "9",
       "infons": {
        "identifier": "8878",
        "type": "GeneOrGeneProduct"
       },
       "text": "SQSTM1",
       "locations": [
        {
         "offset": 185,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "C538098",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Paget's disease of bone",
       "locations": [
        {
         "offset": 241,
         "length": 23
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C538098",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PDB",
       "locations": [
        {
         "offset": 266,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs771966860",
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       "text": "methionine-->valine substitution at codon 404",
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         "offset": 298,
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       ]
      },
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       "id": "13",
       "infons": {
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         "offset": 345,
         "length": 5
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       ]
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       "id": "14",
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       "text": "p62",
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         "offset": 406,
         "length": 3
        }
       ]
      },
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       "id": "15",
       "infons": {
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         "offset": 410,
         "length": 6
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       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "C538098",
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       "text": "PDB",
       "locations": [
        {
         "offset": 436,
         "length": 3
        }
       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patient",
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         "offset": 440,
         "length": 7
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       ]
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       "text": "patient",
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      },
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       "infons": {
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       "text": "PDB",
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        }
       ]
      },
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       "infons": {
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       "text": "M404V",
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         "offset": 646,
         "length": 5
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C538098",
        "type": "DiseaseOrPhenotypicFeature"
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         "offset": 682,
         "length": 3
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       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "C538098",
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       "text": "PDB",
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         "offset": 854,
         "length": 3
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       "id": "23",
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       "text": "patients",
       "locations": [
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         "offset": 858,
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       "id": "24",
       "infons": {
        "identifier": "rs771966860",
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       "text": "M404V",
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         "offset": 991,
         "length": 5
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      {
       "id": "25",
       "infons": {
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       "text": "PDB",
       "locations": [
        {
         "offset": 1044,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1060,
         "length": 7
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D005357",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "polyostotic disease",
       "locations": [
        {
         "offset": 1134,
         "length": 19
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs771966860",
        "type": "SequenceVariant"
       },
       "text": "M404V",
       "locations": [
        {
         "offset": 1317,
         "length": 5
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       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D000469",
        "type": "ChemicalEntity"
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       "text": "alkaline phosphatase",
       "locations": [
        {
         "offset": 1411,
         "length": 20
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "rs771966860",
        "type": "SequenceVariant"
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       "text": "M404V",
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         "offset": 1572,
         "length": 5
        }
       ]
      },
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       "id": "31",
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       "text": "p62",
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         "length": 3
        }
       ]
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       "id": "32",
       "infons": {
        "identifier": "8878",
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       "text": "SQSTM1",
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         "offset": 1598,
         "length": 6
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       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "C538098",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "PDB",
       "locations": [
        {
         "offset": 1636,
         "length": 3
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       ]
      },
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       "id": "34",
       "infons": {
        "identifier": "C538098",
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       "text": "PDB",
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         "offset": 1683,
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       "text": "SQSTM1",
       "locations": [
        {
         "offset": 1903,
         "length": 6
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "C538098",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PDB",
       "locations": [
        {
         "offset": 1963,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "8878",
      "entity2": "D005357",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "8878",
      "entity2": "C538098",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs771966860",
      "entity2": "D005357",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "C538098",
      "entity2": "rs771966860",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "1671881",
   "passages": [
    {
     "offset": 0,
     "text": "Two distinct mutations at a single BamHI site in phenylketonuria.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D010661",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "phenylketonuria",
       "locations": [
        {
         "offset": 49,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 66,
     "text": "Classical phenylketonuria is an autosomal recessive disease caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). The abolition of an invariant BamHI site located in the coding sequence of the PAH gene (exon 7) led to the recognition of two new point mutations at codon 272 and 273 (272gly----stop and 273ser----phe, respectively). Both mutations were detected in north eastern France or Belgium and occurred on the background of RFLP haplotype 7 alleles. The present study supports the view that the clinical heterogeneity in PKU is accounted for by the large variety of mutant genotypes associated with PAH deficiencies.. ",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D010661",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Classical phenylketonuria",
       "locations": [
        {
         "offset": 66,
         "length": 25
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autosomal recessive disease",
       "locations": [
        {
         "offset": 98,
         "length": 27
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "OMIM:261600",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "deficiency of hepatic phenylalanine hydroxylase",
       "locations": [
        {
         "offset": 138,
         "length": 47
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "5053",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 187,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "5053",
        "type": "GeneOrGeneProduct"
       },
       "text": "PAH",
       "locations": [
        {
         "offset": 272,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "rs62514952",
        "type": "SequenceVariant"
       },
       "text": "272gly----stop",
       "locations": [
        {
         "offset": 362,
         "length": 14
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "rs62514953",
        "type": "SequenceVariant"
       },
       "text": "273ser----phe",
       "locations": [
        {
         "offset": 381,
         "length": 13
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D010661",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PKU",
       "locations": [
        {
         "offset": 606,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "OMIM:261600",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "PAH deficiencies",
       "locations": [
        {
         "offset": 684,
         "length": 16
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D010661",
      "entity2": "rs62514952",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010661",
      "entity2": "rs62514953",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "5053",
      "entity2": "D010661",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "5053",
      "entity2": "OMIM:261600",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "rs62514952",
      "entity2": "OMIM:261600",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "rs62514953",
      "entity2": "OMIM:261600",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16867246",
   "passages": [
    {
     "offset": 0,
     "text": "Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1813",
        "type": "GeneOrGeneProduct"
       },
       "text": "DRD2",
       "locations": [
        {
         "offset": 15,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D002746",
        "type": "ChemicalEntity"
       },
       "text": "chlorpromazine",
       "locations": [
        {
         "offset": 38,
         "length": 14
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001480",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "extrapyramidal syndrome",
       "locations": [
        {
         "offset": 61,
         "length": 23
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenic",
       "locations": [
        {
         "offset": 96,
         "length": 13
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 110,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 120,
     "text": "AIM: Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients. METHODS: We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "D001480",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Extrapyramidal syndrome",
       "locations": [
        {
         "offset": 125,
         "length": 23
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001480",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "EPS",
       "locations": [
        {
         "offset": 150,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D014150",
        "type": "ChemicalEntity"
       },
       "text": "antipsychotic drugs",
       "locations": [
        {
         "offset": 192,
         "length": 19
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "1813",
        "type": "GeneOrGeneProduct"
       },
       "text": "D2 receptor",
       "locations": [
        {
         "offset": 247,
         "length": 11
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1813",
        "type": "GeneOrGeneProduct"
       },
       "text": "DRD2",
       "locations": [
        {
         "offset": 372,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenia",
       "locations": [
        {
         "offset": 414,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 428,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "1813",
        "type": "GeneOrGeneProduct"
       },
       "text": "DRD2",
       "locations": [
        {
         "offset": 562,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D002746",
        "type": "ChemicalEntity"
       },
       "text": "chlorpromazine",
       "locations": [
        {
         "offset": 576,
         "length": 14
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D001480",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "EPS",
       "locations": [
        {
         "offset": 599,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenic",
       "locations": [
        {
         "offset": 606,
         "length": 13
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 620,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|INDEL|0141|C",
        "type": "SequenceVariant"
       },
       "text": "-141Cins>del",
       "locations": [
        {
         "offset": 696,
         "length": 12
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|SUB|S|311|C",
        "type": "SequenceVariant"
       },
       "text": "Ser311Cys",
       "locations": [
        {
         "offset": 724,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs6275",
        "type": "SequenceVariant"
       },
       "text": "rs6275",
       "locations": [
        {
         "offset": 735,
         "length": 6
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "rs6277",
        "type": "SequenceVariant"
       },
       "text": "rs6277",
       "locations": [
        {
         "offset": 743,
         "length": 6
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "1813",
        "type": "GeneOrGeneProduct"
       },
       "text": "DRD2",
       "locations": [
        {
         "offset": 768,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenic",
       "locations": [
        {
         "offset": 785,
         "length": 13
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "inpatients",
       "locations": [
        {
         "offset": 799,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D001480",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "EPS",
       "locations": [
        {
         "offset": 819,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D001480",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "EPS",
       "locations": [
        {
         "offset": 838,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "D002746",
        "type": "ChemicalEntity"
       },
       "text": "chlorpromazine",
       "locations": [
        {
         "offset": 893,
         "length": 14
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "c|SUB|S|311|C",
        "type": "SequenceVariant"
       },
       "text": "Ser311Cys",
       "locations": [
        {
         "offset": 1029,
         "length": 9
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs6277",
        "type": "SequenceVariant"
       },
       "text": "rs6277",
       "locations": [
        {
         "offset": 1043,
         "length": 6
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "c|INDEL|0141|C",
        "type": "SequenceVariant"
       },
       "text": "-141Cins>del",
       "locations": [
        {
         "offset": 1189,
         "length": 12
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "rs6275",
        "type": "SequenceVariant"
       },
       "text": "rs6275",
       "locations": [
        {
         "offset": 1210,
         "length": 6
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "rs6275",
        "type": "SequenceVariant"
       },
       "text": "rs6275",
       "locations": [
        {
         "offset": 1281,
         "length": 6
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "1813",
        "type": "GeneOrGeneProduct"
       },
       "text": "DRD2",
       "locations": [
        {
         "offset": 1447,
         "length": 4
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D002746",
        "type": "ChemicalEntity"
       },
       "text": "chlorpromazine",
       "locations": [
        {
         "offset": 1531,
         "length": 14
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1567,
         "length": 8
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D012559",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "schizophrenia",
       "locations": [
        {
         "offset": 1581,
         "length": 13
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "1813",
        "type": "GeneOrGeneProduct"
       },
       "text": "DRD2",
       "locations": [
        {
         "offset": 1663,
         "length": 4
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D001480",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "EPS",
       "locations": [
        {
         "offset": 1672,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1813",
      "entity2": "D012559",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D014150",
      "entity2": "1813",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D012559",
      "entity2": "D002746",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D001480",
      "entity2": "1813",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D001480",
      "entity2": "D014150",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D002746",
      "entity2": "D001480",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "17549393",
   "passages": [
    {
     "offset": 0,
     "text": "A novel IRF6 nonsense mutation (Y67X) in a German family with Van der Woude syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 8,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "p|SUB|Y|67|X",
        "type": "SequenceVariant"
       },
       "text": "Y67X",
       "locations": [
        {
         "offset": 32,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C536528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Van der Woude syndrome",
       "locations": [
        {
         "offset": 62,
         "length": 22
        }
       ]
      }
     ]
    },
    {
     "offset": 86,
     "text": "Van der Woude syndrome (VWS) is the most common type of syndromic orofacial cleft, which accounts for approximately 2% of all cleft lip and palate cases. It is characterised by variable association of lower lip pits, cleft lip and cleft palate, and hypodontia. VWS arises as the result of mutations in the gene encoding interferon regulatory factor 6 (IRF6). The disorder is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Very recently, mutations of the IRF6 gene in exons 2-9 have been found in VWS patients, suggesting that this gene plays an important role in orofacial development. We report a novel mutation of the IRF6 gene in a German family. Five out of the 12 persons affected were able to be investigated. The mutation produced a stop codon within exon 4 of the IRF6 gene. All 5 patients were heterozygous for a base substitution c.201C>A changing the tyrosine codon at amino acid position 67 into a stop codon (p.Y67X) in exon 4. The premature stop codon was responsible for a truncated protein lacking parts of the DNA- binding domain and the complete Smad-interferon regulatory factor-binding domain probably essential for interactions with the Smad transcription factors.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "C536528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Van der Woude syndrome",
       "locations": [
        {
         "offset": 86,
         "length": 22
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C536528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VWS",
       "locations": [
        {
         "offset": 110,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "syndromic orofacial cleft",
       "locations": [
        {
         "offset": 142,
         "length": 25
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D002971,D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cleft lip and palate",
       "locations": [
        {
         "offset": 212,
         "length": 20
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "C536528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lip pits",
       "locations": [
        {
         "offset": 293,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D002971",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cleft lip",
       "locations": [
        {
         "offset": 303,
         "length": 9
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D002972",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cleft palate",
       "locations": [
        {
         "offset": 317,
         "length": 12
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypodontia",
       "locations": [
        {
         "offset": 335,
         "length": 10
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C536528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VWS",
       "locations": [
        {
         "offset": 347,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "interferon regulatory factor 6",
       "locations": [
        {
         "offset": 406,
         "length": 30
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 438,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 586,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "C536528",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VWS",
       "locations": [
        {
         "offset": 628,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 632,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 752,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "IRF6",
       "locations": [
        {
         "offset": 904,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 921,
         "length": 8
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|SUB|C|201|A",
        "type": "SequenceVariant"
       },
       "text": "c.201C>A",
       "locations": [
        {
         "offset": 972,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "p|SUB|Y|67|X",
        "type": "SequenceVariant"
       },
       "text": "tyrosine codon at amino acid position 67 into a stop",
       "locations": [
        {
         "offset": 994,
         "length": 52
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "p|SUB|Y|67|X",
        "type": "SequenceVariant"
       },
       "text": "p.Y67X",
       "locations": [
        {
         "offset": 1054,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "4086",
        "type": "GeneOrGeneProduct"
       },
       "text": "Smad",
       "locations": [
        {
         "offset": 1196,
         "length": 4
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "3664",
        "type": "GeneOrGeneProduct"
       },
       "text": "interferon regulatory factor",
       "locations": [
        {
         "offset": 1201,
         "length": 28
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "4086",
        "type": "GeneOrGeneProduct"
       },
       "text": "Smad",
       "locations": [
        {
         "offset": 1290,
         "length": 4
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "3664",
      "entity2": "4086",
      "type": "Bind",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "3664",
      "entity2": "C536528",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "C536528",
      "entity2": "c|SUB|C|201|A",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "p|SUB|Y|67|X",
      "entity2": "C536528",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17962394",
   "passages": [
    {
     "offset": 0,
     "text": "Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C580539",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X linked nystagmus",
       "locations": [
        {
         "offset": 28,
         "length": 18
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs137852212",
        "type": "SequenceVariant"
       },
       "text": "p.R229G",
       "locations": [
        {
         "offset": 77,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "90167",
        "type": "GeneOrGeneProduct"
       },
       "text": "FRMD7",
       "locations": [
        {
         "offset": 111,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 123,
     "text": "AIMS: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. METHODS: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. RESULTS: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. CONCLUSIONS: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "genetic defect",
       "locations": [
        {
         "offset": 173,
         "length": 14
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C580539",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X linked nystagmus",
       "locations": [
        {
         "offset": 207,
         "length": 18
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C580539",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NYS",
       "locations": [
        {
         "offset": 227,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "90167",
        "type": "GeneOrGeneProduct"
       },
       "text": "FRMD7",
       "locations": [
        {
         "offset": 352,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "c|DUP||CAG|",
        "type": "SequenceVariant"
       },
       "text": "CAG repeat",
       "locations": [
        {
         "offset": 553,
         "length": 10
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "367",
        "type": "GeneOrGeneProduct"
       },
       "text": "androgen receptor",
       "locations": [
        {
         "offset": 571,
         "length": 17
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "C580539",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NYS",
       "locations": [
        {
         "offset": 660,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "rs137852212",
        "type": "SequenceVariant"
       },
       "text": "c.686C>G",
       "locations": [
        {
         "offset": 725,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs137852212",
        "type": "SequenceVariant"
       },
       "text": "arginine at amino acid position 229 by glycine",
       "locations": [
        {
         "offset": 789,
         "length": 46
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs137852212",
        "type": "SequenceVariant"
       },
       "text": "p.R229G",
       "locations": [
        {
         "offset": 837,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "90167",
        "type": "GeneOrGeneProduct"
       },
       "text": "FRMD7",
       "locations": [
        {
         "offset": 863,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs137852212",
        "type": "SequenceVariant"
       },
       "text": "p.R229G",
       "locations": [
        {
         "offset": 1179,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "90167",
        "type": "GeneOrGeneProduct"
       },
       "text": "FRMD7",
       "locations": [
        {
         "offset": 1203,
         "length": 5
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "C580539",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NYS",
       "locations": [
        {
         "offset": 1225,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C580539",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X linked NYS",
       "locations": [
        {
         "offset": 1313,
         "length": 12
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "C580539",
      "entity2": "90167",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "C580539",
      "entity2": "rs137852212",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "18046082",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apolipoprotein E",
       "locations": [
        {
         "offset": 18,
         "length": 16
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "p|SUB|R|150|P",
        "type": "SequenceVariant"
       },
       "text": "arginine 150 proline",
       "locations": [
        {
         "offset": 46,
         "length": 20
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lipoprotein glomerulopathy",
       "locations": [
        {
         "offset": 99,
         "length": 26
        }
       ]
      }
     ]
    },
    {
     "offset": 127,
     "text": "BACKGROUND/AIMS: Lipoprotein glomerulopathy (LPG) is a rare disease characterized by thrombus-like substances in markedly dilated glomerular capillaries and elevated plasma levels of apolipoprotein E (apoE). Previous studies have shown that genetic disorders of apoE may contribute to the pathogenesis of LPG, but LPG may not be caused by apoE gene mutations in Chinese patients. This study investigated the association of a new variant of apoE with LPG in a Chinese family. METHODS: The apoE gene in a family with 4 LPG patients was sequenced. The polymerase chain reaction product of coding region of apoE exon 4 was cloned into pMD 18-T vector and then sequenced. RESULTS: A novel point mutation in exon 4 of the apoE gene was identified in all 4 LPG patients and 1 asymptomatic family member. Sequence analysis confirmed a nucleotide G to C point mutation in exon 4 (base 308) of the apoE gene in all patients and the asymptomatic family member. This missense mutation denotes amino acid substitution of the proline residue for arginine residue at position 150 of apoE. Those patients were all heterozygotes with apoE Guangzhou. One of 2 grandsons was a heterozygous carrier of apoE Guangzhou, although he did not have proteinuria. CONCLUSION: The results of this study suggest that apoE (arginine 150 proline) is a novel apoE variant that etiologically related to LPG. This variant (apoE Guangzhou) may cause a marked molecular conformational change of the apoE and thus impair its binding ability to lipids.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Lipoprotein glomerulopathy",
       "locations": [
        {
         "offset": 144,
         "length": 26
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 172,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D013927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "thrombus",
       "locations": [
        {
         "offset": 212,
         "length": 8
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dilated glomerular capillaries",
       "locations": [
        {
         "offset": 249,
         "length": 30
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apolipoprotein E",
       "locations": [
        {
         "offset": 310,
         "length": 16
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 328,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 389,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 432,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 441,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 466,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 497,
         "length": 8
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 567,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 577,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 615,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 644,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 648,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 730,
         "length": 4
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 843,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 877,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 881,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "c|SUB|G|308|C",
        "type": "SequenceVariant"
       },
       "text": "G to C point mutation in exon 4 (base 308)",
       "locations": [
        {
         "offset": 965,
         "length": 42
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1015,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1032,
         "length": 8
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "p|SUB|R|150|P",
        "type": "SequenceVariant"
       },
       "text": "proline residue for arginine residue at position 150",
       "locations": [
        {
         "offset": 1139,
         "length": 52
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1195,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1207,
         "length": 8
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1244,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1309,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D011507",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "proteinuria",
       "locations": [
        {
         "offset": 1350,
         "length": 11
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
        {
         "offset": 1414,
         "length": 4
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "p|SUB|R|150|P",
        "type": "SequenceVariant"
       },
       "text": "arginine 150 proline",
       "locations": [
        {
         "offset": 1420,
         "length": 20
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
       },
       "text": "apoE",
       "locations": [
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         "offset": 1453,
         "length": 4
        }
       ]
      },
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       "id": "35",
       "infons": {
        "identifier": "C567089",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LPG",
       "locations": [
        {
         "offset": 1496,
         "length": 3
        }
       ]
      },
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       "id": "36",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
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       "text": "apoE",
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         "offset": 1515,
         "length": 4
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       ]
      },
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       "id": "37",
       "infons": {
        "identifier": "348",
        "type": "GeneOrGeneProduct"
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       "text": "apoE",
       "locations": [
        {
         "offset": 1589,
         "length": 4
        }
       ]
      },
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       "id": "38",
       "infons": {
        "identifier": "D008055",
        "type": "ChemicalEntity"
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       "text": "lipids",
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         "offset": 1633,
         "length": 6
        }
       ]
      }
     ]
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   ],
   "relations": [
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     "infons": {
      "entity1": "c|SUB|G|308|C",
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    }
   ]
  },
  {
   "id": "21054465",
   "passages": [
    {
     "offset": 0,
     "text": "Mutational analysis of CYP2C8 in hypertensive patients using denaturing high performance liquid chromatography.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1558",
        "type": "GeneOrGeneProduct"
       },
       "text": "CYP2C8",
       "locations": [
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         "length": 6
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertensive",
       "locations": [
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         "offset": 33,
         "length": 12
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 46,
         "length": 8
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       ]
      }
     ]
    },
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     "offset": 112,
     "text": "WHAT IS KNOWN AND OBJECTIVE: CYP2C8 is involved in the cytochrome P450 (CYP) epoxygenase pathway. Arachidonic acid metabolites such as epoxyeicosatrienenoic acids and hydroxyeicosatetrenoic acids, produced may have a role in hypertension. We aimed to develop a medium through-put method for screening samples of known and new mutations of CYP2C8 using denaturing high performance liquid chromatography (DHPLC). METHODS: DNA samples from 200 subjects (hypertensive patients and healthy controls) were screened for SNPs in CYP2C8 using DHPLC. Genotypes and allelic frequencies of CYP2C8 between the healthy controls and patients with hypertension were compared. RESULTS AND DISCUSSIONS: Six variants were detected and two were new; T deletion at 5063 and substitution of C to T at 33468 in exon 8. Differences in variant frequencies were detected between the controls and hypertensive patients. The controls have significantly higher prevalence of C35322C compared to the patients. The functional significance of the SNP at 35322 requires further study. Having homozygous C35322C could be a protective factor for hypertension. WHAT IS NEW AND CONCLUSION: Denaturing high performance liquid chromatography is useful for population screening to identify new and existing SNPs. A higher frequency of the C35322T SNP was observed among hypertensive patients than control subjects. This potentially important observation requires confirmation and the clinical significance assessed.",
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       "id": "3",
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       "text": "CYP2C8",
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       "text": "cytochrome P450 (CYP) epoxygenase",
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       "text": "Arachidonic acid",
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       "id": "6",
       "infons": {
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       "text": "epoxyeicosatrienenoic acids",
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         "offset": 247,
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       "id": "7",
       "infons": {
        "identifier": "-",
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       "text": "hydroxyeicosatetrenoic acids",
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         "offset": 279,
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       ]
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       "id": "8",
       "infons": {
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       "text": "hypertension",
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       ]
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       "id": "9",
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       "id": "10",
       "infons": {
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       "text": "hypertensive",
       "locations": [
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         "offset": 563,
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       ]
      },
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       "id": "11",
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       "text": "patients",
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       "id": "13",
       "infons": {
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       "text": "CYP2C8",
       "locations": [
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         "length": 6
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       ]
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       "id": "14",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 730,
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       ]
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       "id": "15",
       "infons": {
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       "text": "hypertension",
       "locations": [
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         "offset": 744,
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       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "c|DEL|5063|T",
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       "text": "T deletion at 5063",
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         "offset": 842,
         "length": 18
        }
       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "c|SUB|C|33468|T",
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       "text": "C to T at 33468",
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       ]
      },
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       "id": "18",
       "infons": {
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       "text": "hypertensive",
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       "id": "19",
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       "text": "patients",
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       "id": "20",
       "infons": {
        "identifier": "c|SUB|C|35322|C",
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       "id": "21",
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       "text": "patients",
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       "id": "22",
       "infons": {
        "identifier": "c|SUB|C|35322|C",
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       "text": "C35322C",
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         "length": 7
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       "id": "23",
       "infons": {
        "identifier": "D006973",
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       "text": "hypertension",
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        {
         "offset": 1223,
         "length": 12
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       "id": "24",
       "infons": {
        "identifier": "c|SUB|C|35322|T",
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       "text": "C35322T",
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       "id": "25",
       "infons": {
        "identifier": "D006973",
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       "text": "hypertensive",
       "locations": [
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         "offset": 1442,
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       "id": "26",
       "infons": {
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       "text": "patients",
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  },
  {
   "id": "22711886",
   "passages": [
    {
     "offset": 0,
     "text": "TNFR-associated factor 2 deficiency in B lymphocytes predisposes to chronic lymphocytic leukemia/small lymphocytic lymphoma in mice.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "22030",
        "type": "GeneOrGeneProduct"
       },
       "text": "TNFR-associated factor 2",
       "locations": [
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      },
      {
       "id": "1",
       "infons": {
        "identifier": "D015451",
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       "text": "chronic lymphocytic leukemia",
       "locations": [
        {
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         "length": 28
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D015451",
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       "text": "small lymphocytic lymphoma",
       "locations": [
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       ]
      },
      {
       "id": "3",
       "infons": {
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       "text": "mice",
       "locations": [
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         "offset": 127,
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     ]
    },
    {
     "offset": 133,
     "text": "We have previously shown that transgenic (tg) mice expressing in B lymphocytes both BCL-2 and a TNFR-associated factor 2 (TRAF2) mutant lacking the really interesting new gene and zinc finger domains (TRAF2DN) develop small lymphocytic lymphoma and chronic lymphocytic leukemia with high incidence (Zapata et al. 2004. Proc. Nat. Acad. Sci. USA 101: 16600-16605). Further analysis of the expression of TRAF2 and TRAF2DN in purified B cells demonstrated that expression of both endogenous TRAF2 and tg TRAF2DN was negligible in Traf2DN-tg B cells compared with wild-type mice. This was the result of proteasome-dependent degradation, and rendered TRAF2DN B cells as bona fide TRAF2-deficient B cells. Similar to B cells with targeted Traf2 deletion, Traf2DN-tg mice show expanded marginal zone B cell population and have constitutive p100 NF-kappaB2 processing. Also, TRAF3, X-linked inhibitor of apoptosis, and Bcl-X(L) expression levels were increased, whereas cellular inhibitors of apoptosis 1 and 2 levels were drastically reduced compared with those found in wild-type B cells. Moreover, consistent with previous results, we also show that TRAF2 was required for efficient JNK and ERK activation in response to CD40 engagement. However, TRAF2 was deleterious for BCR-mediated activation of these kinases. In contrast, TRAF2 deficiency had no effect on CD40-mediated p38 MAPK activation but significantly reduced BCR-mediated p38 activation. Finally, we further confirm that TRAF2 was required for CD40-mediated proliferation, but its absence relieved B cells of the need for B cell activating factor for survival. Altogether, our results suggest that TRAF2 deficiency cooperates with BCL-2 in promoting chronic lymphocytic leukemia/small lymphocytic lymphoma in mice, possibly by specifically enforcing marginal zone B cell accumulation, increasing X-linked inhibitor of apoptosis expression, and rendering B cells independent of B cell activating factor for survival.",
     "annotations": [
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       "id": "4",
       "infons": {
        "identifier": "10090",
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       "text": "mice",
       "locations": [
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         "offset": 179,
         "length": 4
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       ]
      },
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       "id": "5",
       "infons": {
        "identifier": "596",
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       "text": "BCL-2",
       "locations": [
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         "offset": 217,
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       ]
      },
      {
       "id": "6",
       "infons": {
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       "text": "TNFR-associated factor 2",
       "locations": [
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      },
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       "id": "7",
       "infons": {
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       "text": "TRAF2",
       "locations": [
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         "offset": 255,
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D015451",
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       "text": "small lymphocytic lymphoma",
       "locations": [
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D015451",
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       "text": "chronic lymphocytic leukemia",
       "locations": [
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       ]
      },
      {
       "id": "10",
       "infons": {
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       "text": "TRAF2",
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       "id": "11",
       "infons": {
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       "text": "TRAF2",
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        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "CVCL_TT54",
        "type": "CellLine"
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       "text": "Traf2DN-tg B",
       "locations": [
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         "offset": 660,
         "length": 12
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "10090",
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       "text": "mice",
       "locations": [
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       ]
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       "id": "14",
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       "text": "proteasome",
       "locations": [
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       ]
      },
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       "id": "15",
       "infons": {
        "identifier": "22030",
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       "text": "TRAF2",
       "locations": [
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         "offset": 808,
         "length": 5
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       "id": "16",
       "infons": {
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       "text": "Traf2",
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      },
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       "id": "17",
       "infons": {
        "identifier": "CVCL_TT54",
        "type": "CellLine"
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       "text": "Traf2DN-tg",
       "locations": [
        {
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         "length": 10
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       ]
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       "id": "18",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "mice",
       "locations": [
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         "offset": 893,
         "length": 4
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       ]
      },
      {
       "id": "19",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "p100 NF-kappaB2",
       "locations": [
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         "offset": 966,
         "length": 15
        }
       ]
      },
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       "id": "20",
       "infons": {
        "identifier": "22031",
        "type": "GeneOrGeneProduct"
       },
       "text": "TRAF3",
       "locations": [
        {
         "offset": 1000,
         "length": 5
        }
       ]
      },
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       "id": "21",
       "infons": {
        "identifier": "11798",
        "type": "GeneOrGeneProduct"
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       "text": "X-linked inhibitor of apoptosis",
       "locations": [
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         "offset": 1007,
         "length": 31
        }
       ]
      },
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       "id": "22",
       "infons": {
        "identifier": "12048",
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       "text": "Bcl-X(L)",
       "locations": [
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         "length": 8
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "11796,11797",
        "type": "GeneOrGeneProduct"
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       "text": "cellular inhibitors of apoptosis 1 and 2",
       "locations": [
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         "offset": 1095,
         "length": 40
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "22030",
        "type": "GeneOrGeneProduct"
       },
       "text": "TRAF2",
       "locations": [
        {
         "offset": 1278,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "26419",
        "type": "GeneOrGeneProduct"
       },
       "text": "JNK",
       "locations": [
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         "offset": 1311,
         "length": 3
        }
       ]
      },
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       "id": "26",
       "infons": {
        "identifier": "26413",
        "type": "GeneOrGeneProduct"
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       "text": "ERK",
       "locations": [
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         "offset": 1319,
         "length": 3
        }
       ]
      },
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       "id": "27",
       "infons": {
        "identifier": "21939",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD40",
       "locations": [
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         "offset": 1349,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "22030",
        "type": "GeneOrGeneProduct"
       },
       "text": "TRAF2",
       "locations": [
        {
         "offset": 1375,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "12518",
        "type": "GeneOrGeneProduct"
       },
       "text": "BCR",
       "locations": [
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         "offset": 1401,
         "length": 3
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "22030",
        "type": "GeneOrGeneProduct"
       },
       "text": "TRAF2",
       "locations": [
        {
         "offset": 1456,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "21939",
        "type": "GeneOrGeneProduct"
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       "text": "CD40",
       "locations": [
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         "offset": 1490,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
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       },
       "text": "p38 MAPK",
       "locations": [
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     "text": "Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by betaine attenuates isoproterenol-induced acute myocardial injury in rats.",
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     "text": "The present study was designed to investigate the cardioprotective effects of betaine on acute myocardial ischemia induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 (STAT3) and apoptotic pathways as the potential mechanism underlying the drug effect. Male Sprague Dawley rats were treated with betaine (100, 200, and 400 mg/kg) orally for 40 days. Acute myocardial ischemic injury was induced in rats by subcutaneous injection of isoproterenol (85 mg/kg), for two consecutive days. Serum cardiac marker enzyme, histopathological variables and expression of protein levels were analyzed. Oral administration of betaine (200 and 400 mg/kg) significantly reduced the level of cardiac marker enzyme in the serum and prevented left ventricular remodeling. Western blot analysis showed that isoproterenol-induced phosphorylation of STAT3 was maintained or further enhanced by betaine treatment in myocardium. Furthermore, betaine (200 and 400 mg/kg) treatment increased the ventricular expression of Bcl-2 and reduced the level of Bax, therefore causing a significant increase in the ratio of Bcl-2/Bax. The protective role of betaine on myocardial damage was further confirmed by histopathological examination. In summary, our results showed that betaine pretreatment attenuated isoproterenol-induced acute myocardial ischemia via the regulation of STAT3 and apoptotic pathways.",
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       "text": "colon cancer",
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         "offset": 2121,
         "length": 12
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       ]
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   "id": "27840894",
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    {
     "offset": 0,
     "text": "Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5251",
        "type": "GeneOrGeneProduct"
       },
       "text": "PHEX",
       "locations": [
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         "offset": 28,
         "length": 4
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       "id": "1",
       "infons": {
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       "id": "2",
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        "identifier": "D063730",
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       "text": "hypophosphatemic rickets",
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     "offset": 91,
     "text": "Inactivating mutations in phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) have been identified as a cause of X-linked hypophosphatemic rickets (XLH; OMIM 307800). In the present study, we enrolled 43 patients from 18 unrelated families clinically diagnosed with hypophosphatemic rickets and 250 healthy controls. For each available individual, all 22 exons with their exon-intron boundaries of the PHEX gene were directly sequenced. The levels of serum fibroblast growth factor 23 (FGF23) were measured as well. Sequencing analysis detected 17 different PHEX gene mutations, and 7 of these were identified as novel: 3 missense mutations, including c.304G>A (p.Gly102Arg) in exon 3, c.229T>C (p.Cys77Arg) in exon 3 and c.824T>C (p.Leu275Pro) in exon 7; 2 deletion mutations, including c.528delT (p.Glu177LysfsX44) in exon 5 and c.1234delA (p.Ser412ValfsX12) in exon 11; and 2 alternative splicing mutations, including c.436_436+1delAG in intron 4 at splicing donor sites and c.1483-1G>C in intron 13 at splicing acceptor sites. Moreover, 6 mutations were proven to be de novo in 6 sporadic cases and the probands were all females. No mutations were found in the 250 healthy controls. The serum levels of FGF23 varied widely among the patients with XLH, and no significant difference was found when compared with those of the healthy controls. On the whole, the findings of this study provide new insight into the spectrum of PHEX mutations and provide potential evidence of a critical domain in PHEX protein. In addition, the finding of an overlap of the serum FGF23 levels between the patients with XLH and the healthy controls indicates its limited diagnostic value in XLH.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "5251",
        "type": "GeneOrGeneProduct"
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       "text": "phosphate-regulating gene with homologies to endopeptidase on the X chromosome",
       "locations": [
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         "offset": 117,
         "length": 78
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "5251",
        "type": "GeneOrGeneProduct"
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       "text": "PHEX",
       "locations": [
        {
         "offset": 197,
         "length": 4
        }
       ]
      },
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       "id": "5",
       "infons": {
        "identifier": "D053098",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "X-linked hypophosphatemic rickets",
       "locations": [
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         "offset": 238,
         "length": 33
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       ]
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       "id": "6",
       "infons": {
        "identifier": "D053098",
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       "text": "XLH",
       "locations": [
        {
         "offset": 273,
         "length": 3
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       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "D053098",
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       "text": "OMIM 307800",
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        {
         "offset": 278,
         "length": 11
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       ]
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       "id": "8",
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       "text": "patients",
       "locations": [
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         "offset": 329,
         "length": 8
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       ]
      },
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       "id": "9",
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        "identifier": "D063730",
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       "text": "hypophosphatemic rickets",
       "locations": [
        {
         "offset": 391,
         "length": 24
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "5251",
        "type": "GeneOrGeneProduct"
       },
       "text": "PHEX",
       "locations": [
        {
         "offset": 527,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "8074",
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       "text": "fibroblast growth factor 23",
       "locations": [
        {
         "offset": 582,
         "length": 27
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       "id": "12",
       "infons": {
        "identifier": "8074",
        "type": "GeneOrGeneProduct"
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       "text": "FGF23",
       "locations": [
        {
         "offset": 611,
         "length": 5
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "5251",
        "type": "GeneOrGeneProduct"
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       "text": "PHEX",
       "locations": [
        {
         "offset": 683,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|SUB|G|304|A",
        "type": "SequenceVariant"
       },
       "text": "c.304G>A",
       "locations": [
        {
         "offset": 777,
         "length": 8
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "p|SUB|G|102|R",
        "type": "SequenceVariant"
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       "text": "p.Gly102Arg",
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        {
         "offset": 787,
         "length": 11
        }
       ]
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       "id": "16",
       "infons": {
        "identifier": "c|SUB|T|229|C",
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       "text": "c.229T>C",
       "locations": [
        {
         "offset": 811,
         "length": 8
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       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "p|SUB|C|77|R",
        "type": "SequenceVariant"
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       "text": "p.Cys77Arg",
       "locations": [
        {
         "offset": 821,
         "length": 10
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|SUB|T|284|C",
        "type": "SequenceVariant"
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       "text": "c.824T>C",
       "locations": [
        {
         "offset": 847,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "p|SUB|L|275|P",
        "type": "SequenceVariant"
       },
       "text": "p.Leu275Pro",
       "locations": [
        {
         "offset": 857,
         "length": 11
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|DEL|528|T",
        "type": "SequenceVariant"
       },
       "text": "c.528delT",
       "locations": [
        {
         "offset": 913,
         "length": 9
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "p|SUB|E|177|K|44",
        "type": "SequenceVariant"
       },
       "text": "p.Glu177LysfsX44",
       "locations": [
        {
         "offset": 924,
         "length": 16
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       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "c|DEL|1234|A",
        "type": "SequenceVariant"
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       "text": "c.1234delA",
       "locations": [
        {
         "offset": 956,
         "length": 10
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       "id": "23",
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        "identifier": "p|SUB|S|412|V|12",
        "type": "SequenceVariant"
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       "text": "p.Ser412ValfsX12",
       "locations": [
        {
         "offset": 968,
         "length": 16
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      {
       "id": "24",
       "infons": {
        "identifier": "c|DEL|436_436+1|AG",
        "type": "SequenceVariant"
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       "text": "c.436_436+1delAG",
       "locations": [
        {
         "offset": 1046,
         "length": 16
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      },
      {
       "id": "25",
       "infons": {
        "identifier": "c|SUB|G|1483-1|C",
        "type": "SequenceVariant"
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       "text": "c.1483-1G>C",
       "locations": [
        {
         "offset": 1103,
         "length": 11
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "8074",
        "type": "GeneOrGeneProduct"
       },
       "text": "FGF23",
       "locations": [
        {
         "offset": 1332,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1362,
         "length": 8
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D053098",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "XLH",
       "locations": [
        {
         "offset": 1376,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "5251",
        "type": "GeneOrGeneProduct"
       },
       "text": "PHEX",
       "locations": [
        {
         "offset": 1553,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "5251",
        "type": "GeneOrGeneProduct"
       },
       "text": "PHEX",
       "locations": [
        {
         "offset": 1623,
         "length": 4
        }
       ]
      },
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       "id": "31",
       "infons": {
        "identifier": "8074",
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       "text": "FGF23",
       "locations": [
        {
         "offset": 1689,
         "length": 5
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       ]
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       "id": "32",
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        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1714,
         "length": 8
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       "id": "33",
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        "identifier": "D053098",
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       "text": "XLH",
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        {
         "offset": 1728,
         "length": 3
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       "id": "34",
       "infons": {
        "identifier": "D053098",
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       "text": "XLH",
       "locations": [
        {
         "offset": 1799,
         "length": 3
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    {
     "offset": 0,
     "text": "Localisation of the Becker muscular dystrophy gene on the short arm of the X chromosome by linkage to cloned DNA sequences.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1756",
        "type": "GeneOrGeneProduct"
       },
       "text": "Becker muscular dystrophy gene",
       "locations": [
        {
         "offset": 20,
         "length": 30
        }
       ]
      }
     ]
    },
    {
     "offset": 124,
     "text": "A linkage study in 30 Becker muscular dystrophy (BMD) kindreds using three cloned DNA sequences from the X chromosome which demonstrate restriction fragment length polymorphisms (RFLPs), suggests that the BMD gene is located on the short arm of the X chromosome, in the p21 region. The genes for Becker and Duchenne dystrophies must therefore be closely linked, if not allelic, and any future DNA probes found to be of practical use in one disorder should be equally applicable to the other. The linkage analysis also provides data on the frequency of recombination along the short arm of the X chromosome, and across the centromeric region.. ",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "D020388",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Becker muscular dystrophy",
       "locations": [
        {
         "offset": 146,
         "length": 25
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D020388",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "BMD",
       "locations": [
        {
         "offset": 173,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "1756",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMD",
       "locations": [
        {
         "offset": 329,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D020388",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Becker and Duchenne dystrophies",
       "locations": [
        {
         "offset": 420,
         "length": 31
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "1756",
      "entity2": "D020388",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "7811247",
   "passages": [
    {
     "offset": 0,
     "text": "X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "X-linked adrenoleukodystrophy",
       "locations": [
        {
         "offset": 0,
         "length": 29
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 31,
         "length": 3
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "215",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 61,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 135,
     "text": "Fragments of the adrenoleukodystrophy (ALD) cDNA from a patient with adolescent ALD were amplified by polymerase chain reaction and subcloned. Bidirectional sequencing of the entire coding ALD gene disclosed a cytosine to guanine transversion at nucleotide 1451 in exon five, resulting in substitution of proline 484 by arginine. Five of nine siblings of the patient, comprising two cerebral ALD, one adrenomyeloneuropathy, one Addison only as well as the symptomatic mother (all accumulating very long chain fatty acids) carried this mutation, which was not found in the unaffected persons, in five unrelated ALD patients, and in twenty controls. We propose that this missense mutation generated the disease per se as well as the metabolic defect; the different phenotypes, however, must have originated by means of additional pathogenetic factors.. ",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "adrenoleukodystrophy",
       "locations": [
        {
         "offset": 152,
         "length": 20
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 174,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 191,
         "length": 7
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 215,
         "length": 3
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "215",
        "type": "GeneOrGeneProduct"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 324,
         "length": 3
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "rs128624214",
        "type": "SequenceVariant"
       },
       "text": "cytosine to guanine transversion at nucleotide 1451",
       "locations": [
        {
         "offset": 345,
         "length": 51
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "rs128624214",
        "type": "SequenceVariant"
       },
       "text": "proline 484 by arginine",
       "locations": [
        {
         "offset": 440,
         "length": 23
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 494,
         "length": 7
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 527,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "adrenomyeloneuropathy",
       "locations": [
        {
         "offset": 536,
         "length": 21
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D000224",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Addison",
       "locations": [
        {
         "offset": 563,
         "length": 7
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D005227",
        "type": "ChemicalEntity"
       },
       "text": "long chain fatty acids",
       "locations": [
        {
         "offset": 633,
         "length": 22
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000326",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ALD",
       "locations": [
        {
         "offset": 745,
         "length": 3
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 749,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "215",
      "entity2": "D000224",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D000326",
      "entity2": "215",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs128624214",
      "entity2": "D000326",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs128624214",
      "entity2": "D000224",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "8944024",
   "passages": [
    {
     "offset": 0,
     "text": "Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence analysis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 39,
         "length": 5
        }
       ]
      }
     ]
    },
    {
     "offset": 125,
     "text": "The ability to scan a large gene rapidly and accurately for all possible heterozygous mutations in large numbers of patient samples will be critical for the future of medicine. We have designed high-density arrays consisting of over 96, 600 oligonucleotides 20-nucleotides (nt) in length to screen for a wide range of heterozygous mutations in the 3. 45-kilobases (kb) exon 11 of the hereditary breast and ovarian cancer gene BRCA1. Reference and test samples were co-hybridized to these arrays and differences in hybridization patterns quantitated by two-colour analysis. Fourteen of fifteen patient samples with known mutations were accurately diagnosed, and no false positive mutations were identified in 20 control samples. Eight single nucleotide polymorphisms were also readily detected. DNA chip-based assays may provide a valuable new technology for high-throughput cost-efficient detection of genetic alterations. ",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 241,
         "length": 7
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "breast and ovarian cancer gene",
       "locations": [
        {
         "offset": 520,
         "length": 30
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "672",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRCA1",
       "locations": [
        {
         "offset": 551,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 718,
         "length": 7
        }
       ]
      }
     ]
    }
   ],
   "relations": []
  },
  {
   "id": "16838170",
   "passages": [
    {
     "offset": 0,
     "text": "Single nucleotide polymorphisms of the HNF4alpha gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3172",
        "type": "GeneOrGeneProduct"
       },
       "text": "HNF4alpha",
       "locations": [
        {
         "offset": 39,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2 diabetes mellitus",
       "locations": [
        {
         "offset": 92,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 140,
     "text": "Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "3172",
        "type": "GeneOrGeneProduct"
       },
       "text": "Hepatocyte nuclear factor 4alpha",
       "locations": [
        {
         "offset": 140,
         "length": 32
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "3172",
        "type": "GeneOrGeneProduct"
       },
       "text": "HNF4alpha",
       "locations": [
        {
         "offset": 174,
         "length": 9
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 254,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "3172",
        "type": "GeneOrGeneProduct"
       },
       "text": "HNF4A",
       "locations": [
        {
         "offset": 355,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3172",
        "type": "GeneOrGeneProduct"
       },
       "text": "HNF4alpha",
       "locations": [
        {
         "offset": 371,
         "length": 9
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D018149",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "impaired glucose tolerance",
       "locations": [
        {
         "offset": 413,
         "length": 26
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D018149",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "IGT",
       "locations": [
        {
         "offset": 441,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2 diabetes mellitus",
       "locations": [
        {
         "offset": 449,
         "length": 24
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D020909",
        "type": "ChemicalEntity"
       },
       "text": "acarbose",
       "locations": [
        {
         "offset": 556,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2 diabetes mellitus",
       "locations": [
        {
         "offset": 606,
         "length": 24
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "3172",
        "type": "GeneOrGeneProduct"
       },
       "text": "HNF4A",
       "locations": [
        {
         "offset": 704,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs4810424",
        "type": "SequenceVariant"
       },
       "text": "rs4810424",
       "locations": [
        {
         "offset": 828,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "rs1884614",
        "type": "SequenceVariant"
       },
       "text": "rs1884614",
       "locations": [
        {
         "offset": 839,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "rs2144908",
        "type": "SequenceVariant"
       },
       "text": "rs2144908",
       "locations": [
        {
         "offset": 854,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs4810424",
        "type": "SequenceVariant"
       },
       "text": "rs4810424",
       "locations": [
        {
         "offset": 944,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs4810424",
        "type": "SequenceVariant"
       },
       "text": "rs4810424",
       "locations": [
        {
         "offset": 1037,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes",
       "locations": [
        {
         "offset": 1148,
         "length": 8
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1169,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D020909",
        "type": "ChemicalEntity"
       },
       "text": "acarbose",
       "locations": [
        {
         "offset": 1258,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 1345,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs4810424",
        "type": "SequenceVariant"
       },
       "text": "rs4810424",
       "locations": [
        {
         "offset": 1390,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "rs2071197",
        "type": "SequenceVariant"
       },
       "text": "rs2071197",
       "locations": [
        {
         "offset": 1401,
         "length": 9
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "rs3818247",
        "type": "SequenceVariant"
       },
       "text": "rs3818247",
       "locations": [
        {
         "offset": 1416,
         "length": 9
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2 diabetes mellitus",
       "locations": [
        {
         "offset": 1531,
         "length": 24
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1627,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "3172",
        "type": "GeneOrGeneProduct"
       },
       "text": "HNF4A",
       "locations": [
        {
         "offset": 1667,
         "length": 5
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D003924",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2 diabetes mellitus",
       "locations": [
        {
         "offset": 1708,
         "length": 24
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "rs2071197",
      "entity2": "rs3818247",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs4810424",
      "entity2": "rs3818247",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs4810424",
      "entity2": "rs2071197",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "rs4810424",
      "entity2": "D003920",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D003920",
      "entity2": "rs2144908",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D003920",
      "entity2": "rs1884614",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "rs2144908",
      "entity2": "D003924",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "rs1884614",
      "entity2": "D003924",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "D020909",
      "entity2": "D018149",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "D020909",
      "entity2": "D003924",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "D003924",
      "entity2": "rs3818247",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "D003924",
      "entity2": "rs2071197",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R12",
     "infons": {
      "entity1": "D003924",
      "entity2": "rs4810424",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R13",
     "infons": {
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      "entity2": "D003924",
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      "novel": "Novel"
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    }
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  {
   "id": "20801540",
   "passages": [
    {
     "offset": 0,
     "text": "Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D007501",
        "type": "ChemicalEntity"
       },
       "text": "iron",
       "locations": [
        {
         "offset": 22,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D000077588",
        "type": "ChemicalEntity"
       },
       "text": "deferasirox",
       "locations": [
        {
         "offset": 50,
         "length": 11
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C536004",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aceruloplasminemia",
       "locations": [
        {
         "offset": 65,
         "length": 18
        }
       ]
      }
     ]
    },
    {
     "offset": 114,
     "text": "BACKGROUND _#38; AIMS: Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders, retinal degeneration, and diabetes mellitus. Ceruloplasmin is a multi-copper ferroxidase that is secreted into plasma and facilitates cellular iron export and iron binding to transferrin. RESULTS: A novel homozygous ceruloplasmin gene mutation, c.2554+1G>T, was identified as the cause of aceruloplasminemia in three affected siblings. Two siblings presented with movement disorders and diabetes. Complementary DNA sequencing showed that this mutation causes skipping of exon 14 and deletion of amino acids 809-852 while preserving the open reading frame. Western blotting of liver extracts and sera of affected patients showed retention of the abnormal protein in the liver. Aceruloplasminemia was associated with severe brain and liver iron overload, where hepatic mRNA expression of the iron hormone hepcidin was increased, corresponding to the degree of iron overload. Hepatic iron concentration normalized after 3 and 5months of iron chelation therapy with deferasirox, which was also associated with reduced insulin demands. During short term treatment there was no clinical or imaging evidence for significant effects on brain iron overload. CONCLUSIONS: Aceruloplasminemia can show an incomplete clinical penetrance but is invariably associated with iron accumulation in the liver and in the brain. Iron accumulation in aceruloplasminemia is a result of defective cellular iron export, where hepcidin regulation is appropriate for the degree of iron overload. Iron chelation with deferasirox was effective in mobilizing hepatic iron but has no effect on brain iron.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "C536004",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "Aceruloplasminemia",
       "locations": [
        {
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         "length": 18
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       ]
      },
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       "id": "4",
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       "text": "autosomal recessive neurodegenerative disease",
       "locations": [
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         "offset": 166,
         "length": 45
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       "text": "iron",
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       "text": "movement disorders",
       "locations": [
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         "offset": 292,
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       ]
      },
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       "id": "7",
       "infons": {
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       "text": "retinal degeneration",
       "locations": [
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         "offset": 312,
         "length": 20
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       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "D003920",
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       "text": "diabetes mellitus",
       "locations": [
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         "offset": 338,
         "length": 17
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       ]
      },
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       "id": "9",
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       "id": "10",
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       "text": "ferroxidase",
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       ]
      },
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       "id": "11",
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       "text": "iron",
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       "text": "iron",
       "locations": [
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         "offset": 471,
         "length": 4
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       ]
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       "text": "transferrin",
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         "offset": 487,
         "length": 11
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       ]
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       "infons": {
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       "text": "ceruloplasmin",
       "locations": [
        {
         "offset": 528,
         "length": 13
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       ]
      },
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       "infons": {
        "identifier": "c|SUB|G|2554+1|T",
        "type": "SequenceVariant"
       },
       "text": "c.2554+1G>T",
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         "offset": 557,
         "length": 11
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "C536004",
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       "text": "aceruloplasminemia",
       "locations": [
        {
         "offset": 601,
         "length": 18
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       ]
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         "offset": 676,
         "length": 18
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       ]
      },
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       "text": "diabetes",
       "locations": [
        {
         "offset": 699,
         "length": 8
        }
       ]
      },
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       "id": "19",
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        "identifier": "c|DEL|809_852|",
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       "text": "deletion of amino acids 809-852",
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       "id": "20",
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       "text": "patients",
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       "id": "21",
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       "text": "Aceruloplasminemia",
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        {
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         "length": 18
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       ]
      },
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       "text": "iron overload",
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       "text": "iron overload",
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       "text": "insulin",
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       "id": "30",
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       "text": "iron overload",
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       "id": "31",
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       "text": "Aceruloplasminemia",
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       "text": "aceruloplasminemia",
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       "text": "hepcidin",
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       "text": "Iron",
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     "offset": 0,
     "text": "The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.",
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       "infons": {
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       "text": "androgen receptor",
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     "offset": 121,
     "text": "Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.",
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       "text": "hypoxic pulmonary remodelling",
       "locations": [
        {
         "offset": 22,
         "length": 29
        }
       ]
      }
     ]
    },
    {
     "offset": 96,
     "text": "The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM-derived progenitor cells, we induced pulmonary remodelling in rats by two-week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM-derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH-induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH-induced increase in c-kit(+) cells in the adventitia of pulmonary arteries. Moreover, sildenafil reduced the number of c-kit(+) cells that colocalize with tyrosine kinase receptor 2 (VEGF-R2) and CD68 (a marker for macrophages), indicating a positive effect on moderating hypoxia-induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia-inducible factor (HIF)-1a. Furthermore, sildenafil depressed the number of CXCR4(+) cells. Collectively, these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM-derived c-kit(+) cells in the pulmonary tissue. The attenuation of the recruitment of BM-derived c-kit(+) cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D066253",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pulmonary remodelling",
       "locations": [
        {
         "offset": 183,
         "length": 21
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D006976",
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       "text": "pulmonary hypertension",
       "locations": [
        {
         "offset": 229,
         "length": 22
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D006976",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "PH",
       "locations": [
        {
         "offset": 253,
         "length": 2
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D000068677",
        "type": "ChemicalEntity"
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       "text": "sildenafil",
       "locations": [
        {
         "offset": 267,
         "length": 10
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D006976",
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       "text": "PH",
       "locations": [
        {
         "offset": 299,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D000068677",
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       "text": "sildenafil",
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        {
         "offset": 420,
         "length": 10
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       ]
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      {
       "id": "8",
       "infons": {
        "identifier": "D066253",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "pulmonary remodelling",
       "locations": [
        {
         "offset": 511,
         "length": 21
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
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       "text": "rats",
       "locations": [
        {
         "offset": 536,
         "length": 4
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       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "D000860",
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       "text": "hypoxia",
       "locations": [
        {
         "offset": 573,
         "length": 7
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       ]
      },
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       "id": "11",
       "infons": {
        "identifier": "D000860",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "CH",
       "locations": [
        {
         "offset": 582,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D010100",
        "type": "ChemicalEntity"
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       "text": "oxygen",
       "locations": [
        {
         "offset": 590,
         "length": 6
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
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       "text": "Rats",
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         "length": 10
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       "id": "15",
       "infons": {
        "identifier": "D000860",
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       "text": "CH",
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         "offset": 728,
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       "id": "17",
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       "text": "oxygen",
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       "text": "sildenafil",
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        {
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         "length": 10
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       "id": "19",
       "infons": {
        "identifier": "D000860",
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       "text": "CH",
       "locations": [
        {
         "offset": 838,
         "length": 2
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       ]
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       "id": "20",
       "infons": {
        "identifier": "D017380",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "right ventricular hypertrophy",
       "locations": [
        {
         "offset": 901,
         "length": 29
        }
       ]
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       "id": "21",
       "infons": {
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       "id": "22",
       "infons": {
        "identifier": "D000860",
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       "text": "CH",
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        {
         "offset": 967,
         "length": 2
        }
       ]
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      {
       "id": "23",
       "infons": {
        "identifier": "64030",
        "type": "GeneOrGeneProduct"
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       "text": "c-kit",
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         "offset": 990,
         "length": 5
        }
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       "id": "24",
       "infons": {
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       "text": "sildenafil",
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       "text": "c-kit",
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         "offset": 1089,
         "length": 5
        }
       ]
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       "id": "26",
       "infons": {
        "identifier": "25589",
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       "text": "tyrosine kinase receptor 2",
       "locations": [
        {
         "offset": 1125,
         "length": 26
        }
       ]
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       "id": "27",
       "infons": {
        "identifier": "25589",
        "type": "GeneOrGeneProduct"
       },
       "text": "VEGF-R2",
       "locations": [
        {
         "offset": 1153,
         "length": 7
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "287435",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD68",
       "locations": [
        {
         "offset": 1166,
         "length": 4
        }
       ]
      },
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       "id": "29",
       "infons": {
        "identifier": "D000860",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypoxia",
       "locations": [
        {
         "offset": 1242,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammation",
       "locations": [
        {
         "offset": 1295,
         "length": 12
        }
       ]
      },
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       "id": "31",
       "infons": {
        "identifier": "29560",
        "type": "GeneOrGeneProduct"
       },
       "text": "hypoxia-inducible factor (HIF)-1a",
       "locations": [
        {
         "offset": 1350,
         "length": 33
        }
       ]
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       "id": "32",
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       "text": "sildenafil",
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       "id": "33",
       "infons": {
        "identifier": "60628",
        "type": "GeneOrGeneProduct"
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       "text": "CXCR4",
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         "offset": 1433,
         "length": 5
        }
       ]
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       "id": "34",
       "infons": {
        "identifier": "D000068677",
        "type": "ChemicalEntity"
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       "text": "sildenafil",
       "locations": [
        {
         "offset": 1537,
         "length": 10
        }
       ]
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       "id": "35",
       "infons": {
        "identifier": "64030",
        "type": "GeneOrGeneProduct"
       },
       "text": "c-kit",
       "locations": [
        {
         "offset": 1597,
         "length": 5
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "64030",
        "type": "GeneOrGeneProduct"
       },
       "text": "c-kit",
       "locations": [
        {
         "offset": 1686,
         "length": 5
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D000068677",
        "type": "ChemicalEntity"
       },
       "text": "sildenafil",
       "locations": [
        {
         "offset": 1704,
         "length": 10
        }
       ]
      },
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       "id": "38",
       "infons": {
        "identifier": "D066253",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pulmonary remodelling",
       "locations": [
        {
         "offset": 1774,
         "length": 21
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       ]
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     "id": "R0",
     "infons": {
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     "id": "R7",
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      "entity1": "D000068677",
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   ]
  },
  {
   "id": "15867855",
   "passages": [
    {
     "offset": 0,
     "text": "Genetic variants of the T-cell immunoglobulin mucin 1 but not the T-cell immunoglobulin mucin 3 gene are associated with asthma in an African American population.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "26762",
        "type": "GeneOrGeneProduct"
       },
       "text": "T-cell immunoglobulin mucin 1",
       "locations": [
        {
         "offset": 24,
         "length": 29
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "T-cell immunoglobulin mucin 3",
       "locations": [
        {
         "offset": 66,
         "length": 29
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "asthma",
       "locations": [
        {
         "offset": 121,
         "length": 6
        }
       ]
      }
     ]
    },
    {
     "offset": 163,
     "text": "BACKGROUND: The T-cell immunoglobulin mucin ( TIM ) proteins and their genetic variants have been suggested to play a role in regulating allergic diseases. OBJECTIVE: Genetic association of the sequence variants for TIM-1 and TIM-3 genes with asthma in an African American population was investigated. METHODS: Both case-control and family-based association analyses were performed for a total of 7 polymorphisms, including 3 single nucleotide polymorphism (SNPs) and 1 insertion/deletion polymorphism in the TIM-1 and 3 SNPs in the TIM-3 genes. The exposure to hepatitis A virus as judged by seropositivity was also examined. RESULTS: In the case-control design, the frequencies of the TT genotype for SNP rs2277025 and the homozygous deletion variant (157delMTTTVP) in the fourth exon of the TIM-1 gene were higher among patients with patients with asthma compared with the controls (odds ratio [OR], 2.779, P = .016; and OR, 3.09, P = .022, respectively). This association was substantiated by haplotype analysis of these and 2 additional SNPs (OR, 2.48; P = .004), and also by family-based tests for the allele and haplotype carrying 157delMTTTVP (P = .009 and P = .048, respectively). Furthermore, this association seems to exist even in the hepatitis A virus-seronegative subjects in our data. None of the 3 variants in TIM-3 genes yielded significant association with either asthma or asthma-related phenotypes. CONCLUSION: Our findings suggest that the genetic variants of the TIM-1 but not the TIM-3 gene contribute to asthma susceptibility in this African-American population.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "26762,84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "T-cell immunoglobulin mucin",
       "locations": [
        {
         "offset": 179,
         "length": 27
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "26762,84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM",
       "locations": [
        {
         "offset": 209,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D004342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "allergic diseases",
       "locations": [
        {
         "offset": 300,
         "length": 17
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "26762",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-1",
       "locations": [
        {
         "offset": 379,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-3",
       "locations": [
        {
         "offset": 389,
         "length": 5
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D001249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "asthma",
       "locations": [
        {
         "offset": 406,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "26762,84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-1 and 3",
       "locations": [
        {
         "offset": 672,
         "length": 11
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-3",
       "locations": [
        {
         "offset": 696,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "208726",
        "type": "OrganismTaxon"
       },
       "text": "hepatitis A virus",
       "locations": [
        {
         "offset": 725,
         "length": 17
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs2277025",
        "type": "SequenceVariant"
       },
       "text": "rs2277025",
       "locations": [
        {
         "offset": 870,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "p|DEL|157|MTTTVP",
        "type": "SequenceVariant"
       },
       "text": "157delMTTTVP",
       "locations": [
        {
         "offset": 917,
         "length": 12
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "26762",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-1",
       "locations": [
        {
         "offset": 957,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 986,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1000,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D001249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "asthma",
       "locations": [
        {
         "offset": 1014,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "p|DEL|157|MTTTVP",
        "type": "SequenceVariant"
       },
       "text": "157delMTTTVP",
       "locations": [
        {
         "offset": 1301,
         "length": 12
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "208726",
        "type": "OrganismTaxon"
       },
       "text": "hepatitis A virus",
       "locations": [
        {
         "offset": 1410,
         "length": 17
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-3",
       "locations": [
        {
         "offset": 1489,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D001249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "asthma",
       "locations": [
        {
         "offset": 1545,
         "length": 6
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D001249",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "asthma",
       "locations": [
        {
         "offset": 1555,
         "length": 6
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "26762",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-1",
       "locations": [
        {
         "offset": 1648,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "84868",
        "type": "GeneOrGeneProduct"
       },
       "text": "TIM-3",
       "locations": [
        {
         "offset": 1666,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D001249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "asthma",
       "locations": [
        {
         "offset": 1691,
         "length": 6
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "infons": {
      "entity1": "84868",
      "entity2": "D004342",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "p|DEL|157|MTTTVP",
      "entity2": "D001249",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "rs2277025",
      "entity2": "D001249",
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      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "26762",
      "entity2": "D004342",
      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R4",
     "infons": {
      "entity1": "26762",
      "entity2": "D001249",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "26684240",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 22,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs113488022",
        "type": "SequenceVariant"
       },
       "text": "V600E",
       "locations": [
        {
         "offset": 27,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "gastroenteropancreatic neuroendocrine tumors",
       "locations": [
        {
         "offset": 45,
         "length": 44
        }
       ]
      }
     ]
    },
    {
     "offset": 91,
     "text": "Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-labeled, single-center phase II study for pazopanib, and integrated our results with previously published results on pancreas (n = 12) and small intestine NETs (n = 50). The mean numbers of somatic mutations in each case varied widely from 20 to 4682. Among 12 GEP-NETs, eight showed mutations of more than one cancer-related gene, including TP53, CNBD1, RB1, APC, BCOR, BRAF, CTNNB1, EGFR, EP300, ERBB3, KDM6A, KRAS, MGA, MLL3, PTEN, RASA1, SMARCB1, SPEN, TBC1D12, and VHL. TP53 was recurrently mutated in three cases, whereas CNBD1 and RB1 mutations were identified in two cases. Three GEP-NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade (G) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment. We found BRAF V600E (G1 NET from rectum and two G3 NETs from colon) and BRAF G593S (G2 NET from pancreas) missense mutations (9.1%) in an independent cohort of 44 GEP-NETs from the rectum (n = 26), colon (n = 7), pancreas (n = 4), small intestine (n = 3), stomach (n = 3) and appendix (n = 1) by Sanger sequencing. All tumor specimens were obtained before chemotherapy. In conclusion, BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP-NETs patients.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "gastroenteropancreatic neuroendocrine tumors",
       "locations": [
        {
         "offset": 111,
         "length": 44
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GEP-NETs",
       "locations": [
        {
         "offset": 157,
         "length": 8
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GEP-NETs",
       "locations": [
        {
         "offset": 334,
         "length": 8
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 348,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "C516667",
        "type": "ChemicalEntity"
       },
       "text": "pazopanib",
       "locations": [
        {
         "offset": 433,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D007414",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intestine NETs",
       "locations": [
        {
         "offset": 536,
         "length": 14
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GEP-NETs",
       "locations": [
        {
         "offset": 652,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancer",
       "locations": [
        {
         "offset": 702,
         "length": 6
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "7157",
        "type": "GeneOrGeneProduct"
       },
       "text": "TP53",
       "locations": [
        {
         "offset": 733,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "168975",
        "type": "GeneOrGeneProduct"
       },
       "text": "CNBD1",
       "locations": [
        {
         "offset": 739,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 746,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "324",
        "type": "GeneOrGeneProduct"
       },
       "text": "APC",
       "locations": [
        {
         "offset": 751,
         "length": 3
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "54880",
        "type": "GeneOrGeneProduct"
       },
       "text": "BCOR",
       "locations": [
        {
         "offset": 756,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 762,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "1499",
        "type": "GeneOrGeneProduct"
       },
       "text": "CTNNB1",
       "locations": [
        {
         "offset": 768,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 776,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "2033",
        "type": "GeneOrGeneProduct"
       },
       "text": "EP300",
       "locations": [
        {
         "offset": 782,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "2065",
        "type": "GeneOrGeneProduct"
       },
       "text": "ERBB3",
       "locations": [
        {
         "offset": 789,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "7403",
        "type": "GeneOrGeneProduct"
       },
       "text": "KDM6A",
       "locations": [
        {
         "offset": 796,
         "length": 5
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "3845",
        "type": "GeneOrGeneProduct"
       },
       "text": "KRAS",
       "locations": [
        {
         "offset": 803,
         "length": 4
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "23269",
        "type": "GeneOrGeneProduct"
       },
       "text": "MGA",
       "locations": [
        {
         "offset": 809,
         "length": 3
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "58508",
        "type": "GeneOrGeneProduct"
       },
       "text": "MLL3",
       "locations": [
        {
         "offset": 814,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "5728",
        "type": "GeneOrGeneProduct"
       },
       "text": "PTEN",
       "locations": [
        {
         "offset": 820,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "5921",
        "type": "GeneOrGeneProduct"
       },
       "text": "RASA1",
       "locations": [
        {
         "offset": 826,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "6598",
        "type": "GeneOrGeneProduct"
       },
       "text": "SMARCB1",
       "locations": [
        {
         "offset": 833,
         "length": 7
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "23013",
        "type": "GeneOrGeneProduct"
       },
       "text": "SPEN",
       "locations": [
        {
         "offset": 842,
         "length": 4
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "23232",
        "type": "GeneOrGeneProduct"
       },
       "text": "TBC1D12",
       "locations": [
        {
         "offset": 848,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "7428",
        "type": "GeneOrGeneProduct"
       },
       "text": "VHL",
       "locations": [
        {
         "offset": 861,
         "length": 3
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "7157",
        "type": "GeneOrGeneProduct"
       },
       "text": "TP53",
       "locations": [
        {
         "offset": 866,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "168975",
        "type": "GeneOrGeneProduct"
       },
       "text": "CNBD1",
       "locations": [
        {
         "offset": 919,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "5925",
        "type": "GeneOrGeneProduct"
       },
       "text": "RB1",
       "locations": [
        {
         "offset": 929,
         "length": 3
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GEP-NET",
       "locations": [
        {
         "offset": 979,
         "length": 7
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 987,
         "length": 8
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "7157",
        "type": "GeneOrGeneProduct"
       },
       "text": "TP53",
       "locations": [
        {
         "offset": 1001,
         "length": 4
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "D007414",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "intestinal grade (G) 1 NET",
       "locations": [
        {
         "offset": 1062,
         "length": 26
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1089,
         "length": 7
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1102,
         "length": 4
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "rs113488022",
        "type": "SequenceVariant"
       },
       "text": "V600E",
       "locations": [
        {
         "offset": 1107,
         "length": 5
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "C516667",
        "type": "ChemicalEntity"
       },
       "text": "pazopanib",
       "locations": [
        {
         "offset": 1147,
         "length": 9
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1177,
         "length": 4
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "rs113488022",
        "type": "SequenceVariant"
       },
       "text": "V600E",
       "locations": [
        {
         "offset": 1182,
         "length": 5
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "D018358",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NET",
       "locations": [
        {
         "offset": 1192,
         "length": 3
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "D018358",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NETs",
       "locations": [
        {
         "offset": 1219,
         "length": 4
        }
       ]
      },
      {
       "id": "46",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1240,
         "length": 4
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "p.G593S",
        "type": "SequenceVariant"
       },
       "text": "G593S",
       "locations": [
        {
         "offset": 1245,
         "length": 5
        }
       ]
      },
      {
       "id": "48",
       "infons": {
        "identifier": "D018358",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NET",
       "locations": [
        {
         "offset": 1255,
         "length": 3
        }
       ]
      },
      {
       "id": "49",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GEP-NETs",
       "locations": [
        {
         "offset": 1331,
         "length": 8
        }
       ]
      },
      {
       "id": "50",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 1487,
         "length": 5
        }
       ]
      },
      {
       "id": "51",
       "infons": {
        "identifier": "673",
        "type": "GeneOrGeneProduct"
       },
       "text": "BRAF",
       "locations": [
        {
         "offset": 1553,
         "length": 4
        }
       ]
      },
      {
       "id": "52",
       "infons": {
        "identifier": "rs113488022",
        "type": "SequenceVariant"
       },
       "text": "V600E",
       "locations": [
        {
         "offset": 1558,
         "length": 5
        }
       ]
      },
      {
       "id": "53",
       "infons": {
        "identifier": "C516667",
        "type": "ChemicalEntity"
       },
       "text": "pazopanib",
       "locations": [
        {
         "offset": 1610,
         "length": 9
        }
       ]
      },
      {
       "id": "54",
       "infons": {
        "identifier": "C535650",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "GEP-NETs",
       "locations": [
        {
         "offset": 1681,
         "length": 8
        }
       ]
      },
      {
       "id": "55",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1690,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "p.G593S",
      "entity2": "D018358",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D007414",
      "entity2": "C516667",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D007414",
      "entity2": "rs113488022",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D007414",
      "entity2": "673",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "7428",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "23232",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "23013",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "6598",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "5921",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "5728",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "58508",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "23269",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R12",
     "infons": {
      "entity1": "3845",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R13",
     "infons": {
      "entity1": "7403",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R14",
     "infons": {
      "entity1": "2033",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R15",
     "infons": {
      "entity1": "1956",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R16",
     "infons": {
      "entity1": "1499",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R17",
     "infons": {
      "entity1": "54880",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R18",
     "infons": {
      "entity1": "324",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R19",
     "infons": {
      "entity1": "5925",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R20",
     "infons": {
      "entity1": "168975",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R21",
     "infons": {
      "entity1": "D009369",
      "entity2": "2065",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R22",
     "infons": {
      "entity1": "7157",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R23",
     "infons": {
      "entity1": "rs113488022",
      "entity2": "D018358",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R24",
     "infons": {
      "entity1": "rs113488022",
      "entity2": "C516667",
      "type": "Negative_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R25",
     "infons": {
      "entity1": "rs113488022",
      "entity2": "C535650",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R26",
     "infons": {
      "entity1": "C535650",
      "entity2": "p.G593S",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R27",
     "infons": {
      "entity1": "C535650",
      "entity2": "C516667",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
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     "offset": 0,
     "text": "MicroRNA deep sequencing in two adult stem cell populations identifies miR-501 as a novel regulator of myosin heavy chain during muscle regeneration.",
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     "text": "MicroRNAs (miRNAs) are important regulators of skeletal muscle regeneration, but the underlying mechanisms are still incompletely understood. Here, comparative miRNA sequencing analysis of myogenic progenitor cells (MPs) and non-myogenic fibroblast-adipocyte progenitors (FAPs) during cardiotoxin (CTX)-induced muscle injury uncovered miR-501 as a novel muscle-specific miRNA. miR-501 is an intronic miRNA and its expression levels in MPs correlated with its host gene, chloride channel, voltage-sensitive 5 (Clcn5). Pharmacological inhibition of miR-501 dramatically blunted the induction of embryonic myosin heavy chain (MYH3) and, to a lesser extent, adult myosin isoforms during muscle regeneration, and promoted small-diameter neofibers. An unbiased target identification approach in primary myoblasts validated gigaxonin as a target of miR-501 that mimicked the effect of miR-501 inhibition on MYH3 expression. In the mdx mouse model, which models a pathological disease state, not only was miR-501 induced in regenerating skeletal muscle, but also its serum levels were increased, which correlated with the disease state of the animals. Our results suggest that miR-501 plays a key role in adult muscle regeneration and might serve as a novel serum biomarker for the activation of adult muscle stem cells.",
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  {
   "id": "21799811",
   "passages": [
    {
     "offset": 0,
     "text": "Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs1801133",
        "type": "SequenceVariant"
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       "text": "677 C>T",
       "locations": [
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         "offset": 22,
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       "id": "1",
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       "infons": {
        "identifier": "D007248",
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       "text": "male infertility",
       "locations": [
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         "offset": 66,
         "length": 16
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       ]
      }
     ]
    },
    {
     "offset": 137,
     "text": "BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies. METHODOLOGY/PRINCIPAL FINDINGS: We undertook genotyping on a total of 837 individuals including well characterized infertile (N=522) and confirmed fertile (N=315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included 'Pubmed', 'Ovid' and 'Google Scholar'. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p=0.0025) and genotypes (CT+TT) (p=0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p=0.000), 1.310 (p=0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility. CONCLUSIONS/SIGNIFICANCE: 677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.",
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       "text": "Methylenetetrahydrofolate reductase",
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       "id": "4",
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       "id": "12",
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       "id": "15",
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        "identifier": "D007248",
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  {
   "id": "15951966",
   "passages": [
    {
     "offset": 0,
     "text": "Screening for exonic copy number mutations at MSH2 and MLH1 by MAPH.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
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       "text": "MSH2",
       "locations": [
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         "offset": 46,
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       "locations": [
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         "offset": 55,
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     "offset": 69,
     "text": "BACKGROUND: Exonic deletions in MSH2 and MLH1 are significant contributors to the mutation spectrum in HNPCC, and heterozygous changes in exon copy number are not detected by conventional mutation screening methods. AIMS: We aimed to develop methods for screening copy number changes in all the exons of the MLH1 and MSH2 genes using a single multiplex amplifiable probe hybridisation (MAPH) assay. METHODS: We developed a probe set consisting of probes from the 19 exons of MLH1 and 16 exons of MSH2, and 3 control probes, and applied it to screening for deletions and duplications using fluorescent detection of amplified fragments. RESULTS: We tested 73 DNA samples from controls and 50 from HNPCC patients in whom no point mutations had been found, and detected 10 copy number changes among the patient samples. A deletion of about 1.4 kb including exon 3 of MSH2 was confirmed by amplification of a junction fragment, and was shown to be the result of an unequal recombination between intronic Alu elements. CONCLUSIONS: MAPH can detect exonic copy number changes in MLH1 and MSH2 in DNA from HNPCC patients. Since finding an exonic deletion or duplication makes full sequence analysis unnecessary, it may be most cost-effective to pre-screen samples by MAPH or MLPA before screening for point mutations.",
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       "text": "MSH2",
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       "text": "MLH1",
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       "id": "8",
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       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
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         "offset": 770,
         "length": 8
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       ]
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       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patient",
       "locations": [
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         "offset": 868,
         "length": 7
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       ]
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       "id": "12",
       "infons": {
        "identifier": "4436",
        "type": "GeneOrGeneProduct"
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       "text": "MSH2",
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         "offset": 932,
         "length": 4
        }
       ]
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       "id": "13",
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        "identifier": "4292",
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       "text": "MLH1",
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         "offset": 1141,
         "length": 4
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       "id": "14",
       "infons": {
        "identifier": "4436",
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       "text": "MSH2",
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        {
         "offset": 1150,
         "length": 4
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       ]
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       "id": "15",
       "infons": {
        "identifier": "D003123",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "HNPCC",
       "locations": [
        {
         "offset": 1167,
         "length": 5
        }
       ]
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       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
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         "offset": 1173,
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      "novel": "No"
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    {
     "id": "R1",
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      "novel": "No"
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    }
   ]
  },
  {
   "id": "17968299",
   "passages": [
    {
     "offset": 0,
     "text": "Analysis of -1082 IL-10 gene polymorphism in Iranian patients with generalized aggressive periodontitis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-10",
       "locations": [
        {
         "offset": 18,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 53,
         "length": 8
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D010520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aggressive periodontitis",
       "locations": [
        {
         "offset": 79,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 105,
     "text": "BACKGROUND: Periodontitis is a multifactorial disease and its severe forms, such as aggressive periodontitis, are suggested to have a genetic basis. Among the genetic factors, polymorphisms in cytokine genes have recently been described in susceptibility to periodontitis. IL-10 is a multi-functional cytokine thought to play a role in the pathogenesis of periodontitis. A substitution G/A polymorphism in the promoter region of the IL-10 gene at position -1082 has been associated with different amounts of IL-10 production. The aim of the present study was to investigate the possible links between -1082(G/A) polymorphism of the IL-10 gene and the generalized form of aggressive periodontitis. MATERIAL/METHODS: This study included 52 Iranian Khorasanian (north-east province of Iran) subjects suffering from generalized aggressive periodontitis referred to the Periodontology Department of Mashhad Dental School. They were compared to 61 age and sex-matched healthy controls of the same race. DNA was isolated from peripheral blood cells and genotyping was performed by means of the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) method. Data were analyzed using the chi-squared test. RESULTS: There was no marked difference in genotype frequencies between the controls and generalized aggressive periodontitis patients (p=0.585). Moreover, no association between patients and normal subjects was found in their allele frequency (p=0.329). CONCLUSIONS: We conclude that the polymorphic nucleotide A at position -1082 of the IL-10 gene is not associated with generalized aggressive periodontitis in the Iranian population.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D010518",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Periodontitis",
       "locations": [
        {
         "offset": 117,
         "length": 13
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D010520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aggressive periodontitis",
       "locations": [
        {
         "offset": 189,
         "length": 24
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D010518",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "periodontitis",
       "locations": [
        {
         "offset": 363,
         "length": 13
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
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       "text": "IL-10",
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        {
         "offset": 378,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D010518",
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       },
       "text": "periodontitis",
       "locations": [
        {
         "offset": 461,
         "length": 13
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|SUB|G||A",
        "type": "SequenceVariant"
       },
       "text": "G/A",
       "locations": [
        {
         "offset": 491,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
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       "text": "IL-10",
       "locations": [
        {
         "offset": 538,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-10",
       "locations": [
        {
         "offset": 613,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|SUB|G|-1082|A",
        "type": "SequenceVariant"
       },
       "text": "-1082(G/A)",
       "locations": [
        {
         "offset": 706,
         "length": 10
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-10",
       "locations": [
        {
         "offset": 737,
         "length": 5
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D010520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aggressive periodontitis",
       "locations": [
        {
         "offset": 776,
         "length": 24
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D010520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aggressive periodontitis",
       "locations": [
        {
         "offset": 929,
         "length": 24
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D010520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aggressive periodontitis",
       "locations": [
        {
         "offset": 1426,
         "length": 24
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1451,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1504,
         "length": 8
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "c|Allele|A|-1082",
        "type": "SequenceVariant"
       },
       "text": "A at position -1082",
       "locations": [
        {
         "offset": 1637,
         "length": 19
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "3586",
        "type": "GeneOrGeneProduct"
       },
       "text": "IL-10",
       "locations": [
        {
         "offset": 1664,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D010520",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "aggressive periodontitis",
       "locations": [
        {
         "offset": 1710,
         "length": 24
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "3586",
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      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "20126413",
   "passages": [
    {
     "offset": 0,
     "text": "U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "CVCL_0022",
        "type": "CellLine"
       },
       "text": "U87MG",
       "locations": [
        {
         "offset": 0,
         "length": 5
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       ]
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       "id": "1",
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       "text": "human",
       "locations": [
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         "offset": 66,
         "length": 5
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       ]
      },
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       "id": "2",
       "infons": {
        "identifier": "D009369",
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       "text": "cancer",
       "locations": [
        {
         "offset": 72,
         "length": 6
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       ]
      }
     ]
    },
    {
     "offset": 90,
     "text": "U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30x genomic sequence coverage using a novel 50-base mate paired strategy with a 1.4kb mean insert library. A total of 1,014,984,286 mate-end and 120,691,623 single-end two-base encoded reads were generated from five slides. All data were aligned using a custom designed tool called BFAST, allowing optimal color space read alignment and accurate identification of DNA variants. The aligned sequence reads and mate-pair information identified 35 interchromosomal translocation events, 1,315 structural variations (>100 bp), 191,743 small (<21 bp) insertions and deletions (indels), and 2,384,470 single nucleotide variations (SNVs). Among these observations, the known homozygous mutation in PTEN was robustly identified, and genes involved in cell adhesion were overrepresented in the mutated gene list. Data were compared to 219,187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy: 93.83% of all SNPs were reliably detected at filtering thresholds that yield greater than 99.99% sequence accuracy. Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels, large deletions, and translocations. In total, 512 genes were homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and 35 by interchromosomal translocations to reveal a highly mutated cell line genome. Of the small homozygously mutated variants, 8 SNVs and 99 indels were novel events not present in dbSNP. These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers. The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "CVCL_0022",
        "type": "CellLine"
       },
       "text": "U87MG",
       "locations": [
        {
         "offset": 90,
         "length": 5
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D005909",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "grade IV glioma",
       "locations": [
        {
         "offset": 118,
         "length": 15
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D009369",
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       "text": "cancer",
       "locations": [
        {
         "offset": 320,
         "length": 6
        }
       ]
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       "id": "6",
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        "identifier": "5728",
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       "text": "PTEN",
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         "offset": 1068,
         "length": 4
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       ]
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       "id": "7",
       "infons": {
        "identifier": "D009369",
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       "text": "cancer",
       "locations": [
        {
         "offset": 1498,
         "length": 6
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009369",
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       },
       "text": "cancer",
       "locations": [
        {
         "offset": 1941,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "CVCL_0022",
        "type": "CellLine"
       },
       "text": "U87MG",
       "locations": [
        {
         "offset": 2028,
         "length": 5
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       ]
      }
     ]
    }
   ],
   "relations": [
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      "type": "Association",
      "novel": "Novel"
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    }
   ]
  },
  {
   "id": "27866394",
   "passages": [
    {
     "offset": 0,
     "text": "Repeated otilonium bromide administration prevents neurotransmitter changes in colon of rats underwent to wrap restraint stress.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "C013934",
        "type": "ChemicalEntity"
       },
       "text": "otilonium bromide",
       "locations": [
        {
         "offset": 9,
         "length": 17
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D018377",
        "type": "ChemicalEntity"
       },
       "text": "neurotransmitter",
       "locations": [
        {
         "offset": 51,
         "length": 16
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rats",
       "locations": [
        {
         "offset": 88,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 129,
     "text": "Otilonium bromide (OB) is a spasmolytic drug successfully used for the treatment of irritable bowel syndrome (IBS). Its efficacy has been attributed to the block of L- and T-type Ca(2+) channels and muscarinic and tachykinin receptors in the smooth muscle. Furthermore, in healthy rats, repeated OB administration modified neurotransmitter expression and function suggesting other mechanisms of action. On this basis, we investigated whether repeated OB treatment prevented the functional and neurochemical changes observed in the colon of rats underwent to wrap restrain stress (WRS) a psychosocial stressor considered suitable to reproduce the main IBS signs and symptoms. In control, WRS and OB/WRS rats functional parameters were measured in vivo and morphological investigations were done ex vivo in the colon. The results showed that OB counteracts most of the neurotransmitters changes caused by WRS. In particular, the drug prevents the decrease in SP-, NK1r-, nNOS-, VIP-, and S100b-immunoreactivity (IR) and the increase in CGRP-, and CRF1r-IR. On the contrary, OB does not affect the increase in CRF2r-IR neurons observed in WRS rats and does not interfere with the mild mucosal inflammation due to WRS. Finally, OB per se increases the Mr2 expression in the muscle wall and decreases the number of the myenteric ChAT-IR neurons. Functional findings show a significantly reduction in the number of spontaneous abdominal contraction in OB treated rats. The ability of OB to block L-type Ca(2+) channels, also expressed by enteric neurons, might represent a possible mechanism through which OB exerts its actions.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "C013934",
        "type": "ChemicalEntity"
       },
       "text": "Otilonium bromide",
       "locations": [
        {
         "offset": 129,
         "length": 17
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C013934",
        "type": "ChemicalEntity"
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       "text": "OB",
       "locations": [
        {
         "offset": 148,
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       ]
      },
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       "id": "5",
       "infons": {
        "identifier": "D043183",
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       "text": "irritable bowel syndrome",
       "locations": [
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       "id": "6",
       "infons": {
        "identifier": "D043183",
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       "text": "IBS",
       "locations": [
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         "offset": 239,
         "length": 3
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       "id": "7",
       "infons": {
        "identifier": "24239,83810",
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       "text": "L- and T-type Ca(2+) channels",
       "locations": [
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        }
       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "1128,6869",
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       "text": "muscarinic and tachykinin receptors",
       "locations": [
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         "offset": 328,
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       ]
      },
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       "id": "9",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "rats",
       "locations": [
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         "offset": 410,
         "length": 4
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       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "C013934",
        "type": "ChemicalEntity"
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       "text": "OB",
       "locations": [
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         "offset": 425,
         "length": 2
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       ]
      },
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       "id": "11",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "neurotransmitter",
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         "length": 16
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       ]
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       "id": "12",
       "infons": {
        "identifier": "C013934",
        "type": "ChemicalEntity"
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       "text": "OB",
       "locations": [
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         "offset": 580,
         "length": 2
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       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
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       "text": "rats",
       "locations": [
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         "offset": 669,
         "length": 4
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D043183",
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       "text": "IBS",
       "locations": [
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         "offset": 780,
         "length": 3
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       ]
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       "id": "15",
       "infons": {
        "identifier": "C013934",
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       "text": "OB",
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         "offset": 824,
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       ]
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       "id": "16",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
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       "text": "rats",
       "locations": [
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         "offset": 831,
         "length": 4
        }
       ]
      },
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       "id": "17",
       "infons": {
        "identifier": "C013934",
        "type": "ChemicalEntity"
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       "text": "OB",
       "locations": [
        {
         "offset": 969,
         "length": 2
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D018377",
        "type": "ChemicalEntity"
       },
       "text": "neurotransmitters",
       "locations": [
        {
         "offset": 996,
         "length": 17
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "24806",
        "type": "GeneOrGeneProduct"
       },
       "text": "SP",
       "locations": [
        {
         "offset": 1086,
         "length": 2
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "24807",
        "type": "GeneOrGeneProduct"
       },
       "text": "NK1r",
       "locations": [
        {
         "offset": 1091,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "24598",
        "type": "GeneOrGeneProduct"
       },
       "text": "nNOS",
       "locations": [
        {
         "offset": 1098,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "117064",
        "type": "GeneOrGeneProduct"
       },
       "text": "VIP",
       "locations": [
        {
         "offset": 1105,
         "length": 3
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "25742",
        "type": "GeneOrGeneProduct"
       },
       "text": "S100b",
       "locations": [
        {
         "offset": 1115,
         "length": 5
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "24241",
        "type": "GeneOrGeneProduct"
       },
       "text": "CGRP",
       "locations": [
        {
         "offset": 1163,
         "length": 4
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "58959",
        "type": "GeneOrGeneProduct"
       },
       "text": "CRF1r",
       "locations": [
        {
         "offset": 1174,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "C013934",
        "type": "ChemicalEntity"
       },
       "text": "OB",
       "locations": [
        {
         "offset": 1201,
         "length": 2
        }
       ]
      },
      {
       "id": "27",
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  {
   "id": "19624920",
   "passages": [
    {
     "offset": 0,
     "text": "Clusters of multidrug-resistant Mycobacterium tuberculosis cases, Europe.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "1773",
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       "text": "Mycobacterium tuberculosis",
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     "offset": 74,
     "text": "Molecular surveillance of multidrug-resistant tuberculosis (MDR TB) was implemented in Europe as case reporting in 2005. For all new MDR TB cases detected from January 2003 through June 2007, countries reported case-based epidemiologic data and DNA fingerprint patterns of MDR TB strains when available. International clusters were detected and analyzed. From 2003 through mid-2007 in Europe, 2,494 cases of MDR TB were reported from 24 European countries. Epidemiologic and molecular data were linked for 593 (39%) cases, and 672 insertion sequence 6110 DNA fingerprint patterns were reported from 19 countries. Of these patterns, 288 (43%) belonged to 18 European clusters; 7 clusters (242/288 cases, 84%) were characterized by strains of the Beijing genotype family, including the largest cluster (175/288 cases, 61%). Both clustering and the Beijing genotype were associated with strains originating in eastern European countries. Molecular cluster detection contributes to identification of transmission profile, risk factors, and control measures.",
     "annotations": [
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       "id": "1",
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       "text": "multidrug-resistant tuberculosis",
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  {
   "id": "29049388",
   "passages": [
    {
     "offset": 0,
     "text": "An inducible mouse model of podocin-mutation-related nephrotic syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
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       "text": "mouse",
       "locations": [
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       "text": "podocin",
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       "id": "2",
       "infons": {
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       "text": "nephrotic syndrome",
       "locations": [
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         "offset": 53,
         "length": 18
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       ]
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     ]
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    {
     "offset": 73,
     "text": "Mutations in the NPHS2 gene, encoding podocin, cause hereditary nephrotic syndrome. The most common podocin mutation, R138Q, is associated with early disease onset and rapid progression to end-stage renal disease. Knock-in mice carrying a R140Q mutation, the mouse analogue of human R138Q, show developmental arrest of podocytes and lethal renal failure at neonatal age. Here we created a conditional podocin knock-in model named NPHS2 R140Q/-, using a tamoxifen-inducible Cre recombinase, which permits to study the effects of the mutation in postnatal life. Within the first week of R140Q hemizygosity induction the animals developed proteinuria, which peaked after 4-5 weeks. Subsequently the animals developed progressive renal failure, with a median survival time of 12 (95% CI: 11-13) weeks. Foot process fusion was observed within one week, progressing to severe and global effacement in the course of the disease. The number of podocytes per glomerulus gradually diminished to 18% compared to healthy controls 12-16 weeks after induction. The fraction of segmentally sclerosed glomeruli was 25%, 85% and 97% at 2, 4 and 8 weeks, respectively. Severe tubulointerstitial fibrosis was present at later disease stage and was correlated quantitatively with the level of proteinuria at early disease stages. While R140Q podocin mRNA expression was elevated, protein abundance was reduced by more than 50% within one week following induction. Whereas miRNA21 expression persistently increased during the first 4 weeks, miRNA-193a expression peaked 2 weeks after induction. In conclusion, the inducible R140Q-podocin mouse model is an auspicious model of the most common genetic cause of human nephrotic syndrome, with a spontaneous disease course strongly reminiscent of the human disorder. This model constitutes a valuable tool to test the efficacy of novel pharmacological interventions aimed to improve podocyte function and viability and attenuate proteinuria, glomerulosclerosis and progressive renal failure.",
     "annotations": [
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       "text": "NPHS2",
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       "text": "nephrotic syndrome",
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       "id": "7",
       "infons": {
        "identifier": "rs74315342",
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       "text": "R138Q",
       "locations": [
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         "offset": 191,
         "length": 5
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       ]
      },
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       "id": "8",
       "infons": {
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       "text": "renal disease",
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         "length": 13
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       ]
      },
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       "id": "9",
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       "text": "mice",
       "locations": [
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         "offset": 296,
         "length": 4
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       ]
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      {
       "id": "10",
       "infons": {
        "identifier": "p|SUB|R|140|Q",
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       "text": "R140Q",
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         "offset": 312,
         "length": 5
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       ]
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       "id": "11",
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       "text": "mouse",
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       "text": "human",
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         "length": 5
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       "text": "R138Q",
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       ]
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       "id": "14",
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       "text": "renal failure",
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       ]
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       "id": "15",
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       "text": "podocin",
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       "text": "tamoxifen",
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         "offset": 526,
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         "length": 5
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       ]
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       "text": "proteinuria",
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         "offset": 709,
         "length": 11
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       ]
      },
      {
       "id": "21",
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       "text": "renal failure",
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         "length": 13
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       ]
      },
      {
       "id": "22",
       "infons": {
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       "text": "tubulointerstitial fibrosis",
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       "text": "proteinuria",
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       ]
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       "id": "24",
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       "text": "podocin",
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       "text": "miRNA21",
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       "text": "miRNA-193a",
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       "id": "28",
       "infons": {
        "identifier": "p|SUB|R|140|Q",
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       "text": "R140Q",
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         "offset": 1676,
         "length": 5
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       ]
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      {
       "id": "29",
       "infons": {
        "identifier": "170484",
        "type": "GeneOrGeneProduct"
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       "text": "podocin",
       "locations": [
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         "offset": 1682,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
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       "text": "mouse",
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       ]
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       "text": "human",
       "locations": [
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         "offset": 1761,
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       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D009404",
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       "text": "nephrotic syndrome",
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         "length": 18
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       ]
      },
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       "id": "33",
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       "text": "human",
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       "text": "proteinuria",
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       ]
      },
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       "id": "35",
       "infons": {
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       "text": "glomerulosclerosis",
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         "length": 18
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       ]
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       "id": "36",
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       "text": "renal failure",
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         "length": 13
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     ]
    }
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      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "rs74315342",
      "entity2": "D051437",
      "type": "Positive_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "p|SUB|R|140|Q",
      "entity2": "D009404",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "p|SUB|R|140|Q",
      "entity2": "D011507",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "p|SUB|R|140|Q",
      "entity2": "D051437",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "17345627",
   "passages": [
    {
     "offset": 0,
     "text": "Over-expression of BMP4 and BMP5 in a child with axial skeletal malformations and heterotopic ossification: a new syndrome.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "652",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP4",
       "locations": [
        {
         "offset": 19,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "653",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP5",
       "locations": [
        {
         "offset": 28,
         "length": 4
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "axial skeletal malformations",
       "locations": [
        {
         "offset": 49,
         "length": 28
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009999",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "heterotopic ossification",
       "locations": [
        {
         "offset": 82,
         "length": 24
        }
       ]
      }
     ]
    },
    {
     "offset": 124,
     "text": "Bone morphogenetic proteins (BMPs) are a highly conserved class of signaling molecules that induce ectopic cartilage and bone formation in vivo. Dysregulated expression of bone morphogenetic protein 4 (BMP4) is found in the cells of patients who have fibrodysplasia ossificans progressiva (FOP), a genetic disorder of axial and appendicular skeletal malformation and progressive heterotopic ossification. Loss of function mutations in the bone morphogenetic protein 5 (bmp5) gene leading to under-expression of BMP5 cause the murine short ear syndrome, characterized by small malformed ears and a broad range of axial skeletal malformations. We found features reminiscent of both the short ear mouse and FOP in a child with malformed external ears, multiple malformations of the axial skeleton, and progressive heterotopic ossification in the neck and back. We examined BMP mRNA expression in transformed lymphocytes by semi-quantitative RT-PCR and protein expression by ELISA assays and immunohistochemistry. Elevated levels of BMP4 and BMP5 mRNA and protein were detected in the patient's cells while levels of BMP2 mRNA were unchanged. Our data suggest that dysregulated expression of BMP4 and BMP5 genes is associated with an array of human axial skeletal abnormalities similar to the short ear mouse and FOP.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "649,650,652,653",
        "type": "GeneOrGeneProduct"
       },
       "text": "Bone morphogenetic proteins",
       "locations": [
        {
         "offset": 124,
         "length": 27
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "649,650,652,653",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMPs",
       "locations": [
        {
         "offset": 153,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001847,D002357",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ectopic cartilage and bone formation",
       "locations": [
        {
         "offset": 223,
         "length": 36
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "652",
        "type": "GeneOrGeneProduct"
       },
       "text": "bone morphogenetic protein 4",
       "locations": [
        {
         "offset": 296,
         "length": 28
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "652",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP4",
       "locations": [
        {
         "offset": 326,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 357,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D009221",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fibrodysplasia ossificans progressiva",
       "locations": [
        {
         "offset": 375,
         "length": 37
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D009221",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FOP",
       "locations": [
        {
         "offset": 414,
         "length": 3
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D001848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "axial and appendicular skeletal malformation",
       "locations": [
        {
         "offset": 442,
         "length": 44
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D009999",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "heterotopic ossification",
       "locations": [
        {
         "offset": 503,
         "length": 24
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "653",
        "type": "GeneOrGeneProduct"
       },
       "text": "bone morphogenetic protein 5",
       "locations": [
        {
         "offset": 563,
         "length": 28
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "653",
        "type": "GeneOrGeneProduct"
       },
       "text": "bmp5",
       "locations": [
        {
         "offset": 593,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "653",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP5",
       "locations": [
        {
         "offset": 635,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "murine",
       "locations": [
        {
         "offset": 650,
         "length": 6
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D004427",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "short ear syndrome",
       "locations": [
        {
         "offset": 657,
         "length": 18
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D001848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "axial skeletal malformations",
       "locations": [
        {
         "offset": 736,
         "length": 28
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 818,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D009221",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FOP",
       "locations": [
        {
         "offset": 828,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D004426",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "malformed external ears",
       "locations": [
        {
         "offset": 848,
         "length": 23
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D001848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "multiple malformations of the axial skeleton",
       "locations": [
        {
         "offset": 873,
         "length": 44
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D009999",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "heterotopic ossification",
       "locations": [
        {
         "offset": 935,
         "length": 24
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "649,650,652,653",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP",
       "locations": [
        {
         "offset": 994,
         "length": 3
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "652",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP4",
       "locations": [
        {
         "offset": 1153,
         "length": 4
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "653",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP5",
       "locations": [
        {
         "offset": 1162,
         "length": 4
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1205,
         "length": 7
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "650",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP2",
       "locations": [
        {
         "offset": 1237,
         "length": 4
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "652",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP4",
       "locations": [
        {
         "offset": 1312,
         "length": 4
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "653",
        "type": "GeneOrGeneProduct"
       },
       "text": "BMP5",
       "locations": [
        {
         "offset": 1321,
         "length": 4
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 1363,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D001848",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "axial skeletal abnormalities",
       "locations": [
        {
         "offset": 1369,
         "length": 28
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "10090",
        "type": "OrganismTaxon"
       },
       "text": "mouse",
       "locations": [
        {
         "offset": 1423,
         "length": 5
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D009221",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "FOP",
       "locations": [
        {
         "offset": 1433,
         "length": 3
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D002357",
      "entity2": "650",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D002357",
      "entity2": "649",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "D002357",
      "entity2": "653",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D002357",
      "entity2": "652",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D001847",
      "entity2": "650",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D001847",
      "entity2": "649",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "D001847",
      "entity2": "653",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R7",
     "infons": {
      "entity1": "D001847",
      "entity2": "652",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R8",
     "infons": {
      "entity1": "653",
      "entity2": "D009221",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R9",
     "infons": {
      "entity1": "653",
      "entity2": "D004427",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R10",
     "infons": {
      "entity1": "D009999",
      "entity2": "653",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R11",
     "infons": {
      "entity1": "D009999",
      "entity2": "652",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R12",
     "infons": {
      "entity1": "652",
      "entity2": "D009221",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R13",
     "infons": {
      "entity1": "652",
      "entity2": "D004427",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R14",
     "infons": {
      "entity1": "D001848",
      "entity2": "653",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R15",
     "infons": {
      "entity1": "D001848",
      "entity2": "652",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "20540798",
   "passages": [
    {
     "offset": 0,
     "text": "Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5144",
        "type": "GeneOrGeneProduct"
       },
       "text": "phosphodiesterase 4D",
       "locations": [
        {
         "offset": 35,
         "length": 20
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "5144",
        "type": "GeneOrGeneProduct"
       },
       "text": "PDE4D",
       "locations": [
        {
         "offset": 57,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D002340",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "carotid atherosclerosis",
       "locations": [
        {
         "offset": 67,
         "length": 23
        }
       ]
      }
     ]
    },
    {
     "offset": 92,
     "text": "BACKGROUND: The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis. METHODS: Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 +/- 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index > or = 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect. RESULTS: In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index > or = 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index > or = 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27). CONCLUSIONS: The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "5144",
        "type": "GeneOrGeneProduct"
       },
       "text": "phosphodiesterase 4D",
       "locations": [
        {
         "offset": 108,
         "length": 20
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "5144",
        "type": "GeneOrGeneProduct"
       },
       "text": "PDE4D",
       "locations": [
        {
         "offset": 130,
         "length": 5
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 183,
         "length": 6
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D050197",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atherogenic",
       "locations": [
        {
         "offset": 260,
         "length": 11
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D050197",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atherosclerosis",
       "locations": [
        {
         "offset": 460,
         "length": 15
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 532,
         "length": 6
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 629,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 983,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 991,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "rs702553",
        "type": "SequenceVariant"
       },
       "text": "Rs702553",
       "locations": [
        {
         "offset": 1078,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "5144",
        "type": "GeneOrGeneProduct"
       },
       "text": "PDE4D",
       "locations": [
        {
         "offset": 1094,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 1156,
         "length": 6
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 1202,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "rs702553",
        "type": "SequenceVariant"
       },
       "text": "rs702553",
       "locations": [
        {
         "offset": 1421,
         "length": 8
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 1568,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1583,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 1770,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 1909,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs702553",
        "type": "SequenceVariant"
       },
       "text": "rs702553",
       "locations": [
        {
         "offset": 1965,
         "length": 8
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "rs702553",
        "type": "SequenceVariant"
       },
       "text": "rs702553",
       "locations": [
        {
         "offset": 1990,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 2029,
         "length": 6
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "men",
       "locations": [
        {
         "offset": 2036,
         "length": 3
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "women",
       "locations": [
        {
         "offset": 2073,
         "length": 5
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "5144",
        "type": "GeneOrGeneProduct"
       },
       "text": "PDE4D",
       "locations": [
        {
         "offset": 2164,
         "length": 5
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D020521",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "stroke",
       "locations": [
        {
         "offset": 2195,
         "length": 6
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D050197",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "atherogenesis",
       "locations": [
        {
         "offset": 2256,
         "length": 13
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D050197",
      "entity2": "rs702553",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "rs702553",
      "entity2": "D020521",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "5144",
      "entity2": "D050197",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R3",
     "infons": {
      "entity1": "5144",
      "entity2": "D020521",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "5144",
      "entity2": "D002340",
      "type": "Association",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "21130517",
   "passages": [
    {
     "offset": 0,
     "text": "Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 13,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 47,
         "length": 11
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 59,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 117,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 123,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 151,
         "length": 4
        }
       ]
      }
     ]
    },
    {
     "offset": 168,
     "text": "AIMS: EGFR mutations now guide the clinical use of EGFR-targeted therapy in lung cancer. However, standard EGFR mutation analysis requires a minimum amount of tumor tissue, which may not be available in certain situations. In this study, we combined a mass spectrometry genotyping assay (Sequenom) with a mutant-enriched PCR (ME-PCR) to detect EGFR mutations in free plasma DNA from patients with lung cancer. METHOD: DNAs were extracted from 31 plasma samples from 31 patients and analyzed by both methods for EGFR Exon 19 deletion and EGFR L858R mutation. Results in plasma DNA samples were compared with EGFR mutation status obtained in tumor DNA (18/31 EGFR mutant). The relationship of EGFR mutation status in tumor and/or plasma samples to overall survival was assessed. RESULTS: The EGFR mutation status in plasma DNA was identical to the primary tumor in 61% of patients (19/31). By mass spectrometry genotyping, the plasma samples contained mutant DNA corresponding to 5/14 EGFR Exon 19 deletions and 3/4 EGFR L858R mutations previously diagnosed in the matched tumors. Two samples were positive in plasma DNA but negative in primary tumor tissue. Results were similar for samples studied by ME-PCR. For patients treated with erlotinib, overall survival was correlated with the presence of EGFR mutation in plasma and/or tumor tissue (p=0.002), with the two patients positive only in plasma DNA showing responses and favorable outcomes. CONCLUSION: The detection of EGFR mutations in plasma DNA samples by mass spectrometry genotyping and ME-PCR is feasible. A positive EGFR result in plasma DNA has a high predictive value for tumor EGFR status and for favorable clinical course on EGFR-targeted therapy and could therefore be useful in guiding clinical decisions in patients with insufficient or unavailable tumor specimens.",
     "annotations": [
      {
       "id": "6",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
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       "text": "EGFR",
       "locations": [
        {
         "offset": 174,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 219,
         "length": 4
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 244,
         "length": 11
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1956",
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       "text": "EGFR",
       "locations": [
        {
         "offset": 275,
         "length": 4
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "tumor",
       "locations": [
        {
         "offset": 327,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
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       "text": "EGFR",
       "locations": [
        {
         "offset": 512,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
        {
         "offset": 551,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D008175",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lung cancer",
       "locations": [
        {
         "offset": 565,
         "length": 11
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 637,
         "length": 8
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
       },
       "text": "EGFR",
       "locations": [
        {
         "offset": 679,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
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       "text": "EGFR",
       "locations": [
        {
         "offset": 705,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "rs121434568",
        "type": "SequenceVariant"
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       "text": "L858R",
       "locations": [
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         "offset": 710,
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       ]
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       "id": "18",
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       "text": "EGFR",
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         "offset": 775,
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       ]
      },
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       "id": "19",
       "infons": {
        "identifier": "D009369",
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       "text": "tumor",
       "locations": [
        {
         "offset": 808,
         "length": 5
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       ]
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      {
       "id": "20",
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         "offset": 825,
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       "id": "21",
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        "identifier": "1956",
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         "offset": 859,
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       "id": "22",
       "infons": {
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       "text": "tumor",
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        {
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       "id": "23",
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       "id": "24",
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       "text": "tumor",
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         "offset": 1022,
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       ]
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       "id": "25",
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       "text": "patients",
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         "offset": 1038,
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      },
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       "id": "26",
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        "identifier": "1956",
        "type": "GeneOrGeneProduct"
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       "text": "EGFR",
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         "offset": 1151,
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
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       "text": "EGFR",
       "locations": [
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         "offset": 1182,
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      },
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       "id": "28",
       "infons": {
        "identifier": "rs121434568",
        "type": "SequenceVariant"
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       "text": "L858R",
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         "offset": 1187,
         "length": 5
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       ]
      },
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       "id": "29",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumors",
       "locations": [
        {
         "offset": 1239,
         "length": 6
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumor",
       "locations": [
        {
         "offset": 1311,
         "length": 5
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
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         "offset": 1381,
         "length": 8
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D000069347",
        "type": "ChemicalEntity"
       },
       "text": "erlotinib",
       "locations": [
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         "offset": 1403,
         "length": 9
        }
       ]
      },
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       "id": "33",
       "infons": {
        "identifier": "1956",
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       "text": "EGFR",
       "locations": [
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         "offset": 1467,
         "length": 4
        }
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      },
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       "id": "34",
       "infons": {
        "identifier": "D009369",
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       "text": "tumor",
       "locations": [
        {
         "offset": 1498,
         "length": 5
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "9606",
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       "text": "patients",
       "locations": [
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         "offset": 1535,
         "length": 8
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       ]
      },
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       "id": "36",
       "infons": {
        "identifier": "1956",
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       "id": "37",
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        "identifier": "1956",
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       "text": "EGFR",
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         "offset": 1747,
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      },
      {
       "id": "38",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumor",
       "locations": [
        {
         "offset": 1805,
         "length": 5
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       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "1956",
        "type": "GeneOrGeneProduct"
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       "text": "EGFR",
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         "offset": 1811,
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       ]
      },
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       "id": "40",
       "infons": {
        "identifier": "1956",
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         "length": 4
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       "id": "41",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 1945,
         "length": 8
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumor",
       "locations": [
        {
         "offset": 1987,
         "length": 5
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      }
     ]
    }
   ],
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     "id": "R0",
     "infons": {
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      "novel": "No"
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     "id": "R1",
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     "infons": {
      "entity1": "1956",
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      "type": "Association",
      "novel": "No"
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    {
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     "infons": {
      "entity1": "1956",
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      "type": "Association",
      "novel": "No"
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   ]
  },
  {
   "id": "28393239",
   "passages": [
    {
     "offset": 0,
     "text": "Psoriasin promotes invasion, aggregation and survival of pancreatic cancer cells; association with disease progression.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 0,
         "length": 9
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 57,
         "length": 17
        }
       ]
      }
     ]
    },
    {
     "offset": 120,
     "text": "Psoriasin (S100A7) is an 11-kDa small calcium binding protein initially isolated from psoriatic skin lesions. It belongs to the S100 family of proteins which play an important role in a range of cell functions including proliferation, differentiation, migration and apoptosis. Aberrant Psoriasin expression has been implicated in a range of cancers and is often associated with poor prognosis. This study examined the role of Psoriasin on pancreatic cancer cell functions and the implication in progression of the disease. Expression of Psoriasin was determined in a cohort of pancreatic tissues comprised of 126 pancreatic tumours and 114 adjacent non-tumour pancreatic tissues. Knockdown and overexpression of Psoriasin in pancreatic cancer cells was performed using specifically constructed plasmids, which either had anti-Psoriasin ribozyme transgene or the full length human Psoriasin coding sequence. Psoriasin knockdown and overexpression was verified using conventional RT-PCR and qPCR. The effect of manipulating Psoriasin expression on pancreatic cancer cell functions was assessed using several in vitro cell function assays. Local invasive pancreatic cancers extended beyond the pancreas expressed higher levels of Psoriasin transcripts compared with the cancers confined to the pancreas. Primary tumours with distant metastases exhibited a reduced expression of Psoriasin. Psoriasin overexpression cell lines exhibited significantly increased growth and migration compared to control cells. In addition, Psoriasin overexpression resulted in increased pancreatic cancer cell invasion which was associated with upregulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. Overexpression of Psoriasin also promoted aggregation and survival of pancreatic cancer cells when they lost anchorage. Taken together, higher expression of Psoriasin was associated with local invasion in pancreatic cancers. Psoriasin expression is associated with pancreatic cancer cell growth, migration, cell-matrix adhesion, and invasion via regulation of MMPs. As such, the proposed implications of Psoriasin in invasion, disease progression and as a potential therapeutic target warrant further investigation.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 120,
         "length": 9
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       ]
      },
      {
       "id": "3",
       "infons": {
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       "text": "S100A7",
       "locations": [
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         "length": 6
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
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       "text": "calcium binding protein",
       "locations": [
        {
         "offset": 158,
         "length": 23
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriatic skin lesions",
       "locations": [
        {
         "offset": 206,
         "length": 22
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "S100",
       "locations": [
        {
         "offset": 248,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 406,
         "length": 9
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancers",
       "locations": [
        {
         "offset": 461,
         "length": 7
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 546,
         "length": 9
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 559,
         "length": 17
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 657,
         "length": 9
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic tumours",
       "locations": [
        {
         "offset": 733,
         "length": 18
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 832,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 845,
         "length": 17
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 946,
         "length": 9
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "human",
       "locations": [
        {
         "offset": 994,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1000,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1027,
         "length": 9
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
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       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1142,
         "length": 9
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 1166,
         "length": 17
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancers",
       "locations": [
        {
         "offset": 1272,
         "length": 18
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1347,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cancers",
       "locations": [
        {
         "offset": 1387,
         "length": 7
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Primary tumours",
       "locations": [
        {
         "offset": 1421,
         "length": 15
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D009362",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "metastases",
       "locations": [
        {
         "offset": 1450,
         "length": 10
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1495,
         "length": 9
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1506,
         "length": 9
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1637,
         "length": 9
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 1684,
         "length": 17
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "4313",
        "type": "GeneOrGeneProduct"
       },
       "text": "matrix metalloproteinase-2",
       "locations": [
        {
         "offset": 1758,
         "length": 26
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "4313",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMP-2",
       "locations": [
        {
         "offset": 1786,
         "length": 5
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "4318",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMP-9",
       "locations": [
        {
         "offset": 1797,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1822,
         "length": 9
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 1874,
         "length": 17
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 1961,
         "length": 9
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancers",
       "locations": [
        {
         "offset": 2009,
         "length": 18
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 2029,
         "length": 9
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "D010190",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pancreatic cancer",
       "locations": [
        {
         "offset": 2069,
         "length": 17
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "4313,4318",
        "type": "GeneOrGeneProduct"
       },
       "text": "MMPs",
       "locations": [
        {
         "offset": 2164,
         "length": 4
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "6278",
        "type": "GeneOrGeneProduct"
       },
       "text": "Psoriasin",
       "locations": [
        {
         "offset": 2208,
         "length": 9
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "D010190",
      "entity2": "4318",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "D010190",
      "entity2": "4313",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "6278",
      "entity2": "D009369",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "6278",
      "entity2": "4318",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "6278",
      "entity2": "4313",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "6278",
      "entity2": "D011565",
      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "6278",
      "entity2": "D010190",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16018252",
   "passages": [
    {
     "offset": 0,
     "text": "Two novel mutations in SRY gene form Chinese sex reversal XY females.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 23,
         "length": 3
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "OMIM:400044",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sex reversal XY",
       "locations": [
        {
         "offset": 45,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 70,
     "text": "The SRY gene (sex determining region on Y chromosome) acts as TDF and is required for regulating male sex determination. SRY represents a transcription factor belonging to the superfamily of genes sharing the HMG-box motif (high-mobility group-box), which acts as DNA binding region. Deletion and inactivating mutations of SRY are among the known causes of XY sex reversal. Here, we described the screening of 10 patients who presented with 46,XY sex reversal for mutations in open reading frame (ORF) of SRY gene. DNA was isolated from blood samples using standard techniques. A 609 bp fragment from the central portion of the SRY gene was amplified, using primers XES-2 and XES-7. The amplified PCR fragments were cloned into the pUCm-T vectors, and direct sequencing were carried out on an ABI 377-3 automated DNA sequencer to detect the mutation. PCR-restriction enzyme digestion was applied to detect the results of DNA sequencing. In two patients,de novo mutations led to an amino acid substitution. An A was replaced by a G in codon 38 upstream of the 5' border outside the HMG box of the SRY gene, resulting in the replacement of the amino acid glutamate by glycine. Another heterozygous T to A transition at the nucleotide position +387 which encodes for a Tyrosine (Tyr) instead of a Term, whereas her father was proven to have the wild-type sequence. These point mutations have been confirmed with PCR-restrict enzyme method. As demonstrated by the Human Gene Mutation Database analysis,homology search, and review of the literature, these two mutations were not described previously and brought the total number of SRY gene nucleotide substitutions (missense/nonsense) to 45. These findings indicated that these amino acid substitutions may be responsible for the sex reversal,not only inside the HMG-box but also outside the HMG-box. The two novel mutations in SRY gene provided valuable information for understanding the molecular mechanism of the patient with 46,XY female sex reversal.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 74,
         "length": 3
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 191,
         "length": 3
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 393,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "OMIM:400044",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "XY sex reversal",
       "locations": [
        {
         "offset": 427,
         "length": 15
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 483,
         "length": 8
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "OMIM:400044",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "46,XY sex reversal",
       "locations": [
        {
         "offset": 511,
         "length": 18
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 575,
         "length": 3
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 698,
         "length": 3
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1014,
         "length": 8
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|SUB|A|CODON38|G",
        "type": "SequenceVariant"
       },
       "text": "A was replaced by a G in codon 38",
       "locations": [
        {
         "offset": 1079,
         "length": 33
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 1166,
         "length": 3
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "p|SUB|E||G",
        "type": "SequenceVariant"
       },
       "text": "glutamate by glycine",
       "locations": [
        {
         "offset": 1223,
         "length": 20
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "c|SUB|T|387|A",
        "type": "SequenceVariant"
       },
       "text": "T to A transition at the nucleotide position +387",
       "locations": [
        {
         "offset": 1266,
         "length": 49
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "c|SUB|Y||X",
        "type": "SequenceVariant"
       },
       "text": "Tyrosine (Tyr) instead of a Term",
       "locations": [
        {
         "offset": 1336,
         "length": 32
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Human",
       "locations": [
        {
         "offset": 1530,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 1697,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "OMIM:400044",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "sex reversal",
       "locations": [
        {
         "offset": 1846,
         "length": 12
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "6736",
        "type": "GeneOrGeneProduct"
       },
       "text": "SRY",
       "locations": [
        {
         "offset": 1944,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 2032,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "OMIM:400044",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "46,XY female sex reversal",
       "locations": [
        {
         "offset": 2045,
         "length": 25
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "OMIM:400044",
      "entity2": "c|SUB|A|CODON38|G",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "OMIM:400044",
      "entity2": "6736",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "OMIM:400044",
      "entity2": "c|SUB|Y||X",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R3",
     "infons": {
      "entity1": "OMIM:400044",
      "entity2": "c|SUB|T|387|A",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R4",
     "infons": {
      "entity1": "OMIM:400044",
      "entity2": "p|SUB|E||G",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    }
   ]
  },
  {
   "id": "16419642",
   "passages": [
    {
     "offset": 0,
     "text": "A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "rs13306592",
        "type": "SequenceVariant"
       },
       "text": "F826Y",
       "locations": [
        {
         "offset": 27,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "4306",
        "type": "GeneOrGeneProduct"
       },
       "text": "mineralocorticoid receptor",
       "locations": [
        {
         "offset": 41,
         "length": 26
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertensives",
       "locations": [
        {
         "offset": 85,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 142,
     "text": "A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "rs41511344",
        "type": "SequenceVariant"
       },
       "text": "S810L",
       "locations": [
        {
         "offset": 187,
         "length": 5
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "4306",
        "type": "GeneOrGeneProduct"
       },
       "text": "mineralocorticoid receptor",
       "locations": [
        {
         "offset": 254,
         "length": 26
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "4306",
        "type": "GeneOrGeneProduct"
       },
       "text": "MR",
       "locations": [
        {
         "offset": 282,
         "length": 2
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "4306",
        "type": "GeneOrGeneProduct"
       },
       "text": "NR3C2",
       "locations": [
        {
         "offset": 299,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 337,
         "length": 12
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 519,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 576,
         "length": 8
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hypertension",
       "locations": [
        {
         "offset": 590,
         "length": 12
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "rs41511344",
        "type": "SequenceVariant"
       },
       "text": "S810L",
       "locations": [
        {
         "offset": 611,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "4306",
        "type": "GeneOrGeneProduct"
       },
       "text": "MR",
       "locations": [
        {
         "offset": 643,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs41511344",
        "type": "SequenceVariant"
       },
       "text": "S810L",
       "locations": [
        {
         "offset": 671,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
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     "text": "Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy.",
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     "text": "BACKGROUND: Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5% of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies. METHODS AND RESULTS: In order to investigate whether the HAART component zidovudine (3'-azido-2',3'-deoxythymidine; AZT) triggers the Fas-dependent cell-death pathway and cause cytoskeletal disruption in a murine model of DCM, 8-week-old transgenic (expressing Fas ligand in the myocardium: FasL Tg) and non-transgenic (NTg) mice received water ad libitum containing different concentrations of AZT (0, 0.07, 0.2, and 0.7 mg/ml). After 6 weeks, cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods. NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function. In contrast, AZT-treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose-dependent manner, with concomitant inflammatory infiltration of both ventricles. These changes were associated with an increased sarcolemmal expression of Fas and FasL, as well as increased activation of caspase 3, translocation of calpain 1 to the sarcolemma and sarcomere, and increased numbers of cells undergoing apoptosis. These were associated with changes in dystrophin and cardiac troponin I localization, as well as loss of sarcolemmal integrity. CONCLUSIONS: The expression of Fas ligand in the myocardium, as identified in HIV-positive patients, might increase the susceptibility to HAART-induced cardiomyopathy due to activation of apoptotic pathways, resulting in cardiac dilation and dysfunction.",
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         "offset": 86,
         "length": 19
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      {
       "id": "2",
       "infons": {
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        "type": "DiseaseOrPhenotypicFeature"
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       "text": "apparent mineralocorticoid excess",
       "locations": [
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     "offset": 145,
     "text": "Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11b-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension.",
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     "text": "Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD).",
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        "type": "OrganismTaxon"
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       "text": "humans",
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         "offset": 253,
         "length": 6
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "nonalcoholic fatty liver disease",
       "locations": [
        {
         "offset": 261,
         "length": 32
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NAFLD",
       "locations": [
        {
         "offset": 295,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
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       "text": "PEMT",
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         "offset": 327,
         "length": 4
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "humans",
       "locations": [
        {
         "offset": 372,
         "length": 6
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D005234",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "fatty liver",
       "locations": [
        {
         "offset": 387,
         "length": 11
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "humans",
       "locations": [
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         "offset": 411,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "NAFLD",
       "locations": [
        {
         "offset": 423,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "10400",
        "type": "GeneOrGeneProduct"
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       "text": "PEMT",
       "locations": [
        {
         "offset": 494,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "V175M",
       "locations": [
        {
         "offset": 517,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
       },
       "text": "V175M",
       "locations": [
        {
         "offset": 537,
         "length": 5
        }
       ]
      },
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       "id": "20",
       "infons": {
        "identifier": "CVCL_0444",
        "type": "CellLine"
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         "offset": 617,
         "length": 14
        }
       ]
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       "id": "21",
       "infons": {
        "identifier": "25511",
        "type": "GeneOrGeneProduct"
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       "text": "PEMT",
       "locations": [
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         "offset": 667,
         "length": 4
        }
       ]
      },
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       "id": "22",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
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       "text": "V175M",
       "locations": [
        {
         "offset": 698,
         "length": 5
        }
       ]
      },
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       "id": "23",
       "infons": {
        "identifier": "rs7946",
        "type": "SequenceVariant"
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       "text": "Met/Met at residue 175",
       "locations": [
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         "offset": 712,
         "length": 22
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       ]
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       "id": "24",
       "infons": {
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       "text": "NAFLD",
       "locations": [
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         "offset": 783,
         "length": 5
        }
       ]
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       "id": "25",
       "infons": {
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       "text": "human",
       "locations": [
        {
         "offset": 902,
         "length": 5
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       ]
      },
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       "id": "26",
       "infons": {
        "identifier": "10400",
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       "text": "PEMT",
       "locations": [
        {
         "offset": 908,
         "length": 4
        }
       ]
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        "type": "SequenceVariant"
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         "offset": 919,
         "length": 5
        }
       ]
      },
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       "id": "28",
       "infons": {
        "identifier": "D065626",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "NAFLD",
       "locations": [
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         "offset": 998,
         "length": 5
        }
       ]
      }
     ]
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   ],
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     "id": "R0",
     "infons": {
      "entity1": "18618",
      "entity2": "D005234",
      "type": "Negative_Correlation",
      "novel": "No"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "25511",
      "entity2": "D065626",
      "type": "Association",
      "novel": "Novel"
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    },
    {
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    },
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    }
   ]
  },
  {
   "id": "19880293",
   "passages": [
    {
     "offset": 0,
     "text": "Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 21,
         "length": 5
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 47,
         "length": 9
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 57,
         "length": 8
        }
       ]
      }
     ]
    },
    {
     "offset": 67,
     "text": "BACKGROUND: Psoriasis is a common dermatological disorder, in which autoimmunity plays an important role. CD4(+)CD25(+) regulatory T cells (T-regs) have been suggested to be involved in the pathogenesis of some autoimmune diseases. T-regs express the fork head/winged helix transcription factor, FOXP3, which appears to be of key importance in the development and function of T-regs. Studies have found that single-nucleotide polymorphisms (SNPs) in the FOXP3 gene contribute to susceptibility to some autoimmune disorders. However, information about FOXP3 gene in psoriasis is limited. OBJECTIVE: This study evaluated the association between FOXP3 gene SNPs and susceptibility to psoriasis in a Han Chinese population. METHODS: In a hospital-based case-control study, 524 patients with psoriasis and 549 psoriasis-free controls were recruited according to age and gender. We investigated four SNPs in the FOXP3 gene (-6054, deletion/ATT; -3279, A/C; -924, A/G; IVS9+459, A/G) in psoriatic patients, and assessed allele and genotype frequencies in psoriatic patients (237 females, 287 males) and normal controls (272 females, 277 males). The polymorphisms were genotyped using the PCR sequence-specific primer (PCR-SSP) technique and PCR-restriction fragment length polymorphism (RFLP) analysis. RESULTS: We found that increased risk of psoriasis was associated with the FOXP3 -3279 AC genotype (adjusted OR, 1.32; 95% CI, 1.01-1.74) and the combined AC+AA genotype (adjusted OR, 1.38; 95% CI, 1.07-1.78), compared with the -3279 CC genotype. We also found that an increased risk of psoriasis was associated with the FOXP3 IVS9+459 GG genotype (adjusted OR, 2.24; 95% CI, 1.41-3.58). However, the combined GA+GG genotype showed no such tendency (adjusted OR=1.28; 95% CI, 1.00-1.64), compared with the IVS9+459 AA genotype. There was no evidence of an increased risk associated with the FOXP3-6054 deletion/ATT or FOXP3-924 A/G genotype. In combined genotype analyses, the FOXP3-3279 AC+AA genotype was more obviously associated in males (adjusted OR=1.60, 95% CI=1.11-2.31) and severe psoriasis patients (PASI score >20; adjusted OR=1.97, 95% CI=1.41-2.75). Meanwhile, the FOXP3 IVS9+459 GA+GG genotype was also associated with severe psoriasis patients (adjusted OR=1.69, 95% CI=1.21-2.36). CONCLUSIONS: FOXP3 polymorphisms appear to contribute to the risk of psoriasis in a Han Chinese population. Larger studies are needed to confirm these findings.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Psoriasis",
       "locations": [
        {
         "offset": 79,
         "length": 9
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D012871",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "dermatological disorder",
       "locations": [
        {
         "offset": 101,
         "length": 23
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "920",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD4",
       "locations": [
        {
         "offset": 173,
         "length": 3
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "3559",
        "type": "GeneOrGeneProduct"
       },
       "text": "CD25",
       "locations": [
        {
         "offset": 179,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D001327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autoimmune diseases",
       "locations": [
        {
         "offset": 278,
         "length": 19
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 363,
         "length": 5
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 521,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autoimmune disorders",
       "locations": [
        {
         "offset": 569,
         "length": 20
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 618,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 632,
         "length": 9
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 710,
         "length": 5
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 748,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 840,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 854,
         "length": 9
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 872,
         "length": 9
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 973,
         "length": 5
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "c|DEL|-6054|ATT",
        "type": "SequenceVariant"
       },
       "text": "-6054, deletion/ATT",
       "locations": [
        {
         "offset": 985,
         "length": 19
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "c|SUB|A|-3279|C",
        "type": "SequenceVariant"
       },
       "text": "-3279, A/C",
       "locations": [
        {
         "offset": 1006,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "c|SUB|A|-924|G",
        "type": "SequenceVariant"
       },
       "text": "-924, A/G",
       "locations": [
        {
         "offset": 1018,
         "length": 9
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "c|SUB|A|IVS9+459|G",
        "type": "SequenceVariant"
       },
       "text": "IVS9+459, A/G",
       "locations": [
        {
         "offset": 1029,
         "length": 13
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriatic",
       "locations": [
        {
         "offset": 1047,
         "length": 9
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1057,
         "length": 8
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriatic",
       "locations": [
        {
         "offset": 1115,
         "length": 9
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1125,
         "length": 8
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 1404,
         "length": 9
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 1438,
         "length": 5
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "c|Allele|AC|-3297",
        "type": "SequenceVariant"
       },
       "text": "-3279 AC",
       "locations": [
        {
         "offset": 1444,
         "length": 8
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "c|Allele|CC|-3279",
        "type": "SequenceVariant"
       },
       "text": "-3279 CC",
       "locations": [
        {
         "offset": 1591,
         "length": 8
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 1650,
         "length": 9
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 1684,
         "length": 5
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "c|Allele|GG|IVS9+459",
        "type": "SequenceVariant"
       },
       "text": "IVS9+459 GG",
       "locations": [
        {
         "offset": 1690,
         "length": 11
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "c|Allele|AA|IVS9+459",
        "type": "SequenceVariant"
       },
       "text": "IVS9+459 AA",
       "locations": [
        {
         "offset": 1869,
         "length": 11
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 1954,
         "length": 5
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "c|DEL|-6054|ATT",
        "type": "SequenceVariant"
       },
       "text": "-6054 deletion/ATT",
       "locations": [
        {
         "offset": 1959,
         "length": 18
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 1981,
         "length": 5
        }
       ]
      },
      {
       "id": "38",
       "infons": {
        "identifier": "c|SUB|A|-924|G",
        "type": "SequenceVariant"
       },
       "text": "-924 A/G",
       "locations": [
        {
         "offset": 1986,
         "length": 8
        }
       ]
      },
      {
       "id": "39",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 2040,
         "length": 5
        }
       ]
      },
      {
       "id": "40",
       "infons": {
        "identifier": "c|Allele|AC|-3279",
        "type": "SequenceVariant"
       },
       "text": "-3279 AC+AA",
       "locations": [
        {
         "offset": 2045,
         "length": 11
        }
       ]
      },
      {
       "id": "41",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 2153,
         "length": 9
        }
       ]
      },
      {
       "id": "42",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 2163,
         "length": 8
        }
       ]
      },
      {
       "id": "43",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
       },
       "text": "FOXP3",
       "locations": [
        {
         "offset": 2241,
         "length": 5
        }
       ]
      },
      {
       "id": "44",
       "infons": {
        "identifier": "c|Allele|GA|IVS9+459",
        "type": "SequenceVariant"
       },
       "text": "IVS9+459 GA+GG",
       "locations": [
        {
         "offset": 2247,
         "length": 14
        }
       ]
      },
      {
       "id": "45",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "psoriasis",
       "locations": [
        {
         "offset": 2303,
         "length": 9
        }
       ]
      },
      {
       "id": "46",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patients",
       "locations": [
        {
         "offset": 2313,
         "length": 8
        }
       ]
      },
      {
       "id": "47",
       "infons": {
        "identifier": "50943",
        "type": "GeneOrGeneProduct"
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       "text": "FOXP3",
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        {
         "offset": 2373,
         "length": 5
        }
       ]
      },
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       "id": "48",
       "infons": {
        "identifier": "D011565",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "psoriasis",
       "locations": [
        {
         "offset": 2429,
         "length": 9
        }
       ]
      }
     ]
    }
   ],
   "relations": [
    {
     "id": "R0",
     "infons": {
      "entity1": "c|Allele|GA|IVS9+459",
      "entity2": "D011565",
      "type": "Positive_Correlation",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|Allele|AC|-3279",
      "entity2": "D011565",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
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  {
   "id": "21903317",
   "passages": [
    {
     "offset": 0,
     "text": "Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5972",
        "type": "GeneOrGeneProduct"
       },
       "text": "renin",
       "locations": [
        {
         "offset": 53,
         "length": 5
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       ]
      },
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       "id": "1",
       "infons": {
        "identifier": "D000740",
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       },
       "text": "anemia",
       "locations": [
        {
         "offset": 77,
         "length": 6
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D033461",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperuricemia",
       "locations": [
        {
         "offset": 85,
         "length": 13
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D051436",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CKD",
       "locations": [
        {
         "offset": 104,
         "length": 3
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       ]
      }
     ]
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     "offset": 109,
     "text": "Homozygous or compound heterozygous mutations in renin (REN) cause renal tubular dysgenesis, which is characterized by death in utero due to kidney failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia, and chronic kidney disease (CKD). To date, only 3 different heterozygous REN mutations have been published. We report mutation analysis of the REN gene in 39 kindreds with hyperuricemia and CKD who previously tested negative for mutations in the UMOD (uromodulin) and HNF1B (hepatocyte nuclear factor 1b) genes. We identified one kindred with a novel thymidine to cytosine mutation at position 28 in the REN complementary DNA, corresponding to a tryptophan to arginine substitution at amino acid 10, which is found within the signal sequence (c.28T>C; p.W10R). On this basis, we conclude that REN mutations are rare events in patients with CKD. Within the kindred, we found affected individuals over 4 generations who carried the novel REN mutation and were characterized by significant anemia, hyperuricemia, and CKD. Anemia was severe and disproportional to the degree of decreased kidney function. Because all heterozygous REN mutations that have been described are localized in the signal sequence, screening of the REN gene for patients with CKD with hyperuricemia and anemia may best be focused on sequencing of exon 1, which encodes the signal peptide.",
     "annotations": [
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       "id": "4",
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        "identifier": "5972",
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       "text": "renin",
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        "identifier": "5972",
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       "text": "REN",
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         "offset": 165,
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       "id": "6",
       "infons": {
        "identifier": "C537048",
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       },
       "text": "renal tubular dysgenesis",
       "locations": [
        {
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       ]
      },
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       "id": "7",
       "infons": {
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       },
       "text": "death",
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         "offset": 228,
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       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "D051437",
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       },
       "text": "kidney failure",
       "locations": [
        {
         "offset": 250,
         "length": 14
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       ]
      },
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       "id": "9",
       "infons": {
        "identifier": "D008171",
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       },
       "text": "pulmonary hypoplasia",
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        {
         "offset": 269,
         "length": 20
        }
       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "C576203",
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       },
       "text": "fetopathy",
       "locations": [
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         "offset": 319,
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       ]
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       "id": "11",
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        "identifier": "D000806",
        "type": "ChemicalEntity"
       },
       "text": "angiotensin-converting enzyme inhibitor",
       "locations": [
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         "offset": 339,
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        }
       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "D057911",
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       },
       "text": "angiotensin receptor blocker",
       "locations": [
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        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "5972",
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       "text": "REN",
       "locations": [
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         "offset": 459,
         "length": 3
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       ]
      },
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       "id": "14",
       "infons": {
        "identifier": "D033461",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperuricemia",
       "locations": [
        {
         "offset": 509,
         "length": 13
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000740",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anemia",
       "locations": [
        {
         "offset": 524,
         "length": 6
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D051436",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "chronic kidney disease",
       "locations": [
        {
         "offset": 536,
         "length": 22
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D051436",
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       "text": "CKD",
       "locations": [
        {
         "offset": 560,
         "length": 3
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "5972",
        "type": "GeneOrGeneProduct"
       },
       "text": "REN",
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         "offset": 605,
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       ]
      },
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       "id": "19",
       "infons": {
        "identifier": "5972",
        "type": "GeneOrGeneProduct"
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       "text": "REN",
       "locations": [
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         "offset": 675,
         "length": 3
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D033461",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "hyperuricemia",
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       ]
      },
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       "id": "21",
       "infons": {
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       "text": "CKD",
       "locations": [
        {
         "offset": 722,
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       ]
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       "id": "22",
       "infons": {
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       "text": "UMOD",
       "locations": [
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         "offset": 778,
         "length": 4
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       ]
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       "id": "23",
       "infons": {
        "identifier": "7369",
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       "text": "uromodulin",
       "locations": [
        {
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         "length": 10
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       ]
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       "id": "24",
       "infons": {
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       },
       "text": "HNF1B",
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       ]
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       "id": "25",
       "infons": {
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       "text": "hepatocyte nuclear factor 1b",
       "locations": [
        {
         "offset": 807,
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       ]
      },
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       "id": "26",
       "infons": {
        "identifier": "c|SUB|T|28|C",
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       },
       "text": "thymidine to cytosine mutation at position 28",
       "locations": [
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         "length": 45
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "5972",
        "type": "GeneOrGeneProduct"
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       "text": "REN",
       "locations": [
        {
         "offset": 936,
         "length": 3
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       ]
      },
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       "id": "28",
       "infons": {
        "identifier": "p|SUB|W|10|R",
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       },
       "text": "tryptophan to arginine substitution at amino acid 10",
       "locations": [
        {
         "offset": 978,
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        }
       ]
      },
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       "id": "29",
       "infons": {
        "identifier": "c|SUB|T|28|C",
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       "text": "c.28T>C",
       "locations": [
        {
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       "id": "30",
       "infons": {
        "identifier": "p|SUB|W|10|R",
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       "text": "p.W10R",
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         "length": 6
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "5972",
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       "text": "REN",
       "locations": [
        {
         "offset": 1125,
         "length": 3
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       ]
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       "id": "32",
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       "text": "patients",
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         "offset": 1158,
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       ]
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       "id": "33",
       "infons": {
        "identifier": "D051436",
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       "text": "CKD",
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         "length": 3
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       ]
      },
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       "id": "34",
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       "text": "REN",
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         "offset": 1268,
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       ]
      },
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       "id": "35",
       "infons": {
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       "text": "anemia",
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       "id": "36",
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       "text": "hyperuricemia",
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       "text": "Anemia",
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       "id": "39",
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       "id": "40",
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       "text": "REN",
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       "text": "patients",
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       "id": "42",
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       "text": "CKD",
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        {
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       "id": "43",
       "infons": {
        "identifier": "D033461",
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       "text": "hyperuricemia",
       "locations": [
        {
         "offset": 1588,
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       "id": "44",
       "infons": {
        "identifier": "D000740",
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       "text": "anemia",
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  {
   "id": "27103577",
   "passages": [
    {
     "offset": 0,
     "text": "On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "19013",
        "type": "GeneOrGeneProduct"
       },
       "text": "PPARa",
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         "length": 5
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       "id": "1",
       "infons": {
        "identifier": "D000860",
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       "text": "hypoxia",
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       "id": "2",
       "infons": {
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       "text": "hypoxic",
       "locations": [
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       ]
      }
     ]
    },
    {
     "offset": 117,
     "text": "The role of peroxisome proliferator-activated receptor a (PPARa)-mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 wk before in vivo contractile function was measured using cine MRI. In isolated, perfused hearts, energetics were measured using (31)P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [(3)H] labeling. Compared with a normoxic, chow-fed control mouse heart, hypoxia decreased PPARa expression, fatty acid oxidation, and mitochondrial uncoupling protein 3 (UCP3) levels, while increasing glycolysis, all of which served to maintain normal ATP concentrations ([ATP]) and thereby, ejection fractions. A high-fat diet increased cardiac PPARa expression, fatty acid oxidation, and UCP3 levels with decreased glycolysis. Hypoxia was unable to alter the high PPARa expression or reverse the metabolic changes caused by the high-fat diet, with the result that [ATP] and contractile function decreased significantly. The adaptive metabolic changes caused by hypoxia in control mouse hearts were found to have occurred already in PPARa-deficient (PPARa(-/-)) mouse hearts and sustained function in hypoxia despite an inability for further metabolic remodeling. We conclude that decreased cardiac PPARa expression is essential for adaptive metabolic remodeling in hypoxia, but is prevented by dietary fat.-Cole, M. A., Abd Jamil, A. H., Heather, L. C., Murray, A. J., Sutton, E. R., Slingo, M., Sebag-Montefiore, L., Tan, S. C., Aksentijevic, D., Gildea, O. S., Stuckey, D. J., Yeoh, K. K., Carr, C. A., Evans, R. D., Aasum, E., Schofield, C. J., Ratcliffe, P. J., Neubauer, S., Robbins, P. A., Clarke, K. On the pivotal role of PPARa in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.",
     "annotations": [
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       "id": "3",
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        "identifier": "19013",
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       "text": "peroxisome proliferator-activated receptor a",
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       "id": "4",
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       "text": "PPARa",
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       "id": "5",
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        "identifier": "D000860",
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       "text": "hypoxia",
       "locations": [
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         "offset": 237,
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       ]
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       "id": "6",
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        "identifier": "10090",
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       "text": "mice",
       "locations": [
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         "offset": 274,
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       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "D000860",
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       "text": "hypoxia",
       "locations": [
        {
         "offset": 294,
         "length": 7
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D005227",
        "type": "ChemicalEntity"
       },
       "text": "fatty acid",
       "locations": [
        {
         "offset": 501,
         "length": 10
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D014316",
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       "text": "(3)H",
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         "offset": 543,
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       ]
      },
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       "id": "10",
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       "text": "mouse",
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      },
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       "id": "11",
       "infons": {
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       "text": "hypoxia",
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         "offset": 615,
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       ]
      },
      {
       "id": "12",
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       "text": "PPARa",
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         "offset": 633,
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       ]
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       "id": "13",
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       "text": "fatty acid",
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       ]
      },
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       "id": "14",
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       "text": "mitochondrial uncoupling protein 3",
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   ]
  },
  {
   "id": "16611040",
   "passages": [
    {
     "offset": 0,
     "text": "Gene therapy for cystic fibrosis airway disease- is clinical success imminent?",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D003550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cystic fibrosis",
       "locations": [
        {
         "offset": 17,
         "length": 15
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       ]
      }
     ]
    },
    {
     "offset": 79,
     "text": "Cystic fibrosis (CF) was one of the first inherited disorders for which gene therapy was seriously considered as a realistic option for treatment, and as such, it has long provided a paradigm for gene therapy of inherited diseases. However, despite the cloning of the cystic fibrosis transmembrane conductance regulator gene in 1989, over 15 years later a practical gene therapy for CF has not eventuated. There are a number of reasons for this, and analysis of the specific issues that have delayed the successful development of gene therapy for CF also provides general insights into the practical complexities involved in the development of gene therapy for inherited disorders. The issues which have prevented the application of gene therapy for CF to date include the lack of suitable gene delivery technologies, the complexities of the interactions between the host and vector, the biology of the lung airways, and the nature of the pathology found in individuals with CF. We will discuss the history of CF gene therapy with specific reference to these and other issues that pre-occupy the field at present: namely, the question of what vectors appear to be suitable for airway gene delivery in CF, what cells must be targeted, how airway epithelium defences can be overcome or eluded to allow efficient gene delivery, how to ensure safe and long-term transgene expression and the need to identify relevant surrogate success measures that can be used to assess the outcome of gene therapy in CF patients.",
     "annotations": [
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       "id": "1",
       "infons": {
        "identifier": "D003550",
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       "text": "Cystic fibrosis",
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         "offset": 79,
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       "id": "2",
       "infons": {
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       "text": "CF",
       "locations": [
        {
         "offset": 96,
         "length": 2
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D030342",
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       },
       "text": "inherited disorders",
       "locations": [
        {
         "offset": 121,
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D030342",
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       },
       "text": "inherited diseases",
       "locations": [
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         "offset": 291,
         "length": 18
        }
       ]
      },
      {
       "id": "5",
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        "identifier": "1080",
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       },
       "text": "cystic fibrosis transmembrane conductance regulator",
       "locations": [
        {
         "offset": 347,
         "length": 51
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D003550",
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       },
       "text": "CF",
       "locations": [
        {
         "offset": 462,
         "length": 2
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D003550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CF",
       "locations": [
        {
         "offset": 626,
         "length": 2
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D030342",
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       },
       "text": "inherited disorders",
       "locations": [
        {
         "offset": 740,
         "length": 19
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D003550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CF",
       "locations": [
        {
         "offset": 829,
         "length": 2
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D003550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CF",
       "locations": [
        {
         "offset": 1054,
         "length": 2
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D003550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CF",
       "locations": [
        {
         "offset": 1089,
         "length": 2
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D003550",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "CF",
       "locations": [
        {
         "offset": 1280,
         "length": 2
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D003550",
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       "text": "CF",
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        {
         "offset": 1577,
         "length": 2
        }
       ]
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       "id": "14",
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       "text": "patients",
       "locations": [
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         "offset": 1580,
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     ]
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   ],
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      "novel": "No"
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    }
   ]
  },
  {
   "id": "17033974",
   "passages": [
    {
     "offset": 0,
     "text": "Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
       },
       "text": "calcium",
       "locations": [
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         "offset": 26,
         "length": 7
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       ]
      },
      {
       "id": "1",
       "infons": {
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       "text": "CACNA2D4",
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      },
      {
       "id": "2",
       "infons": {
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       "text": "cone dystrophy",
       "locations": [
        {
         "offset": 86,
         "length": 14
        }
       ]
      }
     ]
    },
    {
     "offset": 102,
     "text": "Retinal signal transmission depends on the activity of high voltage-gated l-type calcium channels in photoreceptor ribbon synapses. We recently identified a truncating frameshift mutation in the Cacna2d4 gene in a spontaneous mouse mutant with profound loss of retinal signaling and an abnormal morphology of ribbon synapses in rods and cones. The Cacna2d4 gene encodes an l-type calcium-channel auxiliary subunit of the alpha (2) delta type. Mutations in its human orthologue, CACNA2D4, were not yet known to be associated with a disease. We performed mutation analyses of 34 patients who received an initial diagnosis of night blindness, and, in two affected siblings, we detected a homozygous nucleotide substitution (c.2406C-->A) in CACNA2D4. The mutation introduces a premature stop codon that truncates one-third of the corresponding open reading frame. Both patients share symptoms of slowly progressing cone dystrophy. These findings represent the first report of a mutation in the human CACNA2D4 gene and define a novel gene defect that causes autosomal recessive cone dystrophy.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "D002118",
        "type": "ChemicalEntity"
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       "text": "calcium",
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         "offset": 183,
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       ]
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       "id": "4",
       "infons": {
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       "text": "Cacna2d4",
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       "id": "5",
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       "text": "mouse",
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       ]
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       "infons": {
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       "text": "Cacna2d4",
       "locations": [
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         "length": 8
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       ]
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       "id": "7",
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        "identifier": "781",
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       "text": "l-type calcium-channel auxiliary subunit of the alpha (2) delta type",
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         "offset": 475,
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       ]
      },
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       "id": "8",
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       "text": "human",
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         "offset": 562,
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       ]
      },
      {
       "id": "9",
       "infons": {
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       "text": "CACNA2D4",
       "locations": [
        {
         "offset": 580,
         "length": 8
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       ]
      },
      {
       "id": "10",
       "infons": {
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       "text": "patients",
       "locations": [
        {
         "offset": 679,
         "length": 8
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D009755",
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       },
       "text": "night blindness",
       "locations": [
        {
         "offset": 725,
         "length": 15
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       ]
      },
      {
       "id": "12",
       "infons": {
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       "text": "c.2406C-->A",
       "locations": [
        {
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       ]
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       "id": "13",
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       "text": "CACNA2D4",
       "locations": [
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         "length": 8
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       ]
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      {
       "id": "14",
       "infons": {
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       "text": "patients",
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         "length": 8
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000077765",
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       "text": "cone dystrophy",
       "locations": [
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         "offset": 1013,
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       ]
      },
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       "id": "16",
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       "text": "human",
       "locations": [
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         "offset": 1092,
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       ]
      },
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       "infons": {
        "identifier": "93589",
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       "text": "CACNA2D4",
       "locations": [
        {
         "offset": 1098,
         "length": 8
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       ]
      },
      {
       "id": "18",
       "infons": {
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       "text": "cone dystrophy",
       "locations": [
        {
         "offset": 1175,
         "length": 14
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       ]
      }
     ]
    }
   ],
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      "novel": "No"
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    }
   ]
  },
  {
   "id": "24014394",
   "passages": [
    {
     "offset": 0,
     "text": "A homozygous mutation in LYRM7/MZM1L associated with early onset encephalopathy, lactic acidosis, and severe reduction of mitochondrial complex III activity.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "90624",
        "type": "GeneOrGeneProduct"
       },
       "text": "LYRM7",
       "locations": [
        {
         "offset": 25,
         "length": 5
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "90624",
        "type": "GeneOrGeneProduct"
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       "text": "MZM1L",
       "locations": [
        {
         "offset": 31,
         "length": 5
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "encephalopathy",
       "locations": [
        {
         "offset": 65,
         "length": 14
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D000140",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lactic acidosis",
       "locations": [
        {
         "offset": 81,
         "length": 15
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "C565128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "reduction of mitochondrial complex III",
       "locations": [
        {
         "offset": 109,
         "length": 38
        }
       ]
      }
     ]
    },
    {
     "offset": 158,
     "text": "Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we identified a disease-segregating homozygous mutation (c.73G>A) in LYRM7/MZM1L, predicting a drastic change in a highly conserved amino-acid residue (p.Asp25Asn). In a mzm1D yeast strain, the expression of a mzm1(D25N) mutant allele caused temperature-sensitive respiratory growth defect, decreased oxygen consumption, impaired maturation/stabilization of the Rieske Fe-S protein, and reduced complex III activity and amount. LYRM7/MZM1L is a novel disease gene, causing cIII-defective, early onset, severe mitochondrial encephalopathy.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "C565128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "defective complex III (cIII) of the mitochondrial",
       "locations": [
        {
         "offset": 201,
         "length": 49
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "617",
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       "text": "cIII",
       "locations": [
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         "offset": 309,
         "length": 4
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "617",
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       "text": "cIII",
       "locations": [
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         "offset": 381,
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       ]
      },
      {
       "id": "8",
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       "text": "human",
       "locations": [
        {
         "offset": 417,
         "length": 5
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "90624",
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       "text": "LYRM7",
       "locations": [
        {
         "offset": 423,
         "length": 5
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "90624",
        "type": "GeneOrGeneProduct"
       },
       "text": "MZM1L",
       "locations": [
        {
         "offset": 429,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "4932",
        "type": "OrganismTaxon"
       },
       "text": "yeast",
       "locations": [
        {
         "offset": 452,
         "length": 5
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "852104",
        "type": "GeneOrGeneProduct"
       },
       "text": "MZM1",
       "locations": [
        {
         "offset": 458,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "617",
        "type": "GeneOrGeneProduct"
       },
       "text": "cIII",
       "locations": [
        {
         "offset": 513,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 529,
         "length": 7
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D001927",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "encephalopathy",
       "locations": [
        {
         "offset": 562,
         "length": 14
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D000140",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lactic acidosis",
       "locations": [
        {
         "offset": 578,
         "length": 15
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "C565128",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "cIII deficiency",
       "locations": [
        {
         "offset": 617,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "rs587777433",
        "type": "SequenceVariant"
       },
       "text": "c.73G>A",
       "locations": [
        {
         "offset": 710,
         "length": 7
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "90624",
        "type": "GeneOrGeneProduct"
       },
       "text": "LYRM7",
       "locations": [
        {
         "offset": 722,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "90624",
        "type": "GeneOrGeneProduct"
       },
       "text": "MZM1L",
       "locations": [
        {
         "offset": 728,
         "length": 5
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "rs587777433",
        "type": "SequenceVariant"
       },
       "text": "p.Asp25Asn",
       "locations": [
        {
         "offset": 805,
         "length": 10
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "852104",
        "type": "GeneOrGeneProduct"
       },
       "text": "mzm1D",
       "locations": [
        {
         "offset": 823,
         "length": 5
        }
       ]
      },
      {
       "id": "23",
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       "id": "29",
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       "text": "complex III",
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       "id": "32",
       "infons": {
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       "text": "cIII-defective",
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       "id": "33",
       "infons": {
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       "text": "mitochondrial encephalopathy",
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  },
  {
   "id": "15018851",
   "passages": [
    {
     "offset": 0,
     "text": "Comparison of sequential cytomegalovirus isolates in a patient with lymphoma and failing antiviral therapy.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "10358",
        "type": "OrganismTaxon"
       },
       "text": "cytomegalovirus",
       "locations": [
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         "offset": 25,
         "length": 15
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      {
       "id": "1",
       "infons": {
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        "type": "OrganismTaxon"
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       "text": "patient",
       "locations": [
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         "offset": 55,
         "length": 7
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       ]
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      {
       "id": "2",
       "infons": {
        "identifier": "D008223",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "lymphoma",
       "locations": [
        {
         "offset": 68,
         "length": 8
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       ]
      }
     ]
    },
    {
     "offset": 108,
     "text": "BACKGROUND: Long-term anti-cytomegalovirus (CMV) treatments in immunocompromised patients are hampered by resistance to antiviral drugs. Longitudinal changes in the resistance genotype may depend on changes in selective pressure and the complexity of CMV isolates. OBJECTIVE: To evaluate longitudinal changes in the CMV resistance genotype and phenotype along with strain-specific variability in a patient with non-Hodgkin's lymphoma in whom successive anti-CMV treatments failed. STUDY DESIGN: The resistance phenotype and genotype of seven CMV isolates collected from one patient during a 2-year follow-up period were retrospectively analysed. In parallel, we used glycoprotein B (gB) genotyping, and a- and UL10-13-sequence analysis to study CMV interstrain variability. RESULTS: The patient was infected by at least three CMV strains plus variants of the parental strains. Resistance to ganciclovir, cidofovir and foscarnet was successively detected during the follow-up period. UL97 protein kinase changes responsible for resistance to ganciclovir were initially detected at residues 591 and 592, and then at position 594. Decreased sensitivity to foscarnet coincided with the appearance of amino acid substitution N495K in DNA polymerase, whereas cross-resistance to ganciclovir and cidofovir was due to the L501I substitution. CONCLUSIONS: The CMV isolates obtained from our patient were complex mixtures of strains. Changes in resistance genotypes depended on resistance selective pressure and were not linked to interstrain variation.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "D003586",
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       "text": "Long-term anti-cytomegalovirus",
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         "offset": 120,
         "length": 30
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       "id": "4",
       "infons": {
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       "text": "CMV",
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         "offset": 152,
         "length": 3
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       "text": "patients",
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         "offset": 189,
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       "id": "6",
       "infons": {
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       "text": "CMV",
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         "offset": 359,
         "length": 3
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       "id": "7",
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       "text": "CMV",
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         "offset": 424,
         "length": 3
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       "text": "patient",
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         "offset": 506,
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       "infons": {
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       "text": "non-Hodgkin's lymphoma",
       "locations": [
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         "offset": 519,
         "length": 22
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       "id": "10",
       "infons": {
        "identifier": "D003586",
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       "text": "CMV",
       "locations": [
        {
         "offset": 566,
         "length": 3
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D003586",
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       "text": "CMV",
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        {
         "offset": 650,
         "length": 3
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       ]
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       "id": "12",
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       "text": "patient",
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         "length": 7
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       ]
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       "id": "13",
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       "text": "glycoprotein B",
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       "id": "14",
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       "text": "gB",
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       "id": "15",
       "infons": {
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       "text": "CMV",
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         "offset": 853,
         "length": 3
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       "id": "16",
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       "text": "patient",
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       "id": "17",
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       "text": "CMV",
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       "id": "18",
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       "text": "ganciclovir",
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       "infons": {
        "identifier": "D000077404",
        "type": "ChemicalEntity"
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       "text": "cidofovir",
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         "length": 9
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       "id": "20",
       "infons": {
        "identifier": "D017245",
        "type": "ChemicalEntity"
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       "text": "foscarnet",
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         "length": 9
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       "id": "21",
       "infons": {
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        "type": "GeneOrGeneProduct"
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       "text": "UL97 protein kinase",
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         "length": 19
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       "id": "22",
       "infons": {
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        "type": "ChemicalEntity"
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       "text": "ganciclovir",
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       "text": "foscarnet",
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       "id": "24",
       "infons": {
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         "length": 5
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       "id": "25",
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       "text": "ganciclovir",
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       "id": "26",
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       "text": "cidofovir",
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         "length": 9
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       "id": "27",
       "infons": {
        "identifier": "p|SUB|L|501|I",
        "type": "SequenceVariant"
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       "text": "L501I",
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         "offset": 1422,
         "length": 5
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D003586",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "CMV",
       "locations": [
        {
         "offset": 1459,
         "length": 3
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "patient",
       "locations": [
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         "offset": 1490,
         "length": 7
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     "infons": {
      "entity1": "D000077404",
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     "infons": {
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      "entity2": "D015774",
      "type": "Negative_Correlation",
      "novel": "No"
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     "infons": {
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      "type": "Association",
      "novel": "No"
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    }
   ]
  },
  {
   "id": "17671735",
   "passages": [
    {
     "offset": 0,
     "text": "Coincidence of mutations in different connexin genes in Hungarian patients.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 66,
         "length": 8
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       ]
      }
     ]
    },
    {
     "offset": 76,
     "text": "Mutations in the GJB2 gene are the most common cause of hereditary prelingual sensorineural hearing impairment in Europe. Several studies indicate that different members of the connexin protein family interact to form gap junctions in the inner ear. Mutations in different connexin genes may accumulate and, consequently lead to hearing impairment. Therefore, we screened 47 Hungarian GJB2- heterozygous (one mutation in coding exon of the GJB2 gene) patients with hearing impairment for DNA changes in two further connexin genes (GJB6 and GJB3) and in the 5' non-coding region of GJB2 including the splice sites. Eleven out of 47 GJB2-heterozygous patients analyzed carried the splice site mutation -3170G>A in the 5'UTR region of GJB2. One out of these 11 patients showed homozygous -3170G>A genotype in combination with p.R127H. Next to the GJB2 mutations we noted 2 cases of deletion in GJB6 [Delta(GJB6-D13S1830)] and 3 (2 new and 1 described) base substitutions in GJB3 [c.357C>T, c.798C>T and c.94C>T (p.R32W)] which are unlikely disease-causing. Our results suggest the importance of routine screening for the rather frequent -3170G>A mutation (in addition to c.35delG) in patients with hearing impairment.",
     "annotations": [
      {
       "id": "1",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 93,
         "length": 4
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D034381",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "sensorineural hearing impairment",
       "locations": [
        {
         "offset": 154,
         "length": 32
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D034381",
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       "text": "hearing impairment",
       "locations": [
        {
         "offset": 405,
         "length": 18
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
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       "text": "GJB2",
       "locations": [
        {
         "offset": 461,
         "length": 4
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
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       "text": "GJB2",
       "locations": [
        {
         "offset": 516,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
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       "text": "patients",
       "locations": [
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         "offset": 527,
         "length": 8
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D034381",
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       "text": "hearing impairment",
       "locations": [
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         "offset": 541,
         "length": 18
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       ]
      },
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       "id": "8",
       "infons": {
        "identifier": "10804",
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       "text": "GJB6",
       "locations": [
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         "offset": 607,
         "length": 4
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2707",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB3",
       "locations": [
        {
         "offset": 616,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 657,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "2706",
        "type": "GeneOrGeneProduct"
       },
       "text": "GJB2",
       "locations": [
        {
         "offset": 707,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 725,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|SUB|G|-3170|A",
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     "text": "Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome.",
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     "text": "Alpers syndrome is an autosomal recessive mitochondrial DNA depletion disorder that affects children and young adults. It is characterized by a progressive, fatal brain and liver disease. This syndrome has been associated with mutations in POLG, the gene encoding the mitochondrial DNA polymerase (pol gamma). Most patients with Alpers syndrome have been found to be compound heterozygotes, carrying two pathogenic mutations in trans at the POLG locus. POLG is a nuclear-encoded gene whose protein product is imported into mitochondria, where it is essential for mtDNA replication and repair. We studied the skin fibroblasts of a patient with Alpers syndrome having the genotype E873stop/A467T. The E873stop mutation produces a premature termination codon (TAG) in exon 17. The A467T mutation produces a threonine to alanine substitution at a highly conserved site in exon 7. The allele bearing the stop codon (E873-TAG) is predicted to produce a truncated, catalytically inactive polymerase. However, only full-length pol gamma protein was detected by Western blot analysis. Here, we show that transcripts containing this stop codon undergo nonsense-associated alternative splicing and nonsense-mediated decay. More than 95% of the functional POLG mRNA was derived from the allele bearing the A467T mutation and less than 5% contained the E873stop mutation. These events ensured that virtually all POLG protein in the cell was expressed from the A467T allele. Therefore, the Alpers phenotype in this patient was a consequence of a single-copy gene dose of the A467T allele, and selective elimination of transcripts bearing the E873stop mutation.",
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       "text": "Alpers syndrome",
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       "id": "26",
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       "text": "patient",
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         "offset": 1629,
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       ]
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      {
       "id": "27",
       "infons": {
        "identifier": "rs113994095",
        "type": "SequenceVariant"
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       "text": "A467T",
       "locations": [
        {
         "offset": 1689,
         "length": 5
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       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs121918047",
        "type": "SequenceVariant"
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       "text": "E873stop",
       "locations": [
        {
         "offset": 1756,
         "length": 8
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   ],
   "relations": [
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    }
   ]
  },
  {
   "id": "20143913",
   "passages": [
    {
     "offset": 0,
     "text": "Large deletion involving exon 5 of the arylsulfatase B gene caused apparent homozygosity in a mucopolysaccharidosis type VI patient.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "411",
        "type": "GeneOrGeneProduct"
       },
       "text": "arylsulfatase B",
       "locations": [
        {
         "offset": 39,
         "length": 15
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       ]
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      {
       "id": "1",
       "infons": {
        "identifier": "D009087",
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       "text": "mucopolysaccharidosis type VI",
       "locations": [
        {
         "offset": 94,
         "length": 29
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       "id": "2",
       "infons": {
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       "text": "patient",
       "locations": [
        {
         "offset": 124,
         "length": 7
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       ]
      }
     ]
    },
    {
     "offset": 133,
     "text": "Apparent homozygosity for the mutation p.R315X present on exon 5 of the arylsulfatase B (ARSB) gene in a mucopolysaccharidosis type VI patient was solved in this study by further testing for a second mutation. Patient cDNA analysis revealed that the entire exon 5 of the ARSB gene was lacking; this new mutation was identified as c.899-1142del. As the genomic DNA sequencing excluded the presence of splicing mutations, polymerase chain reaction analysis was performed for polymorphisms listed in the NCBI SNP database for the ARSB gene. This allowed the mutation at the genomic DNA level to be identified as g.99367-102002del; this gross deletion, involving the entire exon 5 of the gene and parts of introns 4 and 5 led to a frameshift starting at amino acid 300 and resulting in a protein with 39% amino acids different from the normal enzyme. We stress that extensive DNA analysis needs to be performed in case of apparent homozygosity to avoid potential errors in genetic counseling.",
     "annotations": [
      {
       "id": "3",
       "infons": {
        "identifier": "p|SUB|R|315|X",
        "type": "SequenceVariant"
       },
       "text": "p.R315X",
       "locations": [
        {
         "offset": 172,
         "length": 7
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "411",
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       "text": "arylsulfatase B",
       "locations": [
        {
         "offset": 205,
         "length": 15
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       ]
      },
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       "id": "5",
       "infons": {
        "identifier": "411",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARSB",
       "locations": [
        {
         "offset": 222,
         "length": 4
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009087",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "mucopolysaccharidosis type VI",
       "locations": [
        {
         "offset": 238,
         "length": 29
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       ]
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       "id": "7",
       "infons": {
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       "text": "patient",
       "locations": [
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         "offset": 268,
         "length": 7
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Patient",
       "locations": [
        {
         "offset": 343,
         "length": 7
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "411",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARSB",
       "locations": [
        {
         "offset": 404,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "c|DEL|899_1142|",
        "type": "SequenceVariant"
       },
       "text": "c.899-1142del",
       "locations": [
        {
         "offset": 463,
         "length": 13
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "411",
        "type": "GeneOrGeneProduct"
       },
       "text": "ARSB",
       "locations": [
        {
         "offset": 660,
         "length": 4
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "g|DEL|99367_102002|",
        "type": "SequenceVariant"
       },
       "text": "g.99367-102002del",
       "locations": [
        {
         "offset": 742,
         "length": 17
        }
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      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "g|DEL|99367_102002|",
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      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
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      "type": "Association",
      "novel": "No"
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    },
    {
     "id": "R2",
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      "entity1": "D009087",
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      "type": "Association",
      "novel": "No"
     }
    },
    {
     "id": "R3",
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      "entity1": "D009087",
      "entity2": "c|DEL|899_1142|",
      "type": "Association",
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     }
    }
   ]
  },
  {
   "id": "15579441",
   "passages": [
    {
     "offset": 0,
     "text": "Hypoxia in renal disease with proteinuria and/or glomerular hypertension.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000860",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Hypoxia",
       "locations": [
        {
         "offset": 0,
         "length": 7
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D007674",
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       },
       "text": "renal disease",
       "locations": [
        {
         "offset": 11,
         "length": 13
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D011507",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "proteinuria",
       "locations": [
        {
         "offset": 30,
         "length": 11
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D006973",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "hypertension",
       "locations": [
        {
         "offset": 60,
         "length": 12
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       ]
      }
     ]
    },
    {
     "offset": 74,
     "text": "Despite the increasing need to identify and quantify tissue oxygenation at the cellular level, relatively few methods have been available. In this study, we developed a new hypoxia-responsive reporter vector using a hypoxia-responsive element of the 5' vascular endothelial growth factor untranslated region and generated a novel hypoxia-sensing transgenic rat. We then applied this animal model to the detection of tubulointerstitial hypoxia in the diseased kidney. With this model, we were able to identify diffuse cortical hypoxia in the puromycin aminonucleoside-induced nephrotic syndrome and focal and segmental hypoxia in the remnant kidney model. Expression of the hypoxia-responsive transgene increased throughout the observation period, reaching 2.2-fold at 2 weeks in the puromycin aminonucleoside model and 2.6-fold at 4 weeks in the remnant kidney model, whereas that of vascular endothelial growth factor showed a mild decrease, reflecting distinct behaviors of the two genes. The degree of hypoxia showed a positive correlation with microscopic tubulointerstitial injury in both models. Finally, we identified the localization of proliferating cell nuclear antigen-positive, ED-1-positive, and terminal dUTP nick-end labeled-positive cells in the hypoxic cortical area in the remnant kidney model. We propose here a possible pathological tie between chronic tubulointerstitial hypoxia and progressive glomerular diseases.",
     "annotations": [
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       "id": "4",
       "infons": {
        "identifier": "D000860",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "hypoxia",
       "locations": [
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         "offset": 247,
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       "id": "5",
       "infons": {
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       "text": "hypoxia",
       "locations": [
        {
         "offset": 290,
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "83785",
        "type": "GeneOrGeneProduct"
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       "text": "vascular endothelial growth factor",
       "locations": [
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         "offset": 327,
         "length": 34
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       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D000860",
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       },
       "text": "hypoxia",
       "locations": [
        {
         "offset": 404,
         "length": 7
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       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "10116",
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       "text": "rat",
       "locations": [
        {
         "offset": 431,
         "length": 3
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D000860",
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       },
       "text": "hypoxia",
       "locations": [
        {
         "offset": 509,
         "length": 7
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diseased kidney",
       "locations": [
        {
         "offset": 524,
         "length": 15
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D000860",
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       "text": "hypoxia",
       "locations": [
        {
         "offset": 600,
         "length": 7
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D011692",
        "type": "ChemicalEntity"
       },
       "text": "puromycin aminonucleoside",
       "locations": [
        {
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         "length": 25
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D009404",
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       },
       "text": "nephrotic syndrome",
       "locations": [
        {
         "offset": 649,
         "length": 18
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D000860",
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       "text": "hypoxia",
       "locations": [
        {
         "offset": 692,
         "length": 7
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D000860",
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       "text": "hypoxia",
       "locations": [
        {
         "offset": 747,
         "length": 7
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D011692",
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       "text": "puromycin aminonucleoside",
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       "id": "17",
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       "text": "vascular endothelial growth factor",
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       "id": "18",
       "infons": {
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       "text": "hypoxia",
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         "offset": 1079,
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       "id": "19",
       "infons": {
        "identifier": "D007674",
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       "text": "tubulointerstitial injury",
       "locations": [
        {
         "offset": 1134,
         "length": 25
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "302424",
        "type": "GeneOrGeneProduct"
       },
       "text": "ED-1",
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         "offset": 1264,
         "length": 4
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "C027078",
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       "text": "dUTP",
       "locations": [
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         "offset": 1292,
         "length": 4
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       "id": "22",
       "infons": {
        "identifier": "D000860",
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       "text": "hypoxic",
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         "offset": 1336,
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       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D000860",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "hypoxia",
       "locations": [
        {
         "offset": 1466,
         "length": 7
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       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "D007674",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "glomerular diseases",
       "locations": [
        {
         "offset": 1490,
         "length": 19
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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    {
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     "infons": {
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      "type": "Association",
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    }
   ]
  },
  {
   "id": "15754732",
   "passages": [
    {
     "offset": 0,
     "text": "Novel somatic MEN1 gene alterations in sporadic primary hyperparathyroidism and correlation with clinical characteristics.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 14,
         "length": 4
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D049950",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "primary hyperparathyroidism",
       "locations": [
        {
         "offset": 48,
         "length": 27
        }
       ]
      }
     ]
    },
    {
     "offset": 123,
     "text": "Primary hyperparathyroidism (pHPT) is a common endocrine disease that in more than 95% of cases is sporadic and only in some cases is caused by inherited disorders, isolated or as part of multiple endocrine neoplasia (MEN1 and 2). Somatic mutations of MEN1 gene have also been described in sporadic parathyroid tumors. In our study, we examined the presence of alterations in MEN1 gene in a series of 39 patients who had undergone surgery for sporadic pHPT (35 with parathyroid adenoma or hyperplasia, 4 with a carcinoma). A genotype-phenotype correlation was also analysed. After DNA extraction from paraffin-embedded tissues, we amplified by PCR and sequenced the exons 2-10 of the MEN1 gene. Somatic MEN1 mutations were detected in 6 of the 35 patients with a benign parathyroid lesion examined (17.1%), whereas no alterations were found in the carcinomas. Four novel MEN1 gene mutations were identified as follows: one frameshift mutation (222insT, exon 2), one frameshift deletion (912delTA, exon 5), one in-frame deletion (835del18, exon 4) and one missense mutation (P291A, exon 6). In addition, one missense mutation (L89R, exon 2) and one nonsense mutation (Q536X, exon 10) were previously reported. Moreover, two polymorphisms were also found: one allele carried a R171Q polymorphism (1/39 tumors), while a D418D polymorphism (GAC/GAT) was found in 15 and 8 tumors in hetero (CT) and homozygosity (TT), respectively. In no case (mutations and/or polymorphisms) did we find a genotype-phenotype correlation. In conclusion, our data demonstrate the presence of somatic alterations of the MEN1 tumor suppressor gene in about one fifth of benign sporadic parathyroid tumors. The absence of a genotype-phenotype correlation, however, suggests the involvement of other genetic/epigenetic factors for the full expression of the disease.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D049950",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "Primary hyperparathyroidism",
       "locations": [
        {
         "offset": 123,
         "length": 27
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D049950",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pHPT",
       "locations": [
        {
         "offset": 152,
         "length": 4
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D004700",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "endocrine disease",
       "locations": [
        {
         "offset": 170,
         "length": 17
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inherited disorders",
       "locations": [
        {
         "offset": 267,
         "length": 19
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "D009377",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "multiple endocrine neoplasia",
       "locations": [
        {
         "offset": 311,
         "length": 28
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D018761,D018813",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "MEN1 and 2",
       "locations": [
        {
         "offset": 341,
         "length": 10
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 375,
         "length": 4
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D010282",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "parathyroid tumors",
       "locations": [
        {
         "offset": 422,
         "length": 18
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 499,
         "length": 4
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 527,
         "length": 8
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D049950",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "pHPT",
       "locations": [
        {
         "offset": 575,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D010282",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "parathyroid adenoma or hyperplasia",
       "locations": [
        {
         "offset": 589,
         "length": 34
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D002277",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "carcinoma",
       "locations": [
        {
         "offset": 634,
         "length": 9
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D010232",
        "type": "ChemicalEntity"
       },
       "text": "paraffin",
       "locations": [
        {
         "offset": 724,
         "length": 8
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 807,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 826,
         "length": 4
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 870,
         "length": 8
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       ]
      },
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        "identifier": "D010279",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "benign parathyroid lesion",
       "locations": [
        {
         "offset": 886,
         "length": 25
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       ]
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       "id": "20",
       "infons": {
        "identifier": "D002277",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "carcinomas",
       "locations": [
        {
         "offset": 971,
         "length": 10
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
       },
       "text": "MEN1",
       "locations": [
        {
         "offset": 994,
         "length": 4
        }
       ]
      },
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       "id": "22",
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       "text": "222insT",
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        {
         "offset": 1067,
         "length": 7
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       ]
      },
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       "id": "23",
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       ]
      },
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       "id": "24",
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        {
         "offset": 1152,
         "length": 8
        }
       ]
      },
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       "id": "25",
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        {
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       "id": "26",
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         "offset": 1249,
         "length": 4
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       ]
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         "offset": 1290,
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       ]
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       "text": "R171Q",
       "locations": [
        {
         "offset": 1398,
         "length": 5
        }
       ]
      },
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       "id": "29",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumors",
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        {
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         "length": 6
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       ]
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       "infons": {
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         "offset": 1440,
         "length": 5
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       ]
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       "id": "31",
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        "identifier": "rs2071313",
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       "text": "GAC/GAT",
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        {
         "offset": 1460,
         "length": 7
        }
       ]
      },
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       "id": "32",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumors",
       "locations": [
        {
         "offset": 1491,
         "length": 6
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "4221",
        "type": "GeneOrGeneProduct"
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       "text": "MEN1",
       "locations": [
        {
         "offset": 1719,
         "length": 4
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       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "D009369",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "tumor",
       "locations": [
        {
         "offset": 1724,
         "length": 5
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "D010282",
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       },
       "text": "parathyroid tumors",
       "locations": [
        {
         "offset": 1784,
         "length": 18
        }
       ]
      }
     ]
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   ],
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  },
  {
   "id": "18385794",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "6657",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOX2",
       "locations": [
        {
         "offset": 63,
         "length": 4
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "338917",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHX10",
       "locations": [
        {
         "offset": 72,
         "length": 5
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 87,
         "length": 8
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D000853",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anophthalmia",
       "locations": [
        {
         "offset": 101,
         "length": 12
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008850",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microphthalmia",
       "locations": [
        {
         "offset": 114,
         "length": 14
        }
       ]
      }
     ]
    },
    {
     "offset": 130,
     "text": "PURPOSE: Mutations in the SOX2 and CHX10 genes have been reported in patients with anophthalmia and/or microphthalmia. In this study, we evaluated 34 anophthalmic/microphthalmic patient DNA samples (two sets of siblings included) for mutations and sequence variants in SOX2 and CHX10. METHODS: Conformational sensitive gel electrophoresis (CSGE) was used for the initial SOX2 and CHX10 screening of 34 affected individuals (two sets of siblings), five unaffected family members, and 80 healthy controls. Patient samples containing heteroduplexes were selected for sequence analysis. Base pair changes in SOX2 and CHX10 were confirmed by sequencing bidirectionally in patient samples. RESULTS: Two novel heterozygous mutations and two sequence variants (one known) in SOX2 were identified in this cohort. Mutation c.310 G>T (p. Glu104X), found in one patient, was in the region encoding the high mobility group (HMG) DNA-binding domain and resulted in a change from glutamic acid to a stop codon. The second mutation, noted in two affected siblings, was a single nucleotide deletion c.549delC (p. Pro184ArgfsX19) in the region encoding the activation domain, resulting in a frameshift and premature termination of the coding sequence. The shortened protein products may result in the loss of function. In addition, a novel nucleotide substitution c.*557G>A was identified in the 3'-untranslated region in one patient. The relationship between the nucleotide change and the protein function is indeterminate. A known single nucleotide polymorphism (c. *469 C>A, SNP rs11915160) was also detected in 2 of the 34 patients. Screening of CHX10 identified two synonymous sequence variants, c.471 C>T (p.Ser157Ser, rs35435463) and c.579 G>A (p. Gln193Gln, novel SNP), and one non-synonymous sequence variant, c.871 G>A (p. Asp291Asn, novel SNP). The non-synonymous polymorphism was also present in healthy controls, suggesting non-causality. CONCLUSIONS: These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort.",
     "annotations": [
      {
       "id": "5",
       "infons": {
        "identifier": "6657",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOX2",
       "locations": [
        {
         "offset": 156,
         "length": 4
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "338917",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHX10",
       "locations": [
        {
         "offset": 165,
         "length": 5
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 199,
         "length": 8
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "D000853",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anophthalmia",
       "locations": [
        {
         "offset": 213,
         "length": 12
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "D008850",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microphthalmia",
       "locations": [
        {
         "offset": 233,
         "length": 14
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D000853",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "anophthalmic",
       "locations": [
        {
         "offset": 280,
         "length": 12
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D008850",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "microphthalmic",
       "locations": [
        {
         "offset": 293,
         "length": 14
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 308,
         "length": 7
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "6657",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOX2",
       "locations": [
        {
         "offset": 399,
         "length": 4
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "338917",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHX10",
       "locations": [
        {
         "offset": 408,
         "length": 5
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "6657",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOX2",
       "locations": [
        {
         "offset": 501,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "338917",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHX10",
       "locations": [
        {
         "offset": 510,
         "length": 5
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "Patient",
       "locations": [
        {
         "offset": 634,
         "length": 7
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "6657",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOX2",
       "locations": [
        {
         "offset": 734,
         "length": 4
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "338917",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHX10",
       "locations": [
        {
         "offset": 743,
         "length": 5
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 797,
         "length": 7
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "6657",
        "type": "GeneOrGeneProduct"
       },
       "text": "SOX2",
       "locations": [
        {
         "offset": 897,
         "length": 4
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "c|SUB|G|310|T",
        "type": "SequenceVariant"
       },
       "text": "c.310 G>T",
       "locations": [
        {
         "offset": 943,
         "length": 9
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "p|SUB|E|104|X",
        "type": "SequenceVariant"
       },
       "text": "p. Glu104X",
       "locations": [
        {
         "offset": 954,
         "length": 10
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 980,
         "length": 7
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "p|SUB|E||X",
        "type": "SequenceVariant"
       },
       "text": "glutamic acid to a stop codon",
       "locations": [
        {
         "offset": 1095,
         "length": 29
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "rs587776776",
        "type": "SequenceVariant"
       },
       "text": "c.549delC",
       "locations": [
        {
         "offset": 1212,
         "length": 9
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "rs587776776",
        "type": "SequenceVariant"
       },
       "text": "p. Pro184ArgfsX19",
       "locations": [
        {
         "offset": 1223,
         "length": 17
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "rs77677339",
        "type": "SequenceVariant"
       },
       "text": "c.*557G>A",
       "locations": [
        {
         "offset": 1476,
         "length": 9
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patient",
       "locations": [
        {
         "offset": 1538,
         "length": 7
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "rs11915160",
        "type": "SequenceVariant"
       },
       "text": "c. *469 C>A",
       "locations": [
        {
         "offset": 1677,
         "length": 11
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "rs11915160",
        "type": "SequenceVariant"
       },
       "text": "rs11915160",
       "locations": [
        {
         "offset": 1694,
         "length": 10
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 1739,
         "length": 8
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "338917",
        "type": "GeneOrGeneProduct"
       },
       "text": "CHX10",
       "locations": [
        {
         "offset": 1762,
         "length": 5
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "rs35435463",
        "type": "SequenceVariant"
       },
       "text": "c.471 C>T",
       "locations": [
        {
         "offset": 1813,
         "length": 9
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "rs35435463",
        "type": "SequenceVariant"
       },
       "text": "p.Ser157Ser",
       "locations": [
        {
         "offset": 1824,
         "length": 11
        }
       ]
      },
      {
       "id": "36",
       "infons": {
        "identifier": "rs35435463",
        "type": "SequenceVariant"
       },
       "text": "rs35435463",
       "locations": [
        {
         "offset": 1837,
         "length": 10
        }
       ]
      },
      {
       "id": "37",
       "infons": {
        "identifier": "rs182972044",
        "type": "SequenceVariant"
       },
       "text": "c.579 G>A",
       "locations": [
        {
         "offset": 1853,
         "length": 9
        }
       ]
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     "offset": 0,
     "text": "Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation.",
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     "text": "PURPOSE: We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)-based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy. EXPERIMENTAL DESIGN: DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3-5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004). CONCLUSION: rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule.",
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       "text": "rs1870377",
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         "offset": 1901,
         "length": 9
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       "id": "50",
       "infons": {
        "identifier": "D064420",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "toxicity",
       "locations": [
        {
         "offset": 1951,
         "length": 8
        }
       ]
      },
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       "id": "51",
       "infons": {
        "identifier": "D005472",
        "type": "ChemicalEntity"
       },
       "text": "5-FU",
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         "offset": 1978,
         "length": 4
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     "infons": {
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      "entity1": "rs1870377",
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      "novel": "No"
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    }
   ]
  },
  {
   "id": "15086325",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of three F5 gene mutations associated with inherited coagulation factor V deficiency in two Chinese pedigrees.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "F5",
       "locations": [
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         "offset": 24,
         "length": 2
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D005166",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inherited coagulation factor V deficiency",
       "locations": [
        {
         "offset": 58,
         "length": 41
        }
       ]
      }
     ]
    },
    {
     "offset": 126,
     "text": "To investigate the molecular defects in two Chinese pedigrees with inherited factor V (FV) deficiency. A 37-year-old male (proband 1) and an 18-month-old boy (proband 2) were diagnosed as inherited coagulation FV deficiency by severely reduced plasma levels of FV activity and antigen. All 25 exons and their flanking sequence of F5 gene were amplified by polymerase chain reaction (PCR) for both probands and the PCR products were directly sequenced. Total RNA was extracted from the peripheral lymphocytes of proband 1 for detecting the changes at mRNA level. The homozygous deletion IVS8 -2A>G was identified in the F5 gene of proband 1 and complementary DNA (cDNA) analysis revealed the abolishment of the canonical splicing site by the mutation and the activation of the cryptic acceptor site 24 bp upstream instead. The insertion introduced eight additional amino acids (AA) into the FV protein. Two heterozygous mutations of F5 gene were discovered in proband 2. The 2238-9del AG in exon 13 introduced a premature termination code at 689 AA and the substitution of G6410 by T in exon 23 lead to the missense mutation Gly2079Val. Three F5 gene mutations, IVS8 -2A>G, 2238-9del AG and G6410T, have been identified in two Chinese pedigree with congenital FV deficiency, respectively.",
     "annotations": [
      {
       "id": "2",
       "infons": {
        "identifier": "D005166",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inherited factor V (FV) deficiency",
       "locations": [
        {
         "offset": 193,
         "length": 34
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D005166",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inherited coagulation FV deficiency",
       "locations": [
        {
         "offset": 314,
         "length": 35
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "FV",
       "locations": [
        {
         "offset": 387,
         "length": 2
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "F5",
       "locations": [
        {
         "offset": 456,
         "length": 2
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "c|SUB|A|IVS8-2|G",
        "type": "SequenceVariant"
       },
       "text": "IVS8 -2A>G",
       "locations": [
        {
         "offset": 712,
         "length": 10
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "F5",
       "locations": [
        {
         "offset": 745,
         "length": 2
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "p|INS||8",
        "type": "SequenceVariant"
       },
       "text": "insertion introduced eight additional amino acids",
       "locations": [
        {
         "offset": 952,
         "length": 49
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "FV",
       "locations": [
        {
         "offset": 1016,
         "length": 2
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "F5",
       "locations": [
        {
         "offset": 1058,
         "length": 2
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|DEL|2238_2239|AG",
        "type": "SequenceVariant"
       },
       "text": "2238-9del AG",
       "locations": [
        {
         "offset": 1100,
         "length": 12
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "c|Allele|A|689",
        "type": "SequenceVariant"
       },
       "text": "689 AA",
       "locations": [
        {
         "offset": 1167,
         "length": 6
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "g|SUB|G|6410|T",
        "type": "SequenceVariant"
       },
       "text": "G6410 by T",
       "locations": [
        {
         "offset": 1198,
         "length": 10
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|SUB|G|2079|V",
        "type": "SequenceVariant"
       },
       "text": "Gly2079Val",
       "locations": [
        {
         "offset": 1250,
         "length": 10
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "2153",
        "type": "GeneOrGeneProduct"
       },
       "text": "F5",
       "locations": [
        {
         "offset": 1268,
         "length": 2
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "c|SUB|A|IVS8-2|G",
        "type": "SequenceVariant"
       },
       "text": "IVS8 -2A>G",
       "locations": [
        {
         "offset": 1287,
         "length": 10
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "c|DEL|2238_2239|AG",
        "type": "SequenceVariant"
       },
       "text": "2238-9del AG",
       "locations": [
        {
         "offset": 1299,
         "length": 12
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "g|SUB|G|6410|T",
        "type": "SequenceVariant"
       },
       "text": "G6410T",
       "locations": [
        {
         "offset": 1316,
         "length": 6
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D005166",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "congenital FV deficiency",
       "locations": [
        {
         "offset": 1374,
         "length": 24
        }
       ]
      }
     ]
    }
   ],
   "relations": [
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     "id": "R0",
     "infons": {
      "entity1": "g|SUB|G|6410|T",
      "entity2": "D005166",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R1",
     "infons": {
      "entity1": "c|DEL|2238_2239|AG",
      "entity2": "D005166",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R2",
     "infons": {
      "entity1": "c|SUB|A|IVS8-2|G",
      "entity2": "D005166",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R3",
     "infons": {
      "entity1": "D005166",
      "entity2": "p|INS||8",
      "type": "Association",
      "novel": "Novel"
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    },
    {
     "id": "R4",
     "infons": {
      "entity1": "D005166",
      "entity2": "c|Allele|A|689",
      "type": "Association",
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     }
    },
    {
     "id": "R5",
     "infons": {
      "entity1": "D005166",
      "entity2": "p|SUB|G|2079|V",
      "type": "Association",
      "novel": "Novel"
     }
    },
    {
     "id": "R6",
     "infons": {
      "entity1": "2153",
      "entity2": "D005166",
      "type": "Association",
      "novel": "No"
     }
    }
   ]
  },
  {
   "id": "19300402",
   "passages": [
    {
     "offset": 0,
     "text": "Bradykinin receptors antagonists and nitric oxide synthase inhibitors in vincristine and streptozotocin induced hyperalgesia in chemotherapy and diabetic neuropathy rat model.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D065168",
        "type": "ChemicalEntity"
       },
       "text": "Bradykinin receptors antagonists",
       "locations": [
        {
         "offset": 0,
         "length": 32
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "C080122,C090663,D019335",
        "type": "ChemicalEntity"
       },
       "text": "nitric oxide synthase inhibitors",
       "locations": [
        {
         "offset": 37,
         "length": 32
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D014750",
        "type": "ChemicalEntity"
       },
       "text": "vincristine",
       "locations": [
        {
         "offset": 73,
         "length": 11
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D013311",
        "type": "ChemicalEntity"
       },
       "text": "streptozotocin",
       "locations": [
        {
         "offset": 89,
         "length": 14
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D006930",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperalgesia",
       "locations": [
        {
         "offset": 112,
         "length": 12
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "D003929",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetic neuropathy",
       "locations": [
        {
         "offset": 145,
         "length": 19
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "10116",
        "type": "OrganismTaxon"
       },
       "text": "rat",
       "locations": [
        {
         "offset": 165,
         "length": 3
        }
       ]
      }
     ]
    },
    {
     "offset": 176,
     "text": "PURPOSE: The influence of an irreversible inhibitor of constitutive NO synthase (L-NOArg; 1.0 mg/kg ip), a relatively selective inhibitor of inducible NO synthase (L-NIL; 1.0 mg/kg ip) and a relatively specific inhibitor of neuronal NO synthase (7-NI; 0.1 mg/kg ip), on antihyperalgesic action of selective antagonists of B2 and B1 receptors: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8] bradykinin (HOE 140; 70 nmol/kg ip) or des Arg10 HOE 140 (70 nmol/kg ip) respectively, in model of diabetic (streptozotocin-induced) and toxic (vincristine-induced) neuropathy was investigated. METHODS: The changes in pain thresholds were determined using mechanical stimuli--the modification of the classic paw withdrawal test described by Randall-Selitto. RESULTS: The results of this paper confirm that inhibition of bradykinin receptors and inducible NO synthase but not neuronal NO synthase activity reduces diabetic hyperalgesia. Pretreatment with L-NOArg and L-NIL but not 7-NI, significantly increases antihyperalgesic activity both HOE 140 and des Arg10 HOE 140. It was also shown that both products of inducible NO synthase and neuronal NO synthase activation as well as bradykinin are involved in hyperalgesia produced by vincristine. Moreover, L-NOArg and 7-NI but not L-NIL intensify antihyperalgesic activity of HOE 140 or des-Arg10HOE 140 in toxic neuropathy. CONCLUSIONS: Results of these studies suggest that B1 and B2 receptors are engaged in transmission of nociceptive stimuli in both diabetic and toxic neuropathy. In streptozotocin-induced hyperalgesia, inducible NO synthase participates in pronociceptive activity of bradykinin, whereas in vincristine-induced hyperalgesia bradykinin seemed to activate neuronal NO synthase pathway. Therefore, concomitant administration of small doses of bradykinin receptor antagonists and NO synthase inhibitors can be effective in alleviation of neuropathic pain, even in hospital care.",
     "annotations": [
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       "id": "7",
       "infons": {
        "identifier": "24600",
        "type": "GeneOrGeneProduct"
       },
       "text": "constitutive NO synthase",
       "locations": [
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         "offset": 231,
         "length": 24
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       ]
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       "id": "8",
       "infons": {
        "identifier": "D019335",
        "type": "ChemicalEntity"
       },
       "text": "L-NOArg",
       "locations": [
        {
         "offset": 257,
         "length": 7
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       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "24599",
        "type": "GeneOrGeneProduct"
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       "text": "inducible NO synthase",
       "locations": [
        {
         "offset": 317,
         "length": 21
        }
       ]
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       "id": "10",
       "infons": {
        "identifier": "C090663",
        "type": "ChemicalEntity"
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       "text": "L-NIL",
       "locations": [
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         "offset": 340,
         "length": 5
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "24598",
        "type": "GeneOrGeneProduct"
       },
       "text": "neuronal NO synthase",
       "locations": [
        {
         "offset": 400,
         "length": 20
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "C080122",
        "type": "ChemicalEntity"
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       "text": "7-NI",
       "locations": [
        {
         "offset": 422,
         "length": 4
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       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "25245,81509",
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       "text": "B2 and B1 receptors",
       "locations": [
        {
         "offset": 498,
         "length": 19
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       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "C065679",
        "type": "ChemicalEntity"
       },
       "text": "D-Arg-[Hyp3,Thi5,D-Tic7,Oic8] bradykinin",
       "locations": [
        {
         "offset": 519,
         "length": 40
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "C065679",
        "type": "ChemicalEntity"
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       "text": "HOE 140",
       "locations": [
        {
         "offset": 561,
         "length": 7
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "C078665",
        "type": "ChemicalEntity"
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       "text": "des Arg10 HOE 140",
       "locations": [
        {
         "offset": 588,
         "length": 17
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       "id": "17",
       "infons": {
        "identifier": "D003929,D010523",
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       "text": "diabetic (streptozotocin-induced) and toxic (vincristine-induced) neuropathy",
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       "id": "18",
       "infons": {
        "identifier": "D010146",
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       "text": "pain",
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         "length": 4
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       "id": "19",
       "infons": {
        "identifier": "25245,81509",
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       "text": "bradykinin receptors",
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         "length": 20
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       ]
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       "id": "20",
       "infons": {
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       "text": "inducible NO synthase",
       "locations": [
        {
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         "length": 21
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       ]
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      {
       "id": "21",
       "infons": {
        "identifier": "24598",
        "type": "GeneOrGeneProduct"
       },
       "text": "neuronal NO synthase",
       "locations": [
        {
         "offset": 1024,
         "length": 20
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "D003920,D006930",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetic hyperalgesia",
       "locations": [
        {
         "offset": 1062,
         "length": 21
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D019335",
        "type": "ChemicalEntity"
       },
       "text": "L-NOArg",
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         "offset": 1103,
         "length": 7
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "C090663",
        "type": "ChemicalEntity"
       },
       "text": "L-NIL",
       "locations": [
        {
         "offset": 1115,
         "length": 5
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "C080122",
        "type": "ChemicalEntity"
       },
       "text": "7-NI",
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         "offset": 1129,
         "length": 4
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "C065679",
        "type": "ChemicalEntity"
       },
       "text": "HOE 140",
       "locations": [
        {
         "offset": 1190,
         "length": 7
        }
       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "C078665",
        "type": "ChemicalEntity"
       },
       "text": "des Arg10 HOE 140",
       "locations": [
        {
         "offset": 1202,
         "length": 17
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "24599",
        "type": "GeneOrGeneProduct"
       },
       "text": "inducible NO synthase",
       "locations": [
        {
         "offset": 1261,
         "length": 21
        }
       ]
      },
      {
       "id": "29",
       "infons": {
        "identifier": "24598",
        "type": "GeneOrGeneProduct"
       },
       "text": "neuronal NO synthase",
       "locations": [
        {
         "offset": 1287,
         "length": 20
        }
       ]
      },
      {
       "id": "30",
       "infons": {
        "identifier": "3827",
        "type": "GeneOrGeneProduct"
       },
       "text": "bradykinin",
       "locations": [
        {
         "offset": 1330,
         "length": 10
        }
       ]
      },
      {
       "id": "31",
       "infons": {
        "identifier": "D006930",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "hyperalgesia",
       "locations": [
        {
         "offset": 1357,
         "length": 12
        }
       ]
      },
      {
       "id": "32",
       "infons": {
        "identifier": "D014750",
        "type": "ChemicalEntity"
       },
       "text": "vincristine",
       "locations": [
        {
         "offset": 1382,
         "length": 11
        }
       ]
      },
      {
       "id": "33",
       "infons": {
        "identifier": "D019335",
        "type": "ChemicalEntity"
       },
       "text": "L-NOArg",
       "locations": [
        {
         "offset": 1405,
         "length": 7
        }
       ]
      },
      {
       "id": "34",
       "infons": {
        "identifier": "C080122",
        "type": "ChemicalEntity"
       },
       "text": "7-NI",
       "locations": [
        {
         "offset": 1417,
         "length": 4
        }
       ]
      },
      {
       "id": "35",
       "infons": {
        "identifier": "C090663",
        "type": "ChemicalEntity"
       },
       "text": "L-NIL",
       "locations": [
        {
         "offset": 1430,
         "length": 5
        }
       ]
      },
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     "offset": 0,
     "text": "Association of a FGFR-4 gene polymorphism with bronchopulmonary dysplasia and neonatal respiratory distress.",
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     "text": "BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of premature birth, characterized by impaired alveolar development and inflammation. Pathomechanisms contributing to BPD are poorly understood. However, it is assumed that genetic factors predispose to BPD and other pulmonary diseases of preterm neonates, such as neonatal respiratory distress syndrome (RDS). For association studies, genes upregulated during alveolarization are major candidates for genetic analysis, for example, matrix metalloproteinases (MMPs) and fibroblast growth factors (FGFs) and their receptors (FGFR). OBJECTIVE: Determining genetic risk variants in a Caucasian population of premature neonates with BPD and RDS. Methods. We genotyped 27 polymorphisms within 14 candidate genes via restriction fragment length polymorphism (RFLP): MMP-1, -2, -9, and -12, -16, FGF receptors 2 and 4, FGF-2, -3, -4, -7, and -18, Signal-Regulatory Protein a (SIRPA) and Thyroid Transcription Factor-1 (TTF-1). RESULTS: Five single nucleotide polymorphisms (SNPs) in MMP-9, MMP-12, FGFR-4, FGF-3, and FGF-7 are associated (P < 0.05) with RDS, defined as surfactant application within the first 24 hours after birth. One of them, in FGFR-4 (rs1966265), is associated with both RDS (P = 0.003) and BPD (P = 0.023). CONCLUSION: rs1966265 in FGF receptor 4 is a possible genetic key variant in alveolar diseases of preterm newborns.",
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     "text": "A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.",
     "annotations": [
      {
       "id": "4",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "woman",
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         "offset": 143,
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       "id": "5",
       "infons": {
        "identifier": "D020246",
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       "text": "superior mesenteric vein (SMV) thrombosis",
       "locations": [
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         "offset": 167,
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       "id": "6",
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       "text": "antithrombin",
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       "id": "7",
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       "text": "antithrombin",
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       "id": "8",
       "infons": {
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       "text": "thrombin",
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         "offset": 477,
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       ]
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       "id": "9",
       "infons": {
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       "text": "argatroban",
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       ]
      },
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       "id": "10",
       "infons": {
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       "text": "antithrombin",
       "locations": [
        {
         "offset": 527,
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "D025861",
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       "text": "type I congenital antithrombin deficiency",
       "locations": [
        {
         "offset": 571,
         "length": 41
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "462",
        "type": "GeneOrGeneProduct"
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       "text": "antithrombin",
       "locations": [
        {
         "offset": 660,
         "length": 12
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       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "c|INS|7916_7917|T",
        "type": "SequenceVariant"
       },
       "text": "nucleotide T insertion at 7916 and 7917",
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        {
         "offset": 681,
         "length": 39
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "p|SUB|E|272|X",
        "type": "SequenceVariant"
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       "text": "Glu 272 to stop",
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        {
         "offset": 722,
         "length": 15
        }
       ]
      },
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       "id": "15",
       "infons": {
        "identifier": "C031942",
        "type": "ChemicalEntity"
       },
       "text": "Argatroban",
       "locations": [
        {
         "offset": 765,
         "length": 10
        }
       ]
      },
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       "id": "16",
       "infons": {
        "identifier": "D020152",
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       },
       "text": "congenital antithrombin deficiency",
       "locations": [
        {
         "offset": 830,
         "length": 34
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D020246",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "SMV thrombosis",
       "locations": [
        {
         "offset": 870,
         "length": 14
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      }
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   ],
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    }
   ]
  },
  {
   "id": "16225977",
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    {
     "offset": 0,
     "text": "Amisulpride related tic-like symptoms in an adolescent schizophrenic.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D000077582",
        "type": "ChemicalEntity"
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       "text": "Amisulpride",
       "locations": [
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        }
       ]
      },
      {
       "id": "1",
       "infons": {
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       "text": "tic-like symptoms",
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       ]
      },
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       "id": "2",
       "infons": {
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       "text": "schizophrenic",
       "locations": [
        {
         "offset": 55,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 70,
     "text": "Tic disorders can be effectively treated by atypical antipsychotics such as risperidone, olanzapine and ziprasidone. However, there are two case reports that show tic-like symptoms, including motor and phonic variants, occurring during treatment with quetiapine or clozapine. We present a 15-year-old girl schizophrenic who developed frequent involuntary eye-blinking movements after 5 months of amisulpride treatment (1000 mg per day). The tic-like symptoms resolved completely after we reduced the dose of amisulpride down to 800 mg per day. However, her psychosis recurred after the dose reduction. We then placed her on an additional 100 mg per day of quetiapine. She has been in complete remission under the combined medications for more than one year and maintains a fair role function. No more tic-like symptoms or other side effects have been reported. Together with previously reported cases, our patient suggests that tic-like symptoms might occur in certain vulnerable individuals during treatment with atypical antipsychotics such as quetiapine, clozapine, or amisulpride.",
     "annotations": [
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       "id": "3",
       "infons": {
        "identifier": "D013981",
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       "text": "Tic disorders",
       "locations": [
        {
         "offset": 70,
         "length": 13
        }
       ]
      },
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       "id": "4",
       "infons": {
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       "text": "antipsychotics",
       "locations": [
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         "offset": 123,
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        }
       ]
      },
      {
       "id": "5",
       "infons": {
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       "text": "risperidone",
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       ]
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       "text": "olanzapine",
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         "length": 10
        }
       ]
      },
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       "infons": {
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       "text": "ziprasidone",
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         "offset": 174,
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       ]
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       "id": "8",
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       "text": "tic-like symptoms",
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       ]
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       "text": "quetiapine",
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       "id": "10",
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       "text": "clozapine",
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       ]
      },
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       "id": "11",
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       "text": "schizophrenic",
       "locations": [
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         "length": 13
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       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "D020820",
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       "text": "involuntary eye-blinking movements",
       "locations": [
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         "offset": 413,
         "length": 34
        }
       ]
      },
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       "id": "13",
       "infons": {
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       "text": "amisulpride",
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       "id": "14",
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       "text": "tic-like symptoms",
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        {
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       ]
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       "id": "15",
       "infons": {
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       "text": "amisulpride",
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      },
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       "id": "16",
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       "text": "psychosis",
       "locations": [
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         "offset": 627,
         "length": 9
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       ]
      },
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       "id": "17",
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       "text": "quetiapine",
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       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "-",
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       "text": "tic-like symptoms",
       "locations": [
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         "length": 17
        }
       ]
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       "text": "patient",
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       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "-",
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       "text": "tic-like symptoms",
       "locations": [
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       ]
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       "text": "antipsychotics",
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       ]
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       "text": "quetiapine",
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       ]
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       "id": "23",
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       "text": "clozapine",
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       ]
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       "id": "24",
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       "text": "amisulpride",
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  {
   "id": "20859899",
   "passages": [
    {
     "offset": 0,
     "text": "Syncope caused by hyperkalemia during use of a combined therapy with the angiotensin-converting enzyme inhibitor and spironolactone.",
     "annotations": [
      {
       "id": "0",
       "infons": {
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       "text": "Syncope",
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       "text": "hyperkalemia",
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       "text": "angiotensin-converting enzyme inhibitor",
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       "text": "spironolactone",
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    },
    {
     "offset": 133,
     "text": "A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an aldosterone antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance.",
     "annotations": [
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       "text": "woman",
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      },
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       "text": "myocardial infarction",
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         "offset": 213,
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       ]
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       "text": "loss of consciousness",
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        {
         "offset": 278,
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       "text": "bradycardia",
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        {
         "offset": 314,
         "length": 11
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       ]
      },
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       "text": "hyperkalemia",
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       ]
      },
      {
       "id": "9",
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       "text": "potassium",
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         "offset": 377,
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       ]
      },
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       "id": "10",
       "infons": {
        "identifier": "D011188",
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       "text": "potassium",
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         "offset": 464,
         "length": 9
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       ]
      },
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       "id": "11",
       "infons": {
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       "text": "hyperkalemia",
       "locations": [
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         "offset": 494,
         "length": 12
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       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "D013148",
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       "text": "spiranolactone",
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        {
         "offset": 545,
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       ]
      },
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       "id": "13",
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       "text": "aldosterone",
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         "offset": 564,
         "length": 11
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       ]
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       "id": "14",
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       "text": "ramipril",
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       ]
      },
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       "text": "ACE",
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         "offset": 640,
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       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D006947",
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       "text": "hyperkalemia",
       "locations": [
        {
         "offset": 804,
         "length": 12
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       ]
      },
      {
       "id": "17",
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       "text": "patients",
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       ]
      },
      {
       "id": "18",
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        "identifier": "1636",
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       "text": "ACE",
       "locations": [
        {
         "offset": 855,
         "length": 3
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       ]
      },
      {
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       "infons": {
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       "text": "ARB",
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        {
         "offset": 859,
         "length": 3
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "D011188",
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       "text": "potassium",
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        {
         "offset": 883,
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       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D007674",
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       "text": "renal disturbance",
       "locations": [
        {
         "offset": 926,
         "length": 17
        }
       ]
      }
     ]
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   ],
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     "infons": {
      "entity1": "D057911",
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     "infons": {
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      "type": "Positive_Correlation",
      "novel": "Novel"
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     "infons": {
      "entity1": "1636",
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    },
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      "type": "Cotreatment",
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     "infons": {
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      "type": "Association",
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     "id": "R9",
     "infons": {
      "entity1": "D000450",
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      "type": "Negative_Correlation",
      "novel": "No"
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     "id": "R10",
     "infons": {
      "entity1": "D017257",
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      "type": "Negative_Correlation",
      "novel": "No"
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    },
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     "infons": {
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     "id": "R12",
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   ]
  },
  {
   "id": "15041272",
   "passages": [
    {
     "offset": 0,
     "text": "A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D056728",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2B von Willebrand disease",
       "locations": [
        {
         "offset": 36,
         "length": 30
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "rs61749384",
        "type": "SequenceVariant"
       },
       "text": "R1306W",
       "locations": [
        {
         "offset": 72,
         "length": 6
        }
       ]
      }
     ]
    },
    {
     "offset": 89,
     "text": "Clinical, laboratory and genetic defect of a Taiwanese family with type 2B von Willebrand disease (VWD) were studied. The proband was a 55-year-old woman who gave birth to two daughters and one son aged 30, 29 and 27, respectively. All had abnormal mucocutaneous bleedings since their childhood. In proband, PT, PTT and platelet count were normal; template bleeding time was 14 min; VIII:C was 51%, von Willebrand factor antigen (VWF:Ag), 42% and von Willerand factor ristocetin-cofactor (VWF:RCo, 15%); ristocetin-induced platelet aggregation (RIPA) at 0.3 and 0.6 mg/ml of ristocetin was 16% and 68%, respectively. The enhanced response to ristocetin was identified to be in plasma, not in platelet itself, by mixing studies. Analysis of von Willebrand factor (VWF) multimer of plasma but not of platelets showed absence of high-molecular weight (HMW) multimer. All three children had similar laboratory findings. Exon 28 of VWF gene was amplified using polymerase chain reaction (PCR) and sequenced. The proband and three children were all found to be heterozygous for C to T transition at nucleotide 3916 resulting in Arg 1306 Trp (R1306W) substitution. This mutation in the glycoprotein Ib (GPIb)-binding site has been found to increase the affinity of plasma VWF for platelets, and thus cause loss of HMW multimers and often thrombocytopenia. In conclusion, a first report of type 2B VWD in a Taiwanese Chinese family who show R1306W mutation in VWF gene was described.",
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       "id": "2",
       "infons": {
        "identifier": "D030342",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "genetic defect",
       "locations": [
        {
         "offset": 114,
         "length": 14
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       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D056728",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2B von Willebrand disease",
       "locations": [
        {
         "offset": 156,
         "length": 30
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D014842",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "VWD",
       "locations": [
        {
         "offset": 188,
         "length": 3
        }
       ]
      },
      {
       "id": "5",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
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       "text": "woman",
       "locations": [
        {
         "offset": 237,
         "length": 5
        }
       ]
      },
      {
       "id": "6",
       "infons": {
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       "text": "bleedings",
       "locations": [
        {
         "offset": 352,
         "length": 9
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      },
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       "id": "7",
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       "text": "bleeding",
       "locations": [
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         "offset": 446,
         "length": 8
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       ]
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       "id": "8",
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       "text": "VIII",
       "locations": [
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         "offset": 472,
         "length": 4
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       ]
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       "text": "von Willebrand factor",
       "locations": [
        {
         "offset": 488,
         "length": 21
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       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
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       "text": "VWF",
       "locations": [
        {
         "offset": 519,
         "length": 3
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       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
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       "text": "von Willerand factor",
       "locations": [
        {
         "offset": 536,
         "length": 20
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       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "D012310",
        "type": "ChemicalEntity"
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       "text": "ristocetin",
       "locations": [
        {
         "offset": 557,
         "length": 10
        }
       ]
      },
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       "id": "13",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 578,
         "length": 3
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D001791",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ristocetin-induced platelet aggregation",
       "locations": [
        {
         "offset": 593,
         "length": 39
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       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D001791",
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       "text": "RIPA",
       "locations": [
        {
         "offset": 634,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D012310",
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       "text": "ristocetin",
       "locations": [
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         "offset": 664,
         "length": 10
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       "infons": {
        "identifier": "D012310",
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       "text": "ristocetin",
       "locations": [
        {
         "offset": 731,
         "length": 10
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       ]
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       "id": "18",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
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       "text": "von Willebrand factor",
       "locations": [
        {
         "offset": 829,
         "length": 21
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       ]
      },
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       "id": "19",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 852,
         "length": 3
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       ]
      },
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       "id": "20",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 1016,
         "length": 3
        }
       ]
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       "id": "21",
       "infons": {
        "identifier": "rs61749384",
        "type": "SequenceVariant"
       },
       "text": "C to T transition at nucleotide 3916",
       "locations": [
        {
         "offset": 1161,
         "length": 36
        }
       ]
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       "id": "22",
       "infons": {
        "identifier": "rs61749384",
        "type": "SequenceVariant"
       },
       "text": "Arg 1306 Trp",
       "locations": [
        {
         "offset": 1211,
         "length": 12
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       ]
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       "id": "23",
       "infons": {
        "identifier": "rs61749384",
        "type": "SequenceVariant"
       },
       "text": "R1306W",
       "locations": [
        {
         "offset": 1225,
         "length": 6
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       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "2811",
        "type": "GeneOrGeneProduct"
       },
       "text": "glycoprotein Ib",
       "locations": [
        {
         "offset": 1268,
         "length": 15
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "2811",
        "type": "GeneOrGeneProduct"
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       "text": "GPIb",
       "locations": [
        {
         "offset": 1285,
         "length": 4
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       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
       },
       "text": "VWF",
       "locations": [
        {
         "offset": 1354,
         "length": 3
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       ]
      },
      {
       "id": "27",
       "infons": {
        "identifier": "D013921",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "thrombocytopenia",
       "locations": [
        {
         "offset": 1420,
         "length": 16
        }
       ]
      },
      {
       "id": "28",
       "infons": {
        "identifier": "D056728",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "type 2B VWD",
       "locations": [
        {
         "offset": 1471,
         "length": 11
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       ]
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       "id": "29",
       "infons": {
        "identifier": "rs61749384",
        "type": "SequenceVariant"
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       "text": "R1306W",
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         "offset": 1522,
         "length": 6
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       "id": "30",
       "infons": {
        "identifier": "7450",
        "type": "GeneOrGeneProduct"
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       "text": "VWF",
       "locations": [
        {
         "offset": 1541,
         "length": 3
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  {
   "id": "17395743",
   "passages": [
    {
     "offset": 0,
     "text": "Identification of PVT1 as a candidate gene for end-stage renal disease in type 2 diabetes using a pooling-based genome-wide single nucleotide polymorphism association study.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "5820",
        "type": "GeneOrGeneProduct"
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       "text": "PVT1",
       "locations": [
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         "offset": 18,
         "length": 4
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       "id": "1",
       "infons": {
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       "text": "end-stage renal disease",
       "locations": [
        {
         "offset": 47,
         "length": 23
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      {
       "id": "2",
       "infons": {
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 74,
         "length": 15
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       ]
      }
     ]
    },
    {
     "offset": 174,
     "text": "To identify genetic variants contributing to end-stage renal disease (ESRD) in type 2 diabetes, we performed a genome-wide analysis of 115,352 single nucleotide polymorphisms (SNPs) in pools of 105 unrelated case subjects with ESRD and 102 unrelated control subjects who have had type 2 diabetes for > or =10 years without macroalbuminuria. Using a sliding window statistic of ranked SNPs, we identified a 200-kb region on 8q24 harboring three SNPs showing substantial differences in allelic frequency between case and control pools. These SNPs were genotyped in individuals comprising each pool, and strong evidence for association was found with rs2720709 (P = 0.000021; odds ratio 2.57 [95% CI 1.66-3.96]), which is located in the plasmacytoma variant translocation gene PVT1. We sequenced all exons, exon-intron boundaries, and the promoter of PVT1 and identified 47 variants, 11 of which represented nonredundant markers with minor allele frequency > or =0.05. We subsequently genotyped these 11 variants and an additional 87 SNPs identified through public databases in 319-kb flanking rs2720709 ( approximately 1 SNP/3.5 kb); 23 markers were associated with ESRD at P < 0.01. The strongest evidence for association was found for rs2648875 (P = 0.0000018; 2.97 [1.90-4.65]), which maps to intron 8 of PVT1. Together, these results suggest that PVT1 may contribute to ESRD susceptibility in diabetes.",
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       "infons": {
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       "text": "end-stage renal disease",
       "locations": [
        {
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         "length": 23
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       "id": "4",
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       "text": "ESRD",
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      },
      {
       "id": "5",
       "infons": {
        "identifier": "D003924",
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 253,
         "length": 15
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       "infons": {
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       "text": "ESRD",
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       "id": "7",
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       "text": "type 2 diabetes",
       "locations": [
        {
         "offset": 454,
         "length": 15
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       ]
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        {
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       "id": "9",
       "infons": {
        "identifier": "5820",
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       "text": "PVT1",
       "locations": [
        {
         "offset": 948,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "5820",
        "type": "GeneOrGeneProduct"
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       "text": "PVT1",
       "locations": [
        {
         "offset": 1022,
         "length": 4
        }
       ]
      },
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       "id": "11",
       "infons": {
        "identifier": "rs2720709",
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       },
       "text": "rs2720709",
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        {
         "offset": 1265,
         "length": 9
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       ]
      },
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       "id": "12",
       "infons": {
        "identifier": "D007676",
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       },
       "text": "ESRD",
       "locations": [
        {
         "offset": 1338,
         "length": 4
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "rs2648875",
        "type": "SequenceVariant"
       },
       "text": "rs2648875",
       "locations": [
        {
         "offset": 1409,
         "length": 9
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "5820",
        "type": "GeneOrGeneProduct"
       },
       "text": "PVT1",
       "locations": [
        {
         "offset": 1480,
         "length": 4
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "5820",
        "type": "GeneOrGeneProduct"
       },
       "text": "PVT1",
       "locations": [
        {
         "offset": 1523,
         "length": 4
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D007676",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "ESRD",
       "locations": [
        {
         "offset": 1546,
         "length": 4
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D003920",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "diabetes",
       "locations": [
        {
         "offset": 1569,
         "length": 8
        }
       ]
      }
     ]
    }
   ],
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    },
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    },
    {
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    },
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    },
    {
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    },
    {
     "id": "R6",
     "infons": {
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    }
   ]
  },
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     "text": "Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.",
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     "text": "Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high-vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal-vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high-vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)a- and RARg-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand-induced, WAT-selective, increased retinoic acid response element-mediated signaling; and 3) RAR ligand-dependent reduction of adiponectin expression.-Landrier, J.-F., Kasiri, E., Karkeni, E., Mihaly, J., Beke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Ruhl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.",
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     "text": "Arginase 1 deletion in myeloid cells affects the inflammatory response in allergic asthma, but not lung mechanics, in female mice.",
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     "text": "BACKGROUND: (Over-)expression of arginase may limit local availability of arginine for nitric oxide synthesis. We investigated the significance of arginase1 (ARG1) for the development of airway hyperresponsiveness (AHR) and lung inflammation in female mice with ovalbumin (OVA)-induced allergic asthma. METHODS: Arg1 was ablated in the lung by crossing Arg1 fl/fl and Tie2Cre tg/- mice. OVA sensitization and challenge were conducted, and AHR to methacholine was determined using the Flexivent system. Changes in gene expression, chemokine and cytokine secretion, plasma IgE, and lung histology were quantified using RT-qPCR, ELISA, and immunohistochemistry, respectively. RESULTS: Arg1 ablation had no influence on the development of OVA-induced AHR, but attenuated OVA-induced increases in expression of Arg2 and Nos2, Slc7a1, Slc7a2, and Slc7a7 (arginine transporters), Il4, Il5 and Il13 (TH2-type cytokines), Ccl2 and Ccl11 (chemokines), Ifng (TH1-type cytokine), Clca3 and Muc5ac (goblet cell markers), and OVA-specific IgE. Pulmonary IL-10 protein content increased, but IL-4, IL-5, IL-13, TNFalpha and IFNgamma content, and lung histopathology, were not affected. Arg1 elimination also decreased number and tightness of correlations between adaptive changes in lung function and inflammatory parameters in OVA/OVA-treated female mice. OVA/OVA-treated female mice mounted a higher OVA-IgE response than males, but the correlation between lung function and inflammation was lower. Arg1-deficient OVA/OVA-treated females differed from males in a more pronounced decline of arginine-metabolizing and -transporting genes, higher plasma arginine levels, a smaller OVA-specific IgE response, and no improvement of peripheral lung function. CONCLUSION: Complete ablation of Arg1 in the lung affects mRNA abundance of arginine-transporting and -metabolizing genes, and pro-inflammatory genes, but not methacholine responsiveness or accumulation of inflammatory cells.",
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       "text": "Creatine kinase",
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       "text": "patient",
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       "id": "37",
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       "id": "38",
       "infons": {
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       "text": "patients",
       "locations": [
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         "offset": 2020,
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       "text": "meningitis",
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         "offset": 2137,
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  {
   "id": "20682662",
   "passages": [
    {
     "offset": 0,
     "text": "Lack of association of C-C chemokine receptor 5 DD32 deletion status with rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, and disease severity.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "C-C chemokine receptor 5",
       "locations": [
        {
         "offset": 23,
         "length": 24
        }
       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "DD32 deletion",
       "locations": [
        {
         "offset": 48,
         "length": 13
        }
       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "rheumatoid arthritis",
       "locations": [
        {
         "offset": 74,
         "length": 20
        }
       ]
      },
      {
       "id": "3",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 96,
         "length": 28
        }
       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D008181",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lupus nephritis",
       "locations": [
        {
         "offset": 126,
         "length": 15
        }
       ]
      }
     ]
    },
    {
     "offset": 165,
     "text": "OBJECTIVE: C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (DD32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases. We investigated whether the DD32 deletion is associated with disease susceptibility in a population of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN); and whether it is associated with disease severity. METHODS: DNA samples from 405 RA patients, 97 SLE patients, 113 LN patients, and 431 healthy controls were genotyped for the CCR5 DD32 deletion. Differences in genotype frequencies were tested between patients and controls. Association of genotypes with disease severity was analyzed. RESULTS: Genotype frequencies of each group were in Hardy-Weinberg equilibrium. The genotype frequencies of patients did not differ significantly from controls (CCR5/DD32, DD32/DD32: RA 18.3% and 1.2%, respectively; SLE 17.5% and 2.1%; LN 13.3% and 1.8%; controls 20.0% and 2.8%). However, there was a trend for lower DD32 deletion allele frequency in LN patients compared to controls (p = 0.08). There was no significant association between the CCR5 status and disease severity in RA, SLE, or LN. CONCLUSION: Although an association with LN cannot be excluded, the CCR5 DD32 deletion does not seem to be a disease susceptibility genotype for RA, SLE, or LN. No significant effect of the DD32 deletion on disease severity was demonstrated.",
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      {
       "id": "5",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "C-C chemokine receptor 5",
       "locations": [
        {
         "offset": 176,
         "length": 24
        }
       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 202,
         "length": 4
        }
       ]
      },
      {
       "id": "7",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "inflammation",
       "locations": [
        {
         "offset": 235,
         "length": 12
        }
       ]
      },
      {
       "id": "8",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "32 base-pair (DD32) deletion",
       "locations": [
        {
         "offset": 251,
         "length": 28
        }
       ]
      },
      {
       "id": "9",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 287,
         "length": 4
        }
       ]
      },
      {
       "id": "10",
       "infons": {
        "identifier": "D001327",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "autoimmune diseases",
       "locations": [
        {
         "offset": 438,
         "length": 19
        }
       ]
      },
      {
       "id": "11",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "DD32 deletion",
       "locations": [
        {
         "offset": 487,
         "length": 13
        }
       ]
      },
      {
       "id": "12",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 562,
         "length": 8
        }
       ]
      },
      {
       "id": "13",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "rheumatoid arthritis",
       "locations": [
        {
         "offset": 576,
         "length": 20
        }
       ]
      },
      {
       "id": "14",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "RA",
       "locations": [
        {
         "offset": 598,
         "length": 2
        }
       ]
      },
      {
       "id": "15",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "systemic lupus erythematosus",
       "locations": [
        {
         "offset": 603,
         "length": 28
        }
       ]
      },
      {
       "id": "16",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 633,
         "length": 3
        }
       ]
      },
      {
       "id": "17",
       "infons": {
        "identifier": "D008181",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "lupus nephritis",
       "locations": [
        {
         "offset": 643,
         "length": 15
        }
       ]
      },
      {
       "id": "18",
       "infons": {
        "identifier": "D008181",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "LN",
       "locations": [
        {
         "offset": 660,
         "length": 2
        }
       ]
      },
      {
       "id": "19",
       "infons": {
        "identifier": "D001172",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "RA",
       "locations": [
        {
         "offset": 747,
         "length": 2
        }
       ]
      },
      {
       "id": "20",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 750,
         "length": 8
        }
       ]
      },
      {
       "id": "21",
       "infons": {
        "identifier": "D008180",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "SLE",
       "locations": [
        {
         "offset": 763,
         "length": 3
        }
       ]
      },
      {
       "id": "22",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 767,
         "length": 8
        }
       ]
      },
      {
       "id": "23",
       "infons": {
        "identifier": "D008181",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "LN",
       "locations": [
        {
         "offset": 781,
         "length": 2
        }
       ]
      },
      {
       "id": "24",
       "infons": {
        "identifier": "9606",
        "type": "OrganismTaxon"
       },
       "text": "patients",
       "locations": [
        {
         "offset": 784,
         "length": 8
        }
       ]
      },
      {
       "id": "25",
       "infons": {
        "identifier": "1234",
        "type": "GeneOrGeneProduct"
       },
       "text": "CCR5",
       "locations": [
        {
         "offset": 842,
         "length": 4
        }
       ]
      },
      {
       "id": "26",
       "infons": {
        "identifier": "c|DEL||32",
        "type": "SequenceVariant"
       },
       "text": "DD32 deletion",
       "locations": [
        {
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     "text": "Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate-salt hypertension.",
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       "text": "angiotensin II type 1a receptor",
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     "text": "The aim of this study was to investigate the in vivo role of angiotensin II type 1a (AT1a) receptor in renal damage as a result of hypertension by using transgenic mice with AT1a receptor gene disruption. Transgenic mice that express human liver-type fatty acid binding protein (L-FABP) with or without disruption of the AT1a receptor gene (L-FABP(+/-) AT1a(-/-), and L-FABP(+/-) AT1a(+/+), respectively) were used with urinary L-FABP as an indicator of tubulointerstitial damage. Those female mice were administered subcutaneously deoxycorticosterone acetate (DOCA)-salt tablets plus drinking water that contained 1% saline for 28 d after uninephrectomy. In L-FABP(+/-) AT1a(+/+) mice that received DOCA-salt treatment, hypertension was induced and slight expansion of glomerular area, glomerular sclerosis, and tubulointerstitial damage were observed. In L-FABP(+/-) AT1a(-/-) mice that received DOCA-salt treatment, hypertension was similarly induced and the degree of glomerular damage was significantly more severe than in L-FABP(+/-) AT1a(+/+)-DOCA mice. Urinary L-FABP levels were significantly higher in L-FABP(+/-) AT1a(-/-)-DOCA mice compared with those in L-FABP(+/-) AT1a(+/+)-DOCA mice. Hydralazine treatment significantly attenuated renal damage that was found in L-FABP(+/-) AT1a(-/-)-DOCA mice along with a reduction in blood pressure. In summary, activation of the AT1a receptor may contribute to maintenance of the glomerular structure against hypertensive renal damage.-Hisamichi, M., Kamijo-Ikemori, A., Sugaya, T., Ichikawa, D., Natsuki, T., Hoshino, S., Kimura, K., Shibagaki, Y. Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate-salt hypertension.",
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     "text": "PTPN22 Is a Critical Regulator of Fcg Receptor-Mediated Neutrophil Activation.",
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  {
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    {
     "offset": 0,
     "text": "Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "D049971",
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       "text": "thiazide",
       "locations": [
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       "id": "1",
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       "text": "Na-Cl co-transporter",
       "locations": [
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         "length": 20
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       "infons": {
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       "text": "patients",
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         "length": 8
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     "text": "BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations.",
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         "offset": 278,
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    {
     "offset": 0,
     "text": "Regulatory network of inflammation downstream of proteinase-activated receptors.",
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       "id": "0",
       "infons": {
        "identifier": "D007249",
        "type": "DiseaseOrPhenotypicFeature"
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       "text": "inflammation",
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         "offset": 22,
         "length": 12
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       "id": "1",
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       "text": "proteinase-activated receptors",
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     "offset": 81,
     "text": "BACKGROUND: Protease-activated receptors (PAR) are present in the urinary bladder, and their expression is altered in response to inflammation. PARs are a unique class of G protein-coupled that carry their own ligands, which remain cryptic until unmasked by proteolytic cleavage. Although the canonical signal transduction pathway downstream of PAR activation and coupling with various G proteins is known and leads to the rapid transcription of genes involved in inflammation, the effect of PAR activation on the downstream transcriptome is unknown. We have shown that intravesical administration of PAR-activating peptides leads to an inflammatory reaction characterized by edema and granulocyte infiltration. Moreover, the inflammatory response to intravesical instillation of known pro-inflammatory stimuli such as E. coli lipopolysaccharide (LPS), substance P (SP), and antigen was strongly attenuated by PAR1- and to a lesser extent by PAR2-deficiency. RESULTS: Here, cDNA array experiments determined inflammatory genes whose expression is dependent on PAR1 activation. For this purpose, we compared the alteration in gene expression in wild type and PAR1-/- mice induced by classical pro-inflammatory stimuli (LPS, SP, and antigen). 75 transcripts were considered to be dependent on PAR-1 activation and further annotated in silico by Ingenuity Pathways Analysis (IPA) and gene ontology (GO). Selected transcripts were target validated by quantitative PCR (Q-PCR). Among PAR1-dependent transcripts, the following have been implicated in the inflammatory process: b2m, ccl7, cd200, cd63, cdbpd, cfl1, dusp1, fkbp1a, fth1, hspb1, marcksl1, mmp2, myo5a, nfkbia, pax1, plaur, ppia, ptpn1, ptprcap, s100a10, sim2, and tnfaip2. However, a balanced response to signals of injury requires a transient cellular activation of a panel of genes together with inhibitory systems that temper the overwhelming inflammation. In this context, the activation of genes such as dusp1 and nfkbia seems to counter-balance the inflammatory response to PAR activation by limiting prolonged activation of p38 MAPK and increased cytokine production. In contrast, transcripts such as arf6 and dcnt1 that are involved in the mechanism of PAR re-sensitization would tend to perpetuate the inflammatory reaction in response to common pro-inflammatory stimuli. CONCLUSION: The combination of cDNA array results and genomic networks reveals an overriding participation of PAR1 in bladder inflammation, provides a working model for the involvement of downstream signaling, and evokes testable hypotheses regarding the transcriptome downstream of PAR1 activation. It remains to be determined whether or not mechanisms targeting PAR1 gene silencing or PAR1 blockade will ameliorate the clinical manifestation of cystitis.",
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  {
   "id": "23651211",
   "passages": [
    {
     "offset": 0,
     "text": "Upregulation of T-cell factor-4 isoform-responsive target genes in hepatocellular carcinoma.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "6934",
        "type": "GeneOrGeneProduct"
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       "text": "T-cell factor-4",
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       "id": "1",
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       "locations": [
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     "text": "BACKGROUND: The Wnt/beta-catenin signalling pathway regulates genes involved in cell proliferation, survival, migration and invasion through regulation by T-cell factor (TCF)-4 transcription factor proteins. However, the role of TCF-4 isoforms generated by alternative splicing events in hepatocellular carcinoma (HCC) is unknown. AIM: Here, we investigated TCF-4 isoforms (TCF-4J and K)-responsive target genes that are important in hepatic oncogenesis and tumour development. METHODS: Gene expression microarray was performed on HCC cells overexpressing TCF-4J and K isoforms. Expression level of selected target genes was evaluated and correlations were made between their expression level and that of TCF-4 isoform in 47 pairs of human HCC tumours. RESULTS: Comparison by gene expression microarray revealed that 447 genes were upregulated and 343 downregulated more than 2.0-fold in TCF-4J compared with TCF-4K expressing cells. We validated expression of 18 selected target genes involved in Wnt/beta-catenin, insulin/IGF-1/IRS1 and Notch signalling pathways in 47 pairs of human HCCs and adjacent uninvolved liver tissues. It was observed that 13 genes (CLDN2, STK17B, SPP1, AXIN2, WISP2, MMP7, IRS1, ANXA1, CAMK2N1, ASPH, GPR56, CD24 and JAG1) activated by TCF-4J isoform in HCC cells, were also upregulated in HCC tumours compared with adjacent peritumour tissue; more importantly, 10 genes exhibited a significant correlation with the TCF-4J expression level in tumour. CONCLUSION: TCF-4 isoforms (TCF-4J and K) activated different downstream target genes in HCC. The biological consequence of TCF-4J isoform expression was upregulation of genes associated with tripartite Wnt/beta-catenin, insulin/IGF-1/IRS1 and Notch signal transduction pathway activation, which contribute to the pathogenesis of HCC.",
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     "offset": 0,
     "text": "Nicotine antagonizes caffeine- but not pentylenetetrazole-induced anxiogenic effect in mice.",
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     "text": "RATIONALE: Nicotine and caffeine are widely consumed licit psychoactive drugs worldwide. Epidemiological studies showed that they were generally used concurrently. Although some studies in experimental animals indicate clear pharmacological interactions between them, no studies have shown a specific interaction on anxiety responses. OBJECTIVES: The present study investigates the effects of nicotine on anxiety induced by caffeine and another anxiogenic drug, pentylenetetrazole, in mice. The elevated plus-maze (EPM) test was used to evaluate the effects of drugs on anxiety. METHODS: Adult male Swiss Webster mice (25-32 g) were given nicotine (0.05-0.25 mg/kg s.c.) or saline 10 min before caffeine (70 mg/kg i.p.) or pentylenetetrazole (15 and 30 mg/kg i.p.) injections. After 15 min, mice were evaluated for their open- and closed-arm time and entries on the EPM for a 10-min session. Locomotor activity was recorded for individual groups by using the same treatment protocol with the EPM test. RESULTS: Nicotine (0.05-0.25 mg/kg) itself did not produce any significant effect in the EPM test, whereas caffeine (70 mg/kg) and pentylenetetrazole (30 mg/kg) produced an anxiogenic effect, apparent with decreases in open-arm time and entry. Nicotine (0.25 mg/kg) pretreatment blocked the caffeine- but not pentylenetetrazole-induced anxiety. Administration of each drug and their combinations did not produce any effect on locomotor activity. CONCLUSIONS: Our results suggest that the antagonistic effect of nicotine on caffeine-induced anxiety is specific to caffeine, instead of a non-specific anxiolytic effect. Thus, it may extend the current findings on the interaction between nicotine and caffeine.",
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    {
     "offset": 0,
     "text": "The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice.",
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       "infons": {
        "identifier": "C522803",
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     "text": "PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX.",
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       "text": "H3-receptor",
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     "text": "Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H(3)-receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)-alpha-methylhistamine (RAMH) (5 microg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 microg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia.",
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       "text": "hyperactivity",
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       "text": "THP",
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       "text": "antipsychotic",
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       "text": "histamine H(3)-receptors",
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       "text": "H(3)-receptor antagonists",
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       "infons": {
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       "text": "schizophrenia",
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  {
   "id": "17042884",
   "passages": [
    {
     "offset": 0,
     "text": "Placebo-level incidence of extrapyramidal symptoms (EPS) with quetiapine in controlled studies of patients with bipolar mania.",
     "annotations": [
      {
       "id": "0",
       "infons": {
        "identifier": "D001480",
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       },
       "text": "extrapyramidal symptoms",
       "locations": [
        {
         "offset": 27,
         "length": 23
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       ]
      },
      {
       "id": "1",
       "infons": {
        "identifier": "D001480",
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       "text": "EPS",
       "locations": [
        {
         "offset": 52,
         "length": 3
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       ]
      },
      {
       "id": "2",
       "infons": {
        "identifier": "C069541",
        "type": "ChemicalEntity"
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       "text": "quetiapine",
       "locations": [
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         "offset": 62,
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       "id": "3",
       "infons": {
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       "text": "patients",
       "locations": [
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         "offset": 98,
         "length": 8
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       ]
      },
      {
       "id": "4",
       "infons": {
        "identifier": "D001714",
        "type": "DiseaseOrPhenotypicFeature"
       },
       "text": "bipolar mania",
       "locations": [
        {
         "offset": 112,
         "length": 13
        }
       ]
      }
     ]
    },
    {
     "offset": 127,
     "text": "OBJECTIVES: To evaluate extrapyramidal symptoms (EPS), including akathisia, with quetiapine in patients with bipolar mania. METHODS: Data were analyzed from four similarly designed, randomized, double-blind, 3- to 12-week studies. Two studies evaluated quetiapine monotherapy (up to 800 mg/day) (n = 209) versus placebo (n = 198), with lithium or haloperidol monotherapy as respective active controls. Two studies evaluated quetiapine (up to 800 mg/day) in combination with a mood stabilizer (lithium or divalproex, QTP + Li/DVP) (n = 196) compared to placebo and mood stabilizer (PBO + Li/DVP) (n = 203). Extrapyramidal symptoms were evaluated using the Simpson-Angus Scale (SAS), the Barnes Akathisia Rating Scale (BARS), adverse event reports and anticholinergic drug usage. RESULTS: The incidence of EPS-related adverse events, including akathisia, was no different with quetiapine monotherapy (12.9%) than with placebo (13.1%). Similarly, EPS-related adverse events with QTP + Li/DVP (21.4%) were no different than with PBO + Li/DVP (19.2%). Adverse events related to EPS occurred in 59.6% of patients treated with haloperidol (n = 99) monotherapy, whereas 26.5% of patients treated with lithium (n = 98) monotherapy experienced adverse events related to EPS. The incidence of akathisia was low and similar with quetiapine monotherapy (3.3%) and placebo (6.1%), and with QTP + Li/DVP (3.6%) and PBO + Li/DVP (4.9%). Lithium was associated with a significantly higher incidence (p < 0.05) of tremor (18.4%) than quetiapine (5.6%); cerebellar tremor, which is a known adverse effect of lithium, may have contributed to the elevated rate of tremor in patients receiving lithium therapy. Haloperidol induced a significantly higher incidence (p < 0.001) of akathisia (33.3% versus 5.9%), tremor (30.3% versus 7.8%), and extrapyramidal syndrome (35.4% versus 5.9%) than quetiapine. No significant differences were observed between quetiapine and placebo on SAS and BARS scores. Anticholinergic use was low and similar with quetiapine or placebo. CONCLUSIONS: In bipolar mania, the incidence of EPS, including akathisia, with quetiapine therapy is similar to that with placebo.",
     "annotations": [
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       "id": "5",
       "infons": {
        "identifier": "D001480",
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       "text": "extrapyramidal symptoms",
       "locations": [
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         "length": 23
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      },
      {
       "id": "6",
       "infons": {
        "identifier": "D001480",
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       "locations": [
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         "offset": 176,
         "length": 3
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       ]
      },
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       "id": "7",
       "infons": {
        "identifier": "D017109",
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       "text": "akathisia",
       "locations": [
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         "offset": 192,
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       "locations": [
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       "locations": [
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     "text": "Randomized comparison of olanzapine versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes.",
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     "text": "OBJECTIVE: The authors compared 4-month treatment outcomes for olanzapine versus risperidone in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or risperidone (1-6 mg/day). RESULTS: Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more weight gain occurred with olanzapine than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone. CONCLUSIONS: Clinical outcomes with risperidone were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with olanzapine.",
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     "text": "Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study.",
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     "text": "OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic.",
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     "id": "R7",
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   "id": "17384765",
   "passages": [
    {
     "offset": 0,
     "text": "Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure.",
     "annotations": [
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       "id": "0",
       "infons": {
        "identifier": "D004113",
        "type": "ChemicalEntity"
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       "text": "Succimer",
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       ]
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       "id": "1",
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        "identifier": "D007854",
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       "text": "lead",
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       "id": "2",
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       "text": "rats",
       "locations": [
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       "id": "3",
       "infons": {
        "identifier": "D003072",
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       "text": "cognitive impairment",
       "locations": [
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         "length": 20
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       "id": "4",
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        "type": "ChemicalEntity"
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       "locations": [
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     "text": "BACKGROUND: There is growing pressure for clinicians to prescribe chelation therapy at only slightly elevated blood lead levels. However, very few studies have evaluated whether chelation improves cognitive outcomes in Pb-exposed children, or whether these agents have adverse effects that may affect brain development in the absence of Pb exposure. OBJECTIVES: The present study was designed to answer these questions, using a rodent model of early childhood Pb exposure and treatment with succimer, a widely used chelating agent for the treatment of Pb poisoning. RESULTS: Pb exposure produced lasting impairments in learning, attention, inhibitory control, and arousal regulation, paralleling the areas of dysfunction seen in Pb-exposed children. Succimer treatment of the Pb-exposed rats significantly improved learning, attention, and arousal regulation, although the efficacy of the treatment varied as a function of the Pb exposure level and the specific functional deficit. In contrast, succimer treatment of rats not previously exposed to Pb produced lasting and pervasive cognitive and affective dysfunction comparable in magnitude to that produced by the higher Pb exposure regimen. CONCLUSIONS: These are the first data, to our knowledge, to show that treatment with any chelating agent can alleviate cognitive deficits due to Pb exposure. These findings suggest that it may be possible to identify a succimer treatment protocol that improves cognitive outcomes in Pb-exposed children. However, they also suggest that succimer treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals.",
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       "text": "succimer",
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       "text": "Pb poisoning",
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       "id": "12",
       "infons": {
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       "text": "impairments in learning, attention, inhibitory control, and arousal regulation",
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       "text": "rats",
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       "text": "cognitive deficits",
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       "text": "succimer",
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       "text": "Pb",
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   "id": "17608141",
   "passages": [
    {
     "offset": 0,
     "text": "Attenuation of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity in mice by lipopolysaccharide pretreatment.",
     "annotations": [
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       "infons": {
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       "text": "methamphetamine",
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       "text": "dopaminergic",
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       "text": "neurotoxicity",
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       ]
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       "id": "3",
       "infons": {
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       "text": "mice",
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       "text": "lipopolysaccharide",
       "locations": [
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       ]
      }
     ]
    },
    {
     "offset": 124,
     "text": "Immunological activation has been proposed to play a role in methamphetamine-induced dopaminergic terminal damage. In this study, we examined the roles of lipopolysaccharide, a pro-inflammatory and inflammatory factor, treatment in modulating the methamphetamine-induced nigrostriatal dopamine neurotoxicity. Lipopolysaccharide pretreatment did not affect the basal body temperature or methamphetamine-elicited hyperthermia three days later. Such systemic lipopolysaccharide treatment mitigated methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions in a dose-dependent manner. As the most potent dose (1 mg/kg) of lipopolysaccharide was administered two weeks, one day before or after the methamphetamine dosing regimen, methamphetamine-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid depletions remained unaltered. Moreover, systemic lipopolysaccharide pretreatment (1 mg/kg) attenuated local methamphetamine infusion-produced dopamine and 3,4-dihydroxyphenylacetic acid depletions in the striatum, indicating that the protective effect of lipopolysaccharide is less likely due to interrupted peripheral distribution or metabolism of methamphetamine. We concluded a critical time window for systemic lipopolysaccharide pretreatment in exerting effective protection against methamphetamine-induced nigrostriatal dopamine neurotoxicity.",
     "annotations": [
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       "id": "5",
       "infons": {
        "identifier": "D008694",
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       "text": "methamphetamine",
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       "text": "dopaminergic terminal damage",
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       ]
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       "infons": {
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       "text": "lipopolysaccharide",
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       "text": "inflammatory",
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       ]
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       "text": "inflammatory",
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       ]
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       "text": "3,4-dihydroxyphenylacetic acid",
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     "text": "Ginsenoside Rg1 restores the impairment of learning induced by chronic morphine administration in rats.",
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     "text": "Repetitive transcranial magnetic stimulation for levodopa-induced dyskinesias in Parkinson's disease.",
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     "text": "In a placebo-controlled, single-blinded, crossover study, we assessed the effect of \"real\" repetitive transcranial magnetic stimulation (rTMS) versus \"sham\" rTMS (placebo) on peak dose dyskinesias in patients with Parkinson's disease (PD). Ten patients with PD and prominent dyskinesias had rTMS (1,800 pulses; 1 Hz rate) delivered over the motor cortex for 4 consecutive days twice, once real stimuli and once sham stimulation were used; evaluations were done at the baseline and 1 day after the end of each of the treatment series. Direct comparison between sham and real rTMS effects showed no significant difference in clinician-assessed dyskinesia severity. However, comparison with the baseline showed small but significant reduction in dyskinesia severity following real rTMS but not placebo. The major effect was on dystonia subscore. Similarly, in patient diaries, although both treatments caused reduction in subjective dyskinesia scores during the days of intervention, the effect was sustained for 3 days after the intervention for the real rTMS only. Following rTMS, no side effects and no adverse effects on motor function and PD symptoms were noted. The results suggest the existence of residual beneficial clinical aftereffects of consecutive daily applications of low-frequency rTMS on dyskinesias in PD. The effects may be further exploited for potential therapeutic uses.",
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     "text": "The glycine transporter-1 inhibitor SSR103800 displays a selective and specific antipsychotic-like profile in normal and transgenic mice.",
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     "text": "Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. However, the observation that antagonists of the glutamate N-methyl-D-aspartate (NMDA) receptor produce schizophrenic-like symptoms in humans has led to the idea of a dysfunctioning of the glutamatergic system via its NMDA receptor. As a result, there is a growing interest in the development of pharmacological agents with potential antipsychotic properties that enhance the activity of the glutamatergic system via a modulation of the NMDA receptor. Among them are glycine transporter-1 (GlyT1) inhibitors such as SSR103800, which indirectly enhance NMDA receptor function by increasing the glycine (a co-agonist for the NMDA receptor) levels in the synapse. This study aimed at investigating the potential antipsychotic-like properties of SSR103800, with a particular focus on models of hyperactivity, involving either drug challenge (ie, amphetamine and MK-801) or transgenic mice (ie, NMDA Nr1(neo-/-) and DAT(-/-)). Results showed that SSR103800 (10-30 mg/kg p.o.) blocked hyperactivity induced by the non-competitive NMDA receptor antagonist, MK-801 and partially reversed spontaneous hyperactivity of NMDA Nr1(neo-/-) mice. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT(-/-)) knockout mice (10-30 mg/kg p.o.). Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. Together these findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs.",
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     "text": "Despite increasing reports on nonionic contrast media-induced nephropathy (CIN) in hospitalized adult patients during cardiac procedures, the studies in pediatrics are limited, with even less focus on possible predisposing factors and preventive measures for patients undergoing cardiac angiography. This prospective study determined the incidence of CIN for two nonionic contrast media (CM), iopromide and iohexol, among 80 patients younger than 18 years and compared the rates for this complication in relation to the type and dosage of CM and the presence of cyanosis. The 80 patients in the study consecutively received either iopromide (group A, n = 40) or iohexol (group B, n = 40). Serum sodium (Na), potassium (K), and creatinine (Cr) were measured 24 h before angiography as baseline values, then measured again at 12-, 24-, and 48-h intervals after CM use. Urine samples for Na and Cr also were checked at the same intervals. Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal damage (RIFLE criteria) were used to define CIN and its incidence in the study population. Accordingly, among the 15 CIN patients (18.75%), 7.5% of the patients in group A had increased risk and 3.75% had renal injury, whereas 5% of group B had increased risk and 2.5% had renal injury. Whereas 33.3% of the patients with CIN were among those who received the proper dosage of CM, the percentage increased to 66.6% among those who received larger doses, with a significant difference in the incidence of CIN related to the different dosages of CM (p = 0.014). Among the 15 patients with CIN, 6 had cyanotic congenital heart diseases, but the incidence did not differ significantly from that for the noncyanotic patients (p = 0.243). Although clinically silent, CIN is not rare in pediatrics. The incidence depends on dosage but not on the type of consumed nonionic CM, nor on the presence of cyanosis, and although CIN usually is reversible, more concern is needed for the prevention of such a complication in children.",
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       "text": "contrast media",
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       "text": "nephropathy",
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       "text": "iohexol",
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       "text": "sodium",
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       "text": "potassium",
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       "text": "K",
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       "text": "Cr",
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       "text": "renal failure",
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       "id": "28",
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       "text": "Injury to the kidney",
       "locations": [
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       "id": "29",
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       "text": "Failure of kidney function",
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       "text": "Loss of kidney function",
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       "text": "renal injury",
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       "text": "renal injury",
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       "text": "CIN",
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       "text": "patients",
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       "text": "CIN",
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         "offset": 1771,
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      {
       "id": "45",
       "infons": {
        "identifier": "D006331",
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       "text": "congenital heart diseases",
       "locations": [
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         "offset": 1791,
         "length": 25
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       ]
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       "id": "46",
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       "text": "patients",
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       "text": "cyanosis",
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       "id": "50",
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       "text": "CIN",
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         "offset": 2099,
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    {
     "offset": 0,
     "text": "Elevation of ADAM10, ADAM17, MMP-2 and MMP-9 expression with media degeneration features CaCl2-induced thoracic aortic aneurysm in a rat model.",
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       "id": "0",
       "infons": {
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       "text": "ADAM10",
       "locations": [
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       "text": "CaCl2",
       "locations": [
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         "offset": 89,
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       "id": "5",
       "infons": {
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       "text": "thoracic aortic aneurysm",
       "locations": [
        {
         "offset": 103,
         "length": 24
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       ]
      },
      {
       "id": "6",
       "infons": {
        "identifier": "10116",
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       "text": "rat",
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     "text": "PURPOSE: This study was designed to establish a rat model of thoracic aortic aneurysm (TAA) by calcium chloride (CaCl(2))-induced arterial injury and to explore the potential role of a disintegrin and metalloproteinase (ADAM), matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in TAA formation. METHODS: Thoracic aorta of male Sprague-Dawley rats was exposed to 0.5M CaCl(2) or normal saline (NaCl). After 12weeks, animals were euthanized, and CaCl(2)-treated, CaCl(2)-untreated (n=12) and NaCl-treated aortic segments (n=12) were collected for histological and molecular assessments. MMP-TIMP and ADAM mRNAs were semi-quantitatively analyzed and protein expressions were determined by immunohistochemistry. RESULTS: Despite similar external diameters among CaCl(2)-treated, non-CaCl(2)-treated and NaCl-treated segments, aneurymal alteration (n=6, 50%), media degeneration with regional disruption, fragmentation of elastic fiber, and increased collagen deposition (n=12, 100%) were demonstrated in CaCl(2)-treated segments. MMP-2, MMP-9, ADAM-10 and ADAM-17 mRNA levels were increased in CaCl(2)-treated segments (all p<0.01), with trends of elevation in CaCl(2)-untreated segments, as compared with NaCl-treated segments. Immunohistochemistry displayed significantly increased expressions of MMP-2, MMP-9, ADAM-10 and ADAM-17 (all p<0.01) in intima and media for CaCl(2)-treated segments. TIMP mRNA and tissue levels did not differ obviously among the three aortic segments. CONCLUSION: This study establishes a TAA model by periarterial CaCl(2) exposure in rats, and demonstrates a significant elevation of expression of MMP-2, MMP-9, ADAM10 and ADAM17 in the pathogenesis of vascular remodeling.",
     "annotations": [
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       "text": "thoracic aortic aneurysm",
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       "id": "9",
       "infons": {
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       "text": "TAA",
       "locations": [
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         "offset": 231,
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       "id": "10",
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       "text": "calcium chloride",
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        "identifier": "D014652",
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       "text": "arterial injury",
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         "offset": 274,
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      },
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       "id": "13",
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       "text": "a disintegrin and metalloproteinase",
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      },
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       "text": "ADAM",
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         "offset": 364,
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       "infons": {
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       "text": "matrix metalloproteinases",
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     "offset": 0,
     "text": "Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats.",
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     "text": "In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death.",
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     "offset": 0,
     "text": "Pre-treatment of bupivacaine-induced cardiovascular depression using different lipid formulations of propofol.",
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     "text": "BACKGROUND: Pre-treatment with lipid emulsions has been shown to increase lethal doses of bupivacaine, and the lipid content of propofol may alleviate bupivacaine-induced cardiotoxicity. The aim of this study is to investigate the effects of propofol in intralipid or medialipid emulsions on bupivacaine-induced cardiotoxicity. METHODS: Rats were anaesthetised with ketamine and were given 0.5 mg/kg/min propofol in intralipid (Group P), propofol in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min bupivacaine 0.5% was infused. We recorded time to first dysrhythmia occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to asystole and total amount of bupivacaine consumption. Blood and tissue samples were collected following asystole. RESULTS: The time to first dysrhythmia occurrence, time to 25% and 50% reductions in HR, and time to asystole were longer in Group P than the other groups. The cumulative bupivacaine dose given at those time points was higher in Group P. Plasma bupivacaine levels were significantly lower in Group P than in Group C. Bupivacaine levels in the brain and heart were significantly lower in Group P and Group L than in Group C. CONCLUSION: We conclude that pre-treatment with propofol in intralipid, compared with propofol in medialipid or saline, delayed the onset of bupivacaine-induced cardiotoxic effects as well as reduced plasma bupivacaine levels. Further studies are needed to explore tissue bupivacaine levels of propofol in medialipid and adapt these results to clinical practice.",
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