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BioASQ
{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.
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69acbdb73b2c414cb48a711bb6da31f1
Selexipag is used for which disease?
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{ "text": [ "pulmonary arterial hypertension" ], "char_spans": [ { "start": [ 395 ], "end": [ 425 ] } ], "token_spans": [ { "start": [ 59 ], "end": [ 61 ] } ] }
[ "pulmonary arterial hypertension" ]
BioASQ
Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation.
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796122644c79446f872e37f300157090
In which syndrome is the RPS19 gene most frequently mutated?
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{ "text": [ "Diamond-Blackfan Anemia", "DBA" ], "char_spans": [ { "start": [ 0 ], "end": [ 22 ] }, { "start": [ 25, 1049, 246, 1252, 1183, 376 ], "end": [ 27, 1051, 248, 1254, 1185, 378 ] } ], "token_spans": [ { "start": [ 0 ], "end": [ 2 ] }, { "start": [ 4, 172, 41, 206, 194, 63 ], "end": [ 4, 172, 41, 206, 194, 63 ] } ] }
[ "Diamond-Blackfan Anemia", "Diamond Blackfan anemia", "DBA" ]
BioASQ
Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib is effective to control the tyrosyl phosphorylation of the protein related to the cell signaling. BCR-ABL mRNA is overexpressed in the minimal residual disease (MRD), known as an early sign of relapse. Between December 2005 and June 2008, we measured BCR-ABL mRNA levels in the bone marrow (BM) from patients by quantitative real-time polymerase chain reaction (RQ-PCR) in Aomori Prefectural Central Hospital. Eighty-six samples from 26 patients were collected. Among the 26 CML patients, 11 patients (42%) were in the pretreatment group. Seven (64%) of the 11 patients achieved complete molecular response (CMR). In the post-treatment group consisting of the remaining 15 patients, 9 (60%) patients achieved CMR. The patients receiving imatinib at a dose over 300 mg per day required 13 (6-77) months [median (range)] to achieve CMR. On the other hand, the patients receiving a dose below 300 mg per day required 29.5 (11-84) months [median (range)]. When BCR-ABL mRNA was detected during the treatment course of patients with CMR, careful observation of BCR-ABL mRNA was useful for tracking the clinical course of patients. In conclusion, the BCR-ABL mRNA level was useful for monitoring the clinical course in 26 patients with CML.
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412a49803a00424099cd84a75d92bd63
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
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{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 1409, 172, 515, 362, 48, 1320, 1221 ], "end": [ 1415, 178, 521, 368, 54, 1326, 1227 ] } ], "token_spans": [ { "start": [ 295, 36, 101, 69, 10, 277, 259 ], "end": [ 297, 38, 103, 71, 12, 279, 261 ] } ] }
[ "BCR-ABL" ]
BioASQ
Oral empagliflozin (Jardiance(®)), a sodium glucose cotransporter-2 (SGLT2) inhibitor, is a convenient once-daily treatment for adult patients with type 2 diabetes mellitus. By inhibiting reabsorption of glucose from the proximal tubules in the kidney via inhibition of SGLT2, empagliflozin provides a novel insulin-independent mechanism of lowering blood glucose. In several phase III trials (≤104 weeks' duration; typically 24 weeks' duration) and extension studies (typically ≥76 weeks' treatment), empagliflozin monotherapy or add-on therapy to other antihyperglycaemics, including insulin, improved glycaemic control and reduced bodyweight and systolic blood pressure in adult patients with type 2 diabetes. In a large phase III trial, as add-on therapy to metformin, empagliflozin was shown to be noninferior to glimepiride at 52 and 104 weeks and superior to glimepiride at 104 weeks, in terms of reductions in glycated haemoglobin level (primary endpoint). Empagliflozin was well tolerated by participants in these clinical trials, with most adverse events being mild or moderate in intensity. Empagliflozin treatment appeared to have no intrinsic risk of hypoglycaemia, although hypoglycaemia occurred more frequently when empagliflozin was coadministered with insulin and/or a sulfonylurea. With its insulin-independent mechanism of action, empagliflozin monotherapy or combination therapy with other antidiabetic drugs, including insulin, provides a useful addition to the therapeutic options for the management of type 2 diabetes. This article reviews the pharmacological properties and clinical use of empagliflozin in patients with type 2 diabetes.
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95f5fe67a6334781a72627254072209a
Which protein does empagliflozin inhibit?
{ "tokens": [ "Which", "protein", "does", "empagliflozin", "inhibit", "?" ], "offsets": [ 0, 6, 14, 19, 33, 40 ] }
{ "text": [ "SGLT2" ], "char_spans": [ { "start": [ 270, 69 ], "end": [ 274, 73 ] } ], "token_spans": [ { "start": [ 49, 14 ], "end": [ 49, 14 ] } ] }
[ "SGLT2" ]
BioASQ
Gaucher disease is an inborn recessive autosomal disease due to a partial deficiency of the lysosomal enzyme beta glucocerebrosidase. The deficient activity leads to accumulation of the lipid glucocerebroside in the liver, the spleen and bone marrow with concomitant anemia and thrombocytopenia. Patients with Gaucher disease have been classified in three types: type I is the more common, neurological manifestations occur in types II and III. Enzyme replacement therapy (ERT) with modified placental human glucocerebrosidase (ceredase) or recombinant glucocerebrosidase (cerezyme) is effective in most type I Gaucher disease and has become the current standard care administered to thousand of patients worldwide. ERT has obviated the need for bone marrow transplantation and virtually eliminated the need for splenectomy. We report here the French study including adults and children. ERT of 30 to 60 U/K every two weeks as starting dose was administrated to 108 patients with severe type I Gaucher disease. ERT fully reverse many of the manifestations of the disease. ERT regimen alleviated fatigue, and hematological and visceral signs and symptoms in nearly all severely-ill patients. Skeletal responses to treatment develop much more slowly than hematological or visceral responses. Studies in pediatrics show that the disease is more severe in children. These children should be treated early in the course of their disease to avoid irreparable damage. Hematological manifestation in type II cannot be reversed with enzyme replacement. In type III treatment can rarely reverse neurological deficit. Gaucher disease is also an excellent candidate for gene therapy.
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edb5b97a3a7341bdb6cfc2b80433d4f0
Which enzyme is deficient in Gaucher's disease?
{ "tokens": [ "Which", "enzyme", "is", "deficient", "in", "Gaucher", "'s", "disease", "?" ], "offsets": [ 0, 6, 13, 16, 26, 29, 36, 39, 46 ] }
{ "text": [ "Beta glucocerebrosidase" ], "char_spans": [ { "start": [ 109 ], "end": [ 131 ] } ], "token_spans": [ { "start": [ 17 ], "end": [ 18 ] } ] }
[ "Beta glucocerebrosidase" ]
BioASQ
The effect of levodopa (L-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD, = dopa decarboxylase), L-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of L-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no L-dopa treatment (group 1), L-dopa alone (group 2), L-dopa + benserazide (Madopar) (group 3) and L-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily L-dopa dose compared with group 2, plasma L-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/L-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/L-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3-4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.
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"dose", "deterioration", "and", "on", "-", "off", "phenomena", "." ], "offsets": [ 0, 4, 11, 14, 23, 24, 25, 26, 30, 31, 33, 39, 42, 45, 57, 62, 64, 75, 89, 99, 100, 103, 104, 106, 109, 116, 123, 126, 134, 135, 136, 137, 143, 148, 162, 163, 168, 170, 172, 177, 190, 191, 193, 194, 195, 199, 201, 204, 205, 211, 212, 217, 218, 223, 224, 226, 235, 236, 238, 239, 241, 254, 256, 267, 271, 280, 284, 285, 297, 301, 306, 313, 315, 318, 326, 335, 339, 342, 351, 356, 369, 376, 382, 388, 393, 399, 414, 417, 418, 419, 424, 426, 437, 439, 443, 452, 455, 464, 471, 478, 481, 484, 486, 489, 491, 496, 497, 507, 513, 519, 523, 531, 533, 535, 537, 543, 549, 551, 556, 560, 569, 574, 585, 597, 599, 607, 612, 617, 623, 625, 628, 629, 630, 635, 645, 646, 652, 653, 654, 656, 657, 658, 663, 669, 670, 676, 677, 678, 680, 681, 682, 687, 689, 701, 702, 709, 711, 712, 718, 719, 721, 725, 726, 727, 732, 734, 744, 745, 752, 754, 755, 761, 762, 763, 765, 772, 777, 779, 785, 789, 796, 799, 806, 808, 812, 813, 815, 819, 829, 836, 839, 846, 848, 852, 853, 855, 866, 871, 877, 881, 891, 894, 900, 903, 907, 909, 910, 925, 928, 931, 933, 941, 946, 956, 959, 964, 966, 969, 976, 978, 982, 983, 985, 990, 995, 999, 1005, 1006, 1007, 1012, 1017, 1026, 1031, 1037, 1038, 1040, 1047, 1048, 1049, 1054, 1058, 1064, 1071, 1076, 1078, 1084, 1090, 1092, 1098, 1105, 1108, 1115, 1120, 1124, 1133, 1135, 1139, 1141, 1142, 1143, 1144, 1149, 1155, 1159, 1169, 1176, 1179, 1185, 1187, 1191, 1199, 1202, 1209, 1211, 1215, 1217, 1220, 1229, 1234, 1240, 1241, 1243, 1251, 1257, 1264, 1268, 1273, 1274, 1275, 1276, 1281, 1288, 1299, 1304, 1308, 1319, 1322, 1324, 1325, 1329, 1341, 1343, 1346, 1348, 1361, 1367, 1370, 1376, 1385, 1393, 1396, 1404, 1414, 1418, 1428, 1431, 1438, 1444, 1448, 1454, 1457, 1463, 1473, 1478, 1479, 1480, 1482, 1487, 1489, 1497, 1506, 1522, 1530, 1533, 1540, 1544, 1558, 1564, 1568, 1577, 1580, 1586, 1589, 1599, 1607, 1611, 1617, 1627, 1630, 1634, 1638, 1641, 1649, 1652, 1656, 1661, 1664, 1673, 1682, 1685, 1697, 1705, 1708, 1713, 1722, 1726, 1730, 1733, 1736, 1744, 1747, 1750, 1751, 1753, 1754, 1759, 1773, 1777, 1779, 1780, 1784, 1793 ] }
5aad124ed6b3449e87579c5571aa6c64
Which drug is benserazide usually co-administered with?
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{ "text": [ "L-Dopa" ], "char_spans": [ { "start": [ 725, 1142, 417, 680, 1047, 24, 1005, 193, 1274, 628, 656 ], "end": [ 730, 1147, 422, 685, 1052, 29, 1010, 198, 1279, 633, 661 ] } ], "token_spans": [ { "start": [ 161, 258, 87, 148, 236, 5, 226, 42, 287, 130, 139 ], "end": [ 163, 260, 89, 150, 238, 7, 228, 44, 289, 132, 141 ] } ] }
[ "L-Dopa" ]
BioASQ
Determining clinical probability of pulmonary embolism (PE) with Wells scoring system is the first step towards diagnosis of PE. Definitive diagnosis of PE is confirmed by computed tomography pulmonary angiography (CTPA). This was a prospective study on 80 patients referred to the Institute for Pulmonary Diseases of Vojvodina with suspected PE between April 2010 and August 2012. Clinical probability of PE was determined according to the Wells and modified Wells scoring system. CTPA was performed in 60 patients. The degree of pulmonary vascular obstruction was quantified by the Qanadli index. Low clinical probability of PE was present in one patient (1.6%), moderate in 43 (71.6%) and high in 16 (26.6%) patients. PE was confirmed in 50 (83.3%) patients. There were 21 patients (42%) whose Quanadli index was <25%, 18 (36%) between 25%-50%, while Quanadli index was ≥50 in 11 patients (22%). When compared to CTPA findings, modified Wells scoring system showed 90% sensitivity [95% confidence interval (CI) 78.2%-96.6%], and 20% specificity (95% CI 3.11%-55.6%), positive predictive value (PPV) 84.9% (95% CI 72.4%-93.2%) and negative predictive value (NPV) 28.6% (95% CI 4.5%-70.7%). There was weak positive correlation between Wells score and Quanadli index (r = 0.14; P = 0.29), without statistical significance. Wells score was significantly higher in haemodynamically unstable than in haemodynamically stable patients (6.8 vs 5.6, P = 0.014). There was no statistically significant difference between the values of Quanadli index in these two groups (31.33% vs 26.64%, P = 0.062). Modified Wells criteria have high sensitivity but low specificity in PE diagnostics. The Wells score does not correlate well with the Quanadli index.
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862da8740a8c404c925e5d6116db47e5
What can be predicted with the Wells criteria?
{ "tokens": [ "What", "can", "be", "predicted", "with", "the", "Wells", "criteria", "?" ], "offsets": [ 0, 5, 9, 12, 22, 27, 31, 37, 45 ] }
{ "text": [ "pulmonary embolism" ], "char_spans": [ { "start": [ 36 ], "end": [ 53 ] } ], "token_spans": [ { "start": [ 4 ], "end": [ 5 ] } ] }
[ "pulmonary embolism" ]
BioASQ
We report the case of a Japanese boy whose dysmorphic features were consistent with those of Shprintzen-Goldberg syndrome. The radiological features were characterized by late-onset craniosynostosis, arachnodactyly, undermodeling of short tubular bones, mildly undermodeled and slightly bowed long bones, twisted ribs and tall vertebral bodies with elongated neural arches. Apart from the craniosynostosis, these skeletal changes resembled those of frontometaphyseal dysplasia, a well-known craniotubular dysplasia. Shprintzen-Goldberg syndrome also shares many clinical features with frontometaphyseal dysplasia.
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31b5228a9b2e43878afead6abaf040d4
Which disease is included as an additional feature in the Goldberg-Shprintzen syndrome?
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{ "text": [ "Craniosynostosis" ], "char_spans": [ { "start": [ 389, 182 ], "end": [ 404, 197 ] } ], "token_spans": [ { "start": [ 62, 30 ], "end": [ 62, 30 ] } ] }
[ "Craniosynostosis" ]
BioASQ
Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 μg were used. Bioequivalence between 8 x 200 μg and a new 1,600 μg tablet was evaluated at steady state in healthy male subjects. This was an open-label, 2-treatment, 2-period, crossover, up-titration, phase 1 study. The treatments were selexipag at 1,600 μg b.i.d. for 4.5 days either as 8 x 200 μg tablets (reference: A) or 1 x 1,600 μg tablet (test: B), both preceded by an up-titration phase starting from 400 μg b.i.d. doses, in 200-μg steps every 4th day. Subjects were randomized 1 : 1 to the A-B or B-A sequence. The pharmacokinetics and tolerability of selexipag and its active metabolite, ACT-333679, were investigated. 80 subjects were enrolled in the study: 65 subjects completed the study according to protocol, and 15 subjects withdrew from the study. The most frequent adverse events (AEs) were headache (86%), myalgia (73%), and jaw pain (73%). There was no difference in nature and overall frequency of AEs between the two treatments. Steady state was attained within 3 days of the selexipag 1,600 μg b.i.d. The 90% confidence intervals (CIs) of the geometric mean ratio (B/A) at steady state for AUCτ and Cmax,ss were within (0.80, 1.25) bioequivalence interval: (0.92, 1.06) and (0.95, 1.14), respectively, for selexipag and (0.95, 1.06) and (0.94, 1.07), respectively, for the active metabolite, ACT-333679. Bioequivalence was demonstrated between 8 x 200 μg and 1 x 1,600 μg selexipag at steady state.
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990c3fbed6b34ba08dd9a7685e257613
Selexipag is used for which disease?
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{ "text": [ "pulmonary arterial hypertension" ], "char_spans": [ { "start": [ 120 ], "end": [ 150 ] } ], "token_spans": [ { "start": [ 21 ], "end": [ 23 ] } ] }
[ "pulmonary arterial hypertension" ]
BioASQ
To evaluate and compare outcomes for patients with vestibular schwannoma (VS) treated in a single institution with linac-based stereotactic radiosurgery (SRS) or by fractionated stereotactic radiotherapy (SRT). One hundred and nineteen patients (SRS = 78, SRT = 41) were treated. For both SRS and SRT, beam shaping is performed by a mini-multileaf collimator. For SRS, a median single dose of 12.5 Gy (range, 11-14 Gy), prescribed to the 80% isodose line encompassing the target, was applied. Of the 42 SRT treatments, 32 treatments consisted of 10 fractions of 3-4 Gy, and 10 patients received 25 sessions of 2 Gy, prescribed to the 100% with the 95% isodose line encompassing the planning target volume. Mean largest tumor diameter was 16.6 mm in the SRS and 24.6 mm in the SRT group. Local tumor control, cranial nerve toxicity, and preservation of useful hearing were recorded. Any new treatment-induced cranial nerve neuropathy was scored as a complication. Median follow-up was 62 months (range, 6-136 months), 5 patients progressed, resulting in an overall 5-year local tumor control of 95%. The overall 5-year facial nerve preservation probability was 88% and facial nerve neuropathy was statistically significantly higher after SRS, after prior surgery, for larger tumors, and in Koos Grade ≥3. The overall 5-year trigeminal nerve preservation probability was 96%, not significantly influenced by any of the risk factors. The overall 4-year probability of preservation of useful hearing (Gardner-Robertson score 1 or 2) was 68%, not significantly different between SRS or SRT (59% vs. 82%, p = 0.089, log rank). Linac-based RT results in good local control and acceptable clinical outcome in small to medium-sized vestibular schwannomas (VSs). Radiosurgery for large VSs (Koos Grade ≥3) remains a challenge because of increased facial nerve neuropathy.
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"remains", "a", "challenge", "because", "of", "increased", "facial", "nerve", "neuropathy", "." ], "offsets": [ 0, 3, 12, 16, 24, 33, 37, 46, 51, 62, 73, 74, 76, 78, 86, 89, 91, 98, 110, 115, 120, 121, 127, 140, 153, 154, 157, 159, 162, 165, 178, 191, 204, 205, 208, 209, 211, 215, 223, 227, 236, 245, 246, 250, 252, 254, 256, 260, 262, 264, 266, 271, 278, 280, 284, 289, 293, 297, 300, 302, 307, 315, 318, 328, 331, 333, 337, 338, 348, 358, 360, 364, 367, 369, 371, 378, 385, 390, 393, 398, 401, 402, 407, 409, 411, 412, 415, 417, 418, 420, 431, 434, 438, 440, 442, 450, 455, 468, 472, 478, 480, 484, 491, 493, 496, 500, 503, 507, 517, 519, 522, 533, 543, 546, 549, 559, 562, 563, 564, 566, 568, 570, 574, 577, 586, 595, 598, 607, 610, 612, 614, 616, 627, 630, 634, 637, 639, 644, 648, 650, 652, 660, 665, 678, 682, 691, 698, 704, 706, 711, 719, 725, 734, 738, 743, 746, 749, 753, 757, 761, 766, 769, 772, 776, 780, 785, 787, 793, 799, 806, 808, 816, 822, 830, 832, 836, 849, 852, 859, 867, 872, 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1750, 1751, 1753, 1766, 1770, 1776, 1780, 1781, 1786, 1792, 1794, 1796, 1804, 1806, 1816, 1824, 1827, 1837, 1844, 1850, 1860 ] }
212829ec9421495797a732770b08731b
Which disease can be categorized using the Koos grading system?
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{ "text": [ "vestibular schwannoma" ], "char_spans": [ { "start": [ 51 ], "end": [ 71 ] } ], "token_spans": [ { "start": [ 8 ], "end": [ 9 ] } ] }
[ "vestibular schwannoma" ]
BioASQ
Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.
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d941cbf53efb4218a8348c71b146a2d2
Mutation of which gene is implicated in the Christianson syndrome?
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{ "text": [ "SLC9A6" ], "char_spans": [ { "start": [ 1702, 833, 698, 554, 1065, 1312, 1434, 1850, 676, 284 ], "end": [ 1707, 838, 703, 559, 1070, 1317, 1439, 1855, 681, 289 ] } ], "token_spans": [ { "start": [ 291, 150, 118, 92, 185, 231, 247, 311, 114, 47 ], "end": [ 291, 150, 118, 92, 185, 231, 247, 311, 114, 47 ] } ] }
[ "SLC9A6" ]
BioASQ
The authors reported a 73-year-old alcoholic man with previously-unrecognized situs inversus totalis suffering from left upper quadrant pain. Acute myocardial infarction was diagnosed and coronary angioplasty was performed immediately. However, the massive bleeding from the previously-unfound hepatomas caused hypovolemic shock and fatal outcome. Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs. Although being considered a benign entity, it would disturb diagnosis-making of the visceral diseases owing to the altered anatomy. To our knowledge, the coexistence of the coronary artery disease and ruptured hepatomas in situs inversus totalis, as in our patient, is never described. Recognition of any situs anomalies in time is the key to avoid misdiagnosis, inappropriate managements, and unwanted consequences.
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30297cdd9b004604bfbf3798dd6ebe86
What is situs inversus?
{ "tokens": [ "What", "is", "situs", "inversus", "?" ], "offsets": [ 0, 5, 8, 14, 22 ] }
{ "text": [ "Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs." ], "char_spans": [ { "start": [ 348 ], "end": [ 464 ] } ], "token_spans": [ { "start": [ 53 ], "end": [ 71 ] } ] }
[ "Situs inversus totalis is a rare congenital anomaly with a complete mirror image of the thoracic and abdominal organs." ]
BioASQ
Methylation of certain lysine residues in the N-terminal tails of core histone proteins in nucleosome is of fundamental importance in the regulation of chromatin structure and gene expression. Such histone modification is catalyzed by protein lysine methyltransferases (PKMTs). PKMTs contain a conserved SET domain in almost all of the cases and may transfer one to three methyl groups from S-adenosyl-L-methionine (AdoMet) to the epsilon-amino group of the target lysine residue. Here, quantum mechanical/molecular mechanical molecular dynamics and free-energy simulations are performed on human PKMT SET7/9 and its mutants to understand two outstanding questions for the reaction catalyzed by PKMTs: the mechanism for deprotonation of positively charged methyl lysine (lysine) and origin of product specificity. The results of the simulations suggest that Tyr-335 (an absolute conserved residue in PKMTs) may play the role as the general base for the deprotonation after dissociation of AdoHcy (S-adenosyl-L-homocysteine) and before binding of AdoMet. It is shown that conformational changes could bring Y335 to the target methyl lysine (lysine) for proton abstraction. This mechanism provides an explanation why methyl transfers could be catalyzed by PKMTs processively. The free-energy profiles for methyl transfers are reported and analyzed for wild type and certain mutants (Y305F and Y335F) and the active-site interactions that are of importance for the enzyme's function are discussed. The results of the simulations provide important insights into the catalytic process and lead to a better understanding of experimental observations concerning the origin of product specificity for PKMTs.
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f5801149c94f4f65b82ee302b13c0d29
What is the characteristic domain of histone methyltransferases?
{ "tokens": [ "What", "is", "the", "characteristic", "domain", "of", "histone", "methyltransferases", "?" ], "offsets": [ 0, 5, 8, 12, 27, 34, 37, 45, 63 ] }
{ "text": [ "SET domain" ], "char_spans": [ { "start": [ 304 ], "end": [ 313 ] } ], "token_spans": [ { "start": [ 48 ], "end": [ 49 ] } ] }
[ "SET domain" ]
BioASQ
Ehlers-Danlos syndrome is a complex hereditary connective tissue disorder that is characterized by abnormalities of the skin and joints and visceral and neurological manifestations. At present, at least 11 forms are recognized on the basis of their clinical characteristics, methods of transmission, and biochemical defect. The neurologic manifestations include cerebrovascular disease, peripheral neuropathy, plexopathy, periventricular subependymal heterotopias, and epilepsy. Previously, 2 females were reported to be affected with subependimal periventricular heterotopias and Ehlers-Danlos syndrome type 1. The authors report a new case of a 12-year-old girl with similar clinical and neuroradiological features.
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10de1ab61b0a47219444a92bc141d960
What tissue is most affected in Ehlers-Danlos syndromes?
{ "tokens": [ "What", "tissue", "is", "most", "affected", "in", "Ehlers", "-", "Danlos", "syndromes", "?" ], "offsets": [ 0, 5, 12, 15, 20, 29, 32, 38, 39, 46, 55 ] }
{ "text": [ "connective tissue" ], "char_spans": [ { "start": [ 47 ], "end": [ 63 ] } ], "token_spans": [ { "start": [ 8 ], "end": [ 9 ] } ] }
[ "connective tissue" ]
BioASQ
Periodic limb movement disorder (PLMD) is one of the commonest neurological disorders and causes significant disability, if left untreated. However, it is rarely diagnosed in clinical practice, probably due to lack of awareness and/or lack of necessary diagnostic facilities. Restless leg syndrome (RLS), aging, pregnancy, uraemia, iron deficiency, polyneuropathy are some of the common causes of secondary PLMD. Clinical presentation, polysomnographic findings and management of six patients of PLMD have been discussed in this report.
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f17066e29bca4700bcdd4b135925f533
Which deficiency is the cause of restless leg syndrome?
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{ "text": [ "iron" ], "char_spans": [ { "start": [ 332 ], "end": [ 335 ] } ], "token_spans": [ { "start": [ 59 ], "end": [ 59 ] } ] }
[ "iron" ]
BioASQ
Protective protein/cathepsin A (PPCA) has a serine carboxypeptidase activity of unknown physiological function. We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA). Degradation of lamp2a is important because its level in the lysosomal membrane is a rate-limiting step of CMA. Cells defective in PPCA show reduced rates of lamp2a degradation, higher levels of lamp2a and higher rates of CMA. Restoration of PPCA protease activity increases rates of lamp2a degradation, reduces levels of lysosomal lamp2a and reduces rates of CMA. PPCA associates with lamp2a on the lysosomal membrane and cleaves lamp2a near the boundary between the luminal and transmembrane domains. In addition to the well-studied role of PPCA in targeting and protecting two lysosomal glycosidases, we have defined a role for the proteolytic activity of this multifunctional protein.
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a636a925df634cada0c2d6964688e93a
Which is the receptor for substrates of Chaperone Mediated Autophagy?
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{ "text": [ "LAMP2A" ], "char_spans": [ { "start": [ 628, 312, 580, 237, 491, 682, 727, 454 ], "end": [ 633, 317, 585, 242, 496, 687, 732, 459 ] } ], "token_spans": [ { "start": [ 109, 54, 102, 38, 87, 119, 126, 81 ], "end": [ 109, 54, 102, 38, 87, 119, 126, 81 ] } ] }
[ "LAMP2A", "Lysosome-associated membrane protein 2 isoform A" ]
BioASQ
The focus of this article is acrokeratosis paraneoplastica, one of two disorders that have acquired the eponym Bazex syndrome. To date, all of the patients reported in the literature have had an underlying neoplasm, most commonly squamous cell carcinoma of the upper aerodigestive tract. In this review of 113 cases of acrokeratosis paraneoplastica (mean age, 61 years; 105 males, 8 females), the psoriasiform lesions preceded the diagnosis of the associated malignancy in 73 (67%) of 109 patients, whereas the cutaneous manifestations followed the diagnosis of the neoplasm in only 16 (15%) of 109; in the remainder, the onset of the skin lesions and the diagnosis of the tumor occurred simultaneously. Therefore, awareness of the cutaneous signs of Bazex syndrome is of obvious importance to dermatologists. Evidence in favor of the paraneoplastic nature of this disease is as follows: in 81 (93%) of 87 patients with adequate clinical descriptions, the skin lesions either improved significantly (or resolved) when the underlying neoplasm was treated or they remained unchanged in the setting of persistent disease. Occasionally, the reappearance of skin lesions has signaled a recurrence of the tumor.
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d451ee65e0e14baaa98a29b68092c5fc
Name synonym of Acrokeratosis paraneoplastica.
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{ "text": [ "Bazex syndrome" ], "char_spans": [ { "start": [ 751, 111 ], "end": [ 764, 124 ] } ], "token_spans": [ { "start": [ 139, 18 ], "end": [ 140, 19 ] } ] }
[ "Bazex syndrome" ]
BioASQ
To demonstrate the importance of preventive measures when a case of tuberculosis is detected, identify the causes that favored a tuberculosis outbreak in a school and determine the efficiency of obtaining induced sputum samples. Descriptive, study. The Santa Maria de la Providencia school, located in the municipality of Alcala de Henares in Spain. On April 11, 2005, a case of bacilliform pulmonary tuberculosis was notified in a teacher. Study of contacts in the collective was performed as a programmed intervention. Mantoux skin test and, if positive, chest radiograph were performed in contacts. Treatment of latent or active tuberculosis was recommended according to the result. School exposures were identified and underwent the Mantoux skin test (142 students in years 1, 2, 3, and 4 of compulsory secondary education and 22 teachers). The Mantoux test was positive in 68 students (48 %) and seven teachers (32 %). In seven students with results compatible with active tuberculosis disease, sputum induction was performed and treatment was started. A further two students, identified as contacts, were studied in another center and also started treatment for active tuberculosis disease. Due to the high risk of contagion, study of contacts was extended to the remaining students in compulsory secondary education. In this second phase, 134 students received the Mantoux skin test and seven were Mantoux positive (5.2 %). In all these students, active tuberculosis disease was ruled out. Latent tuberculosis treatment was recommended in all Mantoux-positive contacts.
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432d404973ba41318c6fe93752543d01
The Mantoux test detects what latent infection/disease?
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{ "text": [ "tuberculosis" ], "char_spans": [ { "start": [ 68, 129, 401, 1175, 1461, 1504, 978, 632 ], "end": [ 79, 140, 412, 1186, 1472, 1515, 989, 643 ] } ], "token_spans": [ { "start": [ 11, 21, 70, 210, 263, 270, 178, 110 ], "end": [ 11, 21, 70, 210, 263, 270, 178, 110 ] } ] }
[ "tuberculosis" ]
BioASQ
Parkinson's disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson's disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome-Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity.
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dcbeada03bcb4f4d8ba89ab6cff60b0d
Which is the primary protein component of Lewy bodies?
{ "tokens": [ "Which", "is", "the", "primary", "protein", "component", "of", "Lewy", "bodies", "?" ], "offsets": [ 0, 6, 9, 13, 21, 29, 39, 42, 47, 53 ] }
{ "text": [ "α-synuclein" ], "char_spans": [ { "start": [ 481, 606, 694, 878, 325, 766, 1261, 76, 1178, 999, 565 ], "end": [ 491, 616, 704, 888, 335, 776, 1271, 86, 1188, 1009, 575 ] } ], "token_spans": [ { "start": [ 84, 108, 125, 157, 58, 138, 216, 11, 203, 176, 99 ], "end": [ 86, 110, 127, 159, 60, 140, 218, 13, 205, 178, 101 ] } ] }
[ "alpha-synuclein", "α-synuclein", "αSyn" ]
BioASQ
Phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB) regulates protein synthesis in hippocampal dendrites. CPEB binds the 3' untranslated region (UTR) of cytoplasmic mRNAs and, when phosphorylated, initiates mRNA polyadenylation and translation. We report that, of the protein kinases activated in the hippocampus during synaptic plasticity, calcium/calmodulin-dependent protein kinase II (CaMKII) robustly phosphorylated the regulatory site (threonine 171) in CPEB in vitro. In postsynaptic density fractions or hippocampal neurons, CPEB phosphorylation increased when CaMKII was activated. These increases in CPEB phosphorylation were attenuated by a specific peptide inhibitor of CaMKII and by the general CaM-kinase inhibitor KN-93. Inhibitors of protein phosphatase 1 increased basal CPEB phosphorylation in neurons; this was also attenuated by a CaM-kinase inhibitor. To determine whether CaM-kinase activity regulates CPEB-dependent mRNA translation, hippocampal neurons were transfected with luciferase fused to a 3' UTR containing CPE-binding elements. Depolarization of neurons stimulated synthesis of luciferase; this was abrogated by inhibitors of protein synthesis, mRNA polyadenylation, and CaMKII. These results demonstrate that CPEB phosphorylation and translation are regulated by CaMKII activity and provide a possible mechanism for how dendritic protein synthesis in the hippocampus may be stimulated during synaptic plasticity.
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7d3d225c01ba4d0daa3bfa2341e0caf8
Which kinase is inhibited by the small molecule KN-93?
{ "tokens": [ "Which", "kinase", "is", "inhibited", "by", "the", "small", "molecule", "KN-93", "?" ], "offsets": [ 0, 6, 13, 16, 26, 29, 33, 39, 48, 53 ] }
{ "text": [ "The calcium/calmodulin-dependent protein kinase-II" ], "char_spans": [ { "start": [ 367 ], "end": [ 412 ] } ], "token_spans": [ { "start": [ 57 ], "end": [ 64 ] } ] }
[ "CAMK2", "calcium/calmodulin-dependent protein kinase II", "The calcium/calmodulin-dependent protein kinase-II", "CaM kinase II" ]
BioASQ
The natural phytoalexin resveratrol, found in grapes and red wine, recently rose to public fame for its positive effects on longevity in yeasts, worms and flies. Resveratrol anti-cancer and anti-inflammatory in vitro action on mammalian cell cultures also suggest a possible positive effect on human health and life-expectancy. To study the effects of resveratrol on vertebrate aging is obviously a particularly relevant question. We have studied resveratrol effects in a very short-lived vertebrate: the annual fish Nothobranchius furzeri. Resveratrol treatment prolonged lifespan and delayed the onset of age-related dysfunctions in this fish. This result identifies resveratrol as the first molecule which consistently retards aging in organisms as diverse as yeast, worm, fly and fish, but it also reveals the potential of this short-lived fish as an animal model for pharmacological research. Moreover, being related to stickleback (Gasterosteus aculeatus) the "pufferfishes" Takifugu and Tetraodon, and even more closely related to medaka (Oryzias latipes), it can greatly beneficiate from the recent development of genomic resources for these fish models and in the future become a complete model system for the aging research community.
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28273676388a4bd8b10c28cc78703649
What can Nothobranchius furzeri be used as a model system for?
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{ "text": [ "aging research" ], "char_spans": [ { "start": [ 1219 ], "end": [ 1232 ] } ], "token_spans": [ { "start": [ 212 ], "end": [ 213 ] } ] }
[ "aging research" ]
BioASQ
This study examined the accuracy of the 17-item Dutch version of the Davidson Trauma Scale (DTS) and the four-item SPAN (Startle, Physiological Arousal, Anger and Numbness) to detect survivors at risk for posttraumatic stress disorder (PTSD) within the first 2 weeks after the trauma. 203 civilian survivors of recent trauma with relatively mild symptoms completed the DTS a mean of 8.7 days after experiencing trauma. SPAN scores were computed from the DTS. At a mean of 64.6 days posttrauma, 160 respondents were assessed for diagnosis of PTSD with the Structured Interview for PTSD. Receiver operating characteristic curves showed that the DTS showed good overall screening accuracy (84%). At a cut-off value of 64, the DTS demonstrated a sensitivity of 0.86, a specificity of 0.70, a positive predictive value (PPV) of 0.12, and a negative predictive value (NPV) of 0.98. Overall accuracy of the SPAN was good (89%). At a cut-off of 10 the SPAN showed a sensitivity of 0.86, a specificity of 0.86, a PPV of 0.22, and a NPV of 0.98. The low PPVs were possibly due to the low of prevalence of PTSD in our sample (4.4%). This study shows that both the DTS and the SPAN are comparably accurate in screening early trauma survivors at risk for developing PTSD. The very brief four-item SPAN may be preferred over the longer 17-item DTS especially in settings in which time and resources are limited. Future studies should aim to cross-validate these results in random samples.
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f39ba0ef13d74fbbbee6b6a7495a7da1
Symptoms of which disorder are evaluated with the Davidson Trauma Scale?
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{ "text": [ "PTSD" ], "char_spans": [ { "start": [ 1095, 580, 236, 541, 1253 ], "end": [ 1098, 583, 239, 544, 1256 ] } ], "token_spans": [ { "start": [ 224, 106, 44, 100, 255 ], "end": [ 224, 106, 44, 100, 255 ] } ] }
[ "post-traumatic stress disorder", "PTSD" ]
BioASQ
The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility. Considerable clinical and genetic heterogeneity exists, and more than nine separate forms have been recognized. Recent advances in the molecular analysis of EDS have identify defects responsible for EDS VI (homozygous and compound heterozygous mutations in the lysyl-hydroxylase gene), EDS VIIA and EDS VIIB (mutations in the type I collagene genes), EDS VIIC (deficiency of procollagen N-proteinase), EDS IX (mutations in the MNK gene), and EDS IV (mutations in the type III collagen gene). Of the various types of Ehlers-Danlos syndrome the most severe is type IV (EDS IV). Early studies showed that fibroblasts from EDS IV patients secreted lower than normal amounts of type III procollagen (Pope et al., 1975). Later, the disease was linked to COL3A1, the gene encoding this protein. More recently, with the publication of full length cDNA and partial characterisation of the gene structure, detailed analysis of mutations in EDS IV patients has become possible. Nineteen different mutations in the type III procollagen gene have been reported in different families with EDS IV. Recent results support the hypothesis that in EDS IV, dominant inheritance should be assumed, in sporadic cases also, unless proven otherwise. Very little is known about the genetics or biochemicals defects responsible for the others EDS subtypes, but with the applications of the tools of molecular biology, analysis of these defects if now within reach.
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0fd48e8ecbbf4547af93df0c4d6ecfe0
What tissue is most affected in Ehlers-Danlos syndromes?
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{ "text": [ "connective tissue" ], "char_spans": [ { "start": [ 59 ], "end": [ 75 ] } ], "token_spans": [ { "start": [ 13 ], "end": [ 14 ] } ] }
[ "connective tissue" ]
BioASQ
Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use).
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6e72346d9baf4bee8b690349f4e87241
Which medication should be administered when managing patients with suspected acute opioid overdose?
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[ "naloxone" ]
BioASQ
We immunohistochemically investigated the degeneration processes of the nigro-striatal and nigro-amygdaloid pathways and the relationship between the loss of dopaminergic neurons and Lewy bodies (LB) formation in the substantia nigra using 15 autopsied cases of dementia with Lewy bodies (DLB). The number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and TH-positive axonal terminals in the putamen decreased with a specific pattern. The substantia nigra possessed alpha-synuclein-positive LB-bearing neurons that were almost evenly distributed, while the putamen exhibited diffuse or granular alpha-synuclein-immunostaining. Most of the granular stains were positive for anti-phosphorylated alpha-synuclein antibody, whereas the diffuse stains were negative. These findings suggest that the axonal terminals in the putamen undergo abnormal alpha-synuclein accumulation, but may not always originate from LB-bearing neurons in the substantia nigra. The central amygdaloid nucleus contained anti-alpha-synuclein- and -phosphorylated alpha-synuclein-positive dystrophic axonal terminals, the degree of which was greater for cases with granular staining in the putamen, and which was proportional to the number of alpha-synuclein-positive neurons in the substantia nigra. Thus, the axonal terminals in the central amygdaloid nucleus may have originated from LB-bearing neurons in the substantia nigra. The results of the present study indicate that the nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in DLB, and suggest that the degeneration of the nigro-amygdaloid pathway more strongly reflects LB formation in dopaminergic neurons of the substantia nigra than that of the nigro-striatal pathway. In addition, they indicate that there is no direct relationship between the loss of dopaminergic neurons and LB formation in the substantia nigra.
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838f259cf3d94ed1a4628e26a79fa183
Against which protein is the antibody used for immonostaining of Lewy bodies raised?
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{ "text": [ "alpha-Synuclein" ], "char_spans": [ { "start": [ 619, 1020, 1057, 717, 1236, 490, 866 ], "end": [ 633, 1035, 1071, 731, 1250, 504, 880 ] } ], "token_spans": [ { "start": [ 102, 170, 175, 119, 207, 80, 143 ], "end": [ 104, 172, 177, 121, 209, 82, 145 ] } ] }
[ "alpha-Synuclein" ]
BioASQ
To assess the efficacy and safety of tanezumab, a humanized monoclonal antibody directed against the pain-mediating neurotrophin, nerve growth factor, to treat pain and other symptoms of chronic prostatitis/chronic pelvic pain syndrome in a Phase IIa, proof-of-concept clinical trial powered to provide 2-sided 90% confidence interval around the primary endpoint. Patients received a single intravenous dose of tanezumab (20 mg) or placebo. The primary efficacy endpoint was the change from baseline to week 6 in average daily numerical rating scale pain score. The secondary endpoints included the change from baseline to week 6 in the National Institutes of Health Chronic Prostatitis Symptom Index and urinary symptoms. Safety was also assessed. Overall, 62 patients were randomized (30 to tanezumab and 32 to placebo). At week 6, tanezumab marginally improved the average daily pain (least-squares mean difference from placebo -0.47, 90% confidence interval -1.150-0.209) and urgency episode frequency (least-squares mean difference from placebo -1.37, 90% confidence interval -3.146-0.401). No difference was seen in the National Institutes of Health chronic prostatitis symptom index total score or micturition frequency at week 6. The most common adverse events were paresthesia and arthralgia. The odds of having a ≥ 30% reduction in pain were 1.75-fold greater (90% confidence interval 0.65-4.69) for patients receiving tanezumab versus placebo. Tanezumab might improve symptoms for some patients with chronic prostatitis/chronic pelvic pain syndrome. Although proof of concept was not demonstrated in the present study, additional studies with larger populations and stricter inclusion criteria according to patient phenotype might identify populations in which antinerve growth factor treatment will provide clinical benefit.
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53453018272b4cbaa4e322487a25246c
What is the target of tanezumab?
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{ "text": [ "nerve growth factor" ], "char_spans": [ { "start": [ 130 ], "end": [ 148 ] } ], "token_spans": [ { "start": [ 21 ], "end": [ 23 ] } ] }
[ "nerve growth factor", "NGF" ]
BioASQ
The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected ingestion of dextromethorphan by 1) describing the process by which an ingestion of dextromethorphan might be managed, 2) identifying the key decision elements in managing cases of dextromethorphan ingestion, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline applies to the ingestion of dextromethorphan alone. Co-ingestion of additional substances could require different referral and management recommendations depending on the combined toxicities of the substances. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions might be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. The grade of recommendation is in parentheses. 1) All patients with suicidal intent, intentional abuse, or in cases in which a malicious intent is suspected (e.g., child abuse or neglect) should be referred to an emergency department (Grade D). 2) Patients who exhibit more than mild effects (e.g., infrequent vomiting or somnolence [lightly sedated and arousable with speaking voice or light touch]) after an acute dextromethorphan ingestion should be referred to an emergency department (Grade C). 3) Patients who have ingested 5-7.5 mg/kg should receive poison center-initiated follow-up approximately every 2 hours for up to 4 hours after ingestion. Refer to an emergency department if more than mild symptoms develop (Grade D). 4) Patients who have ingested more than 7.5 mg/kg should be referred to an emergency department for evaluation (Grade C). 5) If the patient is taking other medications likely to interact with dextromethorphan and cause serotonin syndrome, such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors, poison center-initiated follow-up every 2 hours for 8 hours is recommended (Grade D). 6) Patients who are asymptomatic and more than 4 hours have elapsed since the time of ingestion can be observed at home (Grade C). 7) Do not induce emesis (Grade D). 8) Do not use activated charcoal at home. Activated charcoal can be administered to asymptomatic patients who have ingested overdoses of dextromethorphan within the preceding hour. Its administration, if available, should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activated charcoal (Grade D). 9) For patients who have ingested dextromethorphan and are sedated or comatose, naloxone, in the usual doses for treatment of opioid overdose, can be considered for prehospital administration, particularly if the patient has respiratory depression (Grade C). 10) Use intravenous benzodiazepines for seizures and benzodiazepines and external cooling measures for hyperthermia (>104 degrees F, >40 degrees C) for serotonin syndrome. This should be done in consultation with and authorized by EMS medical direction, by a written treatment protocol or policy, or with direct medical oversight (Grade C). 11) Carefully ascertain by history whether other drugs, such as acetaminophen, were involved in the incident and assess the risk for toxicity or for a drug interaction.
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bb05ffd715264fdf8fc2a8c7edaf0d04
Which medication should be administered when managing patients with suspected acute opioid overdose?
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{ "text": [ "naloxone" ], "char_spans": [ { "start": [ 2918 ], "end": [ 2925 ] } ], "token_spans": [ { "start": [ 520 ], "end": [ 520 ] } ] }
[ "naloxone" ]
BioASQ
A mutation in the ubiquilin 2 gene (UBQLN2) was recently identified as a cause of X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and a major component of the inclusion bodies commonly found with a wide variety of ALS. ALS-linked mutations in UBQLN2 are clustered in a unique proline-X-X repeat region, reportedly leading to impairment of the ubiquitin proteasome system. However, the molecular properties of mutant UBQLN2 remain unclear. To gain insight into the pathogenesis of UBQLN2-linked ALS/FTD, we examined the biochemical and cellular characteristics of mutant UBQLN2 in vitro. UBQLN2 localized in Rab11-positive endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN). These vesicles were ubiquitin- and p62-immunopositive and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN vesicles. UBQLN2 was found to be a potent regulator of the levels of the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes. These data suggest a novel disease spectrum and provide new pathological insights into OPTN and UBQLN2, enhancing our understanding of the molecular basis of ALS/FTD.
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de7ad57d11e84ddf995786a4c2ecdfe5
Which human disease is associated with mutated UBQLN2
{ "tokens": [ "Which", "human", "disease", "is", "associated", "with", "mutated", "UBQLN2" ], "offsets": [ 0, 6, 12, 20, 23, 34, 39, 47 ] }
{ "text": [ "ALS", "amyotrophic lateral sclerosis" ], "char_spans": [ { "start": [ 246, 945, 880, 241, 1238, 1329, 1728, 682, 521 ], "end": [ 248, 947, 882, 243, 1240, 1331, 1730, 684, 523 ] }, { "start": [ 91 ], "end": [ 119 ] } ], "token_spans": [ { "start": [ 46, 170, 156, 44, 220, 233, 295, 120, 94 ], "end": [ 46, 170, 156, 44, 220, 233, 295, 120, 94 ] }, { "start": [ 20 ], "end": [ 22 ] } ] }
[ "ALS", "amyotrophic lateral sclerosis" ]
BioASQ
Cerebrolysin (Cere) is a peptidergic nootropic drug with neurotrophic properties which has been used to treat dementia and sequelae of stroke. Use of Cere prevents nuclear structural changes typical of apoptosis and significantly reduces the number of apoptotic cells after several apoptotic stimuli. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disease caused by mutations of the Notch3 gene encoding the Notch3 protein. Notch3 is involved in the regulation of apoptosis, modulating Fas-Ligand (Fas-L)- induced apoptosis. The aim of this study was to evaluate the in vitro protective effects of Cere against oxidative stress-induced apoptosis in cells from CADASIL patients. We used peripheral blood lymphocytes (PBLs) from 15 CADASIL patients (age range 34-70 years); 2-deoxy-D-ribose (dRib), a highly reducing sugar, was used as paradigm pro-apoptotic stimulus. Apoptosis was analyzed by flow cytometry and fluorescence microscopy. Administration of Cere to PBLs from CADASIL patients cultured under standard conditions had no effect on the percentage of apoptotic cells. Administration of Cere to PBLs cultured with dRib caused a significant decrease in apoptosis after 48 h of culture in only 5 patients, whereas in the other 10 patients, Cere treatment was not associated with any significant difference in the percentage of apoptosis. This result showed a protective effect of Cere against oxidative stress-induced apoptosis only in 30 % of the CADASIL patients, suggesting that the Notch3 gene probably does not influence the anti-apoptotic properties of Cere in vitro.
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af0fd3f5bf9540ba8eb2d1ef50fc1544
Which gene is involved in CADASIL?
{ "tokens": [ "Which", "gene", "is", "involved", "in", "CADASIL", "?" ], "offsets": [ 0, 6, 11, 14, 23, 26, 33 ] }
{ "text": [ "Notch3 gene" ], "char_spans": [ { "start": [ 453, 1562 ], "end": [ 463, 1572 ] } ], "token_spans": [ { "start": [ 68, 270 ], "end": [ 69, 271 ] } ] }
[ "Notch3 gene" ]
BioASQ
To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. All publications reporting clinical trials of empagliflozin were eligible for inclusion. Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.
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8e4362d962304849af0e9a9cf344f780
Which protein does empagliflozin inhibit?
{ "tokens": [ "Which", "protein", "does", "empagliflozin", "inhibit", "?" ], "offsets": [ 0, 6, 14, 19, 33, 40 ] }
{ "text": [ "SGLT2" ], "char_spans": [ { "start": [ 621, 81 ], "end": [ 625, 85 ] } ], "token_spans": [ { "start": [ 108, 14 ], "end": [ 108, 14 ] } ] }
[ "SGLT2" ]
BioASQ
Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥ 2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4.4, 3.7 and 20.4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ≥ grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.
{ "tokens": [ "Interleukin-6", "(", "IL6", ")", "plays", "a", "central", "role", "in", "multiple", "myeloma", "pathogenesis", "and", "confers", "resistance", "to", "corticosteroid", "-", "induced", "apoptosis", ".", "We", "therefore", "evaluated", "the", "efficacy", "and", "safety", "of", "siltuximab", ",", "an", "anti", "-", "IL6", "monoclonal", "antibody", ",", "alone", "and", "in", "combination", "with", "dexamethasone", ",", "for", "patients", "with", "relapsed", "or", "refractory", "multiple", "myeloma", "who", "had", "≥", "2", "prior", "lines", "of", "therapy", ",", "one", "of", "which", "had", "to", "be", "bortezomib", "-", "based", ".", "Fourteen", "initial", "patients", "received", "siltuximab", "alone", ",", "10", "of", "whom", "had", "dexamethasone", "added", "for", "suboptimal", "response", ";", "39", "subsequent", "patients", "were", "treated", "with", "concurrent", "siltuximab", "and", "dexamethasone", ".", "Patients", "received", "a", "median", "of", "four", "prior", "lines", "of", "therapy", ",", "83", "%", "were", "relapsed", "and", "refractory", ",", "and", "70", "%", "refractory", "to", "their", "last", "dexamethasone", "-", "containing", "regimen", ".", "Suppression", "of", "serum", "C", "-", "reactive", "protein", "levels", ",", "a", "surrogate", "marker", "of", "IL6", "inhibition", ",", "was", "demonstrated", ".", "There", "were", "no", "responses", "to", "siltuximab", "but", "combination", "therapy", "yielded", "a", "partial", "(", "17", "%", ")", "+", "minimal", "(", "6", "%", ")", "response", "rate", "of", "23", "%", ",", "with", "responses", "seen", "in", "dexamethasone", "-", "refractory", "disease", ".", "The", "median", "time", "to", "progression", ",", "progression", "-", "free", "survival", "and", "overall", "survival", "for", "combination", "therapy", "was", "4.4", ",", "3.7", "and", "20.4", "months", "respectively", ".", "Haematological", "toxicity", "was", "common", "but", "manageable", ".", "Infections", "occurred", "in", "57", "%", "of", "combination", "-", "treated", "patients", ",", "including", "≥", "grade", "3", "infections", "in", "18", "%", ".", "Further", "study", "of", "siltuximab", "in", "modern", "corticosteroid", "-", "containing", "myeloma", "regimens", "is", "warranted", ",", "with", "special", "attention", "to", "infection", "-", "related", "toxicity", "." ], "offsets": [ 0, 14, 15, 18, 20, 26, 28, 36, 41, 44, 53, 61, 74, 78, 86, 97, 100, 114, 115, 123, 132, 134, 137, 147, 157, 161, 170, 174, 181, 184, 194, 196, 199, 203, 204, 208, 219, 227, 229, 235, 239, 242, 254, 259, 272, 274, 278, 287, 292, 301, 304, 315, 324, 332, 336, 340, 342, 344, 350, 356, 359, 366, 368, 372, 375, 381, 385, 388, 391, 401, 402, 407, 409, 418, 426, 435, 444, 455, 460, 462, 465, 468, 473, 477, 491, 497, 501, 512, 520, 522, 525, 536, 545, 550, 558, 563, 574, 585, 589, 602, 604, 613, 622, 624, 631, 634, 639, 645, 651, 654, 661, 663, 665, 667, 672, 681, 685, 695, 697, 701, 703, 705, 716, 719, 725, 730, 743, 744, 755, 762, 764, 776, 779, 785, 786, 787, 796, 804, 810, 812, 814, 824, 831, 834, 838, 848, 850, 854, 866, 868, 874, 879, 882, 892, 895, 906, 910, 922, 930, 938, 940, 948, 949, 951, 952, 954, 956, 964, 965, 966, 967, 969, 978, 983, 986, 988, 989, 991, 996, 1006, 1011, 1014, 1027, 1028, 1039, 1046, 1048, 1052, 1059, 1064, 1067, 1078, 1080, 1091, 1092, 1097, 1106, 1110, 1118, 1127, 1131, 1143, 1151, 1155, 1158, 1160, 1164, 1168, 1173, 1180, 1192, 1194, 1209, 1218, 1222, 1229, 1233, 1243, 1245, 1256, 1265, 1268, 1270, 1272, 1275, 1286, 1287, 1295, 1303, 1305, 1315, 1317, 1323, 1325, 1336, 1339, 1341, 1342, 1344, 1352, 1358, 1361, 1372, 1375, 1382, 1396, 1397, 1408, 1416, 1425, 1428, 1437, 1439, 1444, 1452, 1462, 1465, 1474, 1475, 1483, 1491 ] }
1e1ef110e6154949bc822e542fff38e2
Which interleukin is blocked by Siltuximab?
{ "tokens": [ "Which", "interleukin", "is", "blocked", "by", "Siltuximab", "?" ], "offsets": [ 0, 6, 18, 21, 29, 32, 42 ] }
{ "text": [ "interleukin-6" ], "char_spans": [ { "start": [ 0 ], "end": [ 12 ] } ], "token_spans": [ { "start": [ 0 ], "end": [ 0 ] } ] }
[ "interleukin-6" ]
BioASQ
The efficacy of the BD GeneOhm methicillin-resistant Staphylococcus aureus (MRSA) assay was assessed by analyzing nasal swabs and swabs from other body sites for the presence of MRSA in a low-prevalence area. From 681 patients with a high risk for MRSA carriage, 1,601 specimens were collected and transported in Amies agar. After discordant analysis, the sensitivity, specificity, positive predictive value, and negative predictive value of the BD GeneOhm MRSA assay were 84.3%, 99.2%, 88.4%, and 98.9%, respectively, compared to culture.
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746d6125a1ae4b47b8868da9703ff04b
What is MRSA?
{ "tokens": [ "What", "is", "MRSA", "?" ], "offsets": [ 0, 5, 8, 12 ] }
{ "text": [ "MRSA" ], "char_spans": [ { "start": [ 457, 248, 76, 178 ], "end": [ 460, 251, 79, 181 ] } ], "token_spans": [ { "start": [ 81, 47, 12, 31 ], "end": [ 81, 47, 12, 31 ] } ] }
[ "methicillin-resistant S. aureus", "MRSA" ]
BioASQ
Objective. A study to determine if addition of palatal petechiae to Centor criteria adds more value for clinical diagnosis of acute strep pharyngitis in children. Hypothesis. In children, Centor Criteria does not cover all the symptoms and signs of acute strep pharyngitis. We hypothesize that addition of palatal petechiae to Centor Criteria will increase the possibility of clinical diagnosis of group A streptococcal pharyngitis in children. Methods. One hundred patients with a complaint of sore throat were enrolled in the study. All the patients were examined clinically using the Centor Criteria. They were also examined for other signs and symptoms like petechial lesions over the palate, abdominal pain, and skin rash. All the patients were given rapid strep tests, and throat cultures were sent. No antibiotics were given until culture results were obtained. Results. The sample size was 100 patients. All 100 had fever, sore throat, and erythema of tonsils. Twenty of the 100 patients had tonsillar exudates, 85/100 had tender anterior cervical lymph nodes, and 86/100 had no cough. In total, 9 out of the 100 patients had positive throat cultures. We observed that petechiae over the palate, a very significant sign, is not included in the Centor Criteria. Palatal petechiae were present in 8 out of the 100 patients. Six out of these 8 with palatal petechiae had positive throat culture for strep (75%). Only 7 out of 20 with exudates had positive strep culture. Sixteen out of the 100 patients had rapid strep test positive. Those 84/100 who had negative rapid strep also had negative throat culture. Statistics. We used Fisher's exact test, comparing throat culture positive and negative versus presence of exudates and palatal hemorrhages with positive and negative throat cultures and the resultant P value <.0001. Conclusion. Our study concludes that addition of petechiae over the palate to Centor Criteria will increase the possibility of diagnosing acute group A streptococcal pharyngitis in children.
{ "tokens": [ "Objective", ".", "A", "study", "to", "determine", "if", "addition", "of", "palatal", "petechiae", "to", "Centor", "criteria", "adds", "more", "value", "for", "clinical", "diagnosis", "of", "acute", "strep", "pharyngitis", "in", "children", ".", "Hypothesis", ".", "In", "children", ",", "Centor", "Criteria", "does", "not", "cover", "all", "the", "symptoms", "and", "signs", "of", "acute", "strep", "pharyngitis", ".", "We", "hypothesize", "that", "addition", "of", "palatal", "petechiae", "to", "Centor", "Criteria", "will", "increase", "the", "possibility", "of", "clinical", "diagnosis", "of", "group", "A", "streptococcal", "pharyngitis", "in", "children", ".", "Methods", ".", "One", "hundred", "patients", "with", "a", "complaint", "of", "sore", "throat", "were", "enrolled", "in", "the", "study", ".", "All", "the", "patients", "were", "examined", "clinically", "using", "the", "Centor", "Criteria", ".", "They", "were", "also", "examined", "for", "other", "signs", "and", "symptoms", "like", "petechial", "lesions", "over", "the", "palate", ",", "abdominal", "pain", ",", "and", "skin", "rash", ".", "All", "the", "patients", "were", "given", "rapid", "strep", "tests", ",", "and", "throat", "cultures", "were", "sent", ".", "No", "antibiotics", "were", "given", "until", "culture", "results", "were", "obtained", ".", "Results", ".", "The", "sample", "size", "was", "100", "patients", ".", "All", "100", "had", "fever", ",", "sore", "throat", ",", "and", "erythema", "of", "tonsils", ".", "Twenty", "of", "the", "100", "patients", "had", "tonsillar", "exudates", ",", "85/100", "had", "tender", "anterior", "cervical", "lymph", "nodes", ",", "and", "86/100", "had", "no", "cough", ".", "In", "total", ",", "9", "out", "of", "the", "100", "patients", "had", "positive", "throat", "cultures", ".", "We", "observed", "that", "petechiae", "over", "the", "palate", ",", "a", "very", "significant", "sign", ",", "is", "not", "included", "in", "the", "Centor", "Criteria", ".", "Palatal", "petechiae", "were", "present", "in", "8", "out", "of", "the", "100", "patients", ".", "Six", "out", "of", "these", "8", "with", "palatal", "petechiae", "had", "positive", "throat", "culture", "for", "strep", "(", "75", "%", ")", ".", "Only", "7", "out", "of", "20", "with", "exudates", "had", "positive", "strep", "culture", ".", "Sixteen", "out", "of", "the", "100", "patients", "had", "rapid", "strep", "test", "positive", ".", "Those", "84/100", "who", "had", "negative", "rapid", "strep", "also", "had", "negative", "throat", "culture", ".", "Statistics", ".", "We", "used", "Fisher", "'s", "exact", "test", ",", "comparing", "throat", "culture", "positive", "and", "negative", "versus", "presence", "of", "exudates", "and", "palatal", "hemorrhages", "with", "positive", "and", "negative", "throat", "cultures", "and", "the", "resultant", "P", "value", "<", ".0001", ".", "Conclusion", ".", "Our", "study", "concludes", "that", "addition", "of", "petechiae", "over", "the", "palate", "to", "Centor", "Criteria", "will", "increase", "the", "possibility", "of", "diagnosing", "acute", "group", "A", "streptococcal", "pharyngitis", "in", "children", "." ], "offsets": [ 0, 9, 11, 13, 19, 22, 32, 35, 44, 47, 55, 65, 68, 75, 84, 89, 94, 100, 104, 113, 123, 126, 132, 138, 150, 153, 161, 163, 173, 175, 178, 186, 188, 195, 204, 209, 213, 219, 223, 227, 236, 240, 246, 249, 255, 261, 272, 274, 277, 289, 294, 303, 306, 314, 324, 327, 334, 343, 348, 357, 361, 373, 376, 385, 395, 398, 404, 406, 420, 432, 435, 443, 445, 452, 454, 458, 466, 475, 480, 482, 492, 495, 500, 507, 512, 521, 524, 528, 533, 535, 539, 543, 552, 557, 566, 577, 583, 587, 594, 602, 604, 609, 614, 619, 628, 632, 638, 644, 648, 657, 662, 672, 680, 685, 689, 695, 697, 707, 711, 713, 717, 722, 726, 728, 732, 736, 745, 750, 756, 762, 768, 773, 775, 779, 786, 795, 800, 804, 806, 809, 821, 826, 832, 838, 846, 854, 859, 867, 869, 876, 878, 882, 889, 894, 898, 902, 910, 912, 916, 920, 924, 929, 931, 936, 942, 944, 948, 957, 960, 967, 969, 976, 979, 983, 987, 996, 1000, 1010, 1018, 1020, 1027, 1031, 1038, 1047, 1056, 1062, 1067, 1069, 1073, 1080, 1084, 1087, 1092, 1094, 1097, 1102, 1104, 1106, 1110, 1113, 1117, 1121, 1130, 1134, 1143, 1150, 1158, 1160, 1163, 1172, 1177, 1187, 1192, 1196, 1202, 1204, 1206, 1211, 1223, 1227, 1229, 1232, 1236, 1245, 1248, 1252, 1259, 1267, 1269, 1277, 1287, 1292, 1300, 1303, 1305, 1309, 1312, 1316, 1320, 1328, 1330, 1334, 1338, 1341, 1347, 1349, 1354, 1362, 1372, 1376, 1385, 1392, 1400, 1404, 1410, 1411, 1413, 1414, 1415, 1417, 1422, 1424, 1428, 1431, 1434, 1439, 1448, 1452, 1461, 1467, 1474, 1476, 1484, 1488, 1491, 1495, 1499, 1508, 1512, 1518, 1524, 1529, 1537, 1539, 1545, 1552, 1556, 1560, 1569, 1575, 1581, 1586, 1590, 1599, 1606, 1613, 1615, 1625, 1627, 1630, 1635, 1641, 1644, 1650, 1654, 1656, 1666, 1673, 1681, 1690, 1694, 1703, 1710, 1719, 1722, 1731, 1735, 1743, 1755, 1760, 1769, 1773, 1782, 1789, 1798, 1802, 1806, 1816, 1818, 1824, 1825, 1830, 1832, 1842, 1844, 1848, 1854, 1864, 1869, 1878, 1881, 1891, 1896, 1900, 1907, 1910, 1917, 1926, 1931, 1940, 1944, 1956, 1959, 1970, 1976, 1982, 1984, 1998, 2010, 2013, 2021 ] }
345cc6f39eb0472ebb37229e6f4e34b1
Centor criteria are used for which disease?
{ "tokens": [ "Centor", "criteria", "are", "used", "for", "which", "disease", "?" ], "offsets": [ 0, 7, 16, 20, 25, 29, 35, 42 ] }
{ "text": [ "streptococcal pharyngitis" ], "char_spans": [ { "start": [ 1984, 406 ], "end": [ 2008, 430 ] } ], "token_spans": [ { "start": [ 356, 67 ], "end": [ 357, 68 ] } ] }
[ "streptococcal pharyngitis" ]
BioASQ
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the overproduction of granulocytes, which leads to high white blood cell counts and splenomegaly in patients. Based on clinical symptoms and laboratory findings, CML is classified into three clinical phases, often starting with a chronic phase, progressing to an accelerated phase and ultimately ending in a terminal phase called blast crisis. Blast crisis phase of CML is clinically similar to an acute leukemia; in particular, B-cell acute lymphoblastic leukemia (B-ALL) is a severe form of acute leukemia in blast crisis, and there is no effective therapy for it yet. CML is induced by the BCR-ABL oncogene, whose gene product is a BCR-ABL tyrosine kinase. Currently, inhibition of BCR-ABL kinase activity by its kinase inhibitor such as imatinib mesylate (Gleevec) is a major therapeutic strategy for CML. However, the inability of BCR-ABL kinase inhibitors to completely kill leukemia stem cells (LSCs) indicates that these kinase inhibitors are unlikely to cure CML. In addition, drug resistance due to the development of BCRABL mutations occurs before and during treatment of CML with kinase inhibitors. A critical issue to resolve this problem is to fully understand the biology of LSCs, and to identify key genes that play significant roles in survival and self-renewal of LSCs. In this review, we will focus on LSCs in CML by summarizing and discussing available experimental results, including the original studies from our own laboratory.
{ "tokens": [ "Chronic", "myeloid", "leukemia", "(", "CML", ")", "is", "a", "myeloproliferative", "disease", "characterized", "by", "the", "overproduction", "of", "granulocytes", ",", "which", "leads", "to", "high", "white", "blood", "cell", "counts", "and", "splenomegaly", "in", "patients", ".", "Based", "on", "clinical", "symptoms", "and", "laboratory", "findings", ",", "CML", "is", "classified", "into", "three", "clinical", "phases", ",", "often", "starting", "with", "a", "chronic", "phase", ",", "progressing", "to", "an", "accelerated", "phase", "and", "ultimately", "ending", "in", "a", "terminal", "phase", "called", "blast", "crisis", ".", "Blast", "crisis", "phase", "of", "CML", "is", "clinically", "similar", "to", "an", "acute", "leukemia", ";", "in", "particular", ",", "B", "-", "cell", "acute", "lymphoblastic", "leukemia", "(", "B", "-", "ALL", ")", "is", "a", "severe", "form", "of", "acute", "leukemia", "in", "blast", "crisis", ",", "and", "there", "is", "no", "effective", "therapy", "for", "it", "yet", ".", "CML", "is", "induced", "by", "the", "BCR", "-", "ABL", "oncogene", ",", "whose", "gene", "product", "is", "a", "BCR", "-", "ABL", "tyrosine", "kinase", ".", "Currently", ",", "inhibition", "of", "BCR", "-", "ABL", "kinase", "activity", "by", "its", "kinase", "inhibitor", "such", "as", "imatinib", "mesylate", "(", "Gleevec", ")", "is", "a", "major", "therapeutic", "strategy", "for", "CML", ".", "However", ",", "the", "inability", "of", "BCR", "-", "ABL", "kinase", "inhibitors", "to", "completely", "kill", "leukemia", "stem", "cells", "(", "LSCs", ")", "indicates", "that", "these", "kinase", "inhibitors", "are", "unlikely", "to", "cure", "CML", ".", "In", "addition", ",", "drug", "resistance", "due", "to", "the", "development", "of", "BCRABL", "mutations", "occurs", "before", "and", "during", "treatment", "of", "CML", "with", "kinase", "inhibitors", ".", "A", "critical", "issue", "to", "resolve", "this", "problem", "is", "to", "fully", "understand", "the", "biology", "of", "LSCs", ",", "and", "to", "identify", "key", "genes", "that", "play", "significant", "roles", "in", "survival", "and", "self", "-", "renewal", "of", "LSCs", ".", "In", "this", "review", ",", "we", "will", "focus", "on", "LSCs", "in", "CML", "by", "summarizing", "and", "discussing", "available", "experimental", "results", ",", "including", "the", "original", "studies", "from", "our", "own", "laboratory", "." ], "offsets": [ 0, 8, 16, 25, 26, 29, 31, 34, 36, 55, 63, 77, 80, 84, 99, 102, 114, 116, 122, 128, 131, 136, 142, 148, 153, 160, 164, 177, 180, 188, 190, 196, 199, 208, 217, 221, 232, 240, 242, 246, 249, 260, 265, 271, 280, 286, 288, 294, 303, 308, 310, 318, 323, 325, 337, 340, 343, 355, 361, 365, 376, 383, 386, 388, 397, 403, 410, 416, 422, 424, 430, 437, 443, 446, 450, 453, 464, 472, 475, 478, 484, 492, 494, 497, 507, 509, 510, 511, 516, 522, 536, 545, 546, 547, 548, 551, 553, 556, 558, 565, 570, 573, 579, 588, 591, 597, 603, 605, 609, 615, 618, 621, 631, 639, 643, 646, 649, 651, 655, 658, 666, 669, 673, 676, 677, 681, 689, 691, 697, 702, 710, 713, 715, 718, 719, 723, 732, 738, 740, 749, 751, 762, 765, 768, 769, 773, 780, 789, 792, 796, 803, 813, 818, 821, 830, 839, 840, 847, 849, 852, 854, 860, 872, 881, 885, 888, 890, 897, 899, 903, 913, 916, 919, 920, 924, 931, 942, 945, 956, 961, 970, 975, 981, 982, 986, 988, 998, 1003, 1009, 1016, 1027, 1031, 1040, 1043, 1048, 1051, 1053, 1056, 1064, 1066, 1071, 1082, 1086, 1089, 1093, 1105, 1108, 1115, 1125, 1132, 1139, 1143, 1150, 1160, 1163, 1167, 1172, 1179, 1189, 1191, 1193, 1202, 1208, 1211, 1219, 1224, 1232, 1235, 1238, 1244, 1255, 1259, 1267, 1270, 1274, 1276, 1280, 1283, 1292, 1296, 1302, 1307, 1312, 1324, 1330, 1333, 1342, 1346, 1350, 1351, 1359, 1362, 1366, 1368, 1371, 1376, 1382, 1384, 1387, 1392, 1398, 1401, 1406, 1409, 1413, 1416, 1428, 1432, 1443, 1453, 1466, 1473, 1475, 1485, 1489, 1498, 1506, 1511, 1515, 1519, 1529 ] }
eb81aaa1e4b44724821213505ab1015b
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
{ "tokens": [ "What", "tyrosine", "kinase", ",", "involved", "in", "a", "Philadelphia-", "chromosome", "positive", "chronic", "myelogenous", "leukemia", ",", "is", "the", "target", "of", "Imatinib", "(", "Gleevec", ")", "?" ], "offsets": [ 0, 5, 14, 20, 22, 31, 34, 36, 50, 61, 70, 78, 90, 98, 100, 103, 107, 114, 117, 126, 127, 134, 135 ] }
{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 765, 715, 673, 916 ], "end": [ 771, 721, 679, 922 ] } ], "token_spans": [ { "start": [ 142, 132, 122, 171 ], "end": [ 144, 134, 124, 173 ] } ] }
[ "BCR-ABL" ]
BioASQ
SECIS elements are stem-loop structures located in the 3' untranslated regions (UTRs) of eukaryotic selenoprotein mRNAs that are required for directing cotranslational selenocysteine incorporation at UGA codons. In prokaryotes, stem-loops mediating selenocysteine incorporation are located immediately downstream of the UGA selenocysteine codon, in the coding region. Previous characterization studies of the mammalian SECIS elements of type 1 deiodinase, glutathione peroxidase, and selenoprotein P showed that conserved nucleotides in the loops and unpaired bulges, and base pairing in the stems are required for SECIS function. These initial studies utilized approximately 175-230-nt segments of the 3'UTRs of the selenoprotein mRNAs. Here we define the minimal functional rat type 1 deiodinase SECIS element, a 45-nt segment, the 5' boundary of which corresponds precisely to the 5'-most critical conserved nucleotide identified previously. We also define base pairing requirements in the stem of this element. In view of the presence of SECIS elements in the open reading frames (ORFs) of bacterial selenoproteins, we examine the effects in the type 1 deiodinase of extending the ORF into the SECIS element, and find that this dramatically inhibits SECIS function. Finally, we define a minimal spacing requirement of 51-111 nt between a eukaryotic UGA selenocysteine codon and SECIS element.
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5798e357ab44416ea1ecd5323e3e7ae4
What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?
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[ "SECIS" ]
BioASQ
(i) evaluate the performance of MR-pro-ADM in reflecting the outcome and risk for CAP patients in the emergency department, and (ii) compare the prognostic performance of MR-pro-ADM with that of clinical scores PSI and CURB65. Observational prospective, single-center study in patients with suspected community acquired pneumonia (CAP). Eighty one patients underwent full clinical and laboratory assessment as by protocol, and were followed up a 28 days. Primary endpoints measured were: death, death at 14 days, non-invasive mechanical ventilation (NIMV), endotracheal intubation (EI), ICU admission, overall hospital stay >10 days, emergency department stay >4 days. The discriminative performance of MR-pro-ADM and clinical scores was assessed by AUROC analysis. The distribution for MR-pro-ADM followed an upward trend, increasing with the increase of both PSI (p<0.001) and CURB65 (p<0.001) classes. However, the difference between MRproADM values and score classes was significant only in the case of CURB65 classes 0 and 1 (p = 0.046), 2 (p = 0.013), and 3 (p = 0.011); and with PSI classes 5, 3 (p = 0.044), and 1 (p = 0.020). As to the differences among variables for the six end-points, MR-pro-ADM values in the two groups selected for each considered end-point differed in a statistically significant manner for all endpoints. Both PSI and CURB65 differed significantly for all end-points, except for stay in the ED longer than 4 days and the hospital stay longer than 10 days and endotracheal intubation (only PSI classes differed with statistical significance). ROC analyses evidenced that MR-pro-ADM values gave the greatest AUC for the prediction of death, endotracheal intubation, hospital stay >10 days and DE stay >4 days, compared to the PSI and CURB (though difference not statistically significant). For each endpoint measured, the best thresholds values for Mr-pro-ADM were: 1.6 (specificity 76.5%; sensitivity 77.8%) for death; 2.5 (specificity 88.9%; sensitivity 80.0%) for death at 14 days; 1.5 (specificity 77.0%; sensitivity 87.5%) for NIMV; 2.4 (specificity 88.7%; sensitivity 83.3%) for endotracheal intubation; 0.9 (specificity 53.5%; sensitivity 70.6%) for DE stay greater than 4 days; 1.9 (specificity 82.1%; sensitivity 55.3%) for hospital stay greater than 10 days. The AUC for the combination of MR-pro-ADM and PSI was 81.29% [63.41%-99.17%], but not in a statistically significant manner compared to the AUCs of the single predictors. Conversely, the AUC for the combination of MR-pro-ADM and CURB65 was 87.58% [75.54%-99.62%], which was significantly greater than the AUC of CURB65 (p = 0.047) or PSI (p = 0.017) alone. The present study confirms that assessment of MR-pro-ADM levels in CAP patients in addition to CURB scores increases the prognostic accuracy of CURB alone and may help rule out discrepancies arising from flawed clinical severity classification. With particular reference to patients scoring in the upper classes of CURB and PSI, MR-pro-ADM values provided additional information towards a better risk stratification of those patients. In particular, our results pointed towards two MR-pro-ADM threshold values that appear to predict with a good degree of accuracy the patient's need for non-invasive mechanical ventilation, endotracheal intubation, or intensive care. This aspect, however, deserves further investigation.
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"and", "PSI", "was", "81.29", "%", "[", "63.41%-99.17", "%", "]", ",", "but", "not", "in", "a", "statistically", "significant", "manner", "compared", "to", "the", "AUCs", "of", "the", "single", "predictors", ".", "Conversely", ",", "the", "AUC", "for", "the", "combination", "of", "MR", "-", "pro", "-", "ADM", "and", "CURB65", "was", "87.58", "%", "[", "75.54%-99.62", "%", "]", ",", "which", "was", "significantly", "greater", "than", "the", "AUC", "of", "CURB65", "(", "p", "=", "0.047", ")", "or", "PSI", "(", "p", "=", "0.017", ")", "alone", ".", "The", "present", "study", "confirms", "that", "assessment", "of", "MR", "-", "pro", "-", "ADM", "levels", "in", "CAP", "patients", "in", "addition", "to", "CURB", "scores", "increases", "the", "prognostic", "accuracy", "of", "CURB", "alone", "and", "may", "help", "rule", "out", "discrepancies", "arising", "from", "flawed", "clinical", "severity", "classification", ".", "With", "particular", "reference", "to", "patients", "scoring", "in", 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4a5e280ba4534d708cd9a706f914288a
CURB65 score is used for stratification of which disease?
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{ "text": [ "pneumonia" ], "char_spans": [ { "start": [ 320 ], "end": [ 328 ] } ], "token_spans": [ { "start": [ 62 ], "end": [ 62 ] } ] }
[ "pneumonia" ]
BioASQ
Bazex syndrome (acrokeratosis paraneoplastica) is a rare paraneoplastic syndrome that usually occurs in males over 40 years old and is particularly associated with squamous cell carcinoma of the upper aerodigestive tract and adenopathy above the diaphragm. The objectives of our article are (1) to describe a unique case of acrokeratosis paraneoplastica and (2) to review the current literature regarding skin findings, commonly associated neoplasms, and treatment options relative to this condition. We describe a 68-year-old female with lobular breast carcinoma, complicated by local and distant recurrences, who presented with a 1-year history of prominent acral skin and nail changes. Our patient's clinical skin findings improved significantly following treatment and partial remission of her underlying malignancy. Our patient represents one of few females described with this syndrome, which is especially rare in association with lobular breast carcinoma. Further, the patient's presentation is unique as she was discovered to demonstrate laboratory findings consistent with coexistent porphyria cutanea tarda and relative zinc deficiency.
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b5173fd9f31f44a4b8a0a7793cff9f0f
Name synonym of Acrokeratosis paraneoplastica.
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[ "Bazex syndrome" ]
BioASQ
Selenocysteine (Sec), the 21st amino acid in protein, is encoded by UGA. The Sec insertion sequence (SECIS) element, which is the stem-loop structure present in 3' untranslated regions (UTRs) of eukaryotic selenoprotein-encoding genes, is essential for recognition of UGA as a codon for Sec rather than as a stop signal. We now report the identification of a new eukaryotic selenoprotein, designated selenoprotein M (SelM). The 3-kb human SelM-encoding gene has five exons and is located on chromosome 22 but has not been correctly identified by either Celera or the public Human Genome Project. We characterized human and mouse SelM cDNA sequences and expressed the selenoprotein in various mammalian cell lines. The 3" UTR of the human, mouse, and rat SelM-encoding genes lacks a canonical SECIS element. Instead, Sec is incorporated in response to a conserved mRNA structure, in which cytidines are present in place of the adenosines previously considered invariant. Substitution of adenosines for cytidines did not alter Sec incorporation; however, other mutant structures did not support selenoprotein synthesis, demonstrating that this new form of SECIS element is functional. SelM is expressed in a variety of tissues, with increased levels in the brain. It is localized to the perinuclear structures, and its N-terminal signal peptide is necessary for protein translocation.
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414be8e3552c4a35af6a2803ffbea6d7
What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?
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[ "SECIS" ]
BioASQ
Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called "neurofibromin." It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the "two hit" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NF1 locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NF1 markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.
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0fbe509cc92143e19f8c06a29e4137e7
Which is the gene mutated in type 1 neurofibromatosis?
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[ "NF1" ]
BioASQ
Incorporation of the 21st amino acid, selenocysteine, into proteins is specified in all three domains of life by dynamic translational redefinition of UGA codons. In eukarya and archaea, selenocysteine insertion requires a cis-acting selenocysteine insertion sequence (SECIS) usually located in the 3'UTR of selenoprotein mRNAs. Here we present comparative sequence analysis and experimental data supporting the presence of a second stop codon redefinition element located adjacent to a selenocysteine-encoding UGA codon in the eukaryal gene, SEPN1. This element is sufficient to stimulate high-level (6%) translational redefinition of the SEPN1 UGA codon in human cells. Readthrough levels further increased to 12% when tested in the presence of the SEPN1 3'UTR SECIS. Directed mutagenesis and phylogeny of the sequence context strongly supports the importance of a stem loop starting six nucleotides 3' of the UGA codon. Sequences capable of forming strong RNA structures were also identified 3' adjacent to, or near, selenocysteine-encoding UGA codons in the Sps2, SelH, SelO, and SelT selenoprotein genes.
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c74fb4970f0c433ca0ed2902b475918f
What is the name of the stem loop present in the 3' end of genes encoding for selenoproteins?
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[ "SECIS" ]
BioASQ
The vacuolar H(+)-ATPase (V-ATPase) along with ion channels and transporters maintains vacuolar pH. V-ATPase ATP hydrolysis is coupled with proton transport and establishes an electrochemical gradient between the cytosol and vacuolar lumen for coupled transport of metabolites. Btn1p, the yeast homolog to human CLN3 that is defective in Batten disease, localizes to the vacuole. We previously reported that Btn1p is required for vacuolar pH maintenance and ATP-dependent vacuolar arginine transport. We report that extracellular pH alters both V-ATPase activity and proton transport into the vacuole of wild-type Saccharomyces cerevisiae. V-ATPase activity is modulated through the assembly and disassembly of the V(0) and V(1) V-ATPase subunits located in the vacuolar membrane and on the cytosolic side of the vacuolar membrane, respectively. V-ATPase assembly is increased in yeast cells grown in high extracellular pH. In addition, at elevated extracellular pH, S. cerevisiae lacking BTN1 (btn1-Delta), have decreased V-ATPase activity while proton transport into the vacuole remains similar to that for wild type. Thus, coupling of V-ATPase activity and proton transport in btn1-Delta is altered. We show that down-regulation of V-ATPase activity compensates the vacuolar pH imbalance for btn1-Delta at early growth phases. We therefore propose that Btn1p is required for tight regulation of vacuolar pH to maintain the vacuolar luminal content and optimal activity of this organelle and that disruption in Btn1p function leads to a modulation of V-ATPase activity to maintain cellular pH homeostasis and vacuolar luminal content.
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bb74435049ca4f75a40f7eeaf2c5dd00
What is the effect of a defective CLN3 gene?
{ "tokens": [ "What", "is", "the", "effect", "of", "a", "defective", "CLN3", "gene", "?" ], "offsets": [ 0, 5, 8, 12, 19, 22, 24, 34, 39, 43 ] }
{ "text": [ "Batten disease" ], "char_spans": [ { "start": [ 338 ], "end": [ 351 ] } ], "token_spans": [ { "start": [ 56 ], "end": [ 57 ] } ] }
[ "Batten disease", "juvenile-onset neuronal ceroid lipofuscinosis", "JNCL" ]
BioASQ
Dasatinib (BMS-354825) is a Src/ABL tyrosine kinase inhibitor currently approved for the treatment of chronic myeloid leukemia. Dasatinib has increased potency against ABL compared to the current therapy imatinib, and is effective in many cases where disease is resistant to imatinib. Dasatinib also inhibits many Src-family tyrosine kinases. We have demonstrated in this study that dasatinib is able to block the function of normal human T-lymphocytes in vitro at clinically relevant concentrations. T-cell functions including proliferation, activation and cytokine production were all uniformly inhibited in the presence of dasatinib. We also demonstrated inhibition of TCR signalling through Src-family kinase LCK, and predicted that inhibition of LCK and other kinases involved in T-cell signalling by dasatinib is responsible for the suppression of T-cell function. These findings raise the concern about potential T-cell inhibition in patients taking dasatinib, and suggest a possible application for the treatment of T-cell mediated immune disorders.
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5b937d99df5342ca8ffb9a12ec8714ce
Does dasatinib promote or inhibit T-cell proliferation?
{ "tokens": [ "Does", "dasatinib", "promote", "or", "inhibit", "T", "-", "cell", "proliferation", "?" ], "offsets": [ 0, 5, 15, 23, 26, 34, 35, 36, 41, 54 ] }
{ "text": [ "inhibits" ], "char_spans": [ { "start": [ 300 ], "end": [ 307 ] } ], "token_spans": [ { "start": [ 50 ], "end": [ 50 ] } ] }
[ "inhibits" ]
BioASQ
Reactive oxygen species (ROS) production by NADPH oxidase 1 (NOX1), which is mainly expressed in colon epithelial cells, requires the membrane-bound component p22(PHOX) and the cytosolic partners NOX organizer 1 (NOXO1), NOX activator 1 (NOXA1), and Rac1. Contrary to that of its phagocyte counterpart NOX2, the molecular basis of NOX1 regulation is not clear. Because NOXO1 lacks the phosphorylated region found in its homolog p47(PHOX), the current view is that NOX1 activation occurs without NOXO1 phosphorylation. Here, however, we demonstrate that phorbol myristate acetate (PMA) stimulates NOXO1 phosphorylation in a transfected human embryonic kidney (HEK) 293 epithelial cell model via protein kinase C and identify Ser-154 as the major phosphorylated site. Endogenous NOXO1 from T84 colon epithelial cells was also phosphorylated, suggesting that NOXO1 phosphorylation is physiologically relevant. In transfected HEK-293 cells, PMA-induced phosphorylation on Ser-154 enhanced NOXO1 binding to NOXA1 (+97%) and to the p22(PHOX) C-terminal region (+384%), increased NOXO1 colocalization with p22(PHOX), and allowed optimal ROS production by NOX1 as demonstrated by the use of S154A and S154D mutants compared with that by wild-type NOXO1 (P<0.05). Pulldown experiments revealed that phos-phorylation on Ser-154 was sufficient to markedly enhance NOXO1 binding to NOXA1, which in turn acts as a molecular switch, allowing optimal interaction of NOXO1 with p22(PHOX). This study unexpectedly revealed that full assembly and activation of NOX1 is a tightly regulated process in which NOXO1 phosphorylation on Ser-154 is the initial trigger.
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ce8e78ef06ed459386b6f776879b5c3c
Which NADPH oxidase family member requires interaction with NOXO1 for function?
{ "tokens": [ "Which", "NADPH", "oxidase", "family", "member", "requires", "interaction", "with", "NOXO1", "for", "function", "?" ], "offsets": [ 0, 6, 12, 20, 27, 34, 43, 55, 60, 66, 70, 78 ] }
{ "text": [ "NADPH oxidase 1", "NOX1" ], "char_spans": [ { "start": [ 44 ], "end": [ 58 ] }, { "start": [ 1543, 1148, 464, 61, 331 ], "end": [ 1546, 1151, 467, 64, 334 ] } ], "token_spans": [ { "start": [ 8 ], "end": [ 10 ] }, { "start": [ 275, 205, 90, 12, 66 ], "end": [ 275, 205, 90, 12, 66 ] } ] }
[ "NADPH oxidase 1", "NOX1", "nicotinamide adenine dinucleotide phosphate-oxidase 1" ]
BioASQ
Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH). Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014). The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.
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d69c9463ec08444a919447d7f33855f7
Selexipag is used for which disease?
{ "tokens": [ "Selexipag", "is", "used", "for", "which", "disease", "?" ], "offsets": [ 0, 10, 13, 18, 22, 28, 35 ] }
{ "text": [ "pulmonary arterial hypertension" ], "char_spans": [ { "start": [ 201 ], "end": [ 231 ] } ], "token_spans": [ { "start": [ 38 ], "end": [ 40 ] } ] }
[ "pulmonary arterial hypertension" ]
BioASQ
Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).
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86eebad997b34e70b99bab30bc82e7b6
Which gene is responsible for the development of Sotos syndrome?
{ "tokens": [ "Which", "gene", "is", "responsible", "for", "the", "development", "of", "Sotos", "syndrome", "?" ], "offsets": [ 0, 6, 11, 14, 26, 30, 34, 46, 49, 55, 63 ] }
{ "text": [ "NSD1 gene" ], "char_spans": [ { "start": [ 209 ], "end": [ 217 ] } ], "token_spans": [ { "start": [ 31 ], "end": [ 32 ] } ] }
[ "NSD1 gene" ]
BioASQ
Chronic myeloid leukemia (CML) is a clonal malignant myeloproliferative disorder characterized by the expansion of hematopoietic cells carrying the Philadelphia chromosome (t 9.22). Our main objective was to assess the efficacy of imatinib in CML patients, measured by their survival. Over a six-year period (June 2003 through May 2009), 25 patients were seen regularly for CML at the Lomé Campus teaching hospital. Patients received imatinib after diagnosis and underwent regular laboratory monitoring (quantification of BCR-ABL ratio by RT-PCR). Patients' survival and treatment response were evaluated. Patients' mean age at diagnosis was 40 years (range: 9 to 72 years). Men predominated (17 compared with 7 women). Splenomegaly was found in 80% of cases. The mean leukocyte level was 188.71 g/L (24.4-350). Six patients (24%) had thrombocytosis with a mean platelet count of 491.15 g/L (108-2000). Six patients (24%) died after developing accelerated-phase CML or blast crisis. Estimated overall survival of patients at 6 years was 60%. Molecular biology monitoring detected a secondary G250E mutation with resistance to imatinib in one patient. Standard hematological side effects led to reduction in imatinib doses. The principal nonhematological side effects were weight gain and transient digestible disorders. At six years after diagnosis, imatinib was effective in treating patients with CML, even in sub-Saharan Africa. Mutation-induced resistance required regular molecular biological monitoring to determine the need to switch to later-generation tyrosine kinase inhibitors.
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5d0e918abb8649f49a8cdb096d471c53
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
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{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 522 ], "end": [ 528 ] } ], "token_spans": [ { "start": [ 88 ], "end": [ 90 ] } ] }
[ "BCR-ABL" ]
BioASQ
Chaperone-mediated autophagy is one of several lysosomal pathways of proteolysis. This pathway is activated by physiological stresses such as prolonged starvation. Cytosolic proteins with particular peptide sequence motifs are recognized by a complex of molecular chaperones and delivered to lysosomes. No vesicular traffic is required for this protein degradation pathway, so it differs from microautophagy and macroautophagy. Protein substrates bind to a receptor in the lysosomal membrane, the lysosome-associated membrane protein (lamp) type 2a. Levels of lamp2a in the lysosomal membrane are controlled by alterations in the lamp2a half-life as well as by the dynamic distribution of the protein between the lysosomal membrane and the lumen. Substrate proteins are unfolded before transport into the lysosome lumen, and the transport of substrate proteins requires a molecular chaperone within the lysosomal lumen. The exact roles of this lysosomal chaperone remain to be defined. The mechanisms of chaperone-mediated autophagy are similar to mechanisms of protein import into mitochondria, chloroplasts, and the endoplasmic reticulum.
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2af13c4b405e44c8820036a07143c462
Which is the receptor for substrates of Chaperone Mediated Autophagy?
{ "tokens": [ "Which", "is", "the", "receptor", "for", "substrates", "of", "Chaperone", "Mediated", "Autophagy", "?" ], "offsets": [ 0, 6, 9, 13, 22, 26, 37, 40, 50, 59, 68 ] }
{ "text": [ "LAMP2A" ], "char_spans": [ { "start": [ 630, 560 ], "end": [ 635, 565 ] } ], "token_spans": [ { "start": [ 100, 89 ], "end": [ 100, 89 ] } ] }
[ "LAMP2A", "Lysosome-associated membrane protein 2 isoform A" ]
BioASQ
Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258 (CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies. Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101) is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL.
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5b4281bf26774411a2c18e34edadb7e3
Which enzyme is inhibited by a drug fostamatinib?
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{ "text": [ "spleen tyrosine kinase" ], "char_spans": [ { "start": [ 828 ], "end": [ 849 ] } ], "token_spans": [ { "start": [ 147 ], "end": [ 149 ] } ] }
[ "spleen tyrosine kinase" ]
BioASQ
For the first time a causal treatment of hepatic encephalopathy may be possible by the benzodiazepine antagonist flumazenil. In contrast to all other treatments used so far by flumazenil hepatic encephalopathy improves within minutes. Flumazenil is the first benzodiazepine antagonist which can be used in humans and is a well established for treatment of benzodiazepine overdose. For treatment of hepatic encephalopathy development of a new antagonist with a longer half-life is desirable. However, ut should be stressed that the current experience with flumazenil is limited and that the effects of flumazenil on hepatic encephalopathy is not proven by randomized controlled studies. Therefore, this drug should only be used in clinical studies.
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fc13d80c19934d369960cc64e8a7ed87
Which drug should be used as an antidote in benzodiazepine overdose?
{ "tokens": [ "Which", "drug", "should", "be", "used", "as", "an", "antidote", "in", "benzodiazepine", "overdose", "?" ], "offsets": [ 0, 6, 11, 18, 21, 26, 29, 32, 41, 44, 59, 67 ] }
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[ "flumazenil" ]
BioASQ
It has been reported that the R497K polymorphism of the epidermal growth factor receptor (EGFR) gene has attenuated functions in ligand binding, tyrosine kinase activation, and growth stimulation. On other hand, EGFR gene mutations at kinase domain in non-small cell lung cancer (NSCLC) have been examined for their ability to predict sensitivity to gefitinib or erlotinib. We investigated the EGFR mutations and/or R497K polymorphism statuses in 225 surgically treated NSCLC cases. 192 adenocarcinoma cases were included. The presence or absence of EGFR polymorphism of exon 13 was analyzed by PCR-RFLP method. EGFR mutations at kinase domain were found from 95 of 225 lung cancer patients. In 86.2% of patients, homo- or heterozygous Lys497 allele was present. No correlation existed between R497K EGFR genotype and clinico-pathological features, such as gender, smoking status, and pathological subtypes. EGFR mutation status was not correlated with R497KEGFR genotype of lung cancers. In node-negative patients, R497KEGFR genotype was not correlated with disease outcome. In node-positive patients, however, R497K EGFR was significantly associated with better overall survival. This association was attributable to neo-adjuvant or adjuvant chemotherapy. In 46 total gefitinib treated NSCLC patients, the prognosis was not different between the EGFR wild type (GG) patients and AG+AA patients. R497KEGFR polymorphism might be associated with favorable prognosis of advanced lung cancers and correlated with chemosensitivity.
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98bf14cf3f54411fb46b808b1029b76d
Mutations in which gene determine response to both erlotinib and gefitinib?
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{ "text": [ "epidermal growth factor receptor (EGFR) gene" ], "char_spans": [ { "start": [ 56 ], "end": [ 99 ] } ], "token_spans": [ { "start": [ 11 ], "end": [ 18 ] } ] }
[ "epidermal growth factor receptor (EGFR) gene" ]
BioASQ
Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a single genetic abnormality, characterized by a reciprocal translocation involving chromosomes 9 and 22 (the Philadelphia chromosome). The fusion gene that results (BCR-ABL) produces a constitutively activated tyrosine kinase that exists in different isoforms depending on BCR break-points. Imatinib mesylate is a highly selective inhibitor of this kinase, producing normal blood-counts in 98% of patients in chronic phase CML and disappearance of the Philadelphia chromosome in 86%. However, 17% of patients in the chronic phase will either relapse or develop resistance resulting mainly from one or more point mutations affecting at least 30 amino acids within the Abl kinase protein. This review focuses on the relevant biology of CML, imatinib mesylate resistance mechanisms, and the current status of the next generation of Bcr-Abl inhibitors.
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5640bc900f45497f94ba9ba680a9a645
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
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{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 250, 914 ], "end": [ 256, 920 ] } ], "token_spans": [ { "start": [ 42, 159 ], "end": [ 44, 161 ] } ] }
[ "BCR-ABL" ]
BioASQ
Drosophila melanogaster has a single Adar gene encoding a protein related to mammalian ADAR2 that edits transcripts encoding glutamate receptor subunits. We describe the structure of the Drosophila Adar locus and use ModENCODE information to supplement published data on Adar gene transcription, and splicing. We discuss the roles of ADAR in Drosophila in terms of the two main types of RNA molecules edited and roles of ADARs as RNA-binding proteins. Site-specific RNA editing events in transcripts encoding ion channel subunits were initially found serendipitously and subsequent directed searches for editing sites and transcriptome sequencing have now led to 972 edited sites being identified in 597 transcripts. Four percent of D. melanogaster transcripts are site-specifically edited and these encode a wide range of largely membrane-associated proteins expressed particularly in CNS. Electrophysiological studies on the effects of specific RNA editing events on ion channel subunits do not suggest that loss of RNA editing events in ion channels consistently produce a particular outcome such as making Adar mutant neurons more excitable. This possibility would have been consistent with neurodegeneration seen in Adar mutant fly brains. A further set of ADAR targets are dsRNA intermediates in siRNA generation, derived from transposons and from structured RNA loci. Transcripts with convergent overlapping 3' ends are also edited and the first discovered instance of RNA editing in Drosophila, in the Rnp4F transcript, is an example. There is no evidence yet to show that Adar antagonizes RNA interference in Drosophila. Evidence has been obtained that catalytically inactive ADAR proteins exert effects on microRNA generation and RNA interference. Whether all effects of inactive ADARs are due to RNA-binding or to even further roles of these proteins remains to be determined.
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9bb16ae9ce384988b2c0a173f93c5be4
Which is the major RNA editing enzyme in Drosophila melanogaster?
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[ "ADAR", "adenosine deaminase, RNA-specific" ]
BioASQ
To evaluate the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin added to metformin for 12 weeks in patients with type 2 diabetes. This dose-ranging, double-blind, placebo-controlled trial randomized 495 participants with type 2 diabetes inadequately controlled on metformin [haemoglobin A1c (HbA1c) >7 to ≤10%] to receive 1, 5, 10, 25, or 50 mg empagliflozin once daily (QD), or placebo, or open-label sitagliptin (100 mg QD), added to metformin for 12 weeks. The primary endpoint was change in HbA1c from baseline to week 12 (empagliflozin groups versus placebo). Reductions in HbA1c of -0.09 to -0.56% were observed with empagliflozin after 12 weeks, versus an increase of 0.15% with placebo (baseline: 7.8-8.1%). Compared with placebo, empagliflozin doses from 5 to 50 mg resulted in reductions in fasting plasma glucose (-2 to -28 mg/dl vs. 5 mg/dl with placebo; p < 0.0001) and body weight (-2.3 to -2.9 kg vs. -1.2 kg; p < 0.01). Frequency of adverse events was generally similar with empagliflozin (29.6-48.6%), placebo (36.6%) and sitagliptin (35.2%). Hypoglycaemia rates were very low and balanced among groups. Most frequent adverse events with empagliflozin were urinary tract infections (4.0% vs. 2.8% with placebo) and pollakiuria (2.5% vs. 1.4% with placebo). Genital infections were reported only with empagliflozin (4.0%). Once daily empagliflozin as add-on therapy to metformin was well tolerated except for increased genital infections and resulted in reductions in HbA1c, fasting plasma glucose and body weight in patients with type 2 diabetes inadequately controlled on metformin monotherapy.
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42c9f1c1eae84fa0885493a31db38248
Which protein does empagliflozin inhibit?
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{ "text": [ "SGLT2" ], "char_spans": [ { "start": [ 63 ], "end": [ 67 ] } ], "token_spans": [ { "start": [ 11 ], "end": [ 11 ] } ] }
[ "SGLT2" ]
BioASQ
Paired-like homeodomain transcription factor 1 (PITX1) was proposed to be part of the disease mechanisms of facioscapulohumeral muscular dystrophy (FSHD). We generated a tet-repressible muscle-specific Pitx1 transgenic mouse model which develops phenotypes of muscular dystrophy after the PITX1 expression is induced. In this study, we attempted to block the translation of PITX1 protein using morpholinos. Three groups of the transgenic mice received intravenous injections of phosphorodiamidate morpholino oligomers (PMO) (100 mg/kg), octaguanidinium dendrimer-conjugated morpholino (vivo-morpholino) (10 mg/kg), or phosphate-buffered saline (PBS) after the PITX1 expression was induced. Immunoblotting data showed that PITX1 expression in the triceps and quadriceps was significantly reduced 70% and 63% by the vivo-morpholino treatment, respectively. Muscle pathology of the mice treated with the vivo-morpholino was improved by showing 44% fewer angular-shaped atrophic myofibers. Muscle function determined by grip strength was significantly improved by the vivo-morpholino treatment. The study showed that systemic delivery of the vivo-morpholino reduced the PITX1 expression and improved the muscle phenotypes. Aberrant expression of DUX4 from the last unit of the D4Z4 array has been proposed to be the cause of FSHD. The findings of this study suggest that the same principle may be applied to suppress the aberrantly expressed DUX4 in FSHD.
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e6310084df7a436e828bdf5b509a3937
Which disease is associated with the ectopic expression of the protein encoded by the gene DUX4?
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[ "Facioscapulohumeral dystrophy", "FSHD" ]
BioASQ
To investigate the migraine locus around the C19p13 region through analysis of the NOTCH3 gene (C19p13.2-p13.1), previously shown to be a gene involved in CADASIL and the TNFSF7 gene (C19p13), homologous to the ligands of TNF-alpha and TNF-beta, genes that have previously been associated with migraine. The NOTCH3 gene was analysed by sequencing all exons with known CADASIL mutations in a typical (non-familial hemiplegic) migraine family (MF1) that has previously been shown to be linked to C19p13. The TNFSF7 gene was investigated through SNP association analysis using a matched case-control migraine population. NOTCH3 gene sequencing results for affected members of MF1 proved to be negative for all known sequence variants giving rise to mutations for CADASIL. TNFSF7 gene chi-square results showed non-significant P values across all populations tested against controls, except for the MO subgroup which displayed a possible association with the TNFSF7 SNP (genotype, allele analysis P = 0.036, P = 0.017 respectively). Our results suggest that common migraine is not caused by any known CADASIL mutations in the NOTCH3 gene of interest. However, the TNFSF7 gene displayed signs of involvement in a MO affected population and indicates that further independent studies of this marker are warranted.
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fc24f2392a694a878abd703ed179be42
Which gene is involved in CADASIL?
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{ "text": [ "Notch3 gene" ], "char_spans": [ { "start": [ 83, 1122, 308, 618 ], "end": [ 93, 1132, 318, 628 ] } ], "token_spans": [ { "start": [ 13, 203, 59, 114 ], "end": [ 14, 204, 60, 115 ] } ] }
[ "Notch3 gene" ]
BioASQ
Sedation is an important aspect of care for critically ill newborns. Proper sedation reduces stress during procedures such as mechanical ventilation. Midazolam, a short-acting benzodiazepine, is widely administered as a sedative in newborn intensive care units but is not without side effects. Three term newborns developed myoclonic-like abnormal movements after receiving midazolam. In one, flumazenil controlled the abnormal movements. Flumazenil is a potent benzodiazepine antagonist that competitively blocks the central effects of benzodiazepines. It can reverse the sedative effects of benzodiazepines occurring after diagnostic or therapeutic procedures or after benzodiazepine overdose. Flumazenil may be considered in cases of abnormal movements associated with midazolam. However, further studies are needed to provide guidelines for the administration of this drug in newborns.
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53789d187e204d27ba5d871adbcd3fd2
Which drug should be used as an antidote in benzodiazepine overdose?
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[ "flumazenil" ]
BioASQ
Mowat-Wilson syndrome (MWS) is characterized by severe mental retardation with seizures, specific facial dysmorphism, Hirschsprung disease, anomalies of the corpus callosum, and genitourinary and cardiac malformations. The cause of MWS is a de novo mutation in the ZEB2 gene. This report describes a Turkish boy who was clinically diagnosed with MWS and had his diagnosis confirmed by molecular analysis of the ZEB2 gene. The investigation identified a heterozygous complex rearrangement in exon 8 of ZEB2, specifically a 48-nucleotide deletion and a 44-nucleotide insertion that caused a frameshift. MWS is a relatively newly identified disorder, and even MWS patients without Hirschsprung disease can be diagnosed easily based on clinical findings alone.
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d84bc6e39f2f44b6973107b386e250ba
Which gene is responsible for the development of the Mowat-Wilson syndrome?
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{ "text": [ "ZEB2" ], "char_spans": [ { "start": [ 411, 501, 265 ], "end": [ 414, 504, 268 ] } ], "token_spans": [ { "start": [ 71, 85, 46 ], "end": [ 71, 85, 46 ] } ] }
[ "ZFHX1B", "ZEB2", "SIP-1" ]
BioASQ
Stress signals elicit a wide variety of cellular responses, many of which converge on the phosphorylation of JNK and p38 kinases, the activation of which has been well-characterized. How these kinases are switched off by dephosphorylation is not well understood. Here we describe how diverse cellular stresses affect differently the stability and activity of a JNK-inactivating dual-specificity threonine-tyrosine phosphatase M3/6. Both anisomycin and arsenite activate the JNK pathway and, in addition, inactivate the M3/6 phosphatase. However, while anisomycin treatment of cells leads to M3/6 protein degradation, arsenite appears to inactivate M3/6 directly. These results might have implications for the mechanism of tumour promotion by arsenic.
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b7441dc6481f4a8c8ea767fe70d618bb
Which protein is affected by dusp8 activation?
{ "tokens": [ "Which", "protein", "is", "affected", "by", "dusp8", "activation", "?" ], "offsets": [ 0, 6, 14, 17, 26, 29, 35, 45 ] }
{ "text": [ "JNK" ], "char_spans": [ { "start": [ 474, 361, 109 ], "end": [ 476, 363, 111 ] } ], "token_spans": [ { "start": [ 79, 61, 18 ], "end": [ 79, 61, 18 ] } ] }
[ "JNK" ]
BioASQ
Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations is the major cause of Sotos syndrome characterized by generalized overgrowth, large hands and feet with advanced bone age, craniofacial dysmorphic features, learning disability, and possible susceptibility to tumors. Here, we report on a 14-month-old boy with a reverse phenotype of Sotos syndrome due to the reciprocal duplication of the 5q35.3 region, including the NSD1 gene, detected by array CGH. The phenotype includes delayed bone age, microcephaly, seizures, and failure to thrive. Our case suggests that the gene dosage effect of the NSD1 gene is the likely cause for the reversed phenotype of Sotos syndrome in this patient.
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4dacfcd587cf4e6f8eed4e508e7a454e
Which gene is responsible for the development of Sotos syndrome?
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[ "NSD1 gene" ]
BioASQ
Despite ongoing efforts to decipher the cancer genome, discoveries of new targetable genetic lesions within cancer cells are rare. Therefore, alternative approaches are needed. Signals from the microenvironment are increasingly recognized as drivers of disease progression in hematologic and solid cancers. Consequently, there is growing interest in targeting the tumor-microenvironment cross-talk. This review highlights recent therapeutic advances in targeting the microenvironment in chronic lymphocytic leukemia (CLL). CLL is the poster child for microenvironment-dependent malignancies, because the clonal CLL B cells are highly dependent on external signals for maintenance and expansion. These pathways recapitulate those responsible for normal B-cell expansion in germinal centers. The most prominent, conserved mechanism is B-cell receptor (BCR) signaling, which promotes CLL cell survival and expansion in lymphatic tissue areas designated proliferation centers. BCR signaling now can be targeted by new targeted kinase inhibitors. Small molecule inhibitors of BCR signaling kinases, Bruton's tyrosine kinase (Btk) inhibitor ibrutinib and the phosphoinositide 3'-kinase delta (PI3Kδ) inhibitor GS-1101, are currently transforming the landscape of CLL therapy. This development exemplifies that the microenvironment has become a lively successful area of translational research.
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6999c77ec9e74a558797ede82bccb01b
What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?
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{ "text": [ "Ibrutinib" ], "char_spans": [ { "start": [ 1135 ], "end": [ 1143 ] } ], "token_spans": [ { "start": [ 182 ], "end": [ 182 ] } ] }
[ "Ibrutinib" ]
BioASQ
A 65-year-old white man presented with all the clinical features of acrokeratosis paraneoplastica of Bazex, characterized by violaceous erythema and scaling of the nose, aural helices, fingers, and toes, with keratoderma and severe nail dystrophy. Examination of the patient for possible associated malignancy disclosed an asymptomatic squamous cell carcinoma at the oropharyngeal region. The skin lesions resolved almost completely following radiation therapy of the neoplasm, but the onychodystrophy persisted. This case report illustrates the importance of early recognition of Bazex syndrome.
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fecb8a65f2cf49afa3fcf85558513068
Name synonym of Acrokeratosis paraneoplastica.
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{ "text": [ "Bazex syndrome" ], "char_spans": [ { "start": [ 581 ], "end": [ 594 ] } ], "token_spans": [ { "start": [ 90 ], "end": [ 91 ] } ] }
[ "Bazex syndrome" ]
BioASQ
Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.
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2d94618b5f9d418e967e8d0aff6598aa
Which syndrome is associated with mutations in the LYST gene?
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{ "text": [ "Chediak-Higashi syndrome" ], "char_spans": [ { "start": [ 1253 ], "end": [ 1276 ] } ], "token_spans": [ { "start": [ 210 ], "end": [ 213 ] } ] }
[ "Chediak-Higashi syndrome" ]
BioASQ
The effect of the newly synthesized compound 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) on the Na+-Ca2+ exchanger (NCX) was investigated and compared against that of 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R7943). In addition, the effects of SEA0400 on reperfusion injury in vitro and in vivo were examined. SEA0400 was extremely more potent than KB-R7943 in inhibiting Na+-dependent Ca2+ uptake in cultured neurons, astrocytes, and microglia: IC50s of SEA0400 and KB-R7943 were 5 to 33 nM and 2 to 4 microM, respectively. SEA0400 at the concentration range that inhibited NCX exhibited negligible affinities for the Ca2+ channels, Na+ channels, K+ channels, norepinephrine transporter, and 14 receptors, and did not affect the activities of the Na+/H+ exchanger, Na+,K+-ATPase, Ca2+-ATPase, and five enzymes. SEA0400, unlike KB-R7943, did not inhibit the store-operated Ca2+ entry in cultured astrocytes. SEA0400 attenuated dose- dependently paradoxical Ca2+ challenge-induced production of reactive oxygen species, DNA ladder formation, and nuclear condensation in cultured astrocytes, whereas it did not affect thapsigargin-induced cell injury. Furthermore, administration of SEA0400 reduced infarct volumes after a transient middle cerebral artery occlusion in rat cerebral cortex and striatum. These results indicate that SEA0400 is the most potent and selective inhibitor of NCX, and suggest that the compound may exert protective effects on postischemic brain damage.
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e77f03a3c71044b98123b465164c6cc7
The small molecule SEA0400 is an inhibitor of which ion antiporter/exchanger?
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{ "text": [ "NCX" ], "char_spans": [ { "start": [ 1422, 141, 614 ], "end": [ 1424, 143, 616 ] } ], "token_spans": [ { "start": [ 240, 17, 102 ], "end": [ 240, 17, 102 ] } ] }
[ "Na(+)/Ca(2+) exchanger", "NCX" ]
BioASQ
Quantitative real-time PCR (QPCR) has emerged as an accurate and valuable tool in profiling gene expression levels. One of its many advantages is a lower detection limit compared to other methods of gene expression profiling while using smaller amounts of input for each assay. Automated qPCR setup has improved this field by allowing for greater reproducibility. Its convenient and rapid setup allows for high-throughput experiments, enabling the profiling of many different genes simultaneously in each experiment. This method along with internal plate controls also reduces experimental variables common to other techniques. We recently developed a qPCR assay for profiling of pre-microRNAs (pre-miRNAs) using a set of 186 primer pairs. MicroRNAs have emerged as a novel class of small, non-coding RNAs with the ability to regulate many mRNA targets at the post-transcriptional level. These small RNAs are first transcribed by RNA polymerase II as a primary miRNA (pri-miRNA) transcript, which is then cleaved into the precursor miRNA (pre-miRNA). Pre-miRNAs are exported to the cytoplasm where Dicer cleaves the hairpin loop to yield mature miRNAs. Increases in miRNA levels can be observed at both the precursor and mature miRNA levels and profiling of both of these forms can be useful. There are several commercially available assays for mature miRNAs; however, their high cost may deter researchers from this profiling technique. Here, we discuss a cost-effective, reliable, SYBR-based qPCR method of profiling pre-miRNAs. Changes in pre-miRNA levels often reflect mature miRNA changes and can be a useful indicator of mature miRNA expression. However, simultaneous profiling of both pre-miRNAs and mature miRNAs may be optimal as they can contribute nonredundant information and provide insight into microRNA processing. Furthermore, the technique described here can be expanded to encompass the profiling of other library sets for specific pathways or pathogens.
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"encompass", "the", "profiling", "of", "other", "library", "sets", "for", "specific", "pathways", "or", "pathogens", "." ], "offsets": [ 0, 13, 17, 18, 23, 27, 28, 32, 34, 38, 46, 49, 52, 61, 65, 74, 79, 82, 92, 97, 108, 114, 116, 120, 123, 127, 132, 143, 146, 148, 154, 164, 170, 179, 182, 188, 196, 199, 204, 215, 225, 231, 237, 245, 253, 256, 262, 266, 271, 276, 278, 288, 293, 299, 303, 312, 317, 323, 326, 335, 339, 347, 362, 364, 368, 379, 383, 389, 395, 402, 406, 410, 411, 422, 433, 435, 444, 448, 458, 461, 466, 476, 482, 497, 500, 505, 515, 517, 522, 529, 535, 540, 549, 555, 564, 569, 577, 590, 600, 607, 610, 616, 626, 628, 631, 640, 650, 652, 657, 663, 667, 677, 680, 683, 684, 694, 695, 698, 699, 705, 707, 713, 715, 719, 722, 726, 733, 738, 740, 750, 755, 763, 766, 768, 774, 780, 783, 788, 790, 793, 794, 801, 806, 811, 815, 823, 826, 835, 840, 845, 853, 856, 860, 864, 865, 881, 886, 888, 894, 900, 905, 909, 915, 927, 930, 934, 945, 948, 951, 953, 961, 967, 968, 971, 972, 977, 979, 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1905, 1915, 1918, 1924, 1932, 1937, 1941, 1950, 1959, 1962, 1971 ] }
d5012159612c4b0b9722b00581b7cf34
Which polymerase transcribes pri-miRNAs?
{ "tokens": [ "Which", "polymerase", "transcribes", "pri", "-", "miRNAs", "?" ], "offsets": [ 0, 6, 17, 29, 32, 33, 39 ] }
{ "text": [ "RNA polymerase II" ], "char_spans": [ { "start": [ 930 ], "end": [ 946 ] } ], "token_spans": [ { "start": [ 164 ], "end": [ 166 ] } ] }
[ "RNA polymerase II", "RNAPII" ]
BioASQ
Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. The syndrome is characterized by typical facial features, moderate-to-severe mental retardation, epilepsy and variable congenital malformations, including Hirschsprung disease, genital anomalies, congenital heart disease, agenesis of the corpus callosum, and eye defects. The prevalence of Mowat-Wilson syndrome is currently unknown, but it seems that Mowat-Wilson syndrome is underdiagnosed, particularly in patients without Hirschsprung disease. We report here the first Egyptian case of Mowat-Wilson syndrome who was conceived by intracytoplasmic sperm injection. The patient manifested bilateral sensorineural hearing loss--a new feature not previously reported in cases of Mowat-Wilson syndrome. This report describes the first Egyptian patient of Mowat-Wilson syndrome who was conceived after intracytoplasmic sperm injection, and provides a new evidence for the inclusion of deafness among the congenital defects of the syndrome.
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c3272be6bdea40c9ac22dfe5337dc311
Which gene is responsible for the development of the Mowat-Wilson syndrome?
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{ "text": [ "ZEB2" ], "char_spans": [ { "start": [ 134 ], "end": [ 137 ] } ], "token_spans": [ { "start": [ 26 ], "end": [ 26 ] } ] }
[ "ZFHX1B", "ZEB2", "SIP-1" ]
BioASQ
Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications. Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics. In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood. The use of animal models has been used to further this objective. Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models. Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome. We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias. We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems. Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD.
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b0f3562cb2574620ba46ae33c88d65b3
What is the cause of Tardive dyskinesia?
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[ "Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications." ]
BioASQ
Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine kinases. We examined STAT protein activation in lung cancer cell lines including those with activating mutations in the EGFR and examined upstream kinases responsible for STAT3 phosphorylation and activation using small molecules, antibodies, and RNA interference. We found more pronounced STAT3 activation in cells with activating EGFR mutations, yet inhibition of EGFR activity had no effect on STAT3 activation. Inhibition of JAK1 with small molecules or RNA interference resulted in loss of STAT3 tyrosine phosphorylation and inhibition of cell growth. An interleukin-6 neutralizing antibody, siltuximab (CNTO 328) could inhibit STAT3 tyrosine phosphorylation in a cell-dependent manner. Siltuximab could completely inhibit STAT3 tyrosine phosphorylation in H1650 cells, and this resulted in inhibition of lung cancer cell growth in vivo. Combined EGFR inhibition with erlotinib and siltuximab resulted in dual inhibition of both tyrosine and serine STAT3 phosphorylation, more pronounced inhibition of STAT3 transcriptional activity, and translated into combined effects on lung cancer growth in a mouse model. Our results suggest that JAK1 is responsible for STAT3 activation in lung cancer cells and that indirect attacks on JAK1-STAT3 using an IL-6 neutralizing antibody with or without EGFR inhibition can inhibit lung cancer growth in lung cancer subsets.
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fc6f88c8ca2e451284d7c33fa8b5071a
Which interleukin is blocked by Siltuximab?
{ "tokens": [ "Which", "interleukin", "is", "blocked", "by", "Siltuximab", "?" ], "offsets": [ 0, 6, 18, 21, 29, 32, 42 ] }
{ "text": [ "interleukin-6" ], "char_spans": [ { "start": [ 887 ], "end": [ 899 ] } ], "token_spans": [ { "start": [ 139 ], "end": [ 139 ] } ] }
[ "interleukin-6" ]
BioASQ
Detection of methicillin (meticillin)-resistant Staphylococcus aureus colonization was assessed using combined nose and groin swabs in two commercial PCR assays (the Xpert MRSA assay and the BD GeneOhm MRSA assay). Compared to routine culture, both had similar sensitivities (87.0% versus 84.8%, respectively) and specificities (93.8% versus 92.7%, respectively). Combined PCR assays provide a rapid and more-complete assessment of colonization at a cost similar to that of single-site analysis.
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a21e993c7e5d4f7f8143bd59329ed432
What is MRSA?
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{ "text": [ "MRSA" ], "char_spans": [ { "start": [ 172, 202 ], "end": [ 175, 205 ] } ], "token_spans": [ { "start": [ 24, 30 ], "end": [ 24, 30 ] } ] }
[ "methicillin-resistant S. aureus", "MRSA" ]
BioASQ
A diverse collection of 261 Staphylococcus aureus strains from human, animal, food, and environmental sources were tested for the presence and type of SCCmec elements, antibiotic susceptibility to various antibiotics, and non-ß-lactam antibiotic resistance genes. About 18.39% (48/261) of strains were methicillin-resistant S. aureus (MRSA) including 29.75% (36/121) human strains of which 29 strains were hospital-acquired MRSA (HA-MRSA) and 7 strains were community-associated MRSA (CA-MRSA) and 19.67% (12/61) animal strains that all were CA-MRSA strains. The percentage of CA-MRSA strains from animals was significantly higher than that from human (p<0.01). Most of MRSA strains and a part of methicillin-susceptible S. aureus (MSSA) strains harbored unique combinations of non-ß-lactamase genes aac(6')/aph(2″), aph(3')-III, ant (4',4″), ermA, ermC, mrsA, tetM, and tetK. Antibiotic resistance genes were detected more frequently in HA-MRSA strains than in CA-MRSA strains (p<0.01). MRSA strains and MSSA strains had 22 and 39 antibiotic profiles to 15 tested antibiotics, respectively. The resistant proportion was higher in HA-MRSA strains than in CA-MSSA strains for various antibiotics, as well as higher in MRSA strains than in MSSA strains. Animal MRSA reservoirs (particularly pigs and cows) might represent an important source of human CA-MRSA. CA-MRSA strains might acquire more different resistance genes gradually, depending on the selective pressure of antibiotics in different regions or environments. CA-MRSA is not yet endemic in China, but could be prevalent in future, contributing to its acquiring more resistance genes and huge animal sources. Infection with multidrug-resistant MSSA strains acquired from food, animal, and human sources might also become a significant problem for human medicine, which warrants further study.
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bd18e4066acc45d0970dbce4a776702f
What is MRSA?
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[ "methicillin-resistant S. aureus", "MRSA" ]
BioASQ
CML (chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein. The disease starts in CP (chronic phase), but as a result of genomic instability, it progresses over time to accelerated phase and then to BC (blast crisis), becoming increasingly resistant to therapy. bcr-abl is a constitutively active tyrosine kinase that has been targeted by TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate), nilotinib and dasatinib. We have developed various flow cytometry techniques to enable us to isolate candidate CML stem cells from CP patients at diagnosis that efflux Hoechst dye, express CD34, lack CD38 and are cytokine-non-responsive in culture over periods of up to 12 days in growth factors. These stem cells have been shown to regenerate bcr-abl-positive haemopoiesis in immunocompromised mice upon transplantation. We previously demonstrated that IM was antiproliferative for CML stem cells but did not induce apoptosis. Clinical experience now confirms that IM may not target CML stem cells in vivo with few patients achieving complete molecular remission and relapse occurring rapidly upon drug withdrawal. Our recent efforts have focused on understanding why CML stem cells are resistant to IM and on trying to find novel ways to induce apoptosis of this population. We have shown that CML stem cells express very high levels of functional wild-type bcr-abl; no kinase domain mutations have been detected in the stem cell population. Dasatinib, a more potent multitargeted TKI than IM, inhibits bcr-abl activity more efficiently than IM but still does not induce apoptosis of the stem cell population. Most recently, we have tested a number of novel drug combinations and found that FTIs (farnesyl transferase inhibitors) have activity against CML. BMS-214662 is the most effective of these and induces apoptosis of phenotypically and functionally defined CML stem cells in vitro, as a single agent and in combination with IM or dasatinib. The effect against CML stem cells is selective with little effect on normal stem cells. The drug is also effective against BC CML stem cells and equally effective against wild-type and mutant bcr-abl, including the most resistant mutant T315I. In association with apoptosis, there is activation of caspase 8 and caspase 3, inhibition of the MAPK pathway, IAP-1 (inhibitor of apoptosis protein-1), NF-kappaB (nuclear factor kappaB) and iNOS (inducible nitric oxide synthase). Furthermore, BMS-214662 synergizes with MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors, suggesting a second mechanism other that RAS inhibition for induction of apoptosis. Our intentions are now to explore the activity of BMS-214662 in other cancer stem cell disorders and to move this preclinical work to a clinical trial combining dasatinib with BMS-214662 in CML.
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88390fb06cb44b229884042b868e9663
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
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{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 432, 1538, 2320, 209, 1683, 922 ], "end": [ 438, 1544, 2326, 215, 1689, 928 ] } ], "token_spans": [ { "start": [ 84, 278, 420, 39, 306, 175 ], "end": [ 86, 280, 422, 41, 308, 177 ] } ] }
[ "BCR-ABL" ]
BioASQ
Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
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29f2855a4f1e49cabf0d468c74465cb7
Mutations in which gene determine response to both erlotinib and gefitinib?
{ "tokens": [ "Mutations", "in", "which", "gene", "determine", "response", "to", "both", "erlotinib", "and", "gefitinib", "?" ], "offsets": [ 0, 10, 13, 19, 24, 34, 43, 46, 51, 61, 65, 74 ] }
{ "text": [ "epidermal growth factor receptor (EGFR) gene" ], "char_spans": [ { "start": [ 60 ], "end": [ 103 ] } ], "token_spans": [ { "start": [ 12 ], "end": [ 19 ] } ] }
[ "epidermal growth factor receptor (EGFR) gene" ]
BioASQ
Questions of if and when protein structures change within cells pervade biology and include questions of how the cytoskeleton sustains stresses on cells--particularly in mutant versus normal cells. Cysteine shotgun labeling with fluorophores is analyzed here with mass spectrometry of the spectrin-actin membrane skeleton in sheared red blood cell ghosts from normal and diseased mice. Sheared samples are compared to static samples at 37 °C in terms of cell membrane intensity in fluorescence microscopy, separated protein fluorescence, and tryptic peptide modification in liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spectrin labeling proves to be the most sensitive to shear, whereas binding partners ankyrin and actin exhibit shear thresholds in labeling and both the ankyrin-binding membrane protein band 3 and the spectrin-actin stabilizer 4.1R show minimal differential labeling. Cells from 4.1R-null mice differ significantly from normal in the shear-dependent labeling of spectrin, ankyrin, and band 3: Decreased labeling of spectrin reveals less stress on the mutant network as spectrin dissociates from actin. Mapping the stress-dependent labeling kinetics of α- and β-spectrin by LC-MS/MS identifies Cys in these antiparallel chains that are either force-enhanced or force-independent in labeling, with structural analyses indicating the force-enhanced sites are sequestered either in spectrin's triple-helical domains or in interactions with actin or ankyrin. Shear-sensitive sites identified comprehensively here in both spectrin and ankyrin appear consistent with stress relief through forced unfolding followed by cytoskeletal disruption.
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13e06194c39f4c6793d4a21daead187f
Alpha-spectrin and beta-spectrin subunits form parallel or antiparallel heterodimers?
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{ "text": [ "antiparallel" ], "char_spans": [ { "start": [ 1239 ], "end": [ 1250 ] } ], "token_spans": [ { "start": [ 214 ], "end": [ 214 ] } ] }
[ "antiparallel" ]
BioASQ
The new International League Against Epilepsy (ILAE) classification for focal cortical dysplasia (FCD) differentiates between patients with isolated FCD (type 1) and FCD with an associated hippocampal sclerosis (HS) (type 3a). In contrast to the former FCD classification by Palmini, which considered only histologic features, the novel ILAE classification also relies on magnetic resonance imaging (MRI) findings and presumed pathogenesis. We investigated in a cohort of 100 patients with exclusively temporal FCD if the new subdivision of FCD is reflected in clinical characteristics. Thirty-one patients with FCD type 1 and 50 patients with FCD type 3a in the temporal lobe were included. In all patients MRI and histology of the FCD were available. Both patient groups were compared to 19 patients with temporal FCD type 2 with clearly different histologic appearance. Patients with FCD type 1 and type 3a presented with similar clinical features in many respects. In univariate analyses, no statistically significant differences were found as to age at epilepsy onset (p = 0.07) and epilepsy surgery (p = 0.14), a normal appearing neocortical temporal lobe (p = 0.08) or diagnosis of FCD by visual inspection of MRI (p = 0.08), preoperative seizure frequency (p = 0.06), and the predominance of an epigastric aura (p = 0.08). The postoperative outcome was nearly identical 1 year (p = 0.8) and 2 (p = 0.8), 3 (p = 0.8), 5 (p = 0.7), and 8 (p = 1.0) years postoperatively. Only febrile seizures (p = 0.025) and an aura (p = 0.03) were significantly more frequently reported in patients with FCD type 3a. Similar results were obtained from a multivariate logistic regression analysis. Patients with FCD type 2 were more different: Compared to FCD type 3a, age at epilepsy surgery was significantly lower (p = 0.004) and auras (p = 0.005) were significantly less frequently reported. Epigastric auras (p = 0.04) and febrile seizures (p = 0.025) occurred significantly less frequently in patients with FCD type 2 without HS compared to FCD type 3a. The diagnosis of an FCD was significantly more frequently made (p = 0.03) by visual inspection of the MRI compared to FCD type 1. Clinical features did not allow to clear separation of temporal FCD types 1 and 3a. Statistically significant differences were seen in a history of febrile seizures and the occurrence of auras more common in FCD type 3a. However, FCD type 2 in the same localization but with different histology presented with further differences such as more frequent FCD diagnosis by visual inspection of MRI, earlier operation, and less frequent epigastric auras.
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b9e939ba9f2c4fa89af0a12d34b058f2
Which disorder is rated by Palmini classification?
{ "tokens": [ "Which", "disorder", "is", "rated", "by", "Palmini", "classification", "?" ], "offsets": [ 0, 6, 15, 18, 24, 27, 35, 49 ] }
{ "text": [ "focal cortical dysplasia" ], "char_spans": [ { "start": [ 72 ], "end": [ 95 ] } ], "token_spans": [ { "start": [ 11 ], "end": [ 13 ] } ] }
[ "focal cortical dysplasia" ]
BioASQ
Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor performance in a transgenic mouse model of spinocerebellar ataxia type 3. Temsirolimus inhibits mammalian target of rapamycin and hence upregulates protein degradation by autophagy. Temsirolimus reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. Temsirolimus is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 3. Using this disease model and treatment paradigm, we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin specific peptidase-15, which showed expression changes at both the messenger ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalized following temsirolimus treatment. In this mouse model with relatively mild disease progression, the number of transcripts changed was low and the magnitude of these changes was small. However, the importance of these transcriptional alterations in the pathogenesis of spinocerebellar ataxia type 3 remains unclear.
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179e834f3f064c7188755ef9596db9d9
Which is the protein implicated in Spinocerebellar ataxia type 3?
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{ "text": [ "Ataxin-3" ], "char_spans": [ { "start": [ 1547, 775, 132 ], "end": [ 1554, 782, 139 ] } ], "token_spans": [ { "start": [ 233, 117, 19 ], "end": [ 233, 117, 19 ] } ] }
[ "Ataxin-3" ]
BioASQ
Biallelic mutations of the DNA annealing helicase SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1) cause Schimke immuno-osseous dysplasia (SIOD, MIM 242900), an incompletely penetrant autosomal recessive disorder. Using human, Drosophila and mouse models, we show that the proteins encoded by SMARCAL1 orthologs localize to transcriptionally active chromatin and modulate gene expression. We also show that, as found in SIOD patients, deficiency of the SMARCAL1 orthologs alone is insufficient to cause disease in fruit flies and mice, although such deficiency causes modest diffuse alterations in gene expression. Rather, disease manifests when SMARCAL1 deficiency interacts with genetic and environmental factors that further alter gene expression. We conclude that the SMARCAL1 annealing helicase buffers fluctuations in gene expression and that alterations in gene expression contribute to the penetrance of SIOD.
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549c82a2fcb04e38a84c3f7661eeeaf0
Mutations in which gene cause Schimke immune-osseous dysplasia?
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{ "text": [ "SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1)" ], "char_spans": [ { "start": [ 50 ], "end": [ 153 ] } ], "token_spans": [ { "start": [ 7 ], "end": [ 30 ] } ] }
[ "HARP", "SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1", "SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1)" ]
BioASQ
Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder that can result in considerable sleep disruption. This narrative review provides an overview of RLS diagnosis and reports epidemiologic evidence for an association between RLS and mood disorders. Possible links between RLS, sleep disturbances, and mood disorders are considered, and theoretical pathophysiologic pathways are discussed. Finally, pharmacologic therapies for RLS are summarized. A PubMed search was performed using the search term restless legs syndrome in combination with affective/anxiety, antidepressants, anxiety/anxiety disorder, attention deficit hyperactivity disorder, depression/depressive disorder, mood/mood disorder, neuropsychiatric, panic/panic disorder, psychiatric disorder, and psychosis. English-language articles published between January 1993 and May 2013 were retrieved. Additional studies were identified from the reference lists of relevant publications. 173 publications were retrieved. Articles related to the association between idiopathic RLS and depression, anxiety, and mood disorders were reviewed. In total, 32 epidemiologic studies were identified. These studies were reviewed in detail and ranked according to quality. Data were extracted on the basis of relevance to the topic. Epidemiologic studies were assessed using 3 parameters: methodology, data quality, and generalizability of the results. Each factor was scored from 1 (high quality) to 4 (low quality), giving a total score of between 3 and 12 for each study. RLS and mood disorders are frequently comorbid. Recognition and appropriate treatment of comorbid RLS are particularly important in patients with psychiatric disorders, as RLS is a common medical reason for insomnia, and antidepressant use may exacerbate sensory symptoms.
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f69aed865e4f4461b59e86ff393595b6
Willis-Ekbom disease is also known as?
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{ "text": [ "Restless legs syndrome" ], "char_spans": [ { "start": [ 0, 538 ], "end": [ 21, 559 ] } ], "token_spans": [ { "start": [ 0, 88 ], "end": [ 2, 90 ] } ] }
[ "Restless legs syndrome" ]
BioASQ
Selenoprotein P (SeP) is an extracellular glycoprotein with 8-10 selenocysteines per molecule, containing approximately 50% of total selenium in human serum. An antioxidant function of SeP has been postulated. In the present study, we show that SeP protects low-density lipoproteins (LDL) against oxidation in a cell-free in-vitro system. LDL were isolated from human blood plasma and oxidized with CuCl2, 2,2'-azobis(2-amidinopropane) (AAPH) or peroxynitrite in the presence or absence of SeP, using the formation of conjugated dienes as parameter for lipid peroxidation. SeP delayed the CuCl2- and AAPH-induced LDL oxidation significantly and more efficiently than bovine serum albumin used as control. In contrast, SeP was not capable of inhibiting peroxynitrite-induced LDL oxidation. The protection of LDL against CuCl2- and AAPH-induced oxidation provides evidence for the antioxidant capacity of SeP. Because SeP associates with endothelial membranes, it may act in vivo as a protective factor inhibiting the oxidation of LDL by reactive oxygen species.
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bc72c59b993848e78839cf94591aaa7c
Which is the human selenoprotein that contains several Se-Cys residues?
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{ "text": [ "Selenoprotein P" ], "char_spans": [ { "start": [ 0 ], "end": [ 14 ] } ], "token_spans": [ { "start": [ 0 ], "end": [ 1 ] } ] }
[ "Selenoprotein P" ]
BioASQ
Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.
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3b79b6f68f774f36a9a24a3a0960be22
Which is the protein implicated in Spinocerebellar ataxia type 3?
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{ "text": [ "Ataxin-3" ], "char_spans": [ { "start": [ 206 ], "end": [ 213 ] } ], "token_spans": [ { "start": [ 35 ], "end": [ 35 ] } ] }
[ "Ataxin-3" ]
BioASQ
Parkinson's disease (PD) is a neurodegenerative disease with characteristics and symptoms that are well defined. Nevertheless, its aetiology remains unknown. PD is characterized by the presence of Lewy bodies inside neurons. α-Synuclein (α-syn) is a soluble protein present in the pre-synaptic terminal of neurons. Evidence suggests that α-syn has a fundamental role in PD pathogenesis, given that it is an important component of Lewy bodies localized in the dopaminergic neurons of PD patients. In the present study, we investigated the influence of wild type (WT) and A30P α-syn overexpression on neuroblastoma SH-SY5Y toxicity induced by the conditioned medium (CM) from primary cultures of glia challenged with lipopolysaccharide (LPS) from Escherichia coli. We observed that SH-SY5Y cells transduced with α-syn (WT or A30P) and treated with CM from LPS-activated glia cells show evidence of cell death, which is not reverted by NF-κB inhibition by sodium salicylate or by blockage of P50 (NF-κB subunit). Furthermore, the expression of A30P α-syn in neuroblastoma SH-SY5Y decreases the cell death triggered by the CM of activated glia versus WT α-syn or control group. This effect of A30P α-syn may be due to the low MAPK42/44 phosphorylation. This finding is substantiated by MEK1 inhibition by PD98059, decreasing LDH release by CM in SH-SY5Y cells. Our results suggest that SH-SY5Y cells transduced with α-syn (WT or A30P) and treated with CM from LPS-activated glia cells show cell death, which is not reverted by NF-κB blockage. Additionally, the expression of A30P α-syn on neuroblastoma SH-SY5Y leads to decreased cell death triggered by the CM of activated glia, when compared to WT α-syn or control group. The mechanism underlying this process remains to be completely elucidated, but the present data suggest that MAPK42/44 phosphorylation plays an important role in this process. CRD42015020829.
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770cdf4bff11453d9e85c2d6c5857367
Which is the primary protein component of Lewy bodies?
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{ "text": [ "α-synuclein" ], "char_spans": [ { "start": [ 225 ], "end": [ 235 ] } ], "token_spans": [ { "start": [ 38 ], "end": [ 40 ] } ] }
[ "alpha-synuclein", "α-synuclein", "αSyn" ]
BioASQ
Chaperone-mediated autophagy (CMA) is a selective form of autophagy whose distinctive feature is the fact that substrate proteins are translocated directly from the cytosol across the lysosomal membrane for degradation inside lysosomes. CMA substrates are cytosolic proteins bearing a pentapeptide motif in their sequence that, when recognized by the cytosolic chaperone HSPA8/HSC70, targets them to the surface of the lysosomes. Once there, substrate proteins bind to the lysosome-associated membrane protein type 2 isoform A (LAMP2A), inducing assembly of this receptor protein into a higher molecular weight protein complex that is used by the substrate proteins to reach the lysosomal lumen. CMA is constitutively active in most cells but it is maximally activated under conditions of stress.
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00514408a6c643d68ffbd2cf86d20e0e
Which is the receptor for substrates of Chaperone Mediated Autophagy?
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{ "text": [ "LAMP2A" ], "char_spans": [ { "start": [ 528 ], "end": [ 533 ] } ], "token_spans": [ { "start": [ 86 ], "end": [ 86 ] } ] }
[ "LAMP2A", "Lysosome-associated membrane protein 2 isoform A" ]
BioASQ
Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders. Gastrointestinal manifestations in EDS have been described but their frequency, nature and impact are poorly known. We aimed to assess digestive features in a national cohort of EDS patients. A questionnaire has been sent to 212 EDS patients through the French patient support group, all of which had been formally diagnosed according to the Villefranche criteria. The questionnaire included questions about digestive functional symptoms, the GIQLI (Gastrointestinal Quality of Life Index), KESS scoring system and the Rome III criteria. Overall, 135 patients (64% response rate) completed the questionnaire and 134 were analyzable (123 women; 91%). Mean age and Body Mass Index were respectively 35±14.7 years and 24.3±6.1 kg/m(2). The most common EDS subtype was hypermobility form (n=108; 80.6%). GIQLI and KESS median values were respectively 63.5 (27-117) and 19 [13.5-22]. Eighty four percent of patients had functional bowel disorders (FBD) according to the Rome III criteria. An irritable bowel syndrome according to the same criteria was observed in 64 patients (48%) and 48 patients (36%) reported functional constipation. A gastro-esophageal reflux disease (GERD) was reported in 90 patients (68.7%), significantly associated with a poorer GIQLI (60.5±16.8 versus 75.9±20.3; p<0.0001). GIQLI was also negatively impacted by the presence of an irritable bowel syndrome or functional constipation (p=0.007). There was a significant correlation between FBD and GERD. Natural frequency of gastrointestinal manifestations in EDS seems higher than previously assessed. FBD and GERD are very common in our study population, the largest ever published until now. Their impact is herein shown to be important. A systematic clinical assessment of digestive features should be recommended in EDS.
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922ae9318d264f8ea1e929e98b4bbe0b
What tissue is most affected in Ehlers-Danlos syndromes?
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{ "text": [ "connective tissue" ], "char_spans": [ { "start": [ 69 ], "end": [ 85 ] } ], "token_spans": [ { "start": [ 13 ], "end": [ 14 ] } ] }
[ "connective tissue" ]
BioASQ
3-Methyladenine DNA glycosylase II (AlkA) is a DNA-repair enzyme that removes alkylated bases in DNA via the base-excision repair (BER) pathway. The enzyme belongs to the helix-hairpin-helix (HhH) superfamily of DNA glycosylases and possesses broad substrate specificity. In the genome of Deinococcus radiodurans, two genes encoding putative AlkA have been identified (Dr_2074 and Dr_2584). Dr_2074 is a homologue of human AlkA (MPG or AAG) and Dr_2584 is a homologue of bacterial AlkAs. Here, the three-dimensional structure of Dr_2584 (DrAlkA2) is presented and compared with the previously determined structure of Escherichia coli AlkA (EcAlkA). The results show that the enzyme consists of two helical-bundle domains separated by a wide DNA-binding cleft and contains an HhH motif. Overall, the protein fold is similar to the two helical-bundle domains of EcAlkA, while the third N-terminal mixed α/β domain observed in EcAlkA is absent. Substrate-specificity analyses show that DrAlkA2, like EcAlkA, is able to remove both 3-methyladenine (3meA) and 7-methylguanine (7meG) from DNA; however, the enzyme possesses no activity towards 1,N(6)-ethenoadenine (ℇA) and hypoxanthine (Hx). In addition, it shows activity towards the AlkB dioxygenase substrates 3-methylcytosine (3meC) and 1-methyladenine (1meA). Thus, the enzyme seems to preferentially repair methylated bases with weakened N-glycosidic bonds; this is an unusual specificity for a bacterial AlkA protein and is probably dictated by a combination of the wide DNA-binding cleft and a highly accessible specificity pocket.
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250caa665c8448fb98e285306f80e63e
What type of DNA repair pathways is initiated by AlkA glycosylase?
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{ "text": [ "base excision repair (BER) pathway" ], "char_spans": [ { "start": [ 109 ], "end": [ 142 ] } ], "token_spans": [ { "start": [ 21 ], "end": [ 28 ] } ] }
[ "base-excision repair (BER) pathway", "base excision repair (BER) pathway" ]
BioASQ
Two forms of the inherited long QT syndrome have been known for many years: the autosomal recessive Jervell and Lange-Nielsen form and the autosomal dominant Romano-Ward form. A gene marker at the 11p 15.5 locus has been identified for some, but not all, families with the autosomal dominant form, but as yet the gene has not been identified. It is apparent that mutations of at least four genes, and possibly more, can cause the syndrome. The molecular biology of the syndrome is not yet clarified, but abnormalities of ion channel function are likely, particularly the potassium delayed rectifier current. Proposals for the pathophysiology include an abnormality of a G protein which controls ion channel and adrenergic pathway function, as well as a disturbance of the sympathetic nervous system. The identification of the abnormal gene(s) and the gene products will provide precise information on the molecular physiology of the syndrome.
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83d7f282309948759aa19ff5ddcdd45c
What is the mode of inheritance of Romano Ward long QT syndrome?
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{ "text": [ "autosomal dominant" ], "char_spans": [ { "start": [ 139, 273 ], "end": [ 156, 290 ] } ], "token_spans": [ { "start": [ 26, 54 ], "end": [ 27, 55 ] } ] }
[ "autosomal dominant" ]
BioASQ
Diurnal effects on motor control are evident in the human disease of Restless Leg Syndrome (RLS), which is purported to be linked to brain iron deficiency as well as alterations in dopaminergic systems. Thus, we explored the relationship between daily rhythms, the onset of motor dysregulation and brain iron deficiency in an animal model of iron deficiency. Male and female weanling Sprague-Dawley rats consuming control (CN) or iron-deficient (ID) diets were examined weekly for acoustic startle response (ASR) and prepulse inhibition (PPI) for a 5-week period. Iron deficiency reduced the magnitude, but not timing, of the ASR at specific time points. ASR was elevated 60% at the onset of the dark cycle relative to the median of the light cycle in male CN and ID rats. The respective elevation was 400% and 150% in female CN and ID rats during the first 2 weeks of testing. The diurnal cycle of ASR response was attenuated by 3 weeks of testing in both dietary treatment groups. PPI was not affected by iron deficiency, sex, diurnal cycle or the interaction between these factors. These results thus demonstrate that iron deficiency moderately alters ASR signaling although the inhibitory pathways of ASR do not appear to be affected.
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e001a3c4b9fb42529a630cc6884b137b
Which deficiency is the cause of restless leg syndrome?
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{ "text": [ "iron" ], "char_spans": [ { "start": [ 139, 342, 564, 304, 1007, 1121, 430 ], "end": [ 142, 345, 567, 307, 1010, 1124, 433 ] } ], "token_spans": [ { "start": [ 27, 61, 106, 54, 198, 217, 78 ], "end": [ 27, 61, 106, 54, 198, 217, 78 ] } ] }
[ "iron" ]
BioASQ
Chronic Myeloid Leukemia (CML) has always been an ideal model to understand the molecular pathogenesis of human leukaemias and the way to cure them. This can be ascribed to the fact that CML was the first human cancer demonstrated to be strongly associated to the presence of a recurrent chromosomal translocation (the t(9;22)(q34;q11) that creates the Philadelphia (Ph)-chromosome) and to a specific molecular defect, the formation of a hybrid BCR-ABL gene that generates new fusion proteins endowed with a constitutive tyrosine-kinase (TK) activity, strongly implicated in the pathogenesis of the disease. The introduction into clinical practice of imatinib, (Glivec, Gleevec, Novartis), a potent tyrosine kinase inhibitor of the Bcr-Abl protein as well as of a restricted number of other TKs, has not only produced a substantial improvement in the treatment of CML, but represents a major break-through in the perspective of opening a new era, that of molecularly targeted therapy, in the management of other types of leukemia, lymphoma and cancer in general.
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097ccc6aa9ba4a0fb9739ed812f2180b
What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?
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{ "text": [ "BCR-ABL" ], "char_spans": [ { "start": [ 445, 732 ], "end": [ 451, 738 ] } ], "token_spans": [ { "start": [ 77, 130 ], "end": [ 79, 132 ] } ] }
[ "BCR-ABL" ]
BioASQ
Ca2+ is a ubiquitous intracellular messenger responsible for controlling numerous cellular processes including fertilization, mitosis, neuronal transmission, contraction and relaxation of muscles, gene transcription, and cell death. At rest, the cytoplasmic Ca2+ concentration [Ca2+]i is approximately 100 nM, but this level rises to 500-1,000 nM upon activation. In osteoblasts, the elevation of [Ca2+]i is a result of an increase in the release of Ca2+ from endoplasmic reticulum and/or extracellular Ca2+ influx through voltage gated Ca2+ channels. Many of the cellular effects of Ca2+ are mediated by the Ca2+ binding protein, calmodulin (CaM). Upon binding up to four calcium ions, CaM undergoes a conformational change, which enables it to bind to specific proteins eliciting a specific response. Calmodulin kinase II (CaMKII) is a major target of the Ca(2+)/CaM second messenger system. Once bound to Ca(2+)/CaM, the multimeric CaMKII is released from its autoinhibitory status and maximally activated, which then leads to an intraholoenzyme autophosphorylation reaction. Calcineurin (Cn) is another major target protein that is activated by Ca(2+)/CaM. Cn is a serine-threonine phosphatase that consists of a heterodimeric protein complex composed of a catalytic subunit (CnA) and a regulatory subunit (CnB). Upon activation, Cn directly binds to, and dephosphorylates nuclear factor of activated T cells (NFAT) transcription factors within the cytoplasm allowing them to translocate to the nucleus and participate in the regulation of gene expression. This review will examine the potential mechanisms by which calcium, CaM, CaMKII, and Cn/NFAT control osteoblast proliferation and differentiation.
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4739d60b47ce43b3a2834c15aa922cab
Which calcium/calmodulin dependent protein phosphatase is involved in the activation of the family of NFAT transcription factors (Nuclear Factors of Activated T cells)?
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{ "text": [ "Calcineurin" ], "char_spans": [ { "start": [ 1079 ], "end": [ 1089 ] } ], "token_spans": [ { "start": [ 189 ], "end": [ 189 ] } ] }
[ "Calcineurin", "CaN", "phosphatase 2b" ]
BioASQ
Cells respond to stresses such as osmotic shock and heat shock by activating stress-activated protein kinases (SAPKs), including c-Jun N-terminal kinase (JNK) [1]. Activation of JNK requires phosphorylation of threonine and tyrosine residues in the TPY activation loop motif [2, 3] and can be reversed by the removal of either phosphate group. Numerous JNK phosphatases including dual-specificity phosphatases [4, 5], have been identified. Many stimuli activate JNK by increasing its rate of phosphorylation; however, JNK dephosphorylation is inhibited in cells after heat shock [6], suggesting that a JNK phosphatase(s) is inactivated. M3/6 is a dual-specificity phosphatase selective for JNK [7, 8]. We have previously expressed M3/6 in the mouse bone marrow cell line BAF3 in order to show that JNK activation by IL-3 is necessary for cell survival and proliferation [9]. Here we report that M3/6 dissociates from JNK and appears in an insoluble fraction after heat shock. These data identify M3/6 as a JNK phosphatase that is inactivated by heat shock and provide a molecular mechanism for the activation of JNK by heat shock.
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902996f009de41b18ed94ad607438522
Which protein is affected by dusp8 activation?
{ "tokens": [ "Which", "protein", "is", "affected", "by", "dusp8", "activation", "?" ], "offsets": [ 0, 6, 14, 17, 26, 29, 35, 45 ] }
{ "text": [ "JNK" ], "char_spans": [ { "start": [ 178, 353, 518, 602, 917, 462, 798, 1006, 690, 154, 1112 ], "end": [ 180, 355, 520, 604, 919, 464, 800, 1008, 692, 156, 1114 ] } ], "token_spans": [ { "start": [ 37, 69, 99, 115, 173, 89, 153, 190, 130, 31, 207 ], "end": [ 37, 69, 99, 115, 173, 89, 153, 190, 130, 31, 207 ] } ] }
[ "JNK" ]
BioASQ
Differentiation of cancer stem cells (CSCs) into cancer cells causes increased sensitivity to chemotherapeutic agents. Although inhibition of mammalian target of rapamycin (mTOR) leads to CSC survival, the effect of branched chain amino acids (BCAAs), an mTOR complex 1 (mTORC1) activator remains unknown. In this study, we examined the effects of BCAA on hepatocellular carcinoma (HCC) cells expressing a hepatic CSC marker, EpCAM. We examined the effects of BCAA and/or 5-fluorouracil (FU) on expression of EpCAM and other CSC-related markers, as well as cell proliferation in HCC cells and in a xenograft mouse model. We also characterized CSC-related and mTOR signal-related molecule expression and tumorigenicity in HCC cells with knockdown of Rictor or Raptor, or overexpression of constitutively active rheb (caRheb). mTOR signal-related molecule expression was also examined in BCAA-treated HCC cells. In-vitro BCAA reduced the frequency of EpCAM-positive cells and improved sensitivity to the anti-proliferative effect of 5-FU. Combined 5-FU and BCAA provided better antitumor efficacy than 5-FU alone in the xenograft model. Stimulation with high doses of BCAA activated mTORC1. Knockdown and overexpression experiments revealed that inhibition of mTOR complex 2 (mTORC2) or activation of mTORC1 led to decreased EpCAM expression and little or no tumorigenicity. BCAA may enhance the sensitivity to chemotherapy by reducing the population of cscs via the mTOR pathway. This result suggests the utility of BCAA in liver cancer therapy.
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0720cc54f299433bb58ec7af596a77c9
What does mTOR stands for?
{ "tokens": [ "What", "does", "mTOR", "stands", "for", "?" ], "offsets": [ 0, 5, 10, 15, 22, 25 ] }
{ "text": [ "mammalian target of rapamycin" ], "char_spans": [ { "start": [ 142 ], "end": [ 170 ] } ], "token_spans": [ { "start": [ 21 ], "end": [ 24 ] } ] }
[ "mammalian target of rapamycin" ]
BioASQ
Trimethylation of histone H3 Lys4 (H3K4) is associated with transcriptional activation. One of the chief effectors of H3K4 methylation is mixed-lineage leukemia 1 (MLL1), a gene that is disrupted by chromosomal translocation in acute leukemia and a master regulator of Hox and other genes. In a recent paper, core components of the human MLL histone methyltransferase (MT) complex were found to form a structural platform, with one component (WDR5) mediating association between the specific histone H3K4 substrate and the MT. This novel regulatory mechanism, which is conserved from yeast to human, is required for both methylation and downstream target gene transcription.
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f5a528ae5c1742e2a05b03ecd56fb554
Which is the histone residue methylated by MLL1?
{ "tokens": [ "Which", "is", "the", "histone", "residue", "methylated", "by", "MLL1", "?" ], "offsets": [ 0, 6, 9, 13, 21, 29, 40, 43, 47 ] }
{ "text": [ "H3K4" ], "char_spans": [ { "start": [ 118, 500, 35 ], "end": [ 121, 503, 38 ] } ], "token_spans": [ { "start": [ 20, 90, 6 ], "end": [ 20, 90, 6 ] } ] }
[ "H3K4" ]
BioASQ
In the last few years, several tyrosine kinase inhibitors (TKIs) have been synthesized and become available for preclinical studies and clinical trials. This article summarizes recent achievements in the mechanism of action, pharmacological properties, and clinical activity and toxicity, as well as the emerging role of TKIs in lymphoid malignancies, allergic diseases, and autoimmune disorders. A literature review was conducted of the MEDLINE database PubMed for articles in English. Publications from 2000 through January 2012 were scrutinized. The search terms used were Bruton's tyrosine kinase (Btk) inhibitors, PCI-32765, GDC-0834, LFM-A13, AVL-101, AVL-292, spleen tyrosine kinase (Syk) inhibitors, R343, R406, R112, R788, fostamatinib, BAY-61-3606, C-61, piceatannol, Lyn, imatinib, nilotinib, bafetinib, dasatinib, GDC-0834, PP2, SU6656 in conjunction with lymphoid malignancy, NHL, CLL, autoimmune disease, allergic disease, asthma, and rheumatoid arthritis. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. The use of TKIs, especially inhibitors of Btk, Syk, and Lyn, is a promising new strategy for targeted treatment of B-cell lymphoid malignancies, autoimmune disorders and allergic diseases. However, definitive data from ongoing and future clinical trials will aid in better defining the status of TKIs in the treatment of these disorders.
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fab303bb445f49959138cf04ba36638a
Which enzyme is inhibited by a drug fostamatinib?
{ "tokens": [ "Which", "enzyme", "is", "inhibited", "by", "a", "drug", "fostamatinib", "?" ], "offsets": [ 0, 6, 13, 16, 26, 29, 31, 36, 48 ] }
{ "text": [ "spleen tyrosine kinase" ], "char_spans": [ { "start": [ 667 ], "end": [ 688 ] } ], "token_spans": [ { "start": [ 115 ], "end": [ 117 ] } ] }
[ "spleen tyrosine kinase" ]
BioASQ
In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.
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59303c35c98b49d191c1a3ae65d248b9
Which drug should be used as an antidote in benzodiazepine overdose?
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{ "text": [ "flumazenil" ], "char_spans": [ { "start": [ 564, 1497, 133, 1266, 263, 1400, 1070, 335, 731 ], "end": [ 573, 1506, 142, 1275, 272, 1409, 1079, 344, 740 ] } ], "token_spans": [ { "start": [ 107, 285, 22, 246, 44, 268, 209, 62, 143 ], "end": [ 107, 285, 22, 246, 44, 268, 209, 62, 143 ] } ] }
[ "flumazenil" ]
BioASQ
Restless legs syndrome (RLS) is a clinically important, common disease and should be diagnosed and treated early and adequately. At present, there have been no clinical biomarkers or methodologies that can contribute to the correct diagnosis of RLS, RLS should be diagnosed on the basis of 4 essential criteria: urge to move the legs, improvement after movement, and worsening or occurrence of symptoms in the evening and at rest. When applying the criteria, RLS mimics should be ruled out and comorbid diseases should be taken into account. The origin and pathogenesis of RLS are still under investigation; however, iron deficiency in the brain has been observed on imaging and cerebrospinal fluid analyses of patients with RLS. In contrast, the results of neuroimaging studies evaluating brain dopaminergic functions in patients with RLS have yielded inconclusive results, although involvement of the hypothalamus (A11) is thought to cause impaired dopaminergic modulation in the dorsal horn and intermediolateral nucleus, resulting in the restlessness of legs.
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f86ef5e1ac664cb0a799f69a2e54f94d
Which deficiency is the cause of restless leg syndrome?
{ "tokens": [ "Which", "deficiency", "is", "the", "cause", "of", "restless", "leg", "syndrome", "?" ], "offsets": [ 0, 6, 17, 20, 24, 30, 33, 42, 46, 54 ] }
{ "text": [ "iron" ], "char_spans": [ { "start": [ 617 ], "end": [ 620 ] } ], "token_spans": [ { "start": [ 112 ], "end": [ 112 ] } ] }
[ "iron" ]
BioASQ
The Ehlers-Danlos syndrome encompasses a group of hereditary disorders of the connective tissue, characterized by hyperextensible skin, joint hypermobility; and varying degrees of vessel and tissue fragility. The main forms are classical, hypermobile, vascular, kyphoscoliotic A/B, arthrochalasis A/B and dermatosparaxis types. We report our experience in diagnosis and classification of Ehlers-Danlos-syndrome, especially with the combination of clinical and morphological criteria, at the Department of Dermatology of the University of Heidelberg with more than 600 patients between 1984 and 2004. We classified those types of EDS which are characterized by regular and characteristic ultrastructural changes in the dermal components, primarily collagen, including the classical, hypermobile and vascular types as well as the less-common arthrochalasis and dermatosparaxis types. The combination of clinical and morphologic features facilitates the selection of candidate genes for molecular genetic investigation. Besides the skin, skeleton and vessels, many other organ systems such as eyes and intestine, can be affected in Ehlers-Danlos syndrome. Accordingly, interdisciplinary cooperation (pediatrics, surgery, orthopedics, rheumatology, neurology, genetics) is necessary. As the connective tissue of the skin is accessible for biopsy and diagnostic investigation, dermatologists should be trained in the diagnostic approach and classification of this syndrome.
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93c9b82b1f4f4d52ac7e695d7d49694e
What tissue is most affected in Ehlers-Danlos syndromes?
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{ "text": [ "connective tissue" ], "char_spans": [ { "start": [ 78, 1287 ], "end": [ 94, 1303 ] } ], "token_spans": [ { "start": [ 13, 211 ], "end": [ 14, 212 ] } ] }
[ "connective tissue" ]
BioASQ
SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1), also known as HARP, is an ATP-dependent annealing helicase that stabilizes replication forks during DNA damage. Mutations in this gene are the cause of Schimke immune-osseous dysplasia (SIOD), an autosomal recessive disorder characterized by T-cell immunodeficiency and growth dysfunctions. In this review, we summarize the main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress.
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94ca9bf4ee72459085a2b6464d531562
Mutations in which gene cause Schimke immune-osseous dysplasia?
{ "tokens": [ "Mutations", "in", "which", "gene", "cause", "Schimke", "immune", "-", "osseous", "dysplasia", "?" ], "offsets": [ 0, 10, 13, 19, 24, 30, 38, 44, 45, 53, 62 ] }
{ "text": [ "SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1)", "HARP" ], "char_spans": [ { "start": [ 0 ], "end": [ 103 ] }, { "start": [ 121 ], "end": [ 124 ] } ], "token_spans": [ { "start": [ 0 ], "end": [ 20 ] }, { "start": [ 26 ], "end": [ 26 ] } ] }
[ "SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1)", "HARP" ]
BioASQ
CpG dinucleotides provide hotspots for transitional mutations in a variety of genes, some leading to genetic diseases in humans. Although this phenomenon is attributed to cytosine methylation at such sites, direct and specific observations of CpG methylation at the sites of recurrent mutations are lacking. We have used a bisulfite genomic sequencing method to analyze DNA methylation within three representative exons from the neurofibromatosis type 1 (NF1) gene, well recognized for its high frequency of spontaneous mutations. We observed that the cytosine methylation within NF1 exons 28, 29, and 31 is restricted to CpG dinucleotides, including the CpG dinucleotide present at the site of the recurrent NF1 mutation (C5839T; also referred to as R1947X). At several sites, clone-specific methylation differences were also observed. Our results provide experimental evidence for the hypothesis that methylatable CpGs in the NF1 gene contribute to spontaneous germline mutations associated with this gene, by showing that DNA methylation does occur at all CpGs contained within these representative NF1 exons. As well, the DNA methylation seen at the common mutation site in exon 31 may explain why this site is frequently mutated. Methylation-dependent mutagenesis may also provide a basis for some somatic (second hit) mutations which disable the normal allele and result in the development of NF1 associated symptoms.
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6246c07c53fc4659a83f4955f195a4be
Which is the gene mutated in type 1 neurofibromatosis?
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{ "text": [ "NF1" ], "char_spans": [ { "start": [ 709, 1399, 1102, 580, 928, 455 ], "end": [ 711, 1401, 1104, 582, 930, 457 ] } ], "token_spans": [ { "start": [ 117, 237, 182, 92, 156, 71 ], "end": [ 117, 237, 182, 92, 156, 71 ] } ] }
[ "NF1" ]
BioASQ
The methylation of lysine residues of histones plays a pivotal role in the regulation of chromatin structure and gene expression. Here, we report two crystal structures of SET7/9, a histone methyltransferase (HMTase) that transfers methyl groups to Lys4 of histone H3, in complex with S-adenosyl-L-methionine (AdoMet) determined at 1.7 and 2.3 A resolution. The structures reveal an active site consisting of: (i) a binding pocket between the SET domain and a c-SET helix where an AdoMet molecule in an unusual conformation binds; (ii) a narrow substrate-specific channel that only unmethylated lysine residues can access; and (iii) a catalytic tyrosine residue. The methyl group of AdoMet is directed to the narrow channel where a substrate lysine enters from the opposite side. We demonstrate that SET7/9 can transfer two but not three methyl groups to unmodified Lys4 of H3 without substrate dissociation. The unusual features of the SET domain-containing HMTase discriminate between the un- and methylated lysine substrate, and the methylation sites for the histone H3 tail.
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56ed50d7657b481ea0e2512c19bb0438
What is the characteristic domain of histone methyltransferases?
{ "tokens": [ "What", "is", "the", "characteristic", "domain", "of", "histone", "methyltransferases", "?" ], "offsets": [ 0, 5, 8, 12, 27, 34, 37, 45, 63 ] }
{ "text": [ "SET domain" ], "char_spans": [ { "start": [ 443, 937 ], "end": [ 452, 946 ] } ], "token_spans": [ { "start": [ 85, 176 ], "end": [ 86, 177 ] } ] }
[ "SET domain" ]
BioASQ
Bone pain is a common symptom in bone metastases. The therapies that are currently available include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, steroids and gabapentin which have been demonstrated to improve neuropathic pain. In addition, preclinical studies indicate that agents such as transient receptor potential vanilloid 1 antagonists and cannabinoid 2 receptor agonist could be considered as adjuncts in ameliorating opioid side effects. New drugs are in the clinical phase of development, among which the most promising molecules seem to be anti-nerve growth factor (NGF) antibodies. Anti-NGF antibody therapy may be particularly effective in blocking bone cancer pain because NGF appears to be integrally involved in the upregulation, sensitization and disinhibition of multiple neurotransmitters, ion channels and receptors in the primary afferent nerve. The best way to treat bone metastases pain is to improve the control of skeletal disease burden. Recently, denosumab, a noncytotoxic IgG2 monoclonal antibody with high affinity for human RANKL, has been demonstrated to significantly prevent clinically relevant increase in pain compared with zoledronic acid across the tumor types. Based on these data, it has been suggested that denosumab has the potential to become a new standard of treatment in bone metastases management.
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19f21e68fc4946c181d7758601dee5d5
To the ligand of which receptors does Denosumab (Prolia) bind?
{ "tokens": [ "To", "the", "ligand", "of", "which", "receptors", "does", "Denosumab", "(", "Prolia", ")", "bind", "?" ], "offsets": [ 0, 3, 7, 14, 17, 23, 33, 38, 48, 49, 55, 57, 61 ] }
{ "text": [ "RANKL" ], "char_spans": [ { "start": [ 1065 ], "end": [ 1069 ] } ], "token_spans": [ { "start": [ 175 ], "end": [ 175 ] } ] }
[ "RANKL" ]
BioASQ
Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by alpha-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in alpha-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in alpha-synuclein transgenic mice. By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying alpha-synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural analysis revealed the presence of abundant and abnormal autophagosomes. Similar alterations were observed in the brains of alpha-synuclein transgenic mice. Intra-cerebral infusion of rapamycin, an inhibitor of mTor, or injection of a lentiviral vector expressing Atg7 resulted in reduced accumulation of alpha-synuclein in transgenic mice and amelioration of associated neurodegenerative alterations. This study supports the notion that defects in the autophagy pathway and more specifically in mTor and Atg7 are associated with neurodegeneration in DLB cases and alpha-synuclein transgenic models and supports the possibility that modulators of the autophagy pathway might have potential therapeutic effects.
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2fa17a29be5d4cdb8b61ce90ede60e4a
Which disease of the central nervous system is characterized by the presence of Lewy bodies?
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{ "text": [ "Parkinson's disease (PD)" ], "char_spans": [ { "start": [ 170 ], "end": [ 192 ] } ], "token_spans": [ { "start": [ 26 ], "end": [ 30 ] } ] }
[ "Parkinson's disease (PD)" ]
BioASQ
Histone methyltransferase (HMT)(1) class enzymes that methylate lysine residues of histones or proteins contain a conserved catalytic core termed the SET domain, which shares sequence homology with an independently described sequence motif, the PR domain. Intact PR or SET sequence is required for tumor suppression functions, but it remains unclear whether it is histone methyltransferase activity that underlies tumor suppression. We now show that tumor suppressor RIZ1 (PRDM2) methylates histone H3 on lysine 9, and this activity is reduced by mutations in the PR domain found in human cancers. Also, S-adenosylhomocysteine or methyl donor deficiency inhibits RIZ1 and other H3 lysine 9 methylation activities. These results support the hypothesis that H3 lysine 9 methylation activities of a PR/SET domain have tumor suppression functions and may underlie carcinogenesis associated with dietary methyl donor deficiency.
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bf7e56357754453da53cec3c83cb7ef2
What is the characteristic domain of histone methyltransferases?
{ "tokens": [ "What", "is", "the", "characteristic", "domain", "of", "histone", "methyltransferases", "?" ], "offsets": [ 0, 5, 8, 12, 27, 34, 37, 45, 63 ] }
{ "text": [ "SET domain" ], "char_spans": [ { "start": [ 150, 799 ], "end": [ 159, 808 ] } ], "token_spans": [ { "start": [ 22, 134 ], "end": [ 23, 135 ] } ] }
[ "SET domain" ]
BioASQ
Dapivirine, a non-nucleoside reverse transcriptase inhibitor, is a potent and promising anti-HIV molecule. It is currently being investigated for use as a vaginal microbicide in two dosage forms, a semi-solid gel and a silicone elastomer ring. Quick-dissolving films are promising and attractive dosage forms that may provide an alternative platform for the vaginal delivery of microbicide drug candidates. Vaginal films may provide advantages such as discreet use, no product leakage during use, lack of requirement for an applicator for insertion, rapid drug release and minimal packaging and reduced wastage. Within this study the in vitro bioactivity of dapivirine as compared to the NNRTI UC781 was further established and a quick dissolve film was developed for vaginal application of dapivirine for prevention of HIV infection. The developed film was characterized with respect to its physical and chemical attributes including water content, mechanical strength, drug release profile, permeability, compatibility with lactobacilli and bioactivity. The anti-HIV activity of the formulated dapivirine film was confirmed in in vitro and ex vivo models. Importantly the physical and chemical properties of the film as well as its bioactivity were maintained for a period of 18 months. In conclusion, a vaginal film containing dapivirine was developed and characterized. The film was shown to prevent HIV-1 infection in vitro and ex vivo and have acceptable characteristics which make this film a promising candidate for testing as vaginal microbicide.
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74501bd3f1354fecae7e54e935faa3e9
Which infection can be prevented with Dapivirine?
{ "tokens": [ "Which", "infection", "can", "be", "prevented", "with", "Dapivirine", "?" ], "offsets": [ 0, 6, 16, 20, 23, 33, 38, 48 ] }
{ "text": [ "HIV" ], "char_spans": [ { "start": [ 820, 93, 1065 ], "end": [ 822, 95, 1067 ] } ], "token_spans": [ { "start": [ 140, 17, 178 ], "end": [ 140, 17, 178 ] } ] }
[ "HIV" ]