tbuckley/cabot-search huggingface dataset:
A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
Authors: John F. Peden, Jemma C. Hopewell, Danish Saleheen, John C. Chambers, Jorg Hager, Nicole Soranzo, Rory Collins, John Danesh, Paul Elliott, Martin Farrall, Kathy Stirrups, Weihua Zhang, Anders Hamsten, Sarah Parish, Mark Lathrop, Hugh Watkins, Robert Clarke, Panos Deloukas, Jaspal S. Kooner, Anuj Goel, Halit Ongen, Rona J. Strawbridge, Simon Heath, Anders Mälarstig, Anna Helgadottir, John Öhrvik, Muhammed Murtaza, Simon Potter, Sarah E. Hunt, Marc Delepine, Shapour Jalilzadeh, Tomas Axelsson, Ann-Christine Syvänen, Rhian Gwilliam, Suzannah Bumpstead, Emma Gray, Sarah Edkins, Lasse Folkersen, Theodosios Kyriakou, Anders Franco-Cereceda, Anders Gabrielsen, Udo Seedorf, Per Eriksson, Alison Offer, Louise Bowman, Peter Sleight, Jane Armitage, Richard Peto, Goncalo Abecasis, Nabeel Ahmed, Mark Caulfield, Peter Donnelly, Philippe Froguel, Angad S. Kooner, Mark I. McCarthy, Nilesh J. Samani, James Scott, Joban Sehmi, Angela Silveira, Mai-Lis Hellenius, Ferdinand M. van't Hooft, Gunnar Olsson, Stephan Rust, Gerd Assmann, Simona Barlera, Gianni Tognoni, Maria Grazia Franzosi, Pamela Linksted, Fiona R. Green, Asif Rasheed, Moazzam Zaidi, Nabi Shah, Maria Samuel, Nadeem H. Mallick, Muhammad Azhar, Khan S. Zaman, Abdus Samad, Mohammad Ishaq, Ali R. Gardezi, Fazal-ur-Rehman Memon, Philippe M. Frossard, Tim Spector, Leena Peltonen, Markku S. Nieminen, Juha Sinisalo, Veikko Salomaa, Samuli Ripatti, Derrick Bennett, Karin Leander, Bruna Gigante, Ulf de Faire, Silvia Pietri, Francesca Gori, Roberto Marchioli, Suthesh Sivapalaratnam, John J. P. Kastelein, Mieke D. Trip, Eirini V. Theodoraki, George V. Dedoussis, Jamie C. Engert, Salim Yusuf, Sonia S. Anand
Journal: Nature Genetics (2011)
Genetic Variants in the <i>UDP-glucuronosyltransferase 1A1</i> Gene Predict the Risk of Severe Neutropenia of Irinotecan
Authors: Federico Innocenti, Samir D. Undevia, Lalitha Iyer, Pei Xian Chen, Soma Das, Masha Kocherginsky, Theodore Karrison, Linda Janisch, Jacqueline Ramírez, Charles M. Rudin, Everett E. Vokes, Mark J. Ratain
Journal: Journal of Clinical Oncology (2004)

Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation.Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped.The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51).UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.
Fate of the Stented Arterial Duct
Authors: John L. Gibbs, Orhan Uzun, Michael E.C. Blackburn, Christopher Wren, J.R. Leslie Hamilton, Kevin G. Watterson
Journal: Circulation (1999)

Background —The technical aspects of ductal stenting have been reported, but little is known of the fate of the duct after stent implantation. Methods and Results —Nineteen patients underwent stent implantation to maintain ductal patency. Eight had hypoplastic left heart (HLH) syndrome, 10 had pulmonary atresia, and 1 had tricuspid atresia. Median survival with HLH was 57 (12 to 907) days. Stent implantation was successful in all cases of HLH, but there were no long-term survivors. Two well-palliated infants died at transplantation. Median survival with duct-dependant pulmonary flow was 183 (0 to 1687) days, with 3 patients well at latest follow-up (56, 55, and 9 months, respectively). There were 2 operative deaths due to ductal spasm and 4 late deaths, 1 due to duct thrombosis, 1 due to chronic lung disease, and 2 of unknown cause. Stent implantation failed in 4 of the 11 cases. Assessment of endothelialization was possible in 13 cases; the stent was partially covered in 3 and fully endothelialized in all 10 cases assessed &gt;8 weeks after implantation. In patients stented for inadequate pulmonary flow, ductal intimal hyperplasia occurred by 9 months in all 3 survivors but responded to repeated dilation. Conclusions —Ductal stenting cannot be recommended. In patients with HLH, it provides only short-term palliation even when combined with pulmonary artery banding. With duct-dependent pulmonary blood flow, the procedure carries high risk, and duration of palliation is poor. In patients with bilateral ducts and absent central pulmonary arteries, good palliation may be achieved, but repeated angioplasty is necessary to counteract intimal hyperplasia.
Malignant Pleural Mesothelioma
Authors: Anne S. Tsao, Ignacio Wistuba, Jack A. Roth, Hedy Lee Kindler
Journal: Journal of Clinical Oncology (2009)

Malignant pleural mesothelioma (MPM) is a deadly disease that occurs in 2,000 to 3,000 people each year in the United States. Although MPM is an extremely difficult disease to treat, with the median overall survival ranging between 9 and 17 months regardless of stage, there has been significant progress over the last few years that has reshaped the clinical landscape. This article will provide a comprehensive discussion of the latest developments in the treatment of MPM. We will provide an update of the major clinical trials that impact mesothelioma treatment in the resectable and unresectable settings, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. In addition, there are controversial issues, such as the role of extrapleural pneumonectomy, adjuvant radiotherapy, and use of intensity-modulated radiotherapy versus hemithoracic therapy that will also be addressed in this manuscript.
Pretransplant test-dose pharmacokinetic profiles
Authors: S C Chueh, B D Kahan
Journal: Journal of the American Society of Nephrology (1998)

The purpose of this study was to compare the accuracy of pretransplant test-dose pharmacokinetic (PK) profiling after administration of the microemulsion (CsA-ME; Neoral) versus the corn oil-based (CsA-GC; Sandimmune) gel capsule formulations of cyclosporin A (CsA) to estimate posttransplant CsA bioavailability and to individualize starting drug doses. The absolute oral bioavailability (F), clearance rate (CL), average blood concentration (C[av]), peak concentration (Cmax), and time to Cmax (tmax) values were calculated from paired intravenous and oral pretransplant PK profiles of renal transplant candidates, using CsA-GC (n = 70) or CsA-ME (n = 70) administration. The initial posttransplant oral CsA dose was estimated by linear extrapolation of the observed pretransplant value to the target concentration. Because higher mean F (P < 0.0001), but not CL, values were observed in end-stage renal disease patients after CsA-ME compared with CsA-GC treatment, the predicted starting doses for each therapy were markedly different (P < 0.01). From posttransplant days 5 to 7, 54% of patients treated with CsA-ME had a mean dose-normalized C(av) (C(av)/dose, D) value within 20% of the target concentration, compared with 42% of patients treated with CsA-GC (P = 0.03). Administration of the predicted oral dose of CsA-ME produced a Cmax > 700 ng/ml in 90% of patients from days 2 to 4, and in 97% from days 5 to 7, whereas administration of the predicted oral dose of CsA-GC produced a Cmax > 700 ng/ml in only 64 and 82% of patients during these same time periods, respectively (both P < 0.05). The mean estimated posttransplant F value of CsA-ME was significantly higher than that of CsA-GC; even at postoperative day 5 the value for CsA-GC was significantly lower than the pretransplant estimate (P < 0.01). Therefore, CsA-ME pretransplant PK profiles yield more accurate predictions for appropriate starting drug doses than those of CsA-GC.
Rapid Induction of Tumor-specific Type 1 T Helper Cells in Metastatic Melanoma Patients by Vaccination with Mature, Cryopreserved, Peptide-loaded Monocyte-derived Dendritic Cells
Authors: Beatrice Schuler-Thurner, Erwin S. Schultz, Thomas G. Berger, Georg Weinlich, Susanne Ebner, Petra Woerl, Armin Bender, Bernadette Feuerstein, Peter O. Fritsch, Nikolaus Romani, Gerold Schuler
Journal: The Journal of Experimental Medicine (2002)

There is consensus that an optimized cancer vaccine will have to induce not only CD8+ cytotoxic but also CD4+ T helper (Th) cells, particularly interferon (IFN)-γ–producing, type 1 Th cells. The induction of strong, ex vivo detectable type 1 Th cell responses has not been reported to date. We demonstrate now that the subcutaneous injection of cryopreserved, mature, antigen-loaded, monocyte-derived dendritic cells (DCs) rapidly induces unequivocal Th1 responses (ex vivo detectable IFN-γ–producing effectors as well as proliferating precursors) both to the control antigen KLH and to major histocompatibility complex (MHC) class II–restricted tumor peptides (melanoma-antigen [Mage]-3.DP4 and Mage-3.DR13) in the majority of 16 evaluable patients with metastatic melanoma. These Th1 cells recognized not only peptides, but also DCs loaded with Mage-3 protein, and in case of Mage-3DP4–specific Th1 cells IFN-γ was released even after direct recognition of viable, Mage-3–expressing HLA-DP4+ melanoma cells. The capacity of DCs to rapidly induce Th1 cells should be valuable to evaluate whether Th1 cells are instrumental in targeting human cancer and chronic infections.
Effect of Elevated Glucose on Endothelin-Induced Store-Operated and Non-Store-Operated Calcium Influx in Renal Mesangial Cells
Authors: LETA K. NUTT, ROGER G. O'NEIL
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Early diabetic nephropathy exhibits renal glomerular hyperfiltration and an increase in renal plasma flow. The hyperfiltration is a dysfunctional state that may arise from a hyperglycemic-induced hypocontractility of glomerular mesangial cells that may be associated with depressed Ca 2+ signaling events. The present study was designed to determine the effects of acute (minutes) and chronic (days) elevated glucose levels on endothelin-induced calcium signaling with a particular emphasis on the potential influence on stores and store-operated Ca 2+ influx (SOCI; also called capacitative calcium entry) in glomerular mesangial cells. Primary cultures of rat mesangial cells were grown in either high (30 mM) or normal (5 mM) glucose-containing media and tested in the presence of either high (30 mM) or normal (5 mM) glucose levels. Intracellular calcium levels were monitored with the calcium-sensitive fluorophore fura-2 before and after treatment with either endothelin-1 (10 nM), to induce typical Ca 2+ signals, or the endoplasmic reticulum (ER) Ca-ATPase inhibitor thapsagargin (1 μM), to unload ER Ca 2+ stores. Both acute and chronic exposure to high glucose levels depressed the endothelin-induced calcium signal. However, neither release of Ca 2+ from stores nor SOCI were depressed by high glucose levels. In contrast, an endothelin-induced calcium entry pathway (likely receptor-operated calcium influx), separate from SOCI, was markedly depressed in the presence of both acute and chronic high glucose levels. The depressant effect of high glucose was rapidly (minutes) reversible upon returning to normal glucose levels. It is concluded that high glucose levels depress endothelin-induced calcium signaling in rat mesangial cells by inhibiting non-SOCI Ca 2+ entry pathways, namely the receptor-operated Ca 2+ influx pathway. The glucose-induced alterations in the receptor-operated calcium influx pathway may, in part, contribute to the depressed contractile state of glomerular cells during periods of hyperglycemia.
Cognitive Control and Semantics in Schizophrenia: An Integrated Approach
Authors: Jessica R. Cohen, Brita Elvevåg, Terry E. Goldberg
Journal: American Journal of Psychiatry (2005)

The authors tested whether decisions about incongruencies in the representation and processing of semantic knowledge, thought to be related to cognitive control, are selectively impaired in schizophrenia.Twenty-four patients with schizophrenia and 24 healthy comparison subjects determined the relative size of paired stimuli as they are in the real world. Stimuli were words or images. Real-world "distance" (size difference between stimuli) was manipulated within pairs, as was "congruency" between real-world and presentation size.Although patients were slower overall, both groups exhibited similar effects of "distance" and "congruency"; the task was easier when the real-world size difference between stimuli was greater and when stimuli were congruent in presentation and real-world size.Some aspects of the representation of semantic knowledge are preserved in schizophrenia, and patients use this information to control cognition in the same manner as healthy individuals.
Is raised plasma peptide YY after intestinal resection in the rat responsible for the trophic response?
Authors: A P Savage, G E Gornacz, T E Adrian, M A Ghatei, R A Goodlad, N A Wright, S R Bloom
Journal: Gut (1985)

The relationship between the adaptive response and plasma PYY concentrations after small bowel resection has been investigated. Seventy five per cent proximal small bowel resection resulted in a rise in plasma PYY at six days from 28 +/- 3.1 to 85 +/- 12.3 pmol/l (p less than 0.001) and this difference was maintained to 48 days. Plasma PYY correlates both with crypt cell production rate (CCPR) in the ileum and with plasma enteroglucagon levels. In a second study, PYY or saline was infused over a 12 day period. There were no significant changes in intestinal wet weight or CCPR in any part of the bowel studied. This indicates that it is unlikely that PYY exerts a major trophic effect on the gastrointestinal tract.
Abrogation of Experimental Colitis Correlates with Increased Apoptosis in Mice Deficient for Cd44 Variant Exon 7 (Cd44v7)
Authors: Bianca M. Wittig, Britt Johansson, Margot Zöller, Christoph Schwärzler, Ursula Günthert
Journal: The Journal of Experimental Medicine (2000)

Experimental colitis in mice is characterized by infiltration of activated T helper (Th) cells and macrophages into the lamina propria. Particularly, these cells expressed CD44 variant exon 7 (CD44v7)-containing isoforms. Upregulation of CD44v7 isoforms was induced by CD40 ligation, an inflammation-driving interaction between activated Th cells and macrophages. To define the role of CD44v7 in colitis, mice bearing a targeted deletion for exon v7 were generated. In trinitrobenzene sulfonic acid–induced colitis, wild-type mice developed severe signs of persistent inflammation. Mice lacking CD44v7 initially showed unspecific inflammation, then recovered completely. The pathogenic origin was shown to reside in bone marrow–derived CD44v7+ cells, because adoptive transfer experiments demonstrated an absolute requirement for CD44v7 on hematopoietic cells for maintenance of colitis. Interleukin (IL)-10–deficient mice, which develop a chronic Th1-driven enterocolitis, were crossbred with CD44v6/v7 null mice. In IL-10 × CD44v6/v7 double deficient mice, intestinal inflammation developed only weakly and at an older age. Analysis of cell death in the inflamed lesions revealed that mononuclear cells in the CD44v7 null infiltrates had higher rates of apoptosis than those from wild-type mice. Thus, the region encoded by CD44v7 appears to be essential for survival of effector lymphocytes, resulting in persistence of inflammation.
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study
Authors: Jedd D Wolchok, Bart Neyns, Gerald Linette, Sylvie Negrier, Jose Lutzky, Luc Thomas, William Waterfield, Dirk Schadendorf, Michael Smylie, Troy Guthrie, Jean-Jacques Grob, Jason Chesney, Kevin Chin, Kun Chen, Axel Hoos, Steven J O'Day, Celeste Lebbé
Journal: The Lancet Oncology (2009)
Intrathecal Trastuzumab Halts Progression of CNS Metastases in Breast Cancer
Authors: Guilhem Bousquet, François Darrouzain, Cédric de Bazelaire, David Ternant, Emmanuel Barranger, Sabine Winterman, Isabelle Madelaine-Chambin, Jean-Baptiste Thiebaut, Marc Polivka, Gilles Paintaud, Stéphane Culine, Anne Janin
Journal: Journal of Clinical Oncology (2014)
Predictive factors in in vitro fertilization (IVF): a systematic review and meta-analysis
Authors: L.L. van Loendersloot, M. van Wely, J. Limpens, P.M.M. Bossuyt, S. Repping, F. van der Veen
Journal: Human Reproduction Update (2010)

Various models have been developed for the prediction of pregnancy after in vitro fertilization (IVF). These models differ from one another in the predictors they include. We performed a systematic review and meta-analysis to identify the most relevant predictors for success in IVF. We systematically searched MEDLINE and EMBASE for studies evaluating IVF/ICSI outcome. Studies were included if they reported an unconditional odds ratio (OR) or whenever one could be calculated for one or more of the following factors: age, type of infertility, indication, duration of infertility, basal FSH, number of oocytes, fertilization method, number of embryos transferred and embryo quality. Fourteen studies were identified. A summary OR could be calculated for five factors. We found negative associations between pregnancy and female age [OR: 0.95, 95% confidence interval (CI): 0.94–0.96], duration of subfertility (OR: 0.99, 95% CI: 0.98–1.00) and basal FSH (OR: 0.94, 95% CI: 0.88–1.00). We found a positive association with number of oocytes (OR 1.04, 95% CI: 1.02–1.07). Better embryo quality was associated with higher pregnancy chances. No significant association was found for the type of infertility and fertilization method. A summary OR for IVF indication and number of embryos transferred could not be calculated, because studies reporting on these used different reference categories. Female age, duration of subfertility, bFSH and number of oocytes, all reflecting ovarian function, are predictors of pregnancy after IVF. Better quality studies are necessary, especially studies that focus on embryo factors that are predictive of success in IVF.
Autoimmune, Atopic, and Mental Health Comorbid Conditions Associated With Alopecia Areata in the United States
Authors: Kathie P. Huang, Samyukta Mullangi, Ye Guo, Abrar A. Qureshi
Journal: JAMA Dermatology (2013)

To evaluate the prevalence of comorbid conditions among patients with alopecia areata (AA) seen at tertiary care hospitals in Boston, Massachusetts, during an 11-year period.Retrospective cross-sectional study.Tertiary care hospitals in Boston, including Brigham and Women's Hospital and Massachusetts General Hospital.We identified 3568 individuals with AA seen in the Partners health care system in Boston between January 1, 2000, and January 1, 2011. We performed comprehensive searches of the Research Patient Data Repository using International Classification of Diseases, Ninth Revision code 704.01. We randomly selected 350 patients and manually reviewed their medical records to train and validate a novel artificial intelligence program. This program then used natural language processing to review free-text medical records and confirm a diagnosis of AA. To confirm the algorithm, we manually reviewed a subset of records and found 93.9% validity.The prevalence of comorbid conditions was assessed.Common comorbid conditions included autoimmune diagnoses (thyroid disease in 14.6%, diabetes mellitus in 11.1%, inflammatory bowel disease in (2.0%) [corrected], systemic lupus erythematosus in 4.3%, rheumatoid arthritis in 3.9%, and psoriasis and psoriatic arthritis in (6.3%) [corrected], atopy (allergic rhinitis, asthma, and/or eczema in 38.2% and contact dermatitis and other eczema in 35.9%), and mental health problems (depression or anxiety in 25.5%). We also found high prevalences of hyperlipidemia (24.5%), hypertension (21.9%), and gastroesophageal reflux disease (17.3%). This profile was different from that seen in a comparison psoriasis and psoriatic arthritis group.We found a high prevalence of comorbid conditions among individuals with AA presenting to academic medical centers in Boston. Physicians caring for patients with AA should consider screening for comorbid conditions.
Influence of arterial diameter on vasomotor responses in the porcine coronary vasculature
Authors: S. J Bund, A. A Oldham, A. M Heagerty
Journal: Cardiovascular Research (1994)

The aim was to determine whether regional differences in arterial responses to vasoconstrictor and vasorelaxant agonists exist within the minipig coronary vasculature.Hearts were obtained from miniature pigs (20-40 kg) immediately after death. First and third order arterial branches of the left anterior descending artery were dissected from within the subepicardium and mounted as ring preparations in a small vessel myograph for measurement of isometric tension under standardised conditions. Contractile responses to acetylcholine, noradrenaline, and U46619, and the relaxation responses to noradrenaline, bradykinin, and substance P were measured. Arterial tone was increased with KCl or acetylcholine prior to addition of vasodilator agonists.First order branches were more sensitive to the constrictor influence of acetylcholine than third order branches [pD2 values 6.42(SEM 0.07), n = 13, and 6.26(0.07), n = 13, for first and third order respectively, p < 0.05]. U46619 did not induce contractile responses in arteries less than 210 microns in diameter. Noradrenaline only induced small contractile responses in the presence of propranolol following removal of the endothelium. In arteries preconstricted with 40 mM KCl, noradrenaline induced relaxation which was inhibited by propranolol and was uninfluenced by arterial calibre. In the presence of propranolol, noradrenaline-mediated relaxations of acetylcholine-preconstricted arteries were endothelium dependent and alpha 2 adrenoceptor mediated, and greater in first order than in third order branches [58(5)%, n = 9, and 26(8)%, n = 9, for first and third order branches respectively, p < 0.05]. Relaxations mediated by bradykinin and substance P were not influenced significantly by arterial calibre but were greater in arteries preconstricted with acetylcholine than with KCl.In isolated minipig coronary arteries the vasoconstrictor responses to acetylcholine and U46619, and the endothelium dependent, noradrenaline mediated relaxations, differ according to the branching order studied. These data provide further evidence for a regional heterogeneity of vascular responses in the porcine coronary vasculature.