tbuckley/cabot-search huggingface dataset:
An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans.
Authors: O Lantz, A Bendelac
Journal: The Journal of Experimental Medicine (1994)

The mouse thymus contains a mature T cell subset that is distinguishable from the mainstream thymocytes by several characteristics. It is restricted in its usage of T cell receptor (TCR) V beta genes to V beta 8, V beta 7, and V beta 2. Its surface phenotype is that of activated/memory cells. It carries the natural killer NK1.1 surface marker. Furthermore, though it consists entirely of CD4+ and CD4-8- cells, its selection in the thymus depends solely upon major histocompatibility complex (MHC) class I expression by cells of hematopoietic origin. Forced persistence of CD8, in fact, imparts negative selection. Here, we have studied the TCR repertoire of this subset and found that, whereas the beta chain V-D-J junctions are quite variable, a single invariant alpha chain V alpha 14-J281 is used by a majority of the TCRs. This surprisingly restricted usage of the V alpha 14-J281 alpha chain is dependent on MHC class I expression, but independent of the MHC haplotype. In humans, a similar unusual population including CD4-8- cells can also be found that uses a strikingly homologous, invariant alpha chain V alpha 24-JQ. Thus, this unique V alpha-J alpha combination has been conserved in both species, conferring specificity to some shared nonpolymorphic MHC class I/peptide self-ligand(s). This implies that the T cell subset that it defines has a specialized and important role, perhaps related to its unique ability to secrete a large set of lymphokines including interleukin 4, upon primary stimulation in vitro and in vivo.
Nitric Oxide in the Nervous System
Authors: J Zhang, S H Snyder
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Nitric oxide (NO) has only recently been appreciated as a normal biologic substance with a role in signal transduction. It was first identified as endothelial-derived relaxing factor in blood vessels and as the mediator of the tumoricidal and bactericidal actions of macrophages. NO's role as a neural messenger may be even more prominent. Biosynthesis of NO involves oxidation of the guanidine group of arginine with stoichiometric formation of citrulline. NO synthase is one of the most extensively regulated enzymes in biology. In the periphery, NO is a likely transmitter of nonadrenergic, noncholinergic neurons. In the brain, NO neurons mediate action of glutamate acting at N-methyl-D-aspartate (NMDA) receptors. Excess release of NO appears to account for a major portion of neural damage following vascular stroke.
Rapid Induction of Androgen Receptor Splice Variants by Androgen Deprivation in Prostate Cancer
Authors: Ziyang Yu, Sen Chen, Adam G. Sowalsky, Olga S. Voznesensky, Elahe A. Mostaghel, Peter S. Nelson, Changmeng Cai, Steven P. Balk
Journal: Clinical Cancer Research (2014)

Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer that progresses after castration (castration-resistant prostate cancer; CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear.Prostate cancer xenografts were examined to identify mechanism of progression after castration and abiraterone.AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR coregulators. In contrast, mRNA encoding full-length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared with xenografts before castration, with an increase in AR-V7 relative to AR-FL. This shift toward AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. However, despite the increases in AR-V7 mRNA, it remained a minor transcript (<1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA.AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR. Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand-binding domain.
ACCESSIBILITY CONTROL OF ANTIGEN-RECEPTOR VARIABLE-REGION GENE ASSEMBLY: Role of<i>cis</i>-Acting Elements
Authors: Barry P. Sleckman, James R. Gorman, Frederick W. Alt
Journal: Annual Review of Immunology (1996)

▪ Abstract Antigen receptor variable region genes are assembled from germline variable (V), diversity (D), and joining (J) gene segments. This process requires expression of V(D)J recombinase activity, and “accessibility” of variable gene segments to this recombinase. The exact mechanism by which variable gene segments become accessible during development is not known. However, several studies have shown that cis-acting elements that regulate transcription may also function to regulate accessibility. Here we review the evidence that transcriptional promoters, enhancers, and silencers are involved in regulation of accessibility. The manner in which these elements may combine to regulate accessibility is addressed. In addition, current and potential strategies for identifying and analyzing cis-acting elements that mediate locus accessibility are discussed.
FcgRIII engagement provides activating signals to NKT cells in antibody-induced joint inflammation
Authors: H. Y. Kim
Journal: Journal of Clinical Investigation (2006)

NKT cells promote antibody-induced arthritis, but the mechanism by which NKT cells are activated in this model remains unclear. It has been proposed that Fcgamma receptor (FcgammaR) contributes to NKT cell activation in antibody-induced arthritis. To address this issue, we explored the functions of FcgammaR on NKT cells in antibody-induced arthritis. RT-PCR and flow cytometric analysis demonstrated that NKT cells constitutively express surface FcgammaRIII but not FcgammaRI, -II, or -IV. FcgammaRIII engagement by aggregated IgG on NKT cells enhanced CD25 and CD69 expression, whereas FcgammaR(-/-) mouse NKT cells did not enhance activation. FcgammaRIII engagement on NKT cells enhanced the production of IL-4, IL-10, IL-13, and IFN-gamma, whereas FcgammaR-deficient NKT cells did not alter the production of these cytokines after aggregated IgG treatment. However, FcgammaR-deficient NKT cells were functionally intact in terms of TCR-induced activation. Moreover, adoptive transfer of FcgammaR-deficient NKT cells could not restore inflammation or TGF-beta production in the joint tissues of CD1d(-/-) mice, whereas adoptive transfer of wild-type NKT cells induced arthritis and reduced TGF-beta production in joint tissues. We conclude that FcgammaRIII engagement by IgG in joint tissues provides activating signals to NKT cells in antibody-induced arthritis.
PI3K/AKT/mTOR Inhibitors in Patients With Breast and Gynecologic Malignancies Harboring <i>PIK3CA</i> Mutations
Authors: Filip Janku, Jennifer J. Wheler, Shannon N. Westin, Stacy L. Moulder, Aung Naing, Apostolia M. Tsimberidou, Siqing Fu, Gerald S. Falchook, David S. Hong, Ignacio Garrido-Laguna, Rajyalakshmi Luthra, J. Jack Lee, Karen H. Lu, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance.Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway.Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response.PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.
Escape from Therapy-Induced Accelerated Cellular Senescence in p53-Null Lung Cancer Cells and in Human Lung Cancers
Authors: Rachel S. Roberson, Steven J. Kussick, Eric Vallieres, Szu-Yu J. Chen, Daniel Y. Wu
Journal: Cancer Research (2005)

Abstract Accelerated cellular senescence (ACS) has been described for tumor cells treated with chemotherapy and radiation. Following exposure to genotoxins, tumor cells undergo terminal growth arrest and adopt morphologic and marker features suggestive of cellular senescence. ACS is elicited by a variety of chemotherapeutic agents in the p53-null, p16-deficient human non–small cell H1299 carcinoma cells. After 10 to 21 days, infrequent ACS cells (1 in 106) can bypass replicative arrest and reenter cell cycle. These cells express senescence markers and resemble the parental cells in their transcription profile. We show that these escaped H1299 cells overexpress the cyclin-dependent kinase Cdc2/Cdk1. The escape from ACS can be disrupted by Cdc2/Cdk1 kinase inhibitors or by knockdown of Cdc2/Cdk1 with small interfering RNA and can be promoted by expression of exogenous Cdc2/Cdk1. We also present evidence that ACS occurs in vivo in human lung cancer following induction chemotherapy. Viable tumors following chemotherapy also overexpress Cdc2/Cdk1. We propose that ACS is a mechanism of in vivo tumor response and that mechanisms aberrantly up-regulate Cdc2/Cdk1 promotes escape from the senescence pathway may be involved in a subset of tumors and likely accounts for tumor recurrence/progression.
Lung function disorders screening among the smoking patients in primary health care
Authors: Elena Andreeva, Irina Kudryavtseva, Vladimir Popov
Journal: European Respiratory Journal (2011)

Background:  Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Prevalence of smoking in Russian Federation is one of the highest in the world: 39.1% of the adult population. The airflow limitation is not necessarily accompanied by certain symptoms and therefore some patients do not always seek for medical advice.   Aim:  Early detection of airflow limitation and identification of risk factors for COPD among smoking patients in general practice in Northwest Russia.   Methods:  414 volunteers (smokers and ex-smokers) were invited to make the standardized lung function test and fulfilled the questionnaires (including the symptoms and smoking status). COHb% and carbon monoxide (CO) in exhaled air were established by MicroCO analyzer.   Results:  Mean age was 42.1±13.6 years, 62.3% of the sample was males, and 89% of subjects were current smokers. The average smoking history was 25 pack-years for males and 14.8 for females. Subgroups of potential (smoking>10 pack-years) and high (>25 pack-years) risk of COPD were defined (68.1% and 30.7%, respectively). The high levels of CO and COHb (>3%) were revealed in 25.5% and 35.9% smokers, respectively. The cough and dyspnoea were the main complains (49.0% and 45.7%, respectively). Obstructive ventilation disorders were identified in 41.1% of subjects. The prevalence of obstruction increased with age and smoking history (p   Conclusions:  Early diagnosis of lung function disorders in smoking patients is an opportunity to identify individuals with increased risk of developing COPD.
A Report on the Physiological Action of Chloroform, with a Criticism of the Second Hyderabad Chloroform Commission
Authors: W. H. Gaskell, L. E. Shore
Journal: BMJ (1893)

IN the summer of 1890, when Surgeon-Lieutenant-Colonel Lawrie was in England, he asked one of us (Gaskell) to look over the curves of the Second Hyderabad Chloroform Commission, and make a report on them, supplementing that report with experimental investigation, if necessary.At the very outset it was evident that the Commission did not supply any answer to the most important question connected with the action of chloroform-namely, What is the reason of the fall of blood pressure which always occurs when a large dose of chloroform is administered?Before, therefore, it was possible to report on the curves of the Commission, it was necessary to make up our minds upon the meaning of this fall of blood pressure.For that purpose, we have carried out a number of experiments, and propose in this paper to give the results of those experiments, as well as a criticism of some of the conclusions of the Hyderabad Commission.The funds for this research were most gener-
S80 A Clinical Evaluation of Quantitative, Culture-Independent Methods For the Identification of Bacteria in Cystic Fibrosis Sputum and Broncho-Alveolar Lavage Fluids
Authors: C Holmes, J Shah, D Modha, R Herzallah, H Patel, K Haldar, M Barer, K Rajakumar, E Gaillard
Journal: Thorax (2012)

<h3>Introduction</h3> and objectives: The detection of bacteria contributing to respiratory exacerbations in cystic fibrosis patients is routinely performed using standardised microbiological culture techniques. These methods often fail to identify a significant pathogen in symptomatic patients and have been found to underestimate the burden of fastidious organisms such as <i>Streptococcus pneumoniae</i> in CF sputum. There is also increasing evidence linking respiratory exacerbations to infection with organisms that are not identified by routine microbiology. The primary objective of this cross-sectional study was to test the agreement between standard microbiology and molecular (culture-independent) techniques in detecting five common pathogens in sputum of children with CF. <h3>Methods</h3> Culture-independent microbiology was performed on samples obtained from children experiencing respiratory exacerbations over a 12 month period from April 2010 to March 2011. Sputum samples were either produced spontaneously or obtained either by sputum induction with hyper tonic saline or bronchoalveolar lavage. Aliquots of sputum we refrozen either neat or mixed 1:1 with 0.1% dithiothreiotol, prior to batch extraction of total nucleic acid. Total bacterial load was determined using abroad-range 16S rDNA quantitative real-time PCR. Specific real-time qPCR assays were used to quantify the numbers of <i>Staphylococcus aureus, Haemophilus influenzae, S pneumoniae, Pseudomonas aeruginosa and Moraxella catarrhalis.</i> Routine microbiology was performed by adhering to the laboratory standards published by the UK CF Trust. <h3>Results</h3> Fifty five samples (44 sputum and 11 bronchoalveolar lavage fluid) from 33 children were available for molecular analysis. In 40, the total bacterial load was calculated to be 10<sup>7</sup> or greater per ml of fluid. The qPCRs detected clinically relevant pathogens at significant levels (&gt;1% of total) more frequently than standard microbiology. <h3>Conclusion</h3> We found that standard microbiology alone revealed fewer of the clinically relevant respiratory pathogens studied compared to molecular techniques. PCR based analysis also offers the potential to identify pathogens more rapidly and to detect organisms that are difficult to detect by routine culture. This may have an impact on the choice of antibiotic for the treatment of an exacerbation. Compared to standard microbiology, however, these assays are expensive and not readily available for routine diagnostics.
The World Health Organization: no game of thrones
Authors: K. Abbasi
Journal: BMJ (2014)

Have you heard of the World Health Assembly? Do you have any idea of its purpose or any sense of its effectiveness? Even people who have attended the annual meeting of the 194 member states of the World Health Organization might struggle to answer the second of those questions. The arena at the Palais de Nations in Geneva, where the assembly is held, is designed for important decisions about international health, such as how to respond to the threat of Middle East respiratory syndrome coronavirus or the prioritisation of rapid diagnostic tests for malaria (doi:10.1136/bmj.g4123, doi:10.1136/bmj.g3846, doi:10.1136/bmj.g3730). Politicians, lobbyists, bureaucrats, technocrats, business people, and interpreters—mostly the rulers in the …
White cells, skin blood flow and venous ulcers
Authors: T.R. Cheatle, H.J. Scott, J.H. Scurr, P.D.Coleridge Smith
Journal: British Journal of Dermatology (1991)

Journal Article White cells, skin blood flow and venous ulcers Get access T.R. Cheatle, T.R. Cheatle Department of Surgery, University College and Middlesex School of Medicine, Middlesex Hospital, Mortimer Street, London WIN 8AA, U.K. Mr T.R.Cheatle. Search for other works by this author on: Oxford Academic Google Scholar H.J. Scott, H.J. Scott Department of Surgery, University College and Middlesex School of Medicine, Middlesex Hospital, Mortimer Street, London WIN 8AA, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.H. Scurr, J.H. Scurr Department of Surgery, University College and Middlesex School of Medicine, Middlesex Hospital, Mortimer Street, London WIN 8AA, U.K. Search for other works by this author on: Oxford Academic Google Scholar P.D.Coleridge Smith P.D.Coleridge Smith Department of Surgery, University College and Middlesex School of Medicine, Middlesex Hospital, Mortimer Street, London WIN 8AA, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 125, Issue 3, 1 September 1991, Pages 288–290, https://doi.org/10.1111/j.1365-2133.1991.tb14756.x Published: 01 September 1991
Determinants of Blood Pressure in Preschool Children
Authors: Giacomo D. Simonetti, Rainer Schwertz, Martin Klett, Georg F. Hoffmann, Franz Schaefer, Elke Wühl
Journal: Circulation (2011)

Hypertension is the leading risk factor for cardiovascular disease. Although accumulating evidence suggests tracking of blood pressure from childhood into adult life, there is little information regarding the relative contributions of genetic, prenatal, biological, behavioral, environmental, and social determinants to childhood blood pressure.Blood pressure and an array of potential anthropometric, prenatal, environmental, and familial risk factors for high blood pressure, including parental smoking habits, were determined as part of a screening project in 4236 preschool children (age 5.7 ± 0.4 years). Smoking was reported by 28.5% of fathers and 20.7% of mothers, and by both parents 11.9%. In addition to classic risk factors such as body mass index, prematurity, low birth weight, and parental hypertension, both systolic (+1.0 [95% confidence interval, +0.5 to +1.5] mm Hg; P=0.0001) and diastolic blood pressure (+0.5 [+0.03 to +0.9] mm Hg; P=0.03) were higher in children of smoking parents. Parental smoking independently affected systolic blood pressure (P=0.001) even after correction for other risk factors, such as body mass index, parental hypertension, or birth weight, increasing the likelihood of having a systolic blood pressure in the top 15% of the population by 21% (2% to 44%; P=0.02).In healthy preschool children, parental smoking is an independent risk factor for higher blood pressure, adding to other familial and environmental risk factors. Implementing smoke-free environments at home and in public places may provide a long-term cardiovascular benefit even to young children.
Dissection of the IgE and T-cell recognition of the major group 5 grass pollen allergen Phl p 5
Authors: Margarete Focke-Tejkl, Raffaela Campana, Renate Reininger, Christian Lupinek, Katharina Blatt, Peter Valent, Tea Pavkov-Keller, Walter Keller, Rudolf Valenta
Journal: Journal of Allergy and Clinical Immunology (2013)
Best Practices in Managing Transition to Adulthood for Adolescents With Congenital Heart Disease: The Transition Process and Medical and Psychosocial Issues
Authors: Craig Sable, Elyse Foster, Karen Uzark, Katherine Bjornsen, Mary M. Canobbio, Heidi M. Connolly, Thomas P. Graham, Michelle Z. Gurvitz, Adrienne Kovacs, Alison K. Meadows, Graham J. Reid, John G. Reiss, Kenneth N. Rosenbaum, Paul J. Sagerman, Arwa Saidi, Rhonda Schonberg, Sangeeta Shah, Elizabeth Tong, Roberta G. Williams
Journal: Circulation (2011)
MOLECULAR GENETICS OF T CELL DEVELOPMENT
Authors: Ellen V. Rothenberg, Tom Taghon
Journal: Annual Review of Immunology (2004)

▪ Abstract T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment.
Hypersensitivity Reactions to Chemotherapy Agents in Patients Receiving Chemoimmunotherapy With High-Dose Interleukin 2
Authors: G. R. Heywood, S. A. Rosenberg, J. S. Weber
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Hypersensitivity Reactions to Chemotherapy Agents in Patients Receiving Chemoimmunotherapy With High-Dose Interleukin 2 Get access G. R. Heywood, G. R. Heywood Surgery Branch, Division of Cancer Treatment, National Cancer InstituteBethesda, Md Search for other works by this author on: Oxford Academic PubMed Google Scholar S. A. Rosenberg, S. A. Rosenberg Surgery Branch, Division of Cancer Treatment, National Cancer InstituteBethesda, Md Search for other works by this author on: Oxford Academic PubMed Google Scholar J. S. Weber J. S. Weber Surgery Branch, Division of Cancer Treatment, National Cancer InstituteBethesda, Md Correspondence to present address: J. S. Weber, M.D., Ph.D., Division of Medical Oncology, USC/Norris Cancer Center, 1441 Eastlake Ave., Los Angeles, CA 90033. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 12, 21 June 1995, Pages 915–922, https://doi.org/10.1093/jnci/87.12.915 Published: 21 June 1995 Article history Received: 05 December 1994 Revision received: 15 March 1995 Accepted: 06 April 1995 Published: 21 June 1995