tbuckley/cabot-search huggingface dataset:
GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice
Authors: Elizabeth A. Wohlfert, John R. Grainger, Nicolas Bouladoux, Joanne E. Konkel, Guillaume Oldenhove, Carolina Hager Ribeiro, Jason A. Hall, Ryoji Yagi, Shruti Naik, Ravikiran Bhairavabhotla, William E. Paul, Remy Bosselut, Gang Wei, Keji Zhao, Mohamed Oukka, Jinfang Zhu, Yasmine Belkaid
Journal: Journal of Clinical Investigation (2011)

Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on their capacity to accumulate at inflamed sites and appropriately adapt to their local environment. To date, the factors involved in the control of these aspects of Treg physiology remain poorly understood. Here, we show that the canonical Th2 transcription factor GATA3 is selectively expressed in Tregs residing in barrier sites including the gastrointestinal tract and the skin. GATA3 expression in both murine and human Tregs was induced upon TCR and IL-2 stimulation. Although GATA3 was not required to sustain Treg homeostasis and function at steady state, GATA3 played a cardinal role in Treg physiology during inflammation. Indeed, the intrinsic expression of GATA3 by Tregs was required for their ability to accumulate at inflamed sites and to maintain high levels of Foxp3 expression in various polarized or inflammatory settings. Furthermore, our data indicate that GATA3 limits Treg polarization toward an effector T cell phenotype and acquisition of effector cytokines in inflamed tissues. Overall, our work reveals what we believe to be a new facet in the complex role of GATA3 in T cells and highlights what may be a fundamental role in controlling Treg physiology during inflammation.
Apoptosis: The Biochemistry and Molecular Biology of Programmed Cell Death*
Authors: ROBERT A. SCHWARTZMAN, JOHN A. CIDLOWSKI
Journal: Endocrine Reviews (1993)

DEATH, along with growth and differentiation, is a critical part of the life cycle of a cell. Homeostatic control of cell number is thought to be the result of the dynamic balance between cell proliferation and cell death. It is only in the past few years, however, that attention has been focused on the physiological occurrence of cell death and its role in homeostasis. Researchers have become increasingly more aware during this time that this type of "natural" death, which is now called apoptosis or programmed cell death, is a widespread phenomenon that plays a crucial role in a myriad of physiological and pathological processes. This review first briefly covers some historical perspective on the discovery of apoptotic cell death, the characteristic morphology that accompanies this process, and the numerous cell types and mediators with which programmed cell death is associated. The bulk of the review discusses our current understanding of the biochemical and molecular mechanisms by which apoptosis occurs. Finally, the potential for therapeutic uses of apoptosis is discussed, along with some comments on the physiological importance of programmed cell death and where the future lies for this quickly expanding and exciting field.
Effects of chronic glyceryl trinitrate on left ventricular haemodynamics in a rat model of congestive heart failure: demonstration of a simple animal model for the study of in vivo nitrate tolerance
Authors: J. A. Bauer, H.-L. Fung
Journal: Cardiovascular Research (1990)

Study objective – The aim of the study was to investigate the problem of pharmacological tolerance to nitrate therapy in congestive heart failure, using an animal model.
Cognitive Function, Fatigue, and Menopausal Symptoms in Women Receiving Adjuvant Chemotherapy for Breast Cancer
Authors: Nadine Tchen, Helen G. Juffs, Fiona P. Downie, Qi-Long Yi, Hanxian Hu, Irene Chemerynsky, Mark Clemons, Michael Crump, Paul E. Goss, David Warr, Mary E. Tweedale, Ian F. Tannock
Journal: Journal of Clinical Oncology (2003)

There is evidence that cognitive dysfunction, fatigue, and menopausal symptoms may occur in women receiving adjuvant chemotherapy for breast cancer. Here, we determine their incidence and severity, and interrelationships between them and quality of life.In this study, 110 women receiving adjuvant chemotherapy each nominated a female relative, friend, or neighbor (matched by age) as a control; 100 eligible matched pairs were evaluated. Patients and controls completed the following assessments: the High-Sensitivity Cognitive Screen, and the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life scale with subscales for fatigue (FACT-F) and endocrine symptoms (FACT-ES). They also performed tests of attention and reaction time.Patients and controls were well matched for age and level of education. There was a higher incidence of moderate or severe cognitive impairment in the patient group (16% v 4%; P =.008). Patients experienced much more fatigue than controls (median FACT-F scores, 31 v 46; P <.0001) and more menopausal symptoms (median FACT-ES scores, 58 v 64; P <.0001). Self-reported quality of life of the patients was poorer than for controls, especially in physical and functional domains (median FACT-G scores, 77 v 93; P <.0001). There was strong correlation between fatigue, menopausal symptoms, and quality of life (P <.0001 for each pair), but none were significantly associated with the presence of cognitive dysfunction.Adjuvant chemotherapy causes cognitive dysfunction, fatigue, and menopausal symptoms in women with breast cancer. Priority should be given to the study of strategies that might reduce these toxic effects.
Identification of Ras-Related Nuclear Protein, Targeting Protein for <i>Xenopus</i> Kinesin-like Protein 2, and Stearoyl-CoA Desaturase 1 as Promising Cancer Targets from an RNAi-Based Screen
Authors: Susan E. Morgan-Lappe, Lora A. Tucker, Xiaoli Huang, Qian Zhang, Aparna V. Sarthy, Dorothy Zakula, Lawrence Vernetti, Mark Schurdak, Jieyi Wang, Stephen W. Fesik
Journal: Cancer Research (2007)

Abstract To identify new candidate cancer drug targets, we used RNAi as a tool to functionally evaluate genes that play a role in maintaining human tumor cell survival. We screened a small interfering RNA (siRNA) library directed against ∼3,700 individual genes to assess the ability of siRNAs to induce cell death in an in vitro cell cytotoxicity assay. We found that siRNAs specifically targeting ras-related nuclear protein (Ran), targeting protein for Xenopus kinesin-like protein 2 (TPX2), and stearoyl-CoA desaturase 1 (SCD1), significantly reduced the survival of multiple human tumor cell lines. Further target validation studies revealed that treatment with Ran and TPX2 siRNAs differentially reduced the survival of activated K-Ras–transformed cells compared with their normal isogenic counterparts in which the mutant K-Ras gene had been disrupted (DKS-8). Knockdown of Ran and TPX2 in activated mutant K-Ras cells selectively induced S-phase arrest or transient G2-M arrest phenotypes, respectively, that preceded apoptotic cell death. Given our observations that Ran and TPX2 depletion preferentially reduces the survival of activated K-Ras–transformed cells, these two proteins may serve as useful anticancer targets in tumors expressing the activated K-Ras oncogene. [Cancer Res 2007;67(9):4390–7]
Smooth muscle microparticles as novel biomarkers of vascular remodelling and inflammation in pulmonary arterial hypertension
Authors: Rijan Gurung, Lucie Clapp, Nigel Klein
Journal: European Respiratory Journal (2014)

Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Inflammation is thought to be a key player in PAH and stimulates the release of submicron vesicles known as microparticles (MPs) from various cells including endothelial cells. These MPs have shown to be elevated in pulmonary hypertension and correlate with disease severity. A hallmark of PAH is medial thickening but it is unclear whether MPs might be released from vascular smooth muscle cells into the circulation from PAH patients after endothelial damage. Aim: We investigated whether MPs could be detected and characterised after an inflammatory insult on pulmonary arterial smooth muscle cells (PASMCs) isolated from PAH patients. Methods: Serum with or without the mitogen PDGF-BB was used to stimulate PASMCs and Platelet derived growth factor receptor β (PDGFRβ), endoglin, ICAM1, MCAM, VCAM1, KDR, α smooth muscle actin, sm22α, and annexin V MPs were measured by flow cytometry. Results: Levels of annexin V+ total MPs were significantly increased after PDGF-BB stimulation after 24 hours compared to serum control (p
Continuing the debate about measuring asthma in population studies
Authors: J K Peat
Journal: Thorax (2001)

The reasons for measuring atopy and airway hyperresponsiveness (AHR) and the methods of validating measurements of asthma in population studies continue to be debated. The debate has centred around standards against which to validate asthma measurements but the absence of a "gold standard" makes the criterion validation of measurements difficult. Questionnaires will always be useful but cannot be validated against a doctor diagnosis because of self-selection and recall biases. In practice, measurements should be selected on the merits of what they measure rather than being regarded as validated or non-validated alternatives. The measurement of AHR is invaluable because it is reliable, not influenced by variations in symptom perception or diagnostic trends, and is closely related to the underlying mechanisms of asthma. The value of AHR lies in its high specificity (rate of true negatives) and low sensitivity (rate of false positives) against asthma symptoms which gives additional information about symptomatic subjects. Atopy is also a useful test and, in quantifying its association with asthma, we should not place any currency on ecological evidence. Atopy is a strong risk factor for asthma in the presence of regionally specific allergens and ecological analyses that ignore these effects are diversionary rather than productive. For preventing asthma, we need to identify the group at greatest risk of developing it, measure the risk factors with precision, and develop interventions that are effective in changing environmental exposures and homogenous outcomes. This is the only approach that has the potential to lead to significant public health benefits.
Polymerase Chain Reaction Selects a Novel Disintegrin Proteinase from CD40-Activated Germinal Center Dendritic Cells
Authors: Chris G.F. Mueller, Marie-Clotilde Rissoan, Barbara Salinas, Smina Ait-Yahia, Odile Ravel, Jean-Michel Bridon, Francine Briere, Serge Lebecque, Yong-Jun Liu
Journal: The Journal of Experimental Medicine (1997)

To identify genes expressed by a specific subset of dendritic cells found in vivo a polymerase chain reaction-based cDNA subtraction technique was applied to the recently described germinal center dendritic cells. A novel member of the disintegrin metalloproteinase family was cloned which comprises a not typical zinc-chelating catalytic site most similar to a bacterial metalloproteinase. Dendritic cell precursors or immature dendritic cells express no or low levels of the message. It is induced to high levels upon spontaneous or CD40-dependent maturation and in a mixed lymphocyte reaction. In situ hybridization showed distinct expression of this gene in the germinal center. This, together with the findings that certain disintegrin metalloproteinases regulate the activity of tumor necrosis factor alpha and that metalloproteinases have also been implicated in FasL processing, suggest that this novel molecule may play an important role in dendritic cell function and their interactions with germinal center T cells.
Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury
Authors: Sanket S. Acharya, Wojciech Fendler, Jacqueline Watson, Abigail Hamilton, Yunfeng Pan, Emily Gaudiano, Patryk Moskwa, Payel Bhanja, Subhrajit Saha, Chandan Guha, Kalindi Parmar, Dipanjan Chowdhury
Journal: Science Translational Medicine (2015)

Serum miRNAs can predict long-term radiation-induced hematopoietic injury immediately after radiation and thereby facilitate timely medical intervention and improve overall survival of exposed individuals.
Key communication skills and how to acquire them
Authors: P. Maguire
Journal: BMJ (2002)

Good doctors communicate effectively with patients—they identify patients' problems more accurately, and patients are more satisfied with the care they receive. But what are the necessary communication skills and how can doctors acquire them? When doctors use communication skills effectively, both they and their patients benefit. Firstly, doctors identify their patients' problems more accurately.1 Secondly, their patients are more satisfied with their care and can better understand their problems, investigations, and treatment options. Thirdly, patients are more likely to adhere to treatment and to follow advice on behaviour change.2 Fourthly, patients' distress and their vulnerability to anxiety and depression are lessened. Finally, doctors' own wellbeing is improved.3–5 We present evidence that doctors do not communicate with their patients as well as they should, and we consider possible reasons for this. We also describe the skills essential for effective communication and discuss how doctors can acquire these skills. #### Summary points We used original research studies into doctor-patient communication, particularly those examining the relation between key consultation skills and how well certain tasks (such as explaining treatment options) were achieved. We used key words (“communication skills,” “consultation skills,” and “interviewing skills” whether associated with “training” or not) to search Embase, PsycINFO, and Medline over the past 10 years. We also searched the Cochrane database of abstracts of reviews of effectiveness (DARE). ### Box 1: Key tasks in communication with patients RETURN TO TEXT
Effects of the Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor Avasimibe on Human Atherosclerotic Lesions
Authors: Jean-Claude Tardif, Jean Grégoire, Philippe L. L’Allier, Todd J. Anderson, Olivier Bertrand, Francois Reeves, Lawrence M. Title, Fernando Alfonso, Erick Schampaert, Alita Hassan, Richard McLain, Milton L. Pressler, Reda Ibrahim, Jacques Lespérance, John Blue, Therese Heinonen, Josep Rodés-Cabau
Journal: Circulation (2004)

Background— Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis. Methods and Results— This randomized, double-blind, placebo-controlled trial assessed the effects of avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level &lt;125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was ≈200 mm 3 , and the least squares mean change at end of treatment was 0.7 mm 3 for placebo and 7.7, 4.1, and 4.8 mm 3 for the avasimibe 50, 250, and 750 mg groups, respectively (adjusted P =0.17 [unadjusted P =0.057], 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups ( P =NS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective avasimibe groups ( P &lt;0.05 in all groups). Conclusions— Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in LDL cholesterol.
Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy Trial
Authors: Barton F. Haynes, Peter B. Gilbert, M. Juliana McElrath, Susan Zolla-Pazner, Georgia D. Tomaras, S. Munir Alam, David T. Evans, David C. Montefiori, Chitraporn Karnasuta, Ruengpueng Sutthent, Hua-Xin Liao, Anthony L. DeVico, George K. Lewis, Constance Williams, Abraham Pinter, Youyi Fong, Holly Janes, Allan DeCamp, Yunda Huang, Mangala Rao, Erik Billings, Nicos Karasavvas, Merlin L. Robb, Viseth Ngauy, Mark S. de Souza, Robert Paris, Guido Ferrari, Robert T. Bailer, Kelly A. Soderberg, Charla Andrews, Phillip W. Berman, Nicole Frahm, Stephen C. De Rosa, Michael D. Alpert, Nicole L. Yates, Xiaoying Shen, Richard A. Koup, Punnee Pitisuttithum, Jaranit Kaewkungwal, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Nelson L. Michael, Jerome H. Kim
Journal: New England Journal of Medicine (2012)

In the RV144 trial, the estimated efficacy of a vaccine regimen against human immunodeficiency virus type 1 (HIV-1) was 31.2%. We performed a case–control analysis to identify antibody and cellular immune correlates of infection risk.
Disruption at the <i>PTCHD1</i> Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability
Authors: Abdul Noor, Annabel Whibley, Christian R. Marshall, Peter J. Gianakopoulos, Amelie Piton, Andrew R. Carson, Marija Orlic-Milacic, Anath C. Lionel, Daisuke Sato, Dalila Pinto, Irene Drmic, Carolyn Noakes, Lili Senman, Xiaoyun Zhang, Rong Mo, Julie Gauthier, Jennifer Crosbie, Alistair T. Pagnamenta, Jeffrey Munson, Annette M. Estes, Andreas Fiebig, Andre Franke, Stefan Schreiber, Alexandre F. R. Stewart, Robert Roberts, Ruth McPherson, Stephen J. Guter, Edwin H. Cook, Geraldine Dawson, Gerard D. Schellenberg, Agatino Battaglia, Elena Maestrini, Linda Jeng, Terry Hutchison, Evica Rajcan-Separovic, Albert E. Chudley, Suzanne M. E. Lewis, Xudong Liu, Jeanette J. Holden, Bridget Fernandez, Lonnie Zwaigenbaum, Susan E. Bryson, Wendy Roberts, Peter Szatmari, Louise Gallagher, Michael R. Stratton, Jozef Gecz, Angela F. Brady, Charles E. Schwartz, Russell J. Schachar, Anthony P. Monaco, Guy A. Rouleau, Chi-chung Hui, F. Lucy Raymond, Stephen W. Scherer, John B. Vincent
Journal: Science Translational Medicine (2010)

Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.
Laminar Arrangement of Ventricular Myocytes Influences Electrical Behavior of the Heart
Authors: Darren A. Hooks, Mark L. Trew, Bryan J. Caldwell, Gregory B. Sands, Ian J. LeGrice, Bruce H. Smaill
Journal: Circulation Research (2007)

The response of the heart to electrical shock, electrical propagation in sinus rhythm, and the spatiotemporal dynamics of ventricular fibrillation all depend critically on the electrical anisotropy of cardiac tissue. A long-held view of cardiac electrical anisotropy is that electrical conductivity is greatest along the myocyte axis allowing most rapid propagation of electrical activation in this direction, and that conductivity is isotropic transverse to the myocyte axis supporting a slower uniform spread of activation in this plane. In this context, knowledge of conductivity in two directions, parallel and transverse to the myofiber axis, is sufficient to characterize the electrical action of the heart. Here we present new experimental data that challenge this view. We have used a novel combination of intramural electrical mapping, and experiment-specific computer modeling, to demonstrate that left ventricular myocardium has unique bulk conductivities associated with three microstructurally-defined axes. We show that voltage fields induced by intramural current injection are influenced by not only myofiber direction, but also the transmural arrangement of muscle layers or myolaminae. Computer models of these experiments, in which measured 3D tissue structure was reconstructed in-silico, best matched recorded voltages with conductivities in the myofiber direction, and parallel and normal to myolaminae, set in the ratio 4:2:1, respectively. These findings redefine cardiac tissue as an electrically orthotropic substrate and enhance our understanding of how external shocks may act to successfully reset the fibrillating heart into a uniform electrical state. More generally, the mechanisms governing the destabilization of coordinated electrical propagation into ventricular arrhythmia need to be evaluated in the light of this discovery.