tbuckley/cabot-search huggingface dataset:
Histone Deacetylase 7 Controls Endothelial Cell Growth Through Modulation of β-Catenin
Authors: Andriana Margariti, Anna Zampetaki, Qingzhong Xiao, Boda Zhou, Eirini Karamariti, Daniel Martin, Xiaoke Yin, Manuel Mayr, Hongling Li, Zhongyi Zhang, Elena De Falco, Yanhua Hu, Gillian Cockerill, Qingbo Xu, Lingfang Zeng
Journal: Circulation Research (2010)

Rationale : Histone deacetylase (HDAC)7 is expressed in the early stages of embryonic development and may play a role in endothelial function. Objective : This study aimed to investigate the role of HDAC7 in endothelial cell (EC) proliferation and growth and the underlying mechanism. Methods and Results : Overexpression of HDAC7 by adenoviral gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of β-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G 1 phase elongation. Further assays with the TOPFLASH reporter and quantitative RT-PCR for other β-catenin target genes such as Axin2 confirmed that overexpression of HDAC7 decreased β-catenin activity. Knockdown of HDAC7 by lentiviral short hairpin RNA transfer induced β-catenin nuclear translocation but downregulated cyclin D1, cyclin E1 and E2F2, causing HUVEC hypertrophy. Immunoprecipitation assay and mass spectrometry analysis revealed that HDAC7 directly binds to β-catenin and forms a complex with 14-3-3 ε, ζ, and η proteins. Vascular endothelial growth factor treatment induced HDAC7 degradation via PLCγ-IP3K (phospholipase Cγ–inositol-1,4,5-trisphosphate kinase) signal pathway and partially rescued HDAC7-mediated suppression of proliferation. Moreover, vascular endothelial growth factor stimulation suppressed the binding of HDAC7 with β-catenin, disrupting the complex and releasing β-catenin to translocate into the nucleus. Conclusions : These findings demonstrate that HDAC7 interacts with β-catenin keeping ECs in a low proliferation stage and provides a novel insight into the mechanism of HDAC7-mediated signal pathways leading to endothelial growth.
Controversies in Ulcerative Colitis: A Survey Comparing Decision Making of Experts Versus Community Gastroenterologists
Authors: Brennan M.R. Spiegel, Wayne Ho, Eric Esrailian, Stephan Targan, Peter D.R. Higgins, Corey A. Siegel, Marla Dubinsky, Gil Y. Melmed
Journal: Clinical Gastroenterology and Hepatology (2008)
Glutathione Synthesis in Human Erythrocytes
Authors: Philip W. Majerus, M. J. Brauner, M. B. Smith, Virginia Minnich
Journal: Journal of Clinical Investigation (1971)

The two enzymes required to synthesize glutathione de novo have been purified from human erythrocytes. Glutamylcysteine synthetase was purified 4300-fold and was approximately 80% pure based on polyacrylamide gel electrophoresis. The purified enzyme catalyzes the formation of 30.5 mumoles of gamma-glutamyl-cysteine per mg of protein per hr and is inhibited by sulfhydryl inhibitors. Glutathione synthetase was purified 6000-fold from erythrocytes to homogeneity as determined by polyacrylamide gel electrophoresis. The erythrocyte enzyme has a molecular weight of 150,000 and catalyzes the formation of 35.9 mumoles of glutathione per mg of protein per hr. Comparison of the amino acid composition and some kinetic parameters of yeast glutathione synthetase and the erythrocyte enzyme demonstrate similarities between these enzymes.
Multiple choice question quiz: a valid test for needs assessment in CME in rheumatology and for self assessment
Authors: A Aeschlimann
Journal: Annals of the Rheumatic Diseases (2001)

Drawing from experience in Switzerland, a test of 60 multiple choice questions covering the entire area of rheumatology was constructed and used at the international symposium of rheumatology, EULAR, Geneva 1998. It was introduced as a multiple choice question game, the language was English, and the level of acceptance was very high. Language posed only occasional problems. The reliability of the test for internal consistency was high (Cronbach alpha 0.852). One of the main target groups, the private practitioners, was the largest group of rheumatologists (nearly 50%). Evaluative statements of the participants indicate that it was a highly relevant test for rheumatology. This test is a valuable way for needs assessment in continuing medical education and for self assessment. Importantly, it has been shown that such a test can be conducted at an international level.
Regulation of G Protein-Coupled Receptor Function by Na<sup>+</sup>/H<sup>+</sup>Exchange Regulatory Factors
Authors: Juan A. Ardura, Peter A. Friedman
Journal: Pharmacological Reviews (2011)

Many G protein-coupled receptors (GPCR) exert patterns of cell-specific signaling and function. Mounting evidence now supports the view that cytoplasmic adapter proteins contribute critically to this behavior. Adapter proteins recognize highly conserved motifs such as those for Src homology 3 (SH3), phosphotyrosine-binding (PTB), and postsynaptic density 95/discs-large/zona occludens (PDZ) docking sequences in candidate GPCRs. Here we review the behavior of the Na<sup>+</sup>/H<sup>+</sup> exchange regulatory factor (NHERF) family of PDZ adapter proteins on GPCR signalling, trafficking, and function. Structural determinants of NHERF proteins that allow them to recognize targeted GPCRs are considered. NHERF1 and NHERF2 are capable also of modifying the assembled complex of accessory proteins such as β-arrestins, which have been implicated in regulating GPCR signaling. In addition, NHERF1 and NHERF2 modulate GPCR signaling by altering the G protein to which the receptor binds or affect other regulatory proteins that affect GTPase activity, protein kinase A, phospholipase C, or modify downstream signaling events. Small molecules targeting the site of NHERF1-GPCR interaction are being developed and may become important and selective drug candidates.
Smoking cessation guidelines for health professionals: an update
Authors: R. West
Journal: Thorax (2000)

This paper updates the evidence base and key recommendations of the Health Education Authority (HEA) smoking cessation guidelines for health professionals published in <i>Thorax</i> in 1998. The strategy for updating the evidence base makes use of updated Cochrane reviews supplemented by individual studies where appropriate. This update contains additional detail concerning the effectiveness of interventions as well as comments on issues relating to implementation. The recommendations include clarification of some important issues addressed only in general terms in the original guidelines. The conclusion that smoking cessation interventions delivered through the National Health Service are an extremely cost effective way of preserving life and reducing ill health remains unchanged. The strategy recommended by the guidelines involves: (1) GPs opportunistically advising smokers to stop during routine consultations, giving advice on and/or prescribing effective medications to help them and referring them to specialist cessation services; (2) specialist smokers9 services providing behavioural support (in groups or individually) for smokers who want help with stopping and using effective medications wherever possible; (3) specialist cessation counsellors providing behavioural support for hospital patients and pregnant smokers who want help with stopping; (4) all health professionals involved in smoking cessation encouraging and assisting smokers in use of nicotine replacement therapies (NRT) or bupropion where appropriate. The key points of clarification of the previous guidelines include: (1) primary health care teams and hospitals should create and maintain readily accessible records on the current smoking status of patients; (2) GPs should aim to advise smokers to stop, and record having done so, at least once a year; (3) inpatient, outpatient, and pregnant smokers should be advised to stop as early as possible and the advice recorded in the notes in a readily accessible form; (4) there is currently little scientific basis for matching individual smokers to particular forms of NRT; (5) NHS specialist smokers9 clinics should be the first point of referral for smokers wanting help beyond what can be provided through brief advice from the GP; (6) help from trained health care professionals specialising in smoking cessation such as practice nurses should be available for smokers who do not have access to specialist clinics; (7) the provision of specialist NHS smokers9 clinics should be commensurate with demand; this is currently one or two full time clinics or their equivalent per average sized health authority, but demand may rise as publicity surrounding the services increases.
Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG
Authors: D. Nitti, J. Wils, J. Guimaraes Dos Santos, G. Fountzilas, P.F. Conte, C. Sava, A. Tres, R.C. Coombes, D. Crivellari, A. Marchet, E. Sanchez, J.M. Bliss, J. Homewood, M.L. Couvreur, E. Hall, B. Baron, E. Woods, M. Emson, E. Van Cutsem, M. Lise
Journal: Annals of Oncology (2005)
Book Review Food Safety: Old Habits, New Perspectives By Phyllis Entis. 400 pp. Washington, DC, ASM Press, 2007. $49.95. 978-1-55581-417-5 Food Microbiology: Fundamentals and Frontiers Third edition. Edited by Michael P. Doyle and Larry R. Beuchat. 1038 pp., illustrated. Washington, DC, ASM Press, 2007. $169.95. 978-1-55581-407-6
Authors: Nkuchia M. M'ikanatha
Journal: New England Journal of Medicine (2007)
Methadone Maintenance: Myth and Reality
Authors: CHARLES L. BOWDEN, JAMES F. MADDUX
Journal: American Journal of Psychiatry (1972)

The authors attempt to place methadone maintenance programs in proper perspective by correcting some of the myths surrounding methadone itself and also narcotic addiction in general. They believe that the costs of maintaining a heroin habit are often exaggerated and that rates for abstinence from heroin after treatment, while initially low, tend to improve with time. On the other hand, methadone maintenance does have several specific advantages, which the authors outline. They give suggestions for the clinical implementation of some of their conclusions and also point to areas in need of further study.
The clinician's guide to acid/peptic disorders and motility disorders of the gastrointestinal tract
Authors: E. M El-Omar
Journal: Gut (2007)

Edited by Henry P Parkman, Robert S Fisher. New Jersey: SLACK Incorporated, 2006, £31.85 (paper book), pp 458. ISBN 1-55642-716-6

This book is authored by a group of well-known gastrointestinal (GI) experts based in North America. Each has extensive clinical experience and their collective contribution makes an excellent and thorough account of important areas of GI practice. The book is a new addition to “The Clinicians Guide to GI Series”, which has dealt with other important GI and hepatology topics. The first part of the book takes on the so-called acid/peptic disorders, which essentially encompass gastro-oesophageal reflux disease (GORD) and peptic ulcer disease, and their complications. The second section deals with motility disorders, but concentrates on selected functional disorders of the oesophagus, stomach, small bowel …
The role of sodium in intestinal glucose absorption in man
Authors: Ward A. Olsen, Franz J. Ingelfinger
Journal: Journal of Clinical Investigation (1968)

The effect of luminal sodium on intestinal glucose absorption at a variety of glucose concentrations was studied with a segmental perfusion technique in normal subjects. Uphill glucose transport was inhibited with sodium-free perfusions with either mannitol or Tris-HCl as the osmotic replacement of sodium (P < 0.01-P < 0.001). This effect did not appear to be the result of solvent drag, as increasing net water absorption without supplying sodium to the lumen did not increase glucose absorption. Downhill glucose transport (infusion concentrations of 6.0-27.8 mmoles/liter), on the other hand, was not affected by the absence of sodium in the infusion solution. Glucose concentrations of upper intestinal fluid after normal carbohydrate meals were usually found to exceed serum concentrations; thus, downhill glucose absorption, with, at most, a very limited dependence upon intraluminal sodium concentration, may account for a significant part of normal carbohydrate absorption.
Leukotriene B4 amplifies eosinophil accumulation in response to nematodes
Authors: Michael L. Patnode, Jennifer K. Bando, Matthew F. Krummel, Richard M. Locksley, Steven D. Rosen
Journal: The Journal of Experimental Medicine (2014)

Eosinophil accumulation is a defining feature of the immune response to parasitic worm infection. Tissue-resident cells, such as epithelial cells, are thought to initiate eosinophil recruitment. However, direct recognition of worms by eosinophils has not been explored as a mechanism for amplifying eosinophil accumulation. Here, we report that eosinophils rapidly migrate toward diverse nematode species in three-dimensional culture. These include the mammalian parasite Nippostrongylus brasiliensis and the free-living nematode Caenorhabditis elegans. Surprisingly, collective migration toward worms requires paracrine leukotriene B4 signaling between eosinophils. In contrast, neutrophils show a minimal response to nematodes, yet are able to undergo robust leukotriene-dependent migration toward IgG-coated beads. We further demonstrate that eosinophils accumulate around C. elegans in the lungs of mice. This response is not dependent on bacterial products, CCR3, or complement activation. However, mice deficient in leukotriene signaling show markedly attenuated eosinophil accumulation after injection of C. elegans or N. brasiliensis. Our findings establish that nematode-derived signals can directly induce leukotriene production by eosinophils and that leukotriene signaling is a major contributor to nematode-induced eosinophil accumulation in the lung. The similarity of the eosinophil responses to diverse nematode species suggests that conserved features of nematodes are recognized during parasite infection.
Associations between health behaviours and health related fitness.
Authors: R J Shephard, C Bouchard
Journal: British Journal of Sports Medicine (1996)

To examine relations between health behaviours and health related fitness.Subjects were a convenience sample of 350 healthy adults (172 men, 178 women). Covariance analysis adjusted data for significant influences of age and socioeconomic status. Obesity was assessed by anthropometry and body density. Cardiovascular fitness was assessed and various metabolic measurements were made. Questionnaires on physical activity and health related behaviours were completed.Cigarette abstinence was associated with a small abdominal circumference (men) and a low trunk/extremity skinfold ratio (women). Obesity indices (body mass index, total skinfolds, percent fat, and abdominal circumference) were negatively associated with perceived fitness. Leisure activity and exercise frequency were also negatively linked to some obesity indices. Blood glucose, cholesterol, HDL-cholesterol, and triglycerides were favourably influenced by perceived activity, exercise frequency, and perceived fitness, but not by exercise intensity. Abstinence from coffee was associated with a low cholesterol/HDL ratio (men only). Principal component, discriminant, and multiple logistic regression analyses showed only weak clustering of habitual physical activity with other positive health behaviours.Although multiphasic health promotion programmes are economical, favourable interactions between individual programme elements seem likely to be quite limited.
Physicians' Responsibility in Prevention of Bodily Injuries by the Automobile
Authors: Seymour Charles
Journal: JAMA (1966)

The automobile is the etiological agent in an epidemic accounting for some 50,000 deaths and 4 million injuries each year. This epidemic is outranked as the cause of death in our country today only by cancer and cardiovascular disease.<sup>1-3</sup>The automobile is the first cause of death in young people between the ages of 15 and 24 years, therefore the principal killer of our young parents. The probabilities are that one out of every two Americans will be involved in his lifetime in an injury-producing collision. There are now some 95 million drivers in this country. By 1975 there are expected to be an additional 30 million drivers. At the current rate of increase (17% in the last two years) in the next decade, the annual death rate from the automobile will pass the 100,000 mark and the cost of accidents will climb from 8.2 to 15 billion per
Effect of a Dietary Portfolio of Cholesterol-Lowering Foods Given at 2 Levels of Intensity of Dietary Advice on Serum Lipids in Hyperlipidemia
Authors: David J. A. Jenkins, Peter J. H. Jones, Benoit Lamarche, Cyril W. C. Kendall, Dorothea Faulkner, Luba Cermakova, Iris Gigleux, Vanu Ramprasath, Russell de Souza, Chris Ireland, Darshna Patel, Korbua Srichaikul, Shahad Abdulnour, Balachandran Bashyam, Cheryl Collier, Sandy Hoshizaki, Robert G. Josse, Lawrence A. Leiter, Philip W. Connelly, Jiri Frohlich
Journal: JAMA (2011)

2][3] Nevertheless, the introduction of statins in the late 1980s highlighted the relative ineffectiveness of conventional dietary advice. 4As a result, alternative dietary paradigms have been proposed [5][6][7] and efforts have been made to enhance the ability of conven-tional dietary therapy to reduce serum cholesterol through the inclusion of specific foods or food components with known cholesterol-lowering proper-
Establishment of two interleukin 6 (B cell stimulatory factor 2/interferon beta 2)-dependent human bone marrow-derived myeloma cell lines.
Authors: S Shimizu, R Yoshioka, Y Hirose, S Sugai, J Tachibana, S Konda
Journal: The Journal of Experimental Medicine (1989)

Two IL-6-dependent human multiple myeloma cell lines, ILKM2 and ILKM3, were established from the bone marrow of patients with IgG-K multiple myeloma. Both cell lines had the typical morphology and immunocytochemical features of myeloma cells. The surface phenotype of both cell lines was PCA-1+, OKT10+, CD10(J-5)-, CD19(B4)-, CD20(B1)-, CD21(B2)-, and OKIa-1-. A monoclonal cytoplasmic Ig, IgG-K or K L chain, was positive in ILKM2 or ILKM3, respectively. EBV nuclear antigen was negative in both cell lines. They proliferated in the presence of macrophages or macrophage-derived factors (MDF). Among the recombinant cytokines examined, IL-6 most strongly augmented the growth of both cell lines. The anti-IL-6 antibody completely inhibited the IL-6-dependent growth and almost completely inhibited the MDF- or purified MDF-dependent growth of both cell lines, ILKM2 and ILKM3 are now being maintained in the culture medium containing 2 ng/ml rIL-6. These results suggest that IL-6 produced by macrophages may play an important role in the growth of myeloma cells in vivo and that macrophages or IL-6 can be used for establishing human myeloma cell lines.
Abrogation of Heat Shock Protein 70 Induction as a Strategy to Increase Antileukemia Activity of Heat Shock Protein 90 Inhibitor 17-Allylamino-Demethoxy Geldanamycin
Authors: Fei Guo, Kathy Rocha, Purva Bali, Michael Pranpat, Warren Fiskus, Sandhya Boyapalle, Sandhya Kumaraswamy, Maria Balasis, Benjamin Greedy, E. Simon M. Armitage, Nicholas Lawrence, Kapil Bhalla
Journal: Cancer Research (2005)

17-Allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone association of heat shock protein 90 (hsp90) with the heat shock factor-1 (HSF-1), which induces the mRNA and protein levels of hsp70. Increased hsp70 levels inhibit death receptor and mitochondria-initiated signaling for apoptosis. Here, we show that ectopic overexpression of hsp70 in human acute myelogenous leukemia HL-60 cells (HL-60/hsp70) and high endogenous hsp70 levels in Bcr-Abl-expressing cultured CML-BC K562 cells confers resistance to 17-AAG-induced apoptosis. In HL-60/hsp70 cells, hsp70 was bound to Bax, inhibited 17-AAG-mediated Bax conformation change and mitochondrial localization, thereby inhibiting the mitochondria-initiated events of apoptosis. Treatment with 17-AAG attenuated the levels of phospho-AKT, AKT, and c-Raf but increased hsp70 levels to a similar extent in the control HL-60/Neo and HL-60/hsp70 cells. Pretreatment with 17-AAG, which induced hsp70, inhibited 1-beta-D-arabinofuranosylcytosine or etoposide-induced apoptosis in HL-60 cells. Stable transfection of a small interfering RNA (siRNA) to hsp70 completely abrogated the endogenous levels of hsp70 and blocked 17-AAG-mediated hsp70 induction, resulting in sensitizing K562/siRNA-hsp70 cells to 17-AAG-induced apoptosis. This was associated with decreased binding of Bax to hsp70 and increased 17-AAG-induced Bax conformation change. 17-AAG-mediated decline in the levels of AKT, c-Raf, and Bcr-Abl was similar in K562 and K562/siRNA-hsp70 cells. Cotreatment with KNK437, a benzylidine lactam inhibitor of hsp70 induction and thermotolerance, attenuated 17-AAG-mediated hsp70 induction and increased 17-AAG-induced apoptosis and loss of clonogenic survival of HL-60 cells. Collectively, these data indicate that induction of hsp70 attenuates the apoptotic effects of 17-AAG, and abrogation of hsp70 induction significantly enhances the antileukemia activity of 17-AAG.
Rationing in the NHS
Authors: Rudolf Klein
Journal: BMJ (2007)

The BMA asks the right questions but answering them will be difficult

Over the past two decades or so rationing has been debated more than almost any other area of health policy. However, the debate has been punctuated by periods of relative silence when policy makers have been reluctant to tackle the key problems. The past few years have been one such period as new money appeared to have flushed away old concerns. Now, however, those concerns are back, underlined by the hectic race to balance the National Health Service's books and the realisation that the days of rapid growth in its budget are almost over.

A new factor is adding to these concerns. If in the past the NHS was a model of economy, it was partly because no one had an incentive to maximise activity. But as the new model NHS emerges, payment by results to hospital providers will provide such an incentive. As the NHS inevitably becomes a demand generating machine, so the challenge of accommodating competing demands within a constrained budget will become more acute.

The BMA has therefore …
Focal Segmental Glomerulosclerosis
Authors: Vivette D. D'Agati, Frederick J. Kaskel, Ronald J. Falk
Journal: New England Journal of Medicine (2011)

Focal segmental glomerulosclerosis, which is characterized by progressive glomerular scarring, accounts for about 20% of cases of the nephrotic syndrome in children and 40% in adults. This review considers current approaches to diagnosis and management of the disease.
Pharmacokinetics, Clinical Indications, and Resistance Mechanisms in Molecular Targeted Therapies in Cancer
Authors: Benjamin Izar, Julia Rotow, Justin Gainor, Jeffrey Clark, Bruce Chabner
Journal: Pharmacological Reviews (2013)

The strategy for discovery and development of new cancer drugs has shifted the field from cytotoxic agents to therapies that selectively target oncogenic drivers. In the last decade, a number of targeted cancer therapies have been discovered and proven effective in a variety of hematological and solid malignancies. In this article, we review clinical pharmacokinetic characteristics of the U.S. Food and Drug Administration–approved targeted therapies and provide an overview of key clinical trials that led to approval of these drugs. The major limiting factor of targeted treatment is the development of resistance. We describe general principles of resistance and specific, clinically confirmed mechanisms of resistance to several therapies in different malignancies.