tbuckley/cabot-search huggingface dataset:
Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor
Authors: Bart Everts, Leonie Hussaarts, Nicole N. Driessen, Moniek H.J. Meevissen, Gabriele Schramm, Alwin J. van der Ham, Barbara van der Hoeven, Thomas Scholzen, Sven Burgdorf, Markus Mohrs, Edward J. Pearce, Cornelis H. Hokke, Helmut Haas, Hermelijn H. Smits, Maria Yazdanbakhsh
Journal: The Journal of Experimental Medicine (2012)

Omega-1, a glycosylated T2 ribonuclease (RNase) secreted by Schistosoma mansoni eggs and abundantly present in soluble egg antigen, has recently been shown to condition dendritic cells (DCs) to prime Th2 responses. However, the molecular mechanisms underlying this effect remain unknown. We show in this study by site-directed mutagenesis of omega-1 that both the glycosylation and the RNase activity are essential to condition DCs for Th2 polarization. Mechanistically, we demonstrate that omega-1 is bound and internalized via its glycans by the mannose receptor (MR) and subsequently impairs protein synthesis by degrading both ribosomal and messenger RNA. These experiments reveal an unrecognized pathway involving MR and interference with protein synthesis that conditions DCs for Th2 priming.
Chronic obstructive pulmonary disease among residents of an historically industrialised area
Authors: Anthony C Darby, Judith C Waterhouse, Vivien Stevens, Clare G Billings, Catherine G Billings, Clare M Burton, Charlotte Young, Jeremy Wight, Paul D Blanc, David Fishwick
Journal: Thorax (2012)

To assess the contribution of workplace exposures to chronic obstructive pulmonary disease (COPD) risk in a community with a heavy burden of past industrial employment.A random population sample of Sheffield, U.K. residents aged over 55 years (n=4000), enriched with a hospital-based supplemental sample (n=209), was approached for study. A comprehensive self-completed questionnaire elicited physician-made diagnoses, current symptoms, and past workplace exposures. The latter were defined in three ways: self-reported exposure to vapours, gases, dusts and fumes (VGDF); response to a specific exposure checklist; and through a job exposure matrix (JEM) assigning exposure risk likelihood based on job history independent of respondent-reported exposure. A subset of the study group underwent lung function testing. Population attributable risk fractions (PAR%), adjusted for age, sex and smoking, were calculated for association between workplace exposure and COPD.2001 (50%) questionnaires were returned from the general population sample and 60 (29%) by the hospital supplement. Among 1754 with complete occupational data, any past occupational exposure to VGDF carried an adjusted excess risk for report of a physician's diagnosis of COPD, emphysema, or chronic bronchitis (ORs 3.9; 95% CI 2.7 to 5.8), with a corresponding PAR% value of 58.7% (95% CI 45.6% to 68.7%). The PAR% estimate based on JEM exposure was 31%. From within the subgroup of 571 that underwent lung function testing, VGDF exposure was associated with a PAR% of 20.0% (95% CI -7.2 to 40.3%) for Global initiative for chronic obstructive lung disease (GOLD) 1 (or greater) level of COPD.This heavy industrial community-based population study has confirmed significant associations between reported COPD and both generic VGDF and JEM-defined exposures. This study supports the predominantly international evidence-based notion that workplace conditions are important when considering the current and future respiratory health of the workforce.
Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity
Authors: Syed-Rehan A. Hussain, Carolyn M. Cheney, Amy J. Johnson, Thomas S. Lin, Michael R. Grever, Michael A. Caligiuri, David M. Lucas, John C. Byrd
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The antiapoptotic Bcl-2 family member protein Mcl-1 is dynamically regulated in transformed B-cells, has a short mRNA and protein half-life, and is rapidly processed during apoptosis. Multiple therapies cause down-regulation of Mcl-1 in chronic and acute lymphoid leukemia (CLL and ALL) cells. Mcl-1 has also been reported to mediate resistance to rituximab in CLL. We therefore investigated whether direct reduction of Mcl-1 was sufficient to induce apoptosis and increase sensitivity to rituximab. Experimental Design: We used Mcl-1–specific small interfering RNA in ALL cell lines and tumor cells from CLL patients to block transcription of Mcl-1. Results: We show that Mcl-1 down-regulation alone is sufficient to promote mitochondrial membrane depolarization and apoptosis in ALL and CLL cells. Given the importance of rituximab in B-cell malignancies, we next assessed the influence of Mcl-1 down-regulation on antibody-mediated killing. Mcl-1 down-regulation by small interfering RNA increased sensitivity to rituximab-mediated killing both by direct apoptosis and complement-dependent cytotoxicity, but did not enhance antibody-dependent cellular cytotoxicity. Conclusions: These results show that Mcl-1 is a relevant therapeutic target for ALL and CLL, and its down-regulation has the potential to enhance the therapeutic effect of rituximab in CD20-bearing lymphoid cells.
AUGMENTATION OF THE VIRULENCE OF MURINE COXSACKIE-VIRUS B-3 MYOCARDIOPATHY BY EXERCISE
Authors: Bienvenido G. Gatmaitan, Jacob L. Chason, A. Martin Lerner
Journal: The Journal of Experimental Medicine (1970)

Coxsackievirus B-3 myocardiopathy was induced in weanling mice by intraperitoneal and intracerebral inoculations of the Nancy strain. Acute mortality was 5.5%. The cardiomyopathy is characterized by an early phase lasting about 9 days with myocardial necrosis, associated inflammation, and healing by fibrosis and calcification involving 25 to 50% of the contractile fibers in each affected mouse. Infectious coxsackievirus may be recovered from the heart during this phase. Continuing myocardial inflammatory lesions follow during the later phase, but infectious virus is no longer present. When mice were forced to swim in a preheated pool (33°C) during both phases of their myocardiopathy, virulence was strikingly augmented. Fully half of the mice died of congestive failure, the majority while swimming. Hearts were dilated, hypertrophied, and grossly necrotic. The myocardium was transformed to a completely necrotic, inflammatory, calcifying mass. At the peak of the infectious phase, myocardial replication of coxsackievirus was increased 530 times in nurslings which had been forced to swim. Myositis in hind limbs was more frequent, and inflammatory lesions in perirenal and pericardial fat were more severe in the mice which were forced to swim. When swimming was begun on the 9th day after infection, the virulence and lethality (13.8%) of infection were moderately increased.
Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial
Authors: Wolfgang Göpel, Angela Kribs, Andreas Ziegler, Reinhard Laux, Thomas Hoehn, Christian Wieg, Jens Siegel, Stefan Avenarius, Axel von der Wense, Matthias Vochem, Peter Groneck, Ursula Weller, Jens Möller, Christoph Härtel, Sebastian Haller, Bernhard Roth, Egbert Herting
Journal: The Lancet (2011)
Automation-assisted versus manual reading of cervical cytology (MAVARIC): a randomised controlled trial
Authors: Henry C Kitchener, Roger Blanks, Graham Dunn, Lionel Gunn, Mina Desai, Rebecca Albrow, Jean Mather, Durgesh N Rana, Heather Cubie, Catherine Moore, Rosa Legood, Alastair Gray, Sue Moss
Journal: The Lancet Oncology (2010)
Effect of varying inspired oxygen concentration on diaphragm glutathione metabolism during loaded breathing.
Authors: G S Supinski, D Nethery, R Ciufo, J Renston, A DiMarco
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Recent studies have suggested that loaded breathing elicits alterations in diaphragmatic glutathione levels that may be mediated by free radicals and may also be linked to the development of diaphragm fatigue. While free-radical generation in a number of pathophysiologic conditions is known to be a function of ambient oxygen concentrations, the effect of varying inspired oxygen concentration on the diaphragmatic response to loaded breathing (i.e., on diaphragm fatigue and glutathione levels) has not been studied. In this study, we compared the effect of loaded breathing, continued until respiratory arrest in decerebrate rats breathing room air (RA), with the effect of the same load on animals breathing 100% oxygen (O2). After arrest, the animals' diaphragms were excised, force generation was assessed in vitro, and diaphragmatic levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) were determined. Similar measurements were made on unloaded control animals. We found both similarities and differences in the response to loading in O2- and RA-breathing animals. O2-breathing loaded animals had a greater load endurance, lower blood pressure at the end of loading, higher carbon dioxide levels, and greater high-frequency fatigue at the conclusion of loaded trials than did RA-breathing animals. The degree of low-frequency fatigue was similar, however, in the O2- and RA-breathing loaded groups (i.e, twitch force averaged 7.9 +/- 0.6, 8.4 +/- 0.5, 3.8 +/- 0.9, and 4.5 +/- 0.8 N/cm2, respectively, in the RA/unloaded, O2/unloaded, RA/loaded, and O2/loaded groups, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
In Vivo Interaction of Acrylonitrile and 2-Cyanoethylene Oxide with DNA in Rats
Authors: Hogy Ll, Guengerich Fp
Journal: Cancer Research (1986)

Abstract  Several approaches were used to probe aspects of the mechanism of acrylonitrile carcinogenicity in rats. Acrylonitrile did not appear to increase the rate of DNA synthesis resulting from tissue injury and regeneration in liver or brain, the latter being a target organ. The chemical did cause unscheduled DNA synthesis in rat liver but not brain. The epoxide of acrylonitrile, 2-cyanoethylene oxide, was formed in perfused rat liver; this metabolite accumulated in the perfusate as long as acrylonitrile was available to the organ. When 2-cyano[2,3-14C]ethylene oxide was administered to rats i.p., covalent binding to both liver and brain protein was found, but no covalent binding to nucleic acids could be detected at the level of 0.3 alkylations per 106 bases. No 1,N6-ethenoadenosine or 1,N6-ethenodeoxyadenosine was found in liver nucleic acids after administration of either acrylonitrile or 2-cyanoethylene oxide to rats, with the limits of detection being 0.3 alkylations per 106 RNA bases and 1 alkylation per 106 DNA bases. However, low levels of N7-(2-oxoethyl)guanine were detected in the livers of these rats by means of a radiometric derivative assay (0.014–0.032 alkylations per 106 DNA bases). In the brains of the treated rats the levels of N7-(2-oxoethyl)guanine were not above the limit of detection. These results show that acrylonitrile has some limited potential for genotoxicity in vivo and that the epoxide, with its ability to leave the liver and possibly to enter the brain, can interact with nucleic acids to a limited degree.
Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study
Authors: Sheila A Bingham, Nicholas E Day, Robert Luben, Pietro Ferrari, Nadia Slimani, Teresa Norat, Françoise Clavel-Chapelon, Emmanuelle Kesse, Alexandra Nieters, Heiner Boeing, Anne Tjϕnneland, Kim Overvad, Carmen Martinez, Miren Dorronsoro, Carlos A Gonzalez, Timothy J Key, Antonia Trichopoulou, Androniki Naska, Paolo Vineis, Rosario Tumino, Vittorio Krogh, H Bas Bueno-de-Mesquita, Petra HM Peeters, Göran Berglund, Göran Hallmans, Eiliv Lund, Guri Skeie, Rudolf Kaaks, Elio Riboli
Journal: The Lancet (2003)
Controlling unruly osteoclasts
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The way to the skin Memory CD4 ϩ T cells express characteristic adhesion molecules and chemokine receptors that dictate their recirculation to the tissue in which they first encountered antigen.On page 1045, Baekkevold and colleagues show that T cells may compete for access to the skin and only gain entry if they express the CC-chemokine receptor-4 (CCR4).Previous studies showed that skin-homing and gut-homing CD4 ϩ T cells express distinct chemokine receptors-CCR4 for skin-homing cells and CCR9 for gut-homing cells-and this was mirrored by the expression of the corresponding chemokine ligand in local blood vessels.The authors thus proposed that expression of CCR4 was required for T cells to access the skin (and CCR9 for the gut) but were perplexed by the phenotype of CCR4-deficient mice, which had normal numbers of skin-homing T cells.Another skin-specific chemokine receptor may have compensated for the absence of CCR4.To test this, Baekkevold et al. staged a competition between wild type and CCR4-deficient bone marrow cells in lymphocyte-deficient mice.They found that CCR4 ϩ cells were highly enriched among lymphocytes that trafficked to the skin, particularly during skin inflammation.This suggested that CCR4, although not essential, facilitated the generation of the skin-homing memory T cell population.Recent studies have shown that tissue-specific dendritic cells (DC) impart CD8 ϩ T cells with specific homing instructions and the authors suspect that a DC-derived signal may trigger CCR4 expression and similarly instruct CD4 ϩ T cells.
Human infection with Trypanosoma cruzi induces parasite antigen-specific cytotoxic T lymphocyte responses.
Authors: B Wizel, M Palmieri, C Mendoza, B Arana, J Sidney, A Sette, R Tarleton
Journal: Journal of Clinical Investigation (1998)

Experimental models of Chagas' disease, an infection caused by the intracellular protozoan Trypanosoma cruzi, have demonstrated the crucial immunoprotective role played by CD8(+) T lymphocytes. These cells dominate inflammatory foci in parasitized tissues and their elimination from mice leads to uncontrolled parasite replication and subsequent death of the infected host. A trypomastigote surface antigen, TSA-1, and two amastigote surface molecules, ASP-1 and ASP-2, were recently identified as targets of CD8(+) cytotoxic T lymphocytes (CTL) in T. cruzi-infected mice. Until now, however, there was no evidence for the development of parasite-specific CTL in T. cruzi-infected humans. In this study, human CTL specific for TSA-1-, ASP-1-, and ASP-2-derived peptides were detected in the peripheral blood mononuclear cells from 21 of 24 HLA-A2(+) T. cruzi-infected patients. CTL recognition was antigen specific, A2-restricted, and CD8(+) T cell-dependent. Demonstration of human CTL against T. cruzi and against target molecules identified using the murine model provides important information for the optimal design and evaluation of vaccines to prevent or ameliorate Chagas' disease.
Thrombospondin-2 prevents cardiac injury and dysfunction in viral myocarditis through the activation of regulatory T-cells
Authors: Anna-Pia Papageorgiou, Melissa Swinnen, Davy Vanhoutte, Thierry VandenDriessche, Marinee Chuah, Diana Lindner, Wouter Verhesen, Bart de Vries, Jan D'hooge, Esther Lutgens, Dirk Westermann, Peter Carmeliet, Stephane Heymans
Journal: Cardiovascular Research (2012)

Thrombospondin-2 (TSP-2) modulates matrix integrity and myocyte survival in the hypertensive or ageing heart. Whether TSP-2 may affect cardiac inflammation and injury, in particular during acute viral myocarditis, is completely unknown.Therefore, mortality, cardiac inflammation, and function were assessed in TSP-2-null (KO) and wild-type (WT) mice in human Coxsackie virus B3 (CVB3)-induced myocarditis. TSP-2 KO had an increased mortality when compared with WT mice during viral myocarditis. The absence of TSP-2 resulted in increased cardiac inflammation and injury at 14 days, which resulted in depressed systolic function [fractional shortening (FS); 34 ± 2.6 in WT vs. 24 ± 1.8 in KO mice, P< 0.05] and increased cardiac dilatation (end-diastolic dimensions, mm; 3.7 ± 0.09 in WT vs. 4.8 ± 0.06 in KO mice, P< 0.05) 35 days post-infection. Lack of TSP-2 resulted in a decreased activation of the anti-inflammatory T-regulatory cells, as indicated by a lower number of CD25-positive T-cells, and significantly decreased gene expression of regulatory T-cell markers, Foxp3 and CTLA-4. Finally, overexpression of TSP-2 in WT hearts using cardiotropic vectors derived from adeno-associated virus serotype 9 (AAV9) inhibited cardiac inflammation and injury at 14 days and improved cardiac function at 35 days post-CVB3 infection when compared with control AAV9.TSP-2 has a protective role against cardiac inflammation, injury, and dysfunction in acute viral myocarditis.
GMC calls for law to plug "gaping hole" in registration of EU doctors working in UK
Authors: A. O'Dowd
Journal: BMJ (2010)

The law should be changed so that the clinical skills and competency in English of doctors from other countries in the European Union can be checked, MPs have been told.

The General Medical Council said that the government should consider urgent action to change legislation so that GPs coming from Europe to work out of hours shifts in the UK would be thoroughly tested.

Representatives of the GMC were giving evidence to MPs on the parliamentary health select committee as part of their inquiry into the use of overseas doctors in providing out of hours services.

The committee’s inquiry was sparked by the case of David Gray, …
A Protective Role for the Fifth Complement Component (C5) in Allergic Airway Disease
Authors: Scott M. Drouin, Meenal Sinha, Georgia Sfyroera, John D. Lambris, Rick A. Wetsel
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Reports from our laboratory, as well as those from others, have documented the importance of complement activation, the C3a anaphylatoxin, and its receptor, C3aR, in promoting Th2 effector functions in a mouse model of bronchopulmonary allergy. Although deficiency in the fifth complement component (C5) has been linked to enhanced airway hyperresponsiveness in mice, the contribution of C5 to other major biological hallmarks of asthma has not been evaluated.Accordingly, congenic C5-sufficient and C5-deficient mice were subjected to a mouse model of bronchopulmonary allergy to assess the impact of C5 on pulmonary inflammation and Th2 effector functions in experimental asthma.In contrast to observations reported for C3- and C3aR-deficient animals, C5-deficient mice exhibited significantly increased airway hyperresponsiveness relative to wild-type congenic control mice after antigen challenge. Moreover, challenged C5-deficient mice had a 3.4-fold and 2.7-fold increase in the levels of airway eosinophils and lung interleukin (IL)-4-producing cells, respectively, compared with challenged wild-type mice. Consistent with the numbers of IL-4-producing cells, C5-deficient mice also had increased bronchoalveolar lavage levels of the Th2 cytokines IL-5 and IL-13 and elevated serum levels of total and antigen-specific IgE.These data indicate that C5 plays an important protective role in allergic lung disease by suppressing inflammatory responses and Th2 effector functions observed in this experimental model. The protection provided by the presence of C5 is likely mediated by C5a, suggesting that C5a may play a significant role in tempering inflammation in Th2-driven diseases such as asthma.
A Self-inactivating γ-Retroviral Vector Reduces Manifestations of Mucopolysaccharidosis I in Mice
Authors: Jason A Metcalf, Xiucui Ma, Bruce Linders, Susan Wu, Axel Schambach, Kevin K Ohlemiller, Attila Kovacs, Mark Bigg, Li He, Douglas M Tollefsen, Katherine P Ponder
Journal: Molecular Therapy (2009)

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficiency in alpha-L-iduronidase (IDUA) that results in accumulation of glycosaminoglycans (GAGs) throughout the body, causing numerous clinical defects. Intravenous administration of a gamma-retroviral vector (gamma-RV) with an intact long terminal repeat (LTR) reduced the clinical manifestations of MPS I, but could cause insertional mutagenesis. Although self-inactivating (SIN) gamma-RVs in which the enhancer and promoter elements in the viral LTR are absent after transduction reduces this risk, such vectors could be less effective. This report demonstrates that intravenous (i.v.) injection of a SIN gamma-RV expressing canine IDUA from the liver-specific human alpha(1)-antitrypsin promoter into adult or newborn MPS I mice completely prevents biochemical abnormalities in several organs, and improved bone disease, vision, hearing, and aorta to a similar extent as was seen with administration of the LTR-intact vector to adults. Improvements were less profound than when using an LTR-intact gamma-RV in newborns, which likely reflects a lower level of transduction and expression for the SIN vector-transduced mice, and might be overcome by using a higher dose of SIN vector. A SIN gamma-RV vector ameliorates clinical manifestations of MPS I in mice and should be safer than an LTR-intact gamma-RV.
Therapeutic Targeting of Integrin αvβ6 in Breast Cancer
Authors: Kate M. Moore, Gareth J. Thomas, Stephen W. Duffy, Jane Warwick, Rhian Gabe, Patrick Chou, Ian O. Ellis, Andrew R. Green, Syed Haider, Kellie Brouilette, Antonio Saha, Sabari Vallath, Rebecca Bowen, Claude Chelala, Diana Eccles, William J. Tapper, Alastair M. Thompson, Phillip Quinlan, Lee Jordan, Cheryl Gillett, Adam Brentnall, Shelia Violette, Paul H. Weinreb, Jane Kendrew, Simon T. Barry, Ian R. Hart, J. Louise Jones, John F. Marshall
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundIntegrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.
SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na <sub>v</sub> 1.5 in Cardiomyocytes
Authors: Séverine Petitprez, Anne-Flore Zmoos, Jakob Ogrodnik, Elise Balse, Nour Raad, Said El-Haou, Maxime Albesa, Philip Bittihn, Stefan Luther, Stephan E. Lehnart, Stéphane N. Hatem, Alain Coulombe, Hugues Abriel
Journal: Circulation Research (2010)

The cardiac sodium channel Na(v)1.5 plays a key role in excitability and conduction. The 3 last residues of Na(v)1.5 (Ser-Ile-Val) constitute a PDZ-domain binding motif that interacts with the syntrophin-dystrophin complex. As dystrophin is absent at the intercalated discs, Na(v)1.5 could potentially interact with other, yet unknown, proteins at this site.The aim of this study was to determine whether Na(v)1.5 is part of distinct regulatory complexes at lateral membranes and intercalated discs.Immunostaining experiments demonstrated that Na(v)1.5 localizes at lateral membranes of cardiomyocytes with dystrophin and syntrophin. Optical measurements on isolated dystrophin-deficient mdx hearts revealed significantly reduced conduction velocity, accompanied by strong reduction of Na(v)1.5 at lateral membranes of mdx cardiomyocytes. Pull-down experiments revealed that the MAGUK protein SAP97 also interacts with the SIV motif of Na(v)1.5, an interaction specific for SAP97 as no pull-down could be detected with other cardiac MAGUK proteins (PSD95 or ZO-1). Furthermore, immunostainings showed that Na(v)1.5 and SAP97 are both localized at intercalated discs. Silencing of SAP97 expression in HEK293 and rat cardiomyocytes resulted in reduced sodium current (I(Na)) measured by patch-clamp. The I(Na) generated by Na(v)1.5 channels lacking the SIV motif was also reduced. Finally, surface expression of Na(v)1.5 was decreased in silenced cells, as well as in cells transfected with SIV-truncated channels.These data support a model with at least 2 coexisting pools of Na(v)1.5 channels in cardiomyocytes: one targeted at lateral membranes by the syntrophin-dystrophin complex, and one at intercalated discs by SAP97.