tbuckley/cabot-search huggingface dataset:
Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome
Authors: Joanna Groom, Susan L. Kalled, Anne H. Cutler, Carl Olson, Stephen A. Woodcock, Pascal Schneider, Jurg Tschopp, Teresa G. Cachero, Marcel Batten, Julie Wheway, Davide Mauri, Dana Cavill, Tom P. Gordon, Charles R. Mackay, Fabienne Mackay
Journal: Journal of Clinical Investigation (2002)

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.
Abstract 4625: A biotin-label-based antibody array for high-content profiling of protein expression
Authors: Ruochun Huang, Weidong Jiang, Jean Yang, Ying Qing Mao, Ying Zhang, Weiming Yang, Dongzi Yang, Brett Burkholder, Rani Yan Huang, Ruo-Pan Huang
Journal: Cancer Research (2010)

Abstract Abstract: Profiling protein expression on a global scale will have significant impact on biomedical research, particularly in the discovery and development of drugs and biomarkers. Through the years, several antibody array systems have been invented and developed for multiple protein detection. However, a reliable and high-content system for protein profiling from many biological samples has yet developed. To address this problem, we have developed a high density antibody array and used this technology to uncover the potential biomarkers of ovarian cancer. In this approach, biological samples are conjugated with biotin. Antibody arrays are then used to capture the biotinylated proteins. The presence of proteins captured by the antibody chip is detected using streptavidin-conjugated fluorescent dye (Cy3 equivalent) as a reporter. The signals, which are visualized by laser scanning, are normalized using positive, negative, and internal controls. Using this biotin-label-based antibody array technology, the expression levels of 507 human, 308 mouse, 90 rat target proteins can be simultaneously detected, including cytokines, chemokines, adipokines, growth factors, angiogenic factors, proteases, soluble receptors, soluble adhesion molecules, and other proteins in a variety of samples. Most proteins can be detected at pg/ml and ng/ml levels with a CV of less than 20%. Using human biotin-based antibody arrays, we screened the serum expression profiles of 507 proteins in 47 ovarian cancer patients and 39 normal subjects. A panel of protein expression showed significant difference between normal and cancer (P&amp;lt;0.05). By Classification Analysis and Split-Point Score Analysis of these two groups, a small group of proteins can be used to distinguish ovarian cancer patients from normal subjects and between ovarian cancer patients and normal subjects. Our results suggest the biotin label-based antibody arrays that we have developed have great potential in applications for biomarker discovery. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4625.
The FLIP-Side of Fas Signaling
Authors: Marc L. Hyer, Temesgen Samuel, John C. Reed
Journal: Clinical Cancer Research (2006)

Fas (CD95/APO-1) is a 45-kDa type I transmembrane protein belonging to the tumor necrosis factor superfamily of receptors ([1][1], [2][2]). Fas was identified in 1989 as a cell death inducer of malignant human cancer and leukemia cell lines ([3][3], [4][4]). Fas contains a classic “death domain
Long-Lasting Improvements in Liver Fat and Metabolism Despite Body Weight Regain After Dietary Weight Loss
Authors: Sven Haufe, Verena Haas, Wolfgang Utz, Andreas L. Birkenfeld, Stephanie Jeran, Jana Böhnke, Anja Mähler, Friedrich C. Luft, Jeanette Schulz-Menger, Michael Boschmann, Jens Jordan, Stefan Engeli
Journal: Diabetes Care (2013)

OBJECTIVE Weight loss reduces abdominal and intrahepatic fat, thereby improving metabolic and cardiovascular risk. Yet, many patients regain weight after successful diet-induced weight loss. Long-term changes in abdominal and liver fat, along with liver test results and insulin resistance, are not known. RESEARCH DESIGN AND METHODS We analyzed 50 overweight to obese subjects (46 ± 9 years of age; BMI, 32.5 ± 3.3 kg/m2; women, 77%) who had participated in a 6-month hypocaloric diet and were randomized to either reduced carbohydrates or reduced fat content. Before, directly after diet, and at an average of 24 (range, 17–36) months follow-up, we assessed body fat distribution by magnetic resonance imaging and markers of liver function and insulin resistance. RESULTS Body weight decreased with diet but had increased again at follow-up. Subjects also partially regained abdominal subcutaneous and visceral adipose tissue. In contrast, intrahepatic fat decreased with diet and remained reduced at follow-up (7.8 ± 9.8% [baseline], 4.5 ± 5.9% [6 months], and 4.7 ± 5.9% [follow-up]). Similar patterns were observed for markers of liver function, whole-body insulin sensitivity, and hepatic insulin resistance. Changes in intrahepatic fat und intrahepatic function were independent of macronutrient composition during intervention and were most effective in subjects with nonalcoholic fatty liver disease at baseline. CONCLUSIONS A 6-month hypocaloric diet induced improvements in hepatic fat, liver test results, and insulin resistance despite regaining of weight up to 2 years after the active intervention. Body weight and adiposity measurements may underestimate beneficial long-term effects of dietary interventions.
Hoists and Their Use
Authors: M. A. Chamberlain
Journal: Annals of the Rheumatic Diseases (1981)

Research in human subjects is very important.Apart from the study of disease there is now a widespread acceptance of the view that treatment can be shown to be effective only by controlled clinical trials.This brings physicians to give their patients dummy tablets, to deny them active treatment, and to fail to tell them what is going on.What patient would continue to take dummy tablets if he knew what they were?The surface of this important subject is gently stroked but not scratched in this little book, and it is probably good to remind clinical investigators of their moral obligations from time to time.Relations with regulatory authorities are also discussed, and the British investigator will be pleased to know, from an inside source, that the FDA will not reject his 'foreign data' just because they are 'foreign'.They may not be regarded as 'pivotal,' since it appears that 'foreign' investigators are reluctant to supply case records or report forms to support the honesty and integrity of their work.A continued deep suspicion of foreigners, and their work is clearly justified.Jargon abounds in this publication.Could FDA, for example, give NDA, or could CSM grant NPL in NIH funded REC approved NHLBI CT of BO under HEW regulations using SSN for FECA at RBH? Words do not necessarily help.Once paper concludes that 'multicentre clinical trials require a synthesis of the scientific method and the precepts of modern management.'Among a few very enjoyable and stimulating contributions is a paper on randomised controlled trials of nonpharmacological treatment.This would be enormously helpful to a young physician who wanted to do some research but could not think of a worthwhile project.Much of what physicians and surgeons do is empirical but could be randomised and documented.Though there
Thalidomide Costimulates Primary Human T Lymphocytes, Preferentially Inducing Proliferation, Cytokine Production, and Cytotoxic Responses in the CD8+ Subset
Authors: Patrick A.J. Haslett, Laura G. Corral, Matthew Albert, Gilla Kaplan
Journal: The Journal of Experimental Medicine (1998)

The efficacy of thalidomide (α-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor α. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2–mediated T cell proliferation and interferon γ production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset.
Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study
Authors: C Ding, V Parameswaran, F Cicuttini, J Burgess, G Zhai, S Quinn, G Jones
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To describe the associations between leptin, body composition, sex and knee cartilage volume/defects in older adults. <h3>Methods:</h3> A cross-sectional sample of 190 randomly selected subjects (mean 63 years, range 52–78, 48% female) were studied. Knee cartilage volume and defects were determined using T1-weighted fat saturation MRI. Serum leptin levels were measured by radioimmunoassay. Fat and lean mass were measured by dual energy <i>x</i> ray absorptiometry (DXA). Body mass index (BMI) was calculated. <h3>Results:</h3> In multivariable analysis, serum levels of leptin were negatively associated with total cartilage volume (β: −541 mm3/log transformed unit, 95% CI −861 to −221) but not with prevalent knee cartilage defects. BMI was negatively associated with cartilage volume after adjustment for total lean mass and positively with prevalent knee cartilage defects. However, the association between BMI and cartilage volume disappeared after adjustment for leptin while the association between BMI and cartilage defects remained unchanged. Lastly, sex differences in total cartilage volume decreased substantially after adjustment for leptin (R2 from 51% to 30%). <h3>Conclusions:</h3> This cross-sectional study suggests cartilage volume loss with obesity and female sex is related to leptin and, thus, is hormonally mediated in older adults. By contrast, obesity related knee focal cartilage defects may be more related to non-hormonal factors.
What exactly are we doing to improve low lung cancer survival in the United Kingdom?
Authors: Eric Lim, Sanjay Popat
Journal: Thorax (2013)

When one is presented with a blinded report of survival rates for lung cancer across developed countries, how can one identify the result for the UK? Exactly, choose the one with the poorest outcome. You would be correct more often than not (unless Denmark was included).

In 2007 and 2009, the EUROCARE Group published results of cancer survival identifying the UK among the countries with the lowest survival rates for lung cancer in Europe.1 ,2 As expected, this was met with a degree of outrage and attribution of poor UK results to differences in population characteristics and quality of reporting. An articulate defence launched by Moller et al hypothesised ‘less favourable stage distribution in the United Kingdom’ as the likely explanation for poor UK outcomes compared with other European countries compounded by suspicion of ‘incomplete ascertainment of deaths’ in certain countries reporting high survival results.3 Apart from population characteristics and quality of reporting, socioeconomic status within Europe (a surrogate for healthcare spending for the management of lung cancer) has also been cited rendering such comparisons inequitable.4

This week in Thorax , the International Cancer Benchmarking Partnership published survivorship of patients with lung cancer in six ‘wealthy countries’, namely, Australia, Canada, Denmark, Norway, Sweden, and of course, the UK between 1995 and 2007.5 The socioeconomic status differences have been redressed and stage adjustment rectified. At last, the UK has a chance to perform on an equal footing! So, with baited breath, you ask, …
CD44 is a determinant of inflammatory bone loss
Authors: Silvia Hayer, Günter Steiner, Birgit Görtz, Erika Reiter, Makiyeh Tohidast-Akrad, Michael Amling, Oskar Hoffmann, Kurt Redlich, Jochen Zwerina, Karl Skriner, Frank Hilberg, Erwin F. Wagner, Josef S. Smolen, Georg Schett
Journal: The Journal of Experimental Medicine (2005)

Chronic inflammation is a major trigger of local and systemic bone loss. Disintegration of cell–matrix interaction is a prerequisite for the invasion of inflammatory tissue into bone. CD44 is a type I transmembrane glycoprotein that connects a variety of extracellular matrix proteins to the cell surface. Tumor necrosis factor (TNF) is a major inducer of chronic inflammation and its overexpression leads to chronic inflammatory arthritis. By generating CD44−/− human TNF-transgenic (hTNFtg) mice, we show that destruction of joints and progressive crippling is far more severe in hTNFtg mice lacking CD44, which also develop severe generalized osteopenia. Mutant mice exhibit an increased bone resorption due to enhanced number, size, and resorptive capacity of osteoclasts, whereas bone formation and osteoblast differentiation are not affected. Responsiveness of CD44-deficient osteoclasts toward TNF is enhanced and associated with increased activation of the p38 mitogen-activated protein kinase. These data identify CD44 as a critical inhibitor of TNF-driven joint destruction and inflammatory bone loss.
C-type natriuretic peptide (CNP) suppresses plasminogen activator inhibitor-1 (PAI-1) in vivo
Authors: E KAIRUZ, M BARBER, C ANDERSON, M KANAGASUNDARAM, G DRUMMOND, R WOODS
Journal: Cardiovascular Research (2005)

Elevated vascular plasminogen activator inhibitor-1 (PAI-1) levels are associated with atherosclerosis. In vitro, C-type natriuretic peptide (CNP) has anti-proliferative effects and inhibits the production of PAI-1 in cultured vascular cells. Whether CNP can affect PAI-1 in vivo, particularly in the setting of atherosclerosis, has not been reported.Using the rabbit carotid arterial collar model of intimal hyperplasia (collar in place for 7 days), PAI-1 protein was compared in normal, vehicle (saline)-collared, and CNP-treated-collared arteries from the same animal. PAI-1 levels were measured by immunohistochemistry and densitometry and by Western blot. CNP was either infused into the peri-arterial space within one collar (10 fmol/h) or infused directly into the arterial lumen under one collar (100 pmol/h). In some rabbits (n=8), superoxide production in collared and normal artery segments was measured in vitro by chemiluminescence.PAI-1 was present throughout the vascular wall. Endothelial PAI-1 was elevated in saline-collared arteries (approximately 16%, P<0.05; n=7 rabbits) compared with normal carotid segments. The collar induced both a neointima that contained PAI-1 and the accumulation of macrophages in the adventitia. Peri-arterial CNP reduced PAI-1 (P<0.05) in the endothelium (33%), adventitia (47%) and neointima (39%), compared with levels in the contralateral, saline-collared carotid artery, while macrophage infiltration was reduced. Elevated superoxide production in collared arteries was not altered by chronic in vivo treatment with CNP (n=8). Peri-arterial CNP treatment did not reduce intimal thickening. Intra-luminal CNP (n=6) reduced endothelial, neointimal and total vessel (Western blot) PAI-1, macrophage accumulation, and intimal thickening (all P<0.05).CNP treatment of collared carotid arteries in vivo for 1 week suppressed endothelial and neointimal PAI-1, independently of intimal thickening. The CNP effects were not via superoxide. This is the first evidence that CNP inhibits activated PAI-1, in vivo.
CD4 T cells in murine acquired immunodeficiency syndrome: polyclonal progression to anergy.
Authors: G Muralidhar, S Koch, M Haas, S L Swain
Journal: The Journal of Experimental Medicine (1992)

We have examined the kinetics of changes that occur in the helper T cell subset during murine acquired immunodeficiency syndrome, which occurs after infection with the mix of viruses known as BM5. We find that there is expansion of the CD4 T cells by 2 wk, 50% of the CD4 T cells become large as the disease progresses, and the CD4 T cell population is increasingly comprised of cells with a memory/activated phenotype. These effects are apparent by 2 wk postinfection, and the change is nearly complete by 6-8 wk. The phenotypic shift is paralleled by the loss of the ability of the CD4 T cells to proliferate or to produce interleukin 2 (IL-2), IL-3, IL-4, and interferon gamma in response to stimulation with mitogens, superantigen, or anti-CD3. There is no obvious expansion or deletion of CD4 T cells expressing particular V beta genes, as might be expected if a conventional superantigen were driving the changes. The results suggest, however, that the total CD4 population has been driven to anergy by some potent polyclonal stimulus directly associated with viral infection.
iNOS — Another cardiac target of calcineurin
Authors: J HEGER, G EULER
Journal: Cardiovascular Research (2006)

See article by Obasanji-Blackshire et al.  [3]  (pages 672–683) in this issue. 

The serine–threonine kinase calcineurin was first detected in the nervous system in 1979 [1]. Twenty years later the first report about a role of calcineurin in cardiac hypertrophy appeared [2]. Since then, research on calcineurin function in the heart has strongly intensified. During these years of research, multifunctional roles of calcineurin in cardiac hypertrophy, apoptosis, contractile function, and, as now shown in this issue of Cardiovascular Research [3], preconditioning, have been revealed. These findings point to calcineurin/NFAT signaling as being a central factor in cardiac pathophysiology. However, it is still a matter of debate whether the final result of the signaling cascade is good or bad for the heart.

Several approaches have been used to characterize the role of calcineurin in cardiac hypertrophy. What became evident from these studies is that overexpression of calcineurin or its well-known downstream effector, the transcription factor NFAT, promotes hypertrophic growth of the heart in transgenic mice [2]. However, depending on the hypertrophic stimuli and the developmental stage of the myocytes, calcineurin/NFAT are not always activated and therefore not necessarily involved in hypertrophic growth: under conditions of physiological hypertrophy, as it is induced by exercise training of rats or by growth hormone/insulin-like growth factor 1 treatment of hearts or neonatal cardiomyocytes, the calcineurin/NFAT pathway is not activated [4]. In contrast, under pathological conditions of cardiac hypertrophy induced by pressure overload or after myocardial infarction with progression to heart failure, activation of calcineurin and NFAT occurs [4]. This indicates that calcineurin/NFAT is related to pathological conditions of heart failure. However, the expression of calcineurin/NFAT does not necessarily result in hypertrophy: in skeletal muscle, calcineurin expression … 

* Corresponding author. Physiologisches Institut, Justus-Liebig Universitat, Aulweg 129, 35392 Gieβen, Germany. Tel.: +49 641 9947246; fax: +49 641 9947219. Email address: gerhild.euler{at}physiologie.med.uni-giessen.de
Marrow Transplantation in Thirty "Untransfused" Patients with Severe Aplastic Anemia
Authors: RAINER STORB, E. DONNALL THOMAS, C. DEAN BUCKNER, REGINALD A. CLIFT, H. JOACHIM DEEG, ALEXANDER FEFER, BRIAN W. GOODELL, GEORGE E. SALE, JEAN E. SANDERS, JACK SINGER, PATRICIA STEWART, PAUL L. WEIDEN
Journal: Annals of Internal Medicine (1980)

Thirty patients with severe aplastic anemia had no transfusions of blood products until just before marrow transplantation from HLA-identical family members. They were conditioned for grafting with cyclophosphamide, 50 mg/kg body weight on each of 4 successive days. All 30 had prompt initial marrow engraftment, which was sustained in 27. Twenty-five of the 30 are alive between 9 to 84 (median, 19.5) months. The actuarial projection of survival for 2 to 6 years is 75%. Twenty of the 25 surviving patients have no problems. Five have chronic graft-versus-host disease, resolving in two and active in three. Five patients died with infection or hemorrhage, four of whom had graft-versus-host disease. These data show that early transplantation should be carried out before transfusions are given for any patient with severe aplastic anemia who has an HLA-identical family member. If sensitization to minor transplantation antigens contained in blood products is avoided, the incidence of marrow-graft rejection will decrease, and survival will improve.
Tail Paradox, Partial Identifiability, and Influential Priors in Bayesian Branch Length Inference
Authors: B. Rannala, T. Zhu, Z. Yang
Journal: Molecular Biology and Evolution (2011)

Recent studies have observed that Bayesian analyses of sequence data sets using the program MrBayes sometimes generate extremely large branch lengths, with posterior credibility intervals for the tree length (sum of branch lengths) excluding the maximum likelihood estimates. Suggested explanations for this phenomenon include the existence of multiple local peaks in the posterior, lack of convergence of the chain in the tail of the posterior, mixing problems, and misspecified priors on branch lengths. Here, we analyze the behavior of Bayesian Markov chain Monte Carlo algorithms when the chain is in the tail of the posterior distribution and note that all these phenomena can occur. In Bayesian phylogenetics, the likelihood function approaches a constant instead of zero when the branch lengths increase to infinity. The flat tail of the likelihood can cause poor mixing and undue influence of the prior. We suggest that the main cause of the extreme branch length estimates produced in many Bayesian analyses is the poor choice of a default prior on branch lengths in current Bayesian phylogenetic programs. The default prior in MrBayes assigns independent and identical distributions to branch lengths, imposing strong (and unreasonable) assumptions about the tree length. The problem is exacerbated by the strong correlation between the branch lengths and parameters in models of variable rates among sites or among site partitions. To resolve the problem, we suggest two multivariate priors for the branch lengths (called compound Dirichlet priors) that are fairly diffuse and demonstrate their utility in the special case of branch length estimation on a star phylogeny. Our analysis highlights the need for careful thought in the specification of high-dimensional priors in Bayesian analyses.