tbuckley/cabot-search huggingface dataset:
Evidence for the Presentation of Major Histocompatibility Complex Class I–restricted Epstein-Barr Virus Nuclear Antigen 1 Peptides to CD8+ T Lymphocytes
Authors: Kui Shin Voo, Tihui Fu, Helen Y. Wang, Judy Tellam, Helen E. Heslop, Malcolm K. Brenner, Cliona M. Rooney, Rong-Fu Wang
Journal: The Journal of Experimental Medicine (2004)

The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) is expressed in all EBV-associated tumors, making it an important target for immunotherapy. However, evidence for major histocompatibility complex (MHC) class I–restricted EBNA1 peptides endogenously presented by EBV-transformed B and tumor cells remains elusive. Here we describe for the first time the identification of an endogenously processed human histocompatibility leukocyte antigen (HLA)-B8–restricted EBNA1 peptide that is recognized by CD8+ T cells. T cell recognition could be inhibited by the treatment of target cells with proteasome inhibitors that block the MHC class I antigen processing pathway, but not by an inhibitor (chloroquine) of MHC class II antigen processing. We also demonstrate that new protein synthesis is required for the generation of the HLA-B8 epitope for T cell recognition, suggesting that defective ribosomal products (DRiPs) are the major source of T cell epitopes. Experiments with protease inhibitors indicate that some serine proteases may participate in the degradation of EBNA1 DRiPs before they are further processed by proteasomes. These findings not only provide the first evidence of the presentation of an MHC class I–restricted EBNA1 epitope to CD8+ T cells, but also offer new insight into the molecular mechanisms involved in the processing and presentation of EBNA1.
Changes in Cytoskeletal Protein Composition Indicative of an Epithelial-Mesenchymal Transition in Human Micrometastatic and Primary Breast Carcinoma Cells
Authors: Birthe Willipinski-Stapelfeldt, Sabine Riethdorf, Volker Assmann, Ute Woelfle, Thomas Rau, Guido Sauter, Jochen Heukeshoven, Klaus Pantel
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The bone marrow is a frequent and clinically important homing site for early disseminated breast cancer cells. Here, we aimed to profile the protein expression of these cells using unique cell line models and to evaluate the prognostic relevance of candidate gene expression for breast cancer patients. Experimental Design: To identify expression patterns characteristic for micrometastatic cells, three different cell lines (BC-K1, BC-P1, and BC-S1) established by SV40 immortalization of cancer cells isolated from the bone marrow of patients with breast cancer were compared with MCF-7 breast cancer and SV40 immortalized normal breast ductal cells (MTSV-1.7) using two-dimensional gel electrophoresis followed by MALDI-ToF analysis. The prognostic significance and clinicopathologic associations of selected differentially expressed proteins were evaluated using high-density breast cancer tissue microarrays. Results: In contrast to MCF-7 and MTSV1-7 reference cell lines, all micrometastatic cancer cell lines displayed loss of epithelial cytokeratins (CK8, CK18, and CK19) and ectopic expression of vimentin commonly present in mesenchymal cells. Immunohistochemical analysis of 2,517 samples of breast cancer further showed that loss of cytokeratin and ectopic vimentin expression were significantly associated with a higher tumor grade, high mitotic index, and negative estrogen/progesterone-receptor status. Although in univariate analyses significantly related to clinical outcome, none of the cytokeratins analyzed were independently associated with either overall or cancer-specific survival. Conclusions: Micrometastatic cancer cells exhibit marked changes in the expression pattern of cytoskeletal proteins indicative of an epithelial-mesenchymal transition. This phenotypical change could already be detected in primary tumors and is associated with the aggressive behavior of breast cancer cells in vivo.
Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17
Authors: Muriel Pichavant, Sho Goya, Everett H. Meyer, Richard A. Johnston, Hye Y. Kim, Ponpan Matangkasombut, Ming Zhu, Yoichiro Iwakura, Paul B. Savage, Rosemarie H. DeKruyff, Stephanie A. Shore, Dale T. Umetsu
Journal: The Journal of Experimental Medicine (2008)

Exposure to ozone, which is a major component of air pollution, induces a form of asthma that occurs in the absence of adaptive immunity. Although ozone-induced asthma is characterized by airway neutrophilia, and not eosinophilia, it is nevertheless associated with airway hyperreactivity (AHR), which is a cardinal feature of asthma. Because AHR induced by allergens requires the presence of natural killer T (NKT) cells, we asked whether ozone-induced AHR had similar requirements. We found that repeated exposure of wild-type (WT) mice to ozone induced severe AHR associated with an increase in airway NKT cells, neutrophils, and macrophages. Surprisingly, NKT cell–deficient (CD1d−/− and Jα18−/−) mice failed to develop ozone-induced AHR. Further, treatment of WT mice with an anti-CD1d mAb blocked NKT cell activation and prevented ozone-induced AHR. Moreover, ozone-induced, but not allergen-induced, AHR was associated with NKT cells producing interleukin (IL)-17, and failed to occur in IL-17−/− mice nor in WT mice treated with anti–IL-17 mAb. Thus, ozone exposure induces AHR that requires the presence of NKT cells and IL-17 production. Because NKT cells are required for the development of two very disparate forms of AHR (ozone- and allergen-induced), our results strongly suggest that NKT cells mediate a unifying pathogenic mechanism for several distinct forms of asthma, and represent a unique target for effective asthma therapy.
Exploring a Cancer Biomarker: The Example of C-Reactive Protein
Authors: P. Boffetta
Journal: JNCI Journal of the National Cancer Institute (2010)

An elevated plasma level of C-reactive protein (CRP) is an established biomarker of increased risk of cardiovascular diseases and diabetes ( 1 , 2 ). An association has also been suggested between plasma CRP level and the risk of cancer, particularly lung and colon cancers; however, the evidence is inconclusive because of the lack of large-scale prospective studies in which CRP levels were measured in healthy individuals before the onset of the disease ( 3 ). One explanation for why CRP may identify individuals at increased risk of disease lies in its association with chronic — mostly subclinical — inflammation. There is also some evidence that CRP may act as active contributor to inflammation, and this activity may depend on the conformation of the protein ( 4 ). Whether CRP is only a biomarker or an active player in inflammation might have important clinical implications. The study by Allin et al. ( 5 ) in this issue of the Journal addresses precisely the role of CRP as a biomarker vs as a contributor to carcinogenesis. The study is an elegant example of how genetic variants that have a functional impact can be used to explore associations between environmental factors and disease, and specifi cally to identify and control for confounding factors, based on the approach that has become known as Mendelian randomization, a term fi rst used by Gray and Wheatley in 1991 in the context of treatment of childhood leukemia ( 6 ). The basic principle of Mendelian randomization is that if a genetic variant infl uences a nongenetic (ie, environmental) factor that is relevant to disease risk, and if the same variant has no other associations with the same disease, then the variant predicts disease risk through its infl uence on the risk factor. Therefore, genetic variants with well-characterized functions (or that are in linkage disequilibrium with other variants with a well-characterized function) can be used to characterize associations between environmental factors and disease risk ( 7 ). Furthermore, using genetic variants instead of their environmental counterparts ensures protection from confounding and reverse causality and — at least in some cases — allows one to assess the effect of long-term exposures. The requirements for Mendelian randomization to be useful (strong functional signifi cance of the variant and the absence of an effect on other pathways) are demanding and are not often fulfi lled. There are examples, however, in which the analysis of genetic variants has helped to elucidate the role of environmental exposures, such as polymorphisms in genes encoding alcoholmetabolizing enzymes that explain the possible protective role of alcohol intake in cardiovascular disease as well as its detrimental role in pregnancy outcomes ( 8 , 9 ). The Mendelian randomization approach would be particularly valuable in the case of environmental factors that are not easily measurable.
Effect and cost-effectiveness of step-up versus step-down treatment with antacids, H2-receptor antagonists, and proton pump inhibitors in patients with new onset dyspepsia (DIAMOND study): a primary-care-based randomised controlled trial
Authors: Corine J van Marrewijk, Suhreta Mujakovic, Gerdine AJ Fransen, Mattijs E Numans, Niek J de Wit, Jean WM Muris, Martijn GH van Oijen, Jan BMJ Jansen, Diederik E Grobbee, J André Knottnerus, Robert JF Laheij
Journal: The Lancet (2009)
Differences in blood pressure between arms
Authors: D. H. Kim
Journal: BMJ (2012)

May be diagnostically useful but needs further evaluation as a prognostic marker

A difference in blood pressure readings between arms can be seen in congenital heart disease, aortic dissection, peripheral vascular disease, and unilateral neuromuscular abnormalities. In the absence of these conditions, any discrepancy is small (mean difference: 5 mm Hg and 4 mm Hg for systolic and diastolic blood pressure, respectively).1 About 20% of patients in primary care or secondary care have a between arm blood pressure difference of 10 mm Hg or more and 4% have a difference of 20 mm Hg or more.2 Although such a difference in blood pressure is thought to be a marker of atherosclerosis,3 its clinical significance is not fully understood. In a linked research study (doi:10.1136/bmj.e1327),4 and in a recent meta-analysis,5 Clark and colleagues provide additional evidence on the diagnostic and prognostic relevance of this phenomenon.

In their meta-analysis of cross sectional studies,5 Clark and colleagues reported that a between arm blood pressure difference of 15 mm Hg or more was associated with peripheral vascular disease (sensitivity 15% and specificity 96%) and with cerebrovascular disease (sensitivity 8% and specificity 93%), but not with coronary artery disease. A difference of 10 mm …
A prospective study on gait-related intrinsic risk factors for lower leg overuse injuries
Authors: N Ghani Zadeh Hesar, A Van Ginckel, A Cools, W Peersman, P Roosen, D De Clercq, E Witvrouw
Journal: British Journal of Sports Medicine (2009)

To determine prospectively gait-related risk factors for lower leg overuse injury (LLOI).A prospective cohort study.Male and female recruits from a start-to-run (STR) programme during a 10-week training period.131 healthy subjects (20 men and 111 women), without a history of any lower leg complaint, participated in the study.Before the start of the 10-week STR programme, plantar force measurements during running were performed. During STR, lower leg injuries were diagnosed and registered by a sports physician.Plantar force measurements during running were performed using a footscan pressure plate.During the STR, 27 subjects (five men and 22 women) developed a LLOI. Logistic regression analysis revealed that subjects who developed a LLOI had a significantly more laterally directed force distribution at first metatarsal contact and forefoot flat, a more laterally directed force displacement in the forefoot contact phase, foot flat phase and at heel-off. These subjects also had a delayed change of the centre of force (COF) at forefoot flat, a higher force and loading underneath the lateral border of the foot, and a significantly higher directed force displacement of the COF at forefoot flat.These findings suggest that a less pronated heel strike and a more laterally directed roll-off can be considered as risk factors for LLOI. Clinically, the results of this study can be considered important in identifying individuals at risk of LLOI.
Inpatient management of psoriasis: a multicentre service review to establish national admission standards
Authors: A.L. Woods, K.J. Rutter, L.S. Gardner, V.J. Lewis, S. Saxena, S.A. George, R.J.G. Chalmers, C.E.M. Griffiths, E.L. Speight, A.V. Anstey, L. Ronda, D. McGibbon, J.W.N. Barker, C.H. Smith
Journal: British Journal of Dermatology (2007)

Some patients with psoriasis may require hospital admission to stabilize their condition, although the role of inpatient management is changing given recent advances in therapeutic options, emphasis on community-based care for chronic conditions and limited healthcare resources. There is a need for evidence-based national standards for inpatient management of psoriasis taking account of factors that predict length of stay.To determine which factors predict length of stay for patients with psoriasis requiring inpatient hospital care with a view to setting evidence-based standards for inpatient psoriasis management.A multicentre service review was conducted on all psoriasis admissions over a 9-month period in four dermatology centres in the U.K. We collected data on admission, at discharge and, where possible, at 3 months following discharge. Psoriasis severity was assessed using four validated scoring systems, including Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index. We also recorded length of stay and treatment details.Length of stay varied widely between the four centres, but was similar in the two centres which received a high proportion of tertiary referrals for severe psoriasis (mean 19.7 days, range 1-78, analysis of variance P=0.002). Disease severity, measured by PASI, on admission (mean 15.7, interquartile range 8.3-20.8) was significantly higher in the tertiary centres (P<0.0001). However, there was no significant difference in PASI between centres on discharge. The admission PASI was significantly associated with length of stay (r=0.2, P=0.02). There was no significant correlation between other measures of disease severity and length of stay.Disease severity on admission for patients with psoriasis is greater in tertiary referral centres for psoriasis and is directly associated with length of stay. Length of stay should be used in conjunction with clinical measures such as PASI improvement to set national standards for quality in secondary care.
Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors
Authors: Toshio Shimizu, Patricia M. LoRusso, Kyri P. Papadopoulos, Amita Patnaik, Muralidhar Beeram, Lon S. Smith, Drew W. Rasco, Theresa A. Mays, Glenda Chambers, Anna Ma, Jing Wang, Robert Laliberte, Maurizio Voi, Anthony W. Tolcher
Journal: Clinical Cancer Research (2014)

This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks.Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75-300 mg/m(2)/day) following a standard 3 + 3 dose escalation design.The MTD was determined to be 275 mg/m(2). Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m(2) dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m(2) dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease.CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m(2) is recommended for further clinical testing.
Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper
Authors: B.R. Celli, W. MacNee, A. Agusti, A. Anzueto, B. Berg, A.S. Buist, P.M.A. Calverley, N. Chavannes, T. Dillard, B. Fahy, A. Fein, J. Heffner, S. Lareau, P. Meek, F. Martinez, W. McNicholas, J. Muris, E. Austegard, R. Pauwels, S. Rennard, A. Rossi, N. Siafakas, B. Tiep, J. Vestbo, E. Wouters, R. ZuWallack
Journal: European Respiratory Journal (2004)

The Standards for the Diagnosis and Treatment of Patients with COPD document 2004 updates the position papers on chronic obstructive pulmonary disease (COPD) published by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 1995 1, 2. Both societies felt the need to update the previous documents due to the following. 1) The prevalence and overall importance of COPD as a health problem is increasing. 2) There have been enough advances in the field to require an update, especially adapted to the particular needs of the ATS/ERS constituency. 3) It allows for the creation of a “live” modular document based on the web; it should provide healthcare professionals and patients with a user friendly and reliable authoritative source of information. 4) The care of COPD should be comprehensive, is often multidisciplinary and rapidly changing. 5) Both the ATS and the ERS acknowledge the recent dissemination of the Global Initiative of Obstructive Lung Disease (GOLD) 3 as a major worldwide contribution to the battle against COPD. However, some specific requirements of the members of both societies require adaptation of the broad GOLD initiative. Those requirements include specific recommendations on oxygen therapy, pulmonary rehabilitation, noninvasive ventilation, surgery in and for COPD, sleep, air travel, and end-of-life. In addition, special emphasis has been placed on issues related to the habit of smoking and its control.

### Goals and objectives

The main goals of the updated document are to improve the quality of care provided to patients with COPD and to develop the project using a disease-oriented approach. To achieve these goals, both organisations have developed a modular electronic web-based document with two components. 1) A component for health professionals that intends to: raise awareness of COPD; inform on the latest advances in the overall pathogenesis, diagnosis, monitoring and management of COPD; and …
Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period
Authors: Allison L. Bayer, Aixin Yu, Dennis Adeegbe, Thomas R. Malek
Journal: The Journal of Experimental Medicine (2005)

Although many aspects of CD4+CD25+ T regulatory (Treg) cell development remain largely unknown, signaling through the IL-2R represents one feature for the production of Treg cells. Therefore, the present study was undertaken to further define early developmental steps in the production of Treg cells, including a more precise view on the role of interleukin (IL)-2 in this process. After adoptive transfer of wild-type Treg cells into neonatal IL-2Rβ−/− mice, only a small fraction of donor Treg cells selectively seeded the lymph node (LN). These donor Treg cells underwent rapid and extensive IL-2–dependent proliferation, followed by subsequent trafficking to the spleen. Thus, IL-2 is essential for Treg cell proliferation in neonatal LN. The number and distribution of Treg cells in the periphery of normal neonatal mice closely paralleled that seen for IL-2Rβ−/− mice that received Treg cells. However, for normal neonates, blockade of IL-2 decreased Treg cells in both the thymus and LN. Therefore, two steps of Treg cell development depend upon IL-2 in neonatal mice, thymus production, and subsequent expansion in the LN.
Spongy Degeneration of the Brain in Infancy
Authors: Martin R. Krigman
Journal: JAMA (1967)

This monograph, a translation from the French, is a comprehensive and critical review of the clinical, pathological, and genetic features of a rare, often familial disease. The authors have much to contribute, since they were instrumental in defining spongy degeneration of the brain in infancy as a distinct nosological entity. The initial chapters trace the steps in recognition of this as a new disease and include much of the authors' own material on their early cases, some of it not previously published. In a separate chapter, the cases from the literature are presented in detail and critically reviewed. The problem of differential diagnosis is well treated. Although only one of the chapters is entitled "Histopathology," pathological descriptions appear throughout the book. Gross and microscopic pathology is fully described and aptly illustrated, though the quality of the reproductions is merely adequate. In considering the pathogenesis and the relationship of this entity
Position statement on youth resistance training: the 2014 International Consensus
Authors: Rhodri S Lloyd, Avery D Faigenbaum, Michael H Stone, Jon L Oliver, Ian Jeffreys, Jeremy A Moody, Clive Brewer, Kyle C Pierce, Teri M McCambridge, Rick Howard, Lee Herrington, Brian Hainline, Lyle J Micheli, Rod Jaques, William J Kraemer, Michael G McBride, Thomas M Best, Donald A Chu, Brent A Alvar, Gregory D Myer
Journal: British Journal of Sports Medicine (2013)

The current manuscript has been adapted from the official position statement of the UK Strength and Conditioning Association on youth resistance training. It has subsequently been reviewed and endorsed by leading professional organisations within the fields of sports medicine, exercise science and paediatrics. The authorship team for this article was selected from the fields of paediatric exercise science, paediatric medicine, physical education, strength and conditioning and sports medicine.
Effects of Various Inotropic Interventions on the Dynamic Properties of the Contractile Elements in Heart Muscle of the Cat
Authors: Dirk L. Brutsaert, William W. Parmley, Edmund H. Sonnenblick
Journal: Circulation Research (1970)

Force-velocity-length (FVL) relations were obtained by determining the phase-plane tracings of velocity of shortening vs. length during isotonic contractions. These measurements were then replotted in a three-dimensional graph after correction for the series elastic extension during the isometric phase of the contractions as derived from a quick release contraction. On examining the influence of temperature (29° and 37°), preload, frequency of stimulation (12/min and 24-30/min), paired stimulation (PS), calcium (2.5 mM and 7.5 mM), and iso-proterenol (10 -5 M), it was shown that the surface created by the three-dimensional FVL relations of the contractile element (CE) is unique for a given state of contractility. Furthermore, the course of velocity vs. length is determined only by the instantaneous CE length, regardless of the contractile state of the CE, and is independent of the time after stimulation over a large portion of the shortening. From the intersection of the linear load-shortening relation observed for the CE with the load axis the maximum force (P o ) development of the CE was derived. The highest values of this corrected P o (1.80 ± 0.13 kg/cm 2 ) were seen following inotropic interventions such as PS, calcium, or isoproterenol. Using the corrected P o , truly hyperbolic force-velocity curves were constructed from which V max and the Hill equation constants a and b were derived for the various inotropic interventions.