tbuckley/cabot-search huggingface dataset:
Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis
Authors: Deborah M. Cholon, Nancy L. Quinney, M. Leslie Fulcher, Charles R. Esther, Jhuma Das, Nikolay V. Dokholyan, Scott H. Randell, Richard C. Boucher, Martina Gentzsch
Journal: Science Translational Medicine (2014)

Ivacaftor, a CFTR potentiator drug used for cystic fibrosis, destabilizes rescued ΔF508 CFTR and interferes with the action of drugs that correct CFTR function.
Kallikrein genes are associated with lupus and glomerular basement membrane–specific antibody–induced nephritis in mice and humans
Authors: Kui Liu, Quan-Zhen Li, Angelica M. Delgado-Vega, Anna-Karin Abelson, Elena Sánchez, Jennifer A. Kelly, Li Li, Yang Liu, Jinchun Zhou, Mei Yan, Qiu Ye, Shenxi Liu, Chun Xie, Xin J. Zhou, Sharon A. Chung, Bernardo Pons-Estel, Torsten Witte, Enrique de Ramón, Sang-Cheol Bae, Nadia Barizzone, Gian Domenico Sebastiani, Joan T. Merrill, Peter K. Gregersen, Gary G. Gilkeson, Robert P. Kimberly, Timothy J. Vyse, Il Kim, Sandra D’Alfonso, Javier Martin, John B. Harley, Lindsey A. Criswell, Edward K. Wakeland, Marta E. Alarcón-Riquelme, Chandra Mohan
Journal: Journal of Clinical Investigation (2009)

Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.
Determinants of chronic infection with Staphylococcus aureus in patients with bronchiectasis
Authors: PL Shah, S Mawdsley, K Nash, P Cullinan, PJ Cole, R Wilson
Journal: European Respiratory Journal (1999)

Staphylococcus aureus is an uncommon pathogen in bronchiectasis not caused by cystic fibrosis (CF). The object of this study was to identify characteristics that cause patients to be prone to infection with S. aureus. The study population consisted of patients with bronchiectasis attending the authors' unit, excluding those with a diagnosis of overt CF. All patients had a high resolution computer tomographic scan (HRCT) of the thorax which demonstrated bronchiectasis. Cases that were currently chronically infected with S. aureus (isolated consecutively on more than two occasions &gt;3 months apart) were identified (n = 12) and compared with 74 control patients who had not been chronically infected with S. aureus. Patients were carefully evaluated to determine the aetiology of their disease. Odds ratios (OR) and 95% confidence intervals (CI) as measures of the association between disease characteristics and chronic infection with S. aureus were calculated. The results for patients chronically infected by S. aureus demonstrated significant associations with allergic bronchopulmonary aspergillosis (ABPA; OR = 8.8, 95% CI 1.8-41.9), atypical variants of CF (OR = 12.0, 95% CI 1.8-81.7) or equivocal sweat sodium values (OR = 4.0, 95% CI 1.0-15.3). The associations persisted when the analysis was based on cases (n = 28) in whom S. aureus had ever been isolated from sputum. In the latter analysis there was also a significant association with predominant upper zone disease on HRCT. These results suggest that patients with bronchiectasis in whom S. aureus is isolated from sputum should be carefully evaluated to exclude allergic bronchopulmonary aspergillosis or atypical cystic fibrosis.
Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle.
Authors: P M Stewart, J E Corrie, C H Shackleton, C R Edwards
Journal: Journal of Clinical Investigation (1988)

The first adult case of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) deficiency is described. The impaired conversion of cortisol to cortisone (indicated by urinary cortisol and cortisone metabolites and failure to metabolize 11 alpha-[3H]cortisol to [3H]H2O), was associated with hypertension, hypokalemia, and suppression of the renin-angiotensin-aldosterone system. When established on a fixed Na+/K+ intake, dexamethasone, given orally, produced a natriuresis and potassium retention. Plasma renin activity became detectable. When hydrocortisone (10 mg daily s.c. for 4 d) was added, there was marked Na+ retention, a kaliuresis (urinary Na+/K+ falling from 1.2 to 0.15), with suppression of plasma renin activity and an increase in blood pressure. These changes were also seen with the subject on no treatment. Conversion of cortisone to cortisol was not affected. These results suggest that cortisol acts as a potent mineralocorticoid in 11 beta-OHSD deficiency. The major site for the oxidation of cortisol to cortisone is the kidney. In this patient congenital deficiency of 11 beta-OHSD results in high intrarenal cortisol levels which then act on renal type I mineralocorticoid receptors. This condition can be treated with dexamethasone, which suppresses cortisol secretion and binds to the type II glucocorticoid receptor. We suggest that 11 beta-OHSD exerts a critical paracrine role in determining the specificity of the type I receptor. In the normal state cortisol is converted by 11 beta-OHSD to cortisone which thus allows aldosterone to bind preferentially to the type I receptors in the kidney and gut. In this patient deficiency of 11 beta-OHSD results in high intrarenal cortisol concentrations that then bind to the type I receptor.
Response to Letter Regarding Article, “Improvement in Congenital Heart Surgery in a Developing Country: The Guatemalan Experience”
Authors: Luis A. Larrazábal, Kathy J. Jenkins, Kimberlee Gauvreau, Vladimiro L. Vida, Oscar J. Benavidez, Guillermo A. Gaitán, Flor Garcia, Aldo R. Castañeda
Journal: Circulation (2008)
Quantitative and qualitative 3-dimensional echocardiographic evaluation of aortic coarctation using a fast fan-like data acquisition with an integrated 3-D system: in vitro validation
Authors: E. Avalar, S.P. Ram, P. Paichetti, M. Kozakova, S. DeCastro, T.-L. Hsu, Q.-L. Cao, G. Marx, N. Pandian
Journal: Journal of the American College of Cardiology (1998)
Paget's Disease of Bone
Authors: Michael P Whyte
Journal: New England Journal of Medicine (2006)

A 69-year-old man reports increasing pain in the right leg. Physical examination reveals warmth and anterolateral bowing of the right shin. The serum alkaline phosphatase level is 260 U per liter (normal, 38 to 126 U per liter). A skeletal scintigraphic scan reveals enhanced uptake in only the deformed tibia, where a radiograph shows changes indicative of Paget's disease. His sister, whose alkaline phosphatase level is 160 U per liter, has asymptomatic Paget's disease confined to the left iliac wing. How should their cases be managed?
Integrative Genomics Identified <i>RFC3</i> As an Amplified Candidate Oncogene in Esophageal Adenocarcinoma
Authors: William W. Lockwood, Kelsie L. Thu, Lin Lin, Larissa A. Pikor, Raj Chari, Wan L. Lam, David G. Beer
Journal: Clinical Cancer Research (2012)

Esophageal adenocarcinoma (EAC) is a lethal malignancy that can develop from the premalignant condition, Barrett's esophagus (BE). Currently, there are no validated simple methods to predict which patients will progress to EAC. A better understanding of the genetic mechanisms driving EAC tumorigenesis is needed to identify new therapeutic targets and develop biomarkers capable of identifying high-risk patients that would benefit from aggressive neoadjuvant therapy. We employed an integrative genomics approach to identify novel genes involved in EAC biology that may serve as useful clinical markers.Whole genome tiling-path array comparative genomic hybridization was used to identify significant regions of copy number alteration in 20 EACs and 10 matching BE tissues. Copy number and gene expression data were integrated to identify candidate oncogenes within regions of amplification and multiple additional sample cohorts were assessed to validate candidate genes.We identified RFC3 as a novel, candidate oncogene activated by amplification in approximately 25% of EAC samples. RFC3 was also amplified in BE from a patient whose EAC harbored amplification and was differentially expressed between nonmalignant and EAC tissues. Copy number gains were detected in other cancer types and RFC3 knockdown inhibited proliferation and anchorage-independent growth of cancer cells with increased copy number but had little effect on those without. Moreover, high RFC3 expression was associated with poor patient outcome in multiple cancer types.RFC3 is a candidate oncogene amplified in EAC. RFC3 DNA amplification is also prevalent in other epithelial cancer types and RFC3 expression could serve as a prognostic marker.
Deintensification Candidate Subgroups in Human Papillomavirus–Related Oropharyngeal Cancer According to Minimal Risk of Distant Metastasis
Authors: Brian O'Sullivan, Shao Hui Huang, Lillian L. Siu, John Waldron, Helen Zhao, Bayardo Perez-Ordonez, Ilan Weinreb, John Kim, Jolie Ringash, Andrew Bayley, Laura A. Dawson, Andrew Hope, John Cho, Jonathan Irish, Ralph Gilbert, Patrick Gullane, Angela Hui, Fei-Fei Liu, Eric Chen, Wei Xu
Journal: Journal of Clinical Oncology (2013)

To define human papillomavirus (HPV) -positive oropharyngeal cancers (OPC) suitable for treatment deintensification according to low risk of distant metastasis (DM).OPC treated with radiotherapy (RT) or chemoradiotherapy (CRT) from 2001 to 2009 were included. Outcomes were compared for HPV-positive versus HPV-negative patients. Univariate and multivariate analyses identified outcome predictors. Recursive partitioning analysis (RPA) stratified the DM risk.HPV status was ascertained in 505 (56%) of 899 consecutive OPCs. Median follow-up was 3.9 years. HPV-positive patients (n = 382), compared with HPV-negative patients (n = 123), had higher local (94% v 80%, respectively, at 3 years; P < .01) and regional control (95% v 82%, respectively; P < .01) but similar distant control (DC; 90% v 86%, respectively; P = .53). Multivariate analysis identified that HPV negativity (hazard ratio [HR], 2.9; 95% CI, 2.0 to 5.0), N2b-N3 (HR, 2.9; 95% CI, 1.8 to 4.9), T4 (HR, 1.8; 95% CI, 1.2 to 2.9), and RT alone (HR, 1.8; 95% CI, 1.1 to 2.5) predicted a lower recurrence-free survival (RFS; all P < .01). Smoking pack-years > 10 reduced overall survival (HR, 1.72; 95% CI, 1.1 to 2.7; P = .03) but did not impact RFS (HR, 1.1; 95% CI, 0.7 to 1.9; P = .65). RPA segregated HPV-positive patients into low (T1-3N0-2c; DC, 93%) and high DM risk (N3 or T4; DC, 76%) groups and HPV-negative patients into different low (T1-2N0-2c; DC, 93%) and high DM risk (T3-4N3; DC, 72%) groups. The DC rates for HPV-positive, low-risk N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT, but the rate was lower in the N2c subset managed by RT alone (73% v 92% for CRT; P = .02).HPV-positive T1-3N0-2c patients have a low DM risk, but N2c patients from this group have a reduced DC when treated with RT alone and seem less suited for deintensification strategies that omit chemotherapy.
Phase I Trial of Oral Irinotecan and Temozolomide for Children With Relapsed High-Risk Neuroblastoma: A New Approach to Neuroblastoma Therapy Consortium Study
Authors: Lars M. Wagner, Judith G. Villablanca, Clinton F. Stewart, Kristine R. Crews, Susan Groshen, C. Patrick Reynolds, Julie R. Park, John M. Maris, Randall A. Hawkins, Heike E. Daldrup-Link, Hollie A. Jackson, Katherine K. Matthay
Journal: Journal of Clinical Oncology (2009)

Irinotecan and temozolomide have single-agent activity and schedule-dependent synergy against neuroblastoma. Because protracted administration of intravenous irinotecan is costly and inconvenient, we sought to determine the maximum-tolerated dose (MTD) of oral irinotecan combined with temozolomide in children with recurrent/resistant high-risk neuroblastoma.
Progestagen therapy for recurrent miscarriage
Authors: J. Szekeres-Bartho, J. Balasch
Journal: Human Reproduction Update (2007)

BACKGROUNDRecurrent pregnancy loss (RM) affects 0.5–1% of couples. The pathophysiology of RM is complex. The suggested causes include anatomical, genetic and molecular abnormalities, endocrine disorders, thrombophilias and anti-phospholipid syndrome. In ∼50% of the cases neither of the above can be identified. We aimed at examining the evidence on the role of progesterone in the pathophysiology of RM, and the clinical evidence on effectiveness of progestogen treatment.
Efficacy of RTS,S/AS01E Vaccine against Malaria in Children 5 to 17 Months of Age
Authors: Philip Bejon, John Lusingu, Ally Olotu, Amanda Leach, Marc Lievens, Johan Vekemans, Salum Mshamu, Trudie Lang, Jayne Gould, Marie-Claude Dubois, Marie-Ange Demoitié, Jean-Francois Stallaert, Preeti Vansadia, Terrell Carter, Patricia Njuguna, Ken O. Awuondo, Anangisye Malabeja, Omar Abdul, Samwel Gesase, Neema Mturi, Chris J. Drakeley, Barbara Savarese, Tonya Villafana, W. Ripley Ballou, Joe Cohen, Eleanor M. Riley, Martha M. Lemnge, Kevin Marsh, Lorenz von Seidlein
Journal: New England Journal of Medicine (2008)

Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure.
Do Different Dimensions of the Metabolic Syndrome Change Together Over Time?
Authors: Patrick Maison, Christopher D. Byrne, C. Nicholas Hales, Nicholas E. Day, Nicholas J. Wareham
Journal: Diabetes Care (2001)

The metabolic syndrome is a loosely defined cluster of cardiovascular risk factors including low HDL cholesterol, hypertriglyceridemia, glucose intolerance, and hypertension. Evidence for inclusion of these features in the syndrome has mostly come from cross-sectional studies, and a few studies have examined how the various factors change together over time.We conducted a prospective population-based cohort study of 937 individuals aged 40-65 years who underwent oral glucose tolerance testing on two occasions at 4.5-year intervals. Changes in the components of the metabolic syndrome were analyzed by principal component analysis in the entire population and in a subgroup of 471 individuals who did not receive pharmaceutical therapy for hypertension and dyslipidemia.Principal component analysis identified three independent factors in men: a blood pressure factor (systolic and diastolic blood pressure and BMI), a glucose factor (fasting and 120-min postload glucose, BMI, waist-to-hip ratio [WHR], and fasting insulin level), and a lipid factor (triglycerides and HDL cholesterol, BMI, WHR, and fasting insulin level). In women, an additional factor was identified, which included BMI, WHR, fasting insulin, and triglycerides. Analysis of the contribution of these variables to the different subdimensions indicated that BMI was the central feature of the syndrome in both sexes.This analysis of change in the features of the metabolic syndrome over time provides evidence of the fundamental importance of obesity in the origin of this disorder.
Adherence to the Mediterranean diet and fresh fruit intake are associated with improved asthma control
Authors: R. Barros, A. Moreira, J. Fonseca, J. Ferraz de Oliveira, L. Delgado, M. G. Castel‐Branco, T. Haahtela, C. Lopes, P. Moreira
Journal: Allergy (2008)

The traditional Mediterranean diet is claimed to possess antioxidant and immune-regulatory properties in several chronic diseases. Typical Mediterranean foods have recently been associated with improvement of symptoms of asthma and rhinitis in children. However the effect of adherence to Mediterranean diet on adult asthma outcomes is unknown. We aimed to investigate the association between adherence to Mediterranean diet and asthma control.Cross sectional study of 174 asthmatics, mean (SD) age of 40 (15) years. The patients were defined as controlled, in contrast to noncontrolled, if they showed FEV1 >or= 80% of predicted, exhaled nitric oxide (NO) <or=35 ppb, and Asthma Control Questionnaire score <1. Dietary intake was obtained by a food frequency questionnaire, and Mediterranean diet was assessed by alternate Mediterranean Diet (aMED) Score. Logistic regression models adjusting for confounders were performed to estimate the association between Mediterranean diet and asthma control.Controlled asthmatics (23%) had significantly higher aMED Score, intake of fresh fruit, and lower intake of ethanol compared to noncontrolled (77%). High adherence to Mediterranean diet reduced 78% the risk of noncontrolled asthma after adjusting for gender, age, education, inhaled corticosteroids and energy intake (OR = 0.22; 95% CI = 0.05-0.85; P-trend = 0.028). The higher intake of fresh fruit decreased the probability of having noncontrolled asthma (OR = 0.29; 95% CI = 0.10-0.83; P-trend = 0.015), while the higher intake of ethanol had the opposite effect (OR = 3.16; 95% CI = 1.10-9.11; P-trend = 0.035).High adherence to traditional Mediterranean diet increased the likelihood of asthma to be under control in adults. The study introduces a novel link between diet and asthma control, as measured by symptoms, lung function and exhaled NO.
Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in middle eastern families
Authors: Zippora Brownstein, Lilach M Friedman, Hashem Shahin, Varda Oron-Karni, Nitzan Kol, Amal Abu Rayyan, Thomas Parzefall, Dorit Lev, Stavit Shalev, Moshe Frydman, Bella Davidov, Mordechai Shohat, Michele Rahile, Sari Lieberman, Ephrat Levy-Lahad, Ming K Lee, Noam Shomron, Mary-Claire King, Tom Walsh, Moien Kanaan, Karen B Avraham
Journal: Genome biology (2011)

Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity.A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population.Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in hearing loss.
Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration
Authors: Colette J Smith, Lene Ryom, Rainer Weber, Philippe Morlat, Christian Pradier, Peter Reiss, Justyna D Kowalska, Stephane de Wit, Matthew Law, Wafaa el Sadr, Ole Kirk, Nina Friis-Moller, Antonella d'Arminio Monforte, Andrew N Phillips, Caroline A Sabin, Jens D Lundgren
Journal: The Lancet (2014)
Factors Responsible for Development From Normal Glucose Tolerance to Isolated Postchallenge Hyperglycemia
Authors: Haruhiko Suzuki, Mitsuo Fukushima, Masaru Usami, Masaki Ikeda, Ataru Taniguchi, Yosikatsu Nakai, Toshifumi Matsuura, Akira Kuroe, Koichiro Yasuda, Takeshi Kurose, Yutaka Seino, Yuichiro Yamada
Journal: Diabetes Care (2003)

OBJECTIVE—Isolated postchallenge hyperglycemia (IPH), defined as fasting plasma glucose (FPG) level &amp;lt;7.0 mmol/l and 2-h plasma glucose (PG) level ≥11.1 mmol/l, is a subtype of early-stage diabetes. This study evaluates the metabolic profiles of insulin secretion and insulin sensitivity in IPH to clarify the factors responsible for development of this form of type 2 diabetes. RESEARCH DESIGN AND METHODS—We conducted cross-sectional analysis of 231 Japanese men aged 20–70 years. The subjects were classified into the following three groups, based on the results of a 75-g oral glucose tolerance test (OGTT): 1) normal glucose tolerance (NGT), defined as FPG level &amp;lt;6.1 mmol/l and 2-h PG level &amp;lt;7.8 mmol/l (n = 89); 2) impaired glucose tolerance (IGT), defined as FPG level &amp;lt;7.0 mmol/l and 2-h PG level of 7.8–11.1 mmol/l (n = 94); and 3) IPH (n = 48). We compared the three groups for insulin secretion (insulinogenic index) and insulin sensitivity (index of insulin resistance using homeostasis model assessment [HOMA-IR]). RESULTS—The insulinogenic index in IPH was the lowest of the three groups (P &amp;lt; 0.001 versus NGT). The HOMA-IR in the IGT and IPH groups were significantly higher than in the NGT group (P &amp;lt; 0.001), but both were similar. By linear regression analysis, the insulinogenic index rather than fasting insulin or HOMA-IR was the more significant factor in the 2-h PG level in IGT and IPH. CONCLUSIONS—Subjects with IPH exhibited distinctly impaired early-phase insulin secretion and only mild insulin resistance, indicating that reduced insulin secretion is the primary determinant of deterioration from NGT to IGT and IPH in development of type 2 diabetes in these subjects.