tbuckley/cabot-search huggingface dataset:
Abstract 2547: Targeted sequencing of 5p15 locus defined by non-small cell lung cancer (NSCLC) GWAS using next-generation sequencing.
Authors: Zhaoxi Wang, Yang Zhao, Li Su, Seunggeun Lee, Xihong Lin, David C. Christiani
Journal: Cancer Research (2013)

Recent genome-wide association studies (GWAS) have identified genetic loci associated with lung cancer risk. Direct sequencing is regarded as the ultimate approach for moving beyond genetic mapping to identify causal mutations and define disease candidate genes. We conducted a pilot next-generation sequencing (NGS) of all exons of TERT and CLPTM1L genes within the 5p15 locus from our NSCLC GWAS, replicating previous studies. We performed an amplicon capture-NGS on 138 samples, including 82 NSCLC cases and 56 controls. These results were highly consistent across samples, with the majority covering 85-95% of bases at 100-fold and with only 5 samples failing to achieve 100-fold coverage for at least 80% of bases. We identified 11 SNPs in TERT and 5 SNPs in CLPTM1L. Using our SKAT/SKAT-O method, we found that both genes were associated with NSCLC (TERT, p=0.006; and CLPTM1L, p=0.04). When the SNPs of the two genes were combined, we saw a greater joint effect (p=0.001). In a subgroup analysis focusing on functional SNPs, including 7 and 4 nonsynonymous SNPs in TERT and CLPTM1L, respectively, we found a stronger association with TERT (p=0.0005), as well as an increased joint effect (p=0.0001). Moreover, none of the sequenced subjects had functional SNPs in both TERT and CLPTM1L genes. Furthermore, most nonsynonymous variations seemed clustered either in the cases or in the controls. Bioinformatic annotation of these nonsynonymous SNPs revealed that those clustered in the controls had only benign effects on the encoded protein, whereas those overrepresented in the NSCLC cases had possible damage to the encoded protein. Using Sanger dideoxy-terminator sequencing at an independent core facility and Taqman genotyping, all of the 11 functional SNPs identified by amplicon capture-NGS were confirmed. In summary, the results seem to support the hypotheses that aggregated functional variations, but not the neutral ones, contribute to the risks of NSCLC development. However, the initial finding is not conclusive, as this pilot project was limited by a small sample set and structural variations were not examined.Citation Format: Zhaoxi Wang, Yang Zhao, Li Su, Seunggeun Lee, Xihong Lin, David C. Christiani. Targeted sequencing of 5p15 locus defined by non-small cell lung cancer (NSCLC) GWAS using next-generation sequencing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2547. doi:10.1158/1538-7445.AM2013-2547
P1227 FALDAPREVIR EFFICACY IN HCV GENOTYPE-1-INFECTED PATIENTS IN FOUR PHASE 3 TRIALS: ANALYSIS BY NS3 BASELINE POLYMORPHISMS, GENOTYPE-1 SUBTYPE AND GENOTYPE-1A CLADES
Authors: K. Berger, C. Sarrazin, I.M. Jacobson, D.M. Jensen, P. Ferenci, D. Dieterich, J.O. Stern, A.-M. Quinson, J. Scherer, G. Kukolj
Journal: Journal of Hepatology (2014)
Failure of Right Ventricular Adaptation in Children With Tetralogy of Fallot
Authors: Sushma Reddy, Juan Carlos Osorio, Ana M. Duque, Beth D. Kaufman, Alistair B. Phillips, Jonathan M. Chen, Jan Quaegebeur, Ralph S. Mosca, Seema Mital
Journal: Circulation (2006)

The left ventricle (LV) adapts to chronic hypoxia by expressing protective angiogenic, metabolic, and antioxidant genes to improve O2 delivery and energy production, and to minimize reoxygenation injury. The ability of the right ventricle (RV) to adapt to hypoxia in children with tetralogy of Fallot (TOF) is unknown.Gene expression using real-time polymerase chain reaction was measured in RV myocardium obtained during surgical repair of TOF from 23 patients: 13 cyanotic and 10 acyanotic. Results were compared between the 2 groups and correlated with age at surgery, severity of cyanosis, and early postoperative course. The cyanotic patients were younger at surgery compared with acyanotic (5+/-3 versus 9+/-4 months; P=0.01), had higher hematocrit (43+/-4 versus 38+/-3 grams/dL; P=0.004), and lower O2 saturations (84+/-4% versus 98+/-2%; (P<0.001). Cyanotic patients had a significantly lower expression of vascular endothelial growth factor (VEGF), glycolytic enzymes, and glutathione peroxidase (GPX) (P<0.05), and a higher expression of collagen (P<0.01) compared with acyanotic patients. Gene expression correlated inversely with severity of cyanosis ie, preoperative hematocrit (P<0.01) and positively with preoperative saturation (P<0.05). The relationship between gene expression and cyanosis was independent of age at surgery. Ca2+ handling genes did not correlate with the severity of hypoxia. Lower angiogenic, glycolytic, and antioxidant gene expression correlated with increasing postoperative lactate (P<0.05).The RV fails to up regulate adaptive pathways in response to increasing hypoxia in children with TOF. The implications of an early maladaptive response of the RV on long-term RV function require further investigation.
Genital Chlamydial Infections
Authors: Jeffrey F. Peipert
Journal: New England Journal of Medicine (2003)

A 19-year-old woman visits her primary care provider for counseling about contraception. She became sexually active one year earlier and has had a new sexual partner for the past three months. Her partner currently uses a condom intermittently. She reports no medical problems, and her physical examination is unremarkable. Is testing for Chlamydia trachomatis indicated?
Are complications of endoscopic sphincterotomy age related?
Authors: G T Deans, P Sedman, D F Martin, C M S Royston, C K Leow, W E G Thomas, W A Brough
Journal: Gut (1997)

Background —Endoscopic retrograde cholangiopancreatography sphincterotomy is increasingly performed in younger patients undergoing laparoscopic cholecystectomy. However, the safety of endo- scopic sphincterotomy in this age group, relative to that in older patients, is unknown. Aim —To determine whether the development of short term complications following endoscopic sphincterotomy is age related. Patients and methods —A prospective multicentre audit of 958 patients (mean age 73, range 14–97, years) undergoing a total of 1000 endoscopic sphincterotomies. Results —Two deaths occurred, both from postsphincterotomy acute pancreatitis. Postprocedural complications developed in 24 patients: pancreatitis in 10, ascending cholangitis in seven, bleeding in four, and retroperitoneal perforation in three. There were six complications (five cases of pancreatitis and one bleed; 2.2%) and no deaths in the 281 (29.3%) patients aged under 65 years. In comparison, 18 (2.6%) of the 677 patients aged over 65 years developed a complication (cholangitis in seven, pancreatitis in five, bleeding in three, and perforation in three). Patients under 35, 45, 55, and 65 years were not at significantly increased risk of complication than those over these ages (relative risk for those under compared with those over 65 years 0.83, 95% confidence intervals 0.41–1.67, p=0.74). Conclusion —Short term complications following endoscopic sphincterotomy are not related to age. Younger patients undergoing laparoscopic cholecystectomy need not be denied endoscopic sphincterotomy for fear that the risks are greater than if they undergo surgical exploration of the common bile duct.
Acute Renal Failure Associated with Carbon Tetrachloride Intoxication
Authors: Peter S. New
Journal: JAMA (1962)

DESPITE the widespread use of carbon tetrachloride as a cleaning solvent, acute renal failure secondary to intoxication with this agent is infrequent. Presumably, time of exposure, adequacy of ventilation, and frequency of use have some bearing on the development of poisoning. These contributing factors are relatively well recognized by all, but others of importance apparently are not, for there continues to be a low but significant incidence of this illness. Since 1955 we have encountered 19 cases of acute renal failure related to carbon tetrachloride exposure.  Review of our data has revealed several interesting points. Some important clues to early diagnosis have become apparent, and public health aspects relative to exposure deserve re-emphasis.  Findings  The data from the 19 patients are summarized in Tables 1 and 2.   Exposure —Inhalation was the predominant route of exposure. Only 2 patients drank carbon tetrachloride, one in an attempt to commit suicide. In the other
Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study
Authors: Steven M. Kornblau, Deborah E. Banker, Derek Stirewalt, Danny Shen, Elizabeth Lemker, Srdan Verstovsek, Zeev Estrov, Stefan Faderl, Jorge Cortes, Miloslav Beran, C. Ellen Jackson, Wenjing Chen, Elihu Estey, Frederick R. Appelbaum
Journal: Blood (2006)
Hypotensive effect of taurine. Possible involvement of the sympathetic nervous system and endogenous opiates.
Authors: T Fujita, Y Sato
Journal: Journal of Clinical Investigation (1988)

We studied the role of diminished sympathetic nervous system (SNS) activity and endogenous opiate activation in the hypotensive action of taurine, a sulfur amino acid, in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Supplementation of taurine could prevent the development of DOCA-salt hypertension in rats, but failed to change blood pressure in vehicle-treated control rats. Cardiac NE turnover, which was determined from the rate of decline of tissue NE concentration after the administration of alpha-methyl-p-tyrosine, was markedly accelerated in DOCA-salt rats, but 1% taurine supplement restored it to normal. Moreover, naloxone (2 mg/kg), the specific opiate antagonist, increased blood pressure in taurine-treated DOCA-salt rats, restoring it to levels similar to those in the DOCA-salt rats. In contrast, taurine did not decrease cardiac NE turnover in the control rats, nor did naloxone increase blood pressure in the taurine-treated control rats. Moreover, supplementation of taurine increased both beta-endorphin-like immunoreactive material and taurine contents in the hypothalamus of DOCA-salt rats, whereas it did not increase beta-endorphin in that of control rats despite increased taurine contents. Thus, taurine not only normalized the increased cardiac SNS activity but also elicited an opiate-mediated vasodepressor response only in DOCA-salt rats. It is suggested, therefore, that endogenous opiate activation, which is intimately related to SNS suppression, may contribute to the antihypertensive effect of taurine in sodium chloride hypertension.
Pulmonary Tuberculosis: Bacteriology, Pathology, Diagnosis, Management, Epidemiology, and Prevention
Authors: Sol Roy Rosenthal
Journal: JAMA (1965)

<b>Formenkreis der extrapulmonalen hämatogenen Tuberkulose.</b>Handbuch der Tuberkulose. Band IV. Edited by J. Hein, H. Kleinschmidt, and E. Uehlinger. 955 pp, 438 illus. 248 marks. Thieme Verlag, West Germany (Intercontinental Medical Book Corp., 381 Park Ave S, New York 16), 1964 These two volumes on tuberculosis complement each other, for the one in English is on pulmonary tuberculosis and the other, in German, on extrapulmonary hematogenous tuberculosis. In the preface of the book by Pagel et al, the authors state, "It was the persistent request for the book from developing countries that prompted the publishers and the authors to submit a fourth edition." From this statement it should not be inferred that tuberculosis is a disease of the past in highly developed countries. Even in the United States, beginning in 1963, there has been a definite rise in the incidence of tuberculosis in many of the large urban centers. Dr.
Screening for abdominal aortic aneurysms.
Authors: M. Sowter, M. Lewis
Journal: BMJ (1992)

Ruptured aneurysm of the abdominal aorta is a common preventable cause of death, accounting for 2% of all deaths in men over 60 years of age. Population screening could prevent such deaths. Aortic diameter (which can be measured accurately on ultrasound) is a strong predictor of the risk of rupture, which is about 17% per year with aortic diameter £ 6 cm, but below 0.5% per year with aortic diameter < 5 cm, with uncertainty regarding risk in the range 5.0-5.9 cm. Adopting an aortic diameter cut-off of 6.0 cm, the detection rate is estimated to be 86% (that is, 86% of all men who would rupture an aortic aneurysm could be identified and offered surgery) and the false positive rate only 0.6% (that is, 0.6% of men who would not rupture an aortic aneurysm would be so identified). In men with aortic diameter 2 6 cm, the risk of rupture of 17% per year greatly outweighs the peri-operative mortality of about 5%. A national screening programme for men over 60 years of age could prevent 2000 deaths per year and should commence. Uncertainty remains regarding the frequency with which men with smaller aneurysms should be re-examined and the value of intervention among those with an aortic diameter of 5.0-5.9 cm, but the screening programme itself would generate data to help resolve these issues.
Intracoronary administration of saralasin: effects on cardiac arrhythmias induced by ischaemia and reperfusion in the anaesthetised dog
Authors: C. Ribuot, N. Yamaguchi, D. Godin, L. Jette, R. Nadeau
Journal: Cardiovascular Research (1992)

Objective: The aim was to study (1) the effects of intracoronary saralasin, an angiotensin II receptor antagonist, on ischaemia induced and reperfusion induced regional cardiac noradrenaline release and ventricular arrhythmias; and (2) the implication of angiotensin II in coronary constriction during myocardial ischaemia. Methods: Eighteen adult mongrel dogs, weight 22.6(SD 1.1) kg, anaesthetised with sodium pentobarbitone, were used for the study. The left anterior descending coronary artery was ligated for 60 min and then reperfused for 30 min. Saralasin (60 μg·kg−1, n=9) or its vehicle (Ringer lactate, n=9) was injected into the artery at the beginning of the occlusion period. Two epicardial veins, one running parallel to the left anterior descending coronary artery and the other parallel to the circumflex coronary artery, were cannulated for the measurement of their respective blood flows and of noradrenaline, lactate, and creatine kinase release. Results: Saralasin decreased the incidence of ventricular fibrillation during coronary occlusion (from 44% in the vehicle treated group to 0% in the saralasin treated group, p=0.0412). This effect was accompanied by significant vasodilatation in both epicardial veins during myocardial ischaemia. Neither the increases in noradrenaline, lactate, and creatine kinase release nor the incidence and duration of the ventricular arrhythmias following reperfusion were modified by the administration of saralasin. Conclusions: Intracoronary saralasin in the early phase of myocardial ischaemia increases the epicardial venous blood flow significantly, suggesting that angiotensin II is implicated in coronary constriction during ischaemia. This haemodynamic effect is accompanied by a significant decrease in the incidence of ventricular fibrillation. However, the renin-angiotensin system does not appear to be implicated in the reperfusion induced noradrenaline release nor in the incidence of the ventricular arrhythmias. Cardiovascular Research 1992;26:968–972
Immunotoxicity of heavy metals in relation to Great Lakes.
Authors: J Bernier, P Brousseau, K Krzystyniak, H Tryphonas, M Fournier
Journal: Environmental Health Perspectives (1995)

Heavy metals including mercury, lead, and cadmium are present throughout the ecosystem and are detectable in small amounts in the Great Lakes water and fish. The main route of exposure of humans to these metals is via the ingestion of contaminated food, especially fish. Extensive experimental investigations indicated that heavy metals alter a number of parameters of the host's immune system and lead to increased susceptibility to infections, autoimmune diseases, and allergic manifestations. The existing limited epidemiologic data and data derived from in vitro systems in which human peripheral blood leukocytes were used suggested that the human immune system may also be at increased risk following exposure to these metals. The magnitude of the risk that the presence of such metals in the Great Lakes may pose to the human immune system, and consequently to their health, is not known. In this review, the available data with respect to potential adverse effects of heavy metals on the immune system of humans and experimental animals are discussed, and additional data requirements are suggested.
Sox2 Requirement in Sonic Hedgehog-Associated Medulloblastoma
Authors: Julia Ahlfeld, Rebecca Favaro, Pierfrancesco Pagella, Hans A. Kretzschmar, Silvia Nicolis, Ulrich Schüller
Journal: Cancer Research (2013)

The transcription factor Sox2 has been shown to play essential roles during embryonic development as well as in cancer. To more precisely understand tumor biology and to identify potential therapeutical targets, we thoroughly investigated the expression and function of Sox2 in medulloblastoma, a malignant embryonic brain tumor that initiates in the posterior fossa and eventually spreads throughout the entire cerebrospinal axis. We examined a large series of tumor samples (n = 188) to show that SOX2 is specifically expressed in Sonic hedgehog (SHH)-associated medulloblastoma with an interesting preponderance in adolescent and adult cases. We further show that cerebellar granule neuron precursors (CGNP), which are believed to serve as the cell of origin for this medulloblastoma subgroup, express Sox2 in early stages. Also, Shh-associated medulloblastoma can be initiated from such Sox2-positive CGNPs in mice. Independent of their endogenous Sox2 expression, constitutive activation of Shh signaling in CGNPs resulted in significantly enhanced proliferation and ectopic expression of Sox2 in vitro and Sox2-positive medulloblastoma in vivo. Genetic ablation of Sox2 from murine medulloblastoma did not affect survival, most likely due to a compensatory overexpression of Sox3. However, acute deletion of Sox2 from primary cultures of CGNPs with constitutive Shh signaling significantly decreased proliferation, whereas overexpression of Sox2 enhanced proliferation of murine medulloblastoma cells. We conclude that Sox2 is a marker for Shh-dependent medulloblastomas where it is required and sufficient to drive tumor cell proliferation.
High altitude may alter oxygen availability and renal metabolism in diabetics as measured by hyperpolarized [1-13C]pyruvate magnetic resonance imaging
Authors: Christoffer Laustsen, Sara Lycke, Fredrik Palm, Jakob A. Østergaard, Bo M. Bibby, Rikke Nørregaard, Allan Flyvbjerg, Michael Pedersen, Jan H. Ardenkjaer-Larsen
Journal: Kidney International (2013)
Defective nuclear IKKα function in patients with ectodermal dysplasia with immune deficiency
Authors: Stephane T. Temmerman, Chi A. Ma, Yongge Zhao, Jeffrey Keenan, Ivona Aksentijevich, Margaret Fessler, Margaret R. Brown, Alan Knutsen, Ralph Shapiro, Ashish Jain
Journal: Journal of Clinical Investigation (2011)

Ectodermal dysplasia with immune deficiency (EDI) is an immunological and developmental disorder caused by alterations in the gene encoding NF-κB essential modulator (NEMO; also known as IκB kinase γ subunit [IKKγ]). Missense mutations in the gene encoding NEMO are associated with reduced signal-induced nuclear translocation of NF-κB proteins, resulting in defective expression of NF-κB target genes. Here, we report 2 unrelated male patients with EDI, both of whom have normal NEMO coding sequences, but exhibit a marked reduction in expression of full-length NEMO protein. TLR4 stimulation of APCs from these patients induced normal cytoplasmic activation and nuclear translocation of NF-κB. However, cells deficient in full-length NEMO were defective in expression of NF-κB-regulated cytokines, such as IL-12, suggesting a downstream defect in chromatin accessibility for NF-κB transcription factors. TLR4-stimulated APCs from the patients were defective in IKKα-dependent H3 histone phosphorylation at the IL-12 promoter and recruitment of NF-κB heterodimers RelA and cRel to the promoter. Expression of a super-active form of IKKα restored IL-12 production in a NEMO knockdown human monocytic cell line following LPS treatment. Our findings suggest that NEMO regulates the nuclear function of IKKα and offer new insights into the mechanisms underlying diminished NF-κB signaling in patients with EDI.
Vegetarianism and Gout
Authors: J. Haddon
Journal: BMJ (1898)

<h3>Abstract</h3> A major challenge in single-cell biology is identifying cell-type-specific gene functions, which may substantially improve precision medicine. Differential expression analysis of genes is a popular, yet insufficient approach, and complementary methods that associate function with cell type are required. Here, we describe scHumanNet (https://github.com/netbiolab/scHumanNet), a single-cell network analysis platform for resolving cellular heterogeneity across gene functions in humans. Based on cell-type-specific networks (CSNs) constructed under the guidance of the HumanNet reference interactome, scHumanNet displayed higher functional relevance to the cellular context than CSNs built by other methods on single-cell transcriptome data. Cellular deconvolution of gene signatures based on network compactness across cell types revealed breast cancer prognostic markers associated with T cells. scHumanNet could also prioritize genes associated with particular cell types using CSN centrality and identified the differential hubness of CSNs between disease and healthy conditions. We demonstrated the usefulness of scHumanNet by uncovering T-cell-specific functional effects of <i>GITR</i>, a prognostic gene for breast cancer, and functional defects in autism spectrum disorder genes specific for inhibitory neurons. These results suggest that scHumanNet will advance our understanding of cell-type specificity across human disease genes.
Failure to maintain the benefits of home-based intervention in adolescents with poorly controlled type 1 diabetes.
Authors: J J Couper, J Taylor, M J Fotheringham, M Sawyer
Journal: Diabetes Care (1999)

OBJECTIVE: To determine whether a 6-month home-based intervention program in adolescents with poorly controlled diabetes improves metabolic control and whether benefits are maintained after the intervention. RESEARCH DESIGN AND METHODS: Adolescents with a mean HbA1c of &amp;gt; 9.0% over the preceding 12 months received either routine care in a diabetes clinic and an ambulatory intervention for 6 months (n = 37) or routine care only (n = 32). A diabetes educator provided monthly home visits and weekly phone contact to educate and support the adolescents in setting goals for insulin adjustment, blood glucose monitoring, and target blood glucose range. There was no systematic change in the frequency of insulin injections. After the intervention, there was a 12-month follow-up when the intervention and control groups both received only routine care. Outcome measures were HbA1c and Diabetes Knowledge Assessment (DKN). RESULTS: During the intervention, mean HbA1c fell (baseline: 11.1 +/- 1.3%, 6 months: 9.7 +/- 1.6%; P = 0.0001) and mean knowledge scores increased (P = 0.0001) in the intervention group but not in control subjects. However, this improvement in HbA1c and increase in knowledge was not maintained in the intervention group at 12- and 18-month follow-up assessments. Parents' knowledge scores also improved significantly from baseline levels in the intervention group at 6 and 12 months (P = 0.001, P = 0.005, respectively). CONCLUSIONS: An ambulatory program improves metabolic control and knowledge in adolescents with poorly controlled type 1 diabetes; however, it is effective only while the intervention is maintained.