tbuckley/cabot-search huggingface dataset:
The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease
Authors: D. Poeckel, C. D. Funk
Journal: Cardiovascular Research (2010)

Leukotrienes (LTs) derived from 5-lipoxygenase (5-LO) activity are most widely known for their actions during acute inflammation and asthma. 5-LO/LT pathway involvement in cardiovascular disease (CVD) pathogenesis has come to the forefront based on provocative human genetic/population and animal studies leading to the hypothesis that this pathway promotes atherosclerosis, abdominal aortic aneurysm, and myocardial infarction/reperfusion injury via increased leucocyte chemotaxis, vascular inflammation and enhanced permeability, and subsequent tissue/matrix degeneration. A series of pre-clinical studies have tested this hypothesis by means of genetic or pharmacological inhibition of either the LT biosynthesis axis (5-LO, 5-LO-activating protein, LTA4 hydrolase, LTC4 synthase) or the cognate LT receptors. Here, we summarize, compare, and analyse these animal studies and relate their findings to human disease pathogenesis. We draw a complex picture of 5-LO/LT participation in cardiovascular disorders, which is further complicated by marked differences between species. Moreover, we discuss how the cytokine footprint of the respective pathological conditions determines the expression level and hence, the contribution of components of the pathway to the overall disease state. Current knowledge implies a role for 5-LO and LTs during the early/acute phase of CVD, but our understanding of a putative 5-LO/LT involvement in more advanced stages of CVD is limited, thereby preventing simple extrapolation of findings from animal studies to humans.
THE EFFECT OF EPITHELIAL REMNANT AND WHOLE ORGAN GRAFTS OF THYMUS ON THE RECOVERY OF THYMECTOMIZED IRRADIATED MICE
Authors: Esther F. Hays
Journal: The Journal of Experimental Medicine (1969)

Work has been presented which suggests that thymus epithelial reticular cells are not effective in restoring the microscopic morphology of lymphoid tissues and their immunologic capacities. They function in recruiting precursors of thymus lymphocytes from the host animals to produce an organ which, after it becomes architecturally normal, can reconstitute the defective host. Intact thymus grafts in situ from 10-14 days, but not for shorter periods of time, have been shown to result in a return toward normal of these two parameters. Evidence is offered to show that few dividing cellular components in the lymphoid tissue originate from the thymus remnant grafts, and that a minor cellular component is contributed by the intact grafts. These data support the concept that the structural and functional development of the lymphatic tissue in thymectomized animals is dependent on thymus lymphoid cells and/or their products, and that the epithelial-reticular cells do not have a direct action in peripheral lymphoid reconstitution.
Lipid-Related Markers and Cardiovascular Disease Prediction
Authors: E Di Angelantonio, P Gao, L Pennells, S Kaptoge, M Caslake, A Thompson, A S Butterworth, N Sarwar, D Wormser, D Saleheen, C M Ballantyne, B M Psaty, J Sundström, P M Ridker, D Nagel, R F Gillum, I Ford, P Ducimetiere, S Kiechl, W Koenig, Dullaart Rpf., G Assmann, R B D'Agostino, G R Dagenais, J A Cooper, D Kromhout, A Onat, R W Tipping, A Gómez-de-la-Cámara, A Rosengren, S E Sutherland, J Gallacher, Fowkes Fgr., E Casiglia, A Hofman, V Salomaa, E Barrett-Connor, R Clarke, E Brunner, J W Jukema, L A Simons, M Sandhu, N J Wareham, Khaw K-T., J Kauhanen, J T Salonen, W J Howard, B G Nordestgaard, A M Wood, S G Thompson, S M Boekholdt, N Sattar, C Packard, V Gudnason, J Danesh
Journal: JAMA (2012)

<h3>Context</h3>The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.<h3>Objective</h3>To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A<sub>2</sub> to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.<h3>Design, Setting, and Participants</h3>Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).<h3>Main Outcome Measures</h3>Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (&lt;10%), intermediate (10%-&lt;20%), and high (≥20%) risk.<h3>Results</h3>The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A<sub>2</sub> mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A<sub>2</sub> mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.<h3>Conclusion</h3>In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A<sub>2</sub> mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.
Economic aspects of treatment options in rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis
Authors: Monika Schoels, John Wong, David L Scott, Angela Zink, Pamela Richards, Robert Landewé, Josef S Smolen, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2010)

To review the cost effectiveness of rheumatoid arthritis (RA) treatments and inform the clinical recommendations by the European League Against Rheumatism.A systematic literature search and review of the health economic evidence on RA treatment options was performed.Despite diverse methodological approaches, health economic analyses are concordant: at onset of disease, traditional disease-modifying antirheumatic drugs (DMARDs) are cost effective-that is, treatment merits outweigh treatment costs. If DMARDs fail, therapeutic escalation with tumour necrosis factor alpha inhibitors (TNFi) is cost effective when standard dosing schemes are employed. If TNFi fail, rituximab or abatacept is cost effective. Economic evidence for switching TNFi remains sparse.The costly sequelae of insufficiently controlled RA justify intensive escalations of treatment in this disease. By maintaining function, patients are kept in the work process, reducing indirect costs. Quality of life is improved at an expense commonly accepted for chronic diseases. Effective control of disease activity seems to be a prudent use of societal resources.
Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion
Authors: Roch Houot, Matthew J. Goldstein, Holbrook E. Kohrt, June H. Myklebust, Ash A. Alizadeh, Jack T. Lin, Jonathan M. Irish, James A. Torchia, Arne Kolstad, Lieping Chen, Ronald Levy
Journal: Blood (2009)
Contemporary Approach to Aortic and Mitral Regurgitation
Authors: Jeffrey S. Borer, Robert O. Bonow
Journal: Circulation (2003)

emodynamically severe aortic regurgitation (AR) and mitral regurgitation (MR) are among the most predictable causes of heart failure (HF) and sudden death (SD).During the past 4 decades, surgery has become the primary intervention for patients with these diseases.However, timing of operation is a "moving target": surgical techniques have improved dramatically; noninvasive methods have developed for objective interrogation of cardiac size and function, continually enhancing knowledge of natural history and its predictors, and an increasing array of nonsurgical treatments show potential to beneficially alter the natural course of disease.Consequently, the benefit-to-risk relation underlying management decisions changes continually.Simultaneously, the myocardial cellular and molecular pathophysiology of valvular regurgitation is being progressively elucidated, promising new clinical evaluation strategies and novel treatments.The net result of these factors has been progressively earlier application of valve surgery and continuing discussion about the correct mix of drugs, surgery, and watchful waiting.Guidelines for management of patients with valvular heart diseases were developed by the American College of Cardiology and American Heart Association 5 years ago 1 and generally remain applicable, but new information mandates periodic review. Scope of the ProblemDisease prevalence is not known precisely.However, extrapolation from natural history data suggests that Ͼ5 000 000 persons have moderate to severe valvular regurgitation in the United States alone.Prevalence has grown steadily for many years.New York's State-Wide Planning and Research Cooperative System (SPARCS) database, a compulsory hospital reporting system, indicates that AR and MR discharge diagnoses increased almost 4-fold during the past 20 years, whereas total hospitalizations declined by 20% (Figure 1). 2 Several factors may account for the increase, including a shift in distribution of disease etiology from acquired (eg, rheumatic) to genetically determined (now predominant in all age groups) [3][4][5][6] ; the strong tendency of the latter for slow anatomic/functional progression (delaying clinical sequelae until after procreation) [3][4][5][6][7] ; and control of diseases that formerly caused earlier deaths, because prevalence (and hemodynamic severity) increases directly with age. 8,9Recent echocardio-graphic screening by the Framingham Study, in an unselected population, found MR prevalence increased 1.3-fold and AR increased 2.3-fold with each decade of life. 8
Augmentation of macrophage complement receptor function in vitro. I. Characterization of the cellular interactions required for the generation of a T-lymphocyte product that enhances macrophage complement receptor function.
Authors: J A Griffin, F M Griffin
Journal: The Journal of Experimental Medicine (1979)

The function of complement receptors of mouse peritoneal macrophages was converted in vitro from mediating only attachment of macrophage complement receptor function was achieved by treating freshly explanted macrophages with supernates from cultures containing T lymphocytes and appropriately triggered macrophages. Fc receptor-mediated phagocyctosis by macrophages was required for the production of active supernates, for neither ingestion via the cells' complement receptors nor ingestion via nonimmunologic means was a sufficient stimulus for the macrophages' participation in the generation of supernatant activity. Fc receptor-triggered macrophages interacted by a contact dependent, but histocompatibility independent, mechanism with T lymphocytes, thereby signalling the lymphocytes to elaborate the active product. The possible significance of enhanced macrophage complement receptor function in inflammation, host defense against microbial pathogens, immune complex disease, and neoplasia is discussed.
Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer
Authors: Jihong Ma, Marie C. DeFrances, Chunbin Zou, Carla Johnson, Robert Ferrell, Reza Zarnegar
Journal: Journal of Clinical Investigation (2009)

The HGF gene is transcriptionally silenced in normal differentiated breast epithelial cells, but its repression fails to occur in mammary carcinoma tissues and cell lines. The molecular mechanisms underpinning aberrant HGF expression in breast cancer cells are unknown. Here we report the discovery of a DNA element located 750 bp upstream from the transcription start site in the human HGF promoter that acts as a transcriptional repressor and is a target of deletion mutagenesis in human breast cancer cells and tissues. This HGF promoter element consists of a mononucleotide repeat of 30 deoxyadenosines (30As), which we have termed "deoxyadenosine tract element" (DATE). Functional studies revealed that truncation mutations within DATE have profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions, leading to constitutive activation of the HGF promoter in human breast carcinoma cell lines. We found that 51% of African Americans and 15% of individuals of mixed European descent with breast cancer harbor a truncated DATE variant (25As or fewer) in their breast tumors and that the truncated allele is associated with cancer incidence and aberrant HGF expression. Notably, breast cancer patients with the truncated DATE variant are substantially younger than those with a wild-type genotype. We also suggest that DATE may be used as a potential genetic marker to identify individuals with a higher risk of developing breast cancer.
NADPH Oxidase In Ragweed Pollen Promotes Th2 Differentiation Of Naïve T-cells And Induces IL-33 Secretion From BMDCs Via TLR4 And MYD88 Dependent Pathways
Authors: A. Kalita, H. Qi, H. Murai, A. Kurosky, I. Boldogh, T. Hazra, D. Corry, S. Sur
Journal: Journal of Allergy and Clinical Immunology (2011)
Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection
Authors: Katja Giersch, Lena Allweiss, Tassilo Volz, Martina Helbig, Jeanette Bierwolf, Ansgar W. Lohse, Joerg M. Pollok, Joerg Petersen, Maura Dandri, Marc Lütgehetmann
Journal: Journal of Hepatology (2015)
Mortality among patients with ankylosing spondylitis after a single treatment course with x rays.
Authors: P G Smith, R Doll
Journal: BMJ (1982)

Mortality was studied in 14 111 patients with ankylosing spondylitis given a single course of x-ray treatment during 1935-54. Mortality from all causes combined was 66% greater than that of members of the general population of England and Wales. There were substantial excesses of deaths from non-neoplastic conditions, but these appeared to be associated with the disease itself rather than its treatment. A nearly fivefold excess of deaths from leukaemia and a 62% excess of deaths from cancers of sites that would have been in the radiation fields ("heavily irradiated sites") were likely to have been a direct consequence of the radiation treatment itself. The excess death rate from leukaemia was greatest three to five years after treatment and was close to zero after 18 years. In contrast, the excess of cancers of heavily irradiated sites did not become apparent until nine or more years after irradiation and continued for a further 11 years. More than 20 years after irradiation the excess risk declined, but the fall was not statistically significant. The number of cancers of sites not considered to be in the radiation beams was 20% greater than expected. This excess, although not statistically significant, may also have been due to radiation scattered from beams directed at other parts of the body. The risk of a radiation-induced leukaemia or other cancer was related to the age of the patient at the time of treatment. Those irradiated when aged 55 years or more had an excess death rate from leukaemia more than 15 times that of those treated under 25 years of age, and a similar difference was apparent for cancers of heavily irradiated sites. The radiation dose to the bone marrow was estimated for the patients who died with leukaemia and for a 1 in 15 sample of the total study population. The excess risk of leukaemia varied erratically with radiation dose owing, perhaps, in part to the increase in the proportion of the cells in the bone marrow that are sterilised with increasing doses. A mathematical model using a linear leukaemia induction rate and exponential cell sterilisation fitted the data reasonably well, and the results suggested that for low radiation doses about two deaths from leukaemia would be induced per million people per rad of x rays per year for up to 20 years after exposure. Because of the failure to find a clear dose-response relationship this estimate must be regarded with caution, but it is in reasonable agreement with that derived from studies of the atomic bomb survivors.
Quantitative ultrasonic characterization of the nature of atherosclerotic plaques in human aorta.
Authors: B Barzilai, J E Saffitz, J G Miller, B E Sobel
Journal: Circulation Research (1987)

To determine the feasibility of quantitative ultrasonic techniques to define the composition of atherosclerotic plaques, samples of freshly excised human aortas were sewn to a sample holder and immersed in a saline bath for ultrasonic interrogation. Integrated backscatter of a 2-microsecond portion of the backscattered radiofrequency signal was measured with a 10 MHz focused transducer. Integrated backscatter was calculated by normalizing the root-mean-square voltage of the gated signal to the root-mean-square voltage obtained by replacing the tissue sample with a nearly perfect reflector. Microscopic examination of the 124 interrogated sites allowed differentiation of normal, fibrous, fibrofatty, and calcified regions. A site was considered calcified if it contained any histochemically detectable calcium. Values of integrated backscatter were markedly elevated from calcified regions (-30.0 +/- 6.4 dB, n = 25; mean +/- SD; p less than 0.001) compared to normal (-43.2 +/- 2.4 dB, n = 20) and fibrofatty (-43.9 +/- 3.4 dB, n = 43) sites. Values from fibrous regions (-40.7 +/- 3.8 dB, n = 36) were also significantly different compared with the calcified and fibrofatty regions (p less than 0.001). Thus, we have demonstrated that quantitative ultrasonic backscatter identifies and differentiates calcification and fibrosis in atherosclerotic sites offering promise for the noninvasive assessment of the pathologic status of the arterial wall.
Are <b> <i>ATM</i> </b> Mutations 7271T→G and IVS10-6T→G Really High-Risk Breast Cancer-Susceptibility Alleles?
Authors: Csilla I. Szabo, Mieke Schutte, Annegien Broeks, Jeanine J. Houwing-Duistermaat, Yvonne R. Thorstenson, Francine Durocher, Rogier A. Oldenburg, Marijke Wasielewski, Fabrice Odefrey, Deborah Thompson, Arno N. Floore, Jaennelle Kraan, Jan G. M. Klijn, Ans M. W. van den Ouweland, Teresa M. U. Wagner, Peter Devilee, Jacques Simard, Laura J. van ‘t Veer, David E. Goldgar, Hanne Meijers-Heijboer
Journal: Cancer Research (2004)

Abstract Two mutations of the ATM gene were recently suggested to confer breast cancer risks similar to mutations of BRCA1 or BRCA2. Here, we set out to confirm these findings in 961 families with non-BRCA1/BRCA2 breast cancer from diverse geographical regions. We did not detect the ATM 7271T→G mutation in any family. The ATM IVS10–6T→G mutation was detected in eight families, which was similar to its frequency among population-matched control individuals (pooled Mantel-Haenszel odds ratio = 1.60; 95% confidence interval = 0.48 to 5.35; P = 0.44). Bayesian analysis of linkage in the ATM IVS10–6T→G-positive families showed an overall posterior probability of causality for this mutation of 0.008. We conclude that the ATM IVS10–6T→G mutation does not confer a significantly elevated breast cancer risk and that ATM 7271T→G is a rare event in familial breast cancer.
Delayed Coverage in Malapposed and Side-Branch Struts With Respect to Well-Apposed Struts in Drug-Eluting Stents
Authors: Juan Luis Gutiérrez-Chico, Evelyn Regar, Eveline Nüesch, Takayuki Okamura, Joanna Wykrzykowska, Carlo di Mario, Stephan Windecker, Gerrit-Anne van Es, Pierre Gobbens, Peter Jüni, Patrick W. Serruys
Journal: Circulation (2011)

Background— Pathology studies on fatal cases of very late stent thrombosis have described incomplete neointimal coverage as common substrate, in some cases appearing at side-branch struts. Intravascular ultrasound studies have described the association between incomplete stent apposition (ISA) and stent thrombosis, but the mechanism explaining this association remains unclear. Whether the neointimal coverage of nonapposed side-branch and ISA struts is delayed with respect to well-apposed struts is unknown. Methods and Results— Optical coherence tomography studies from 178 stents implanted in 99 patients from 2 randomized trials were analyzed at 9 to 13 months of follow-up. The sample included 38 sirolimus-eluting, 33 biolimus-eluting, 57 everolimus-eluting, and 50 zotarolimus-eluting stents. Optical coherence tomography coverage of nonapposed side-branch and ISA struts was compared with well-apposed struts of the same stent by statistical pooled analysis with a random-effects model. A total of 34 120 struts were analyzed. The risk ratio of delayed coverage was 9.00 (95% confidence interval, 6.58 to 12.32) for nonapposed side-branch versus well-apposed struts, 9.10 (95% confidence interval, 7.34 to 11.28) for ISA versus well-apposed struts, and 1.73 (95% confidence interval, 1.34 to 2.23) for ISA versus nonapposed side-branch struts. Heterogeneity of the effect was observed in the comparison of ISA versus well-apposed struts (H=1.27; I 2 =38.40) but not in the other comparisons. Conclusions— Coverage of ISA and nonapposed side-branch struts is delayed with respect to well-apposed struts in drug-eluting stents, as assessed by optical coherence tomography. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00389220, NCT00617084.
Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies
Authors: Nezam Altorok, Pei-Suen Tsou, Patrick Coit, Dinesh Khanna, Amr H Sawalha
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The aetiology of systemic sclerosis (SSc) is not clear, but there is an emerging evidence of gene-specific epigenetic dysregulation in the pathogenesis of SSc. <h3>Methods</h3> We performed a genome-wide DNA methylation study in dermal fibroblasts in six diffuse cutaneous SSc (dSSc) patients, six limited cutaneous SSc (lSSc) patients compared with 12 age-matched, sex-matched and ethnicity-matched healthy controls. Cytosine methylation was quantified in more than 485 000 methylation sites across the genome. Differentially methylated CpG sites between patients and controls with a fold difference ≥1.2 were identified. Quantitative real-time RT-PCR was performed to assess correlation between DNA methylation changes and gene expression levels. <h3>Results</h3> We identified 2710 and 1021 differentially methylated CpG sites in dSSc and lSSc, respectively. Of the differentially methylated sites, 61% in dSSc and 90% in lSSc were hypomethylated. There were only 203 CpG sites differentially methylated in both dSSc and lSSc, representing 118 hypomethylated and 6 hypermethylated genes. Common hypomethylated genes include <i>ITGA9,</i> encoding an α integrin. Other relevant genes such as <i>ADAM12, COL23A1, COL4A2</i> and <i>MYO1E</i>, and transcription factors genes <i>RUNX1</i>, <i>RUNX2</i> and <i>RUNX3</i> were also hypomethylated in both dSSc and lSSc. Pathway analysis of differentially methylated genes in both dSSc and lSSc revealed enrichment of genes involved in extracellular matrix–receptor interaction and focal adhesion. We demonstrate significant correlation between DNA methylation status and gene expression in the majority of genes evaluated. <h3>Conclusions</h3> Our data highlight common and subset-specific aberrancies in dSSc and lSSc fibroblasts at the epigenomic levels and identify novel candidate genes in SSc.