tbuckley/cabot-search huggingface dataset:
The VIVA Trial
Authors: Timothy D. Henry, Brian H. Annex, George R. McKendall, Michael A. Azrin, John J. Lopez, Frank J. Giordano, P.K. Shah, James T. Willerson, Raymond L. Benza, Daniel S. Berman, C. Michael Gibson, Alex Bajamonde, Amy Chen Rundle, Jennifer Fine, Edward R. McCluskey
Journal: Circulation (2003)

Background— Recombinant human vascular endothelial growth factor protein (rhVEGF) stimulates angiogenesis in animal models and was well tolerated in Phase I clinical trials. VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) is a double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intracoronary and intravenous infusions of rhVEGF. Methods and Results— A total of 178 patients with stable exertional angina, unsuitable for standard revascularization, were randomized to receive placebo, low-dose rhVEGF (17 ng · kg −1 · min −1 ), or high-dose rhVEGF (50 ng · kg −1 · min −1 ) by intracoronary infusion on day 0, followed by intravenous infusions on days 3, 6, and 9. Exercise treadmill tests, angina class, and quality of life assessments were performed at baseline, day 60, and day 120. Myocardial perfusion imaging was performed at baseline and day 60. At day 60, the change in exercise treadmill test (ETT) time from baseline was not different between groups (placebo, +48 seconds; low dose, +30 seconds; high dose, +30 seconds). Angina class and quality of life were significantly improved within each group, with no difference between groups. By day 120, placebo-treated patients demonstrated reduced benefit in all three measures, with no significant difference compared with low-dose rhVEGF. In contrast, high-dose rhVEGF resulted in significant improvement in angina class ( P =0.05) and nonsignificant trends in ETT time ( P =0.15) and angina frequency ( P =0.09) as compared with placebo. Conclusions— rhVEGF seems to be safe and well tolerated. rhVEGF offered no improvement beyond placebo in all measurements by day 60. By day 120, high-dose rhVEGF resulted in significant improvement in angina and favorable trends in ETT time and angina frequency.
CD4 expression is differentially required for deletion of MLS-1a-reactive T cells.
Authors: V A Wallace, A Rahemtulla, E Timms, J Penninger, T W Mak
Journal: The Journal of Experimental Medicine (1992)

Clonal deletion of thymocytes expressing potentially self-reactive T cell receptors (TCRs) occurs during thymocyte ontogeny. Mice deficient for CD4 expression provide a unique model system to study the contribution of the CD4 molecule in negative selection of T cells reactive against the major histocompatibility complex class II-associated retroviral self-superantigen, Mls-1a. In the presence of Mls-1a determinants, mature CD8+ T cells expressing V beta 6, 8.1, and 9 were deleted in CD4-deficient mice, thus demonstrating that TCR affinity for Mls-1a is sufficient for deletion and that a signal through CD4 was not required. However, in instances where the TCR affinity for Mls-1a is low, as in the case of V beta 7+ T cells, CD4 expression was required for clonal deletion. These results demonstrate that for Mls-1a-mediated clonal deletion of T cells, the requirement for the accessory or coreceptor function of CD4 depends on the affinity of the TCR.
Cooperative Interaction of <i>trp</i> Melastatin Channel Transient Receptor Potential (TRPM2) With Its Splice Variant TRPM2 Short Variant Is Essential for Endothelial Cell Apoptosis
Authors: Claudie M. Hecquet, Min Zhang, Manish Mittal, Stephen M. Vogel, Anke Di, Xiaopei Gao, Marcelo G. Bonini, Asrar B. Malik
Journal: Circulation Research (2013)

Rationale: Oxidants generated by activated endothelial cells are known to induce apoptosis, a pathogenic feature of vascular injury and inflammation from multiple pathogeneses. The melastatin-family transient receptor potential 2 (TRPM2) channel is an oxidant-sensitive Ca 2+ permeable channel implicated in mediating apoptosis; however, the mechanisms of gating of the supranormal Ca 2+ influx required for initiating of apoptosis are not understood. Objective: Here, we addressed the role of TRPM2 and its interaction with the short splice variant TRPM2 short variant (TRPM2-S) in mediating the Ca 2+ entry burst required for induction of endothelial cell apoptosis. Methods and Results: We observed that TRPM2-S was basally associated with TRPM2 in the endothelial plasmalemma, and this interaction functioned to suppress TRPM2-dependent Ca 2+ gating constitutively. Reactive oxygen species production in endothelial cells or directly applying reactive oxygen species induced protein kinase C-α activation and phosphorylation of TRPM2 at Ser 39. This in turn stimulated a large entry of Ca 2+ and activated the apoptosis pathway. A similar TRPM2-dependent endothelial apoptosis mechanism was seen in intact vessels. The protein kinase C-α–activated phosphoswitch opened the TRPM2 channel to allow large Ca 2+ influx by releasing TRPM2-S inhibition of TRPM2, which in turn activated caspase-3 and cleaved the caspase substrate poly(ADP-ribose) polymerase. Conclusions: Here, we describe a fundamental mechanism by which activation of the trp superfamily TRPM2 channel induces apoptosis of endothelial cells. The signaling mechanism involves reactive oxygen species–induced protein kinase C-α activation resulting in phosphorylation of TRPM2-S that allows enhanced TRPM2-mediated gating of Ca 2+ and activation of the apoptosis program. Strategies aimed at preventing the uncoupling of TRPM2-S from TRPM2 and subsequent Ca 2+ gating during oxidative stress may mitigate endothelial apoptosis and its consequences in mediating vascular injury and inflammation.
A novel approach to identifying regulatory motifs in distantly related genomes.
Authors: Ruth Van Hellemont, Pieter Monsieurs, Gert Thijs, Bart De Moor, Yves Van de Peer, Kathleen Marchal
Journal: Genome biology (2005)

Abstract Although proven successful in the identification of regulatory motifs, phylogenetic footprinting methods still show some shortcomings. To assess these difficulties, most apparent when applying phylogenetic footprinting to distantly related organisms, we developed a two-step procedure that combines the advantages of sequence alignment and motif detection approaches. The results on well-studied benchmark datasets indicate that the presented method outperforms other methods when the sequences become either too long or too heterogeneous in size.
Immature rat uterotrophic assay of bisphenol A.
Authors: K Yamasaki, M Sawaki, M Takatsuki
Journal: Environmental Health Perspectives (2000)

We used the immature rat uterotrophic assay to determine the estrogenicity of bisphenol A (BPA). We administered BPA (in sesame oil) to rats subcutaneously (sc; 0, 8, 40, and 160 mg/kg/day) or orally (0, 40, 160, and 800 mg/kg/day) for 3 days beginning on postnatal day (PND) 18; rats were sacrificed 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all groups given BPA sc. After oral administration, uterine relative weight increased in 160 and 800 mg/kg BPA groups, and wet and blotted weights increased in the 800 mg/kg BPA group. Plasma concentrations of BPA at 1 hr after the last administration were detected in all groups given BPA sc and in groups given 160 and 800 mg/kg BPA orally, with a dose-response effect. The study was then reproduced under the same conditions. After sc injections, uterine wet and blotted weights increased in the 40 and 160 mg/kg BPA groups, and relative weight increased in all groups given BPA sc. By contrast, uterine wet, blotted, and relative weights increased only in the 160 and 800 mg/kg oral BPA groups. Also, to examine time-course changes in uterine weight, we administered BPA (in sesame oil) sc from PND 18 to PND 20 for 3 days at doses of 0, 8, 40, and 160 mg/kg/day; uterine weights were then measured at 6, 12, 18, and 24 hr after the last administration. Uterine wet, blotted, and relative weights increased in all BPA groups at 6 and 24 hr and in 40 and 160 mg/kg BPA groups at 12 hr. By contrast, at 18 hr, uterine wet, blotted, and relative blotted weights increased in all BPA groups and relative wet weight increased in 40 and 160 mg/kg BPA groups. The percentage increases in uterine wet and relative weights of 40 and 160 mg/kg BPA groups at 6 hr were higher than those at 24 hr relative to the controls, but the coefficient of variation in these weights in the group given 8 mg/kg BPA at 24 hr was smaller than that at 6 hr. These findings demonstrate BPA-induced uterotrophy in the immature uterotrophic assay in rats administered 8 mg/kg/day sc and in rats given 160 mg/kg/day orally, and suggest that the autopsy at 24 hr after the last administration is suitable.
Antifluorescein affinity columns. Isolation and immunocompetence of lymphocytes that bind fluoresceinated antigens in vivo or in vitro.
Authors: D W Scott
Journal: The Journal of Experimental Medicine (1976)

A new method for the isolation of specific immunocompetent lymphocytes has been described in which lymphocyte populations are exposed to fluoresceinated antigens (FLAGs) in vivo or in vitro, and the FLAG-binding cells retained on antifluorescein affinity columns. Specific cells are then eluted with an unrelated FL-labeled protein and shown to be fully immunocompetent. This methodology has been applied successfully in diverse antigenic systems including polymerized flagellin and TNP-specific B cells and alloantigen-reactive cytotoxic T lymphocytes. The method is rapid, inexpensive (requiring only antifluorescein beads), and can be applied to any antigens (or antibodies) in which a fluorescein group can be introduced.
Semaphorin 7A plays a critical role in TGF-β1–induced pulmonary fibrosis
Authors: Hye-Ryun Kang, Chun Geun Lee, Robert J. Homer, Jack A. Elias
Journal: The Journal of Experimental Medicine (2007)

Semaphorin (SEMA) 7A regulates neuronal and immune function. In these studies, we tested the hypothesis that SEMA 7A is also a critical regulator of tissue remodeling. These studies demonstrate that SEMA 7A and its receptors, plexin C1 and β1 integrins, are stimulated by transforming growth factor (TGF)-β1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-β1–induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-β1 stimulated SEMA 7A via a largely Smad 3–independent mechanism and stimulated SEMA 7A receptors, matrix proteins, CCN proteins, fibroblast growth factor 2, interleukin 13 receptor components, proteases, antiprotease, and apoptosis regulators via Smad 2/3–independent and SEMA 7A–dependent mechanisms. SEMA 7A also played an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. TGF-β1 and bleomycin also activated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB)/AKT via SEMA 7A–dependent mechanisms, and PKB/AKT inhibition diminished TGF-β1–induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-β1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-β1–induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-β1, highlighting the importance of these findings for other fibrotic stimuli.
Transcriptional Control of the Terminal Fate of Monoaminergic Neurons
Authors: Nuria Flames, Oliver Hobert
Journal: Annual Review of Neuroscience (2011)

Monoaminergic neurons are critical functional components of all nervous systems across phylogeny. The terminally differentiated state of individual types of monoaminergic neurons is defined by the coordinated expression of a battery of genes that instructs the synthesis and transport of specific monoamines, such as serotonin or dopamine. Dysfunction or deregulation of several of these enzymes and transporter system has been proposed to be the underlying basis of several pathological conditions. We review here the state of knowledge of the nature of the transcriptional regulatory programs that control the expression of what we term monoaminergic gene batteries (enzymes and transporters for specific monoamines) and thereby define the terminally differentiated state of monoaminergic neurons. We review several case studies in vertebrate and invertebrate model systems and propose that the coordinated expression of the genes that define individual monoaminergic cell types may be brought about by transcriptional coregulatory strategies.
Prognostic Impact of ANX7-GTPase in Metastatic and HER2-Negative Breast Cancer Patients
Authors: Meera Srivastava, Lukas Bubendorf, Mark Raffeld, Christoph Bucher, Jochen Torhorst, Guido Sauter, Cara Olsen, Olli P. Kallioniemi, Ofer Eidelman, Harvey B. Pollard
Journal: Clinical Cancer Research (2004)

ANX7-GTPase located on chromosome 10q21 is significantly altered and associated with hormone-refractory metastatic prostate cancers. Therefore, we investigated whether levels of ANX7 correlate with breast cancer progression and survivalA diagnostic tumor tissue microarray containing 525 human breast tissue specimens at different stages of the disease was assayed for ANX7 using immunocytochemical methods with ANX7 monoclonal antibody. A separate prognostic tumor tissue microarray containing 553 human breast tissue specimens annotated with clinicopathological parameters was assayed for ANX7, HER2, estrogen receptor, progesterone receptor, and p53 protein.We report here for the first time that the expression of ANX7-GTPase is significantly enhanced and associated with the presence of metastatic disease (P < 0.0001) in the 525 human breast tissue specimens analyzed. Furthermore, using a separate 553 case retrospective prognostic tumor tissue microarray, we found that increased ANX7 expression is also significantly associated with poor overall patient survival (P < 0.014). This is particularly true when restricted to patients in whom the BRE clinical grade is 2 (P < 0.001) or for whom there is a lack of HER2 expression (P < 0.002). Finally, Cox regression analysis shows that as the expression of ANX7 rises, the probability of survival decreases by more than 10-fold for those patients with HER2-negative tumors. These latter patients represented 66% of the population affected with breast cancer in this study.High levels of ANX7 in tumor correlate strongly with poor survival of HER2-negative patients and the most aggressive forms of breast cancer. This is the first study to demonstrate that ANX7 antibody has the potential for development into an in vivo diagnostic and therapeutic tool. This simple and reliable immunohistochemical assay may therefore become an important biomarker for metastatic breast cancer diagnosis and management of HER2-negative breast tumor patients.
Resistance to second-line injectables and treatment outcomes in multidrug-resistant and extensively drug-resistant tuberculosis cases
Authors: G. B. Migliori, C. Lange, R. Centis, G. Sotgiu, R. Mutterlein, H. Hoffmann, K. Kliiman, G. De Iaco, F. N. Lauria, M. D. Richardson, A. Spanevello, D. M. Cirillo, None TBNET Study Group
Journal: European Respiratory Journal (2008)

No information is currently available on the influence of injectable second-line drugs on treatment outcomes of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) patients. To investigate this issue, a large series of MDR- and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation (Archangels Oblast) between 1999 and 2006 were analysed. All study sites performed drug susceptibility testing for first- and second-line anti-TB drugs, laboratory quality assurance and treatment delivery according to World Health Organization recommendations. Out of 4,583 culture-confirmed cases, 240 MDR- and 48 XDR-TB cases had a definitive outcome recorded (treatment success, death, failure). Among MDR- and XDR-TB cases, capreomycin resistance yielded a higher proportion of failure and death than capreomycin-susceptible cases. Resistance to capreomycin was independently associated with unfavourable outcome (logistic regression analysis: odds ratio 3.51). In the treatment of patients with multidrug-resistant and extensively drug-resistant tuberculosis, resistance to the injectable drug capreomycin was an independent predictor for therapy failure in this cohort. As <i>Mycobacterium tuberculosis</i> drug resistance is increasing worldwide, there is an urgent need for novel interventions in the fight against tuberculosis.
A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection
Authors: Wataru Akahata, Zhi-Yong Yang, Hanne Andersen, Siyang Sun, Heather A Holdaway, Wing-Pui Kong, Mark G Lewis, Stephen Higgs, Michael G Rossmann, Srinivas Rao, Gary J Nabel
Journal: Nature Medicine (2010)
Fifty shades of grey: concussion complexities and constructive conclusions
Authors: Jonathan Patricios, Michael Makdissi
Journal: British Journal of Sports Medicine (2015)

Concussion remains prominent in the medical and scientific literature but its assessment and management remain somewhat ‘grey’ and ill defined. The key issues related to concussion are widely discussed in the public arena. While these discussions should contribute to an improved understanding of concussion in the broader community, confusing messages are being driven by different agendas.

Quarrie and Murphy1 question the relevance of current concussion consensus definitions, particularly as they translate to the real world. The authors make pragmatic recommendations. Specifically, they suggest that the increasing incidence of concussion may be partly due to the expanded ‘theoretical’ definition, and that changes in the manner in which the SCAT3 is implemented and interpreted may more accurately diagnose the condition.

Similarly, a number of recent articles have highlighted the fact that the ‘theoretical definition’ of concussion, as outlined in the current Zurich statement, lacks sensitivity and specificity. Furthermore, basic concepts of concussion management, such as a period of absolute rest and graded return to play, lack a strong evidence base.2 ,3 Increasingly, concussion in sport appears to have become ‘a grey area about grey matter’, with an increasingly wide net cast to capture more cases, the management of which remains subject to varied opinion and some conjecture.

‘Shades of grey’ are not unique …
Value of neuropsychological testing after head injuries in football
Authors: P McCrory, M Makdissi, G Davis, A Collie
Journal: British Journal of Sports Medicine (2005)

This paper reviews the pros and cons of the traditional paper and pencil and the newer computerised neuropsychological tests in the management of sports concussion. The differences between diagnosing concussion on the field and neuropsychological assessment at follow up and decision making with regard to return to play are described. The authors also discuss the issues involved in interpreting the results of neuropsychological testing (comparison with population norms versus player’s own baseline test results) and potential problems of such testing in football. Finally, suggested recommendations for neuropsychological testing in football are given.
Multiple sclerosis: major histocompatibility complexity and antigen presentation
Authors: Sreeram V Ramagopalan, George C Ebers
Journal: Genome Medicine (2009)

Multiple sclerosis (MS), like many putative autoimmune diseases, has been known to be associated with the human leukocyte antigen (HLA) class II region for more than 3 decades. However, exactly how HLA class II alleles increase the risk of MS is not yet conclusively known. Recent work in large human cohorts has highlighted the fact that nearly all common HLA-DRB1 allelotypes are either positively or negatively associated with the disease, detracting from allele-specific antigen presentation as the sole mechanism of MHC associated disease susceptibility. Here, we put into context recent data on the HLA class II region in MS, including allelic heterogeneity, gene-environment interactions and epigenetics. It is clear that a complete understanding of the epistatic interactions and epigenetic features of this region will be crucial to comprehending disease pathogenesis.
Increased incidence of life-threatening ventricular arrhythmias in implantable defibrillator patients after the World Trade Center attack
Authors: Jonathan S. Steinberg, Aysha Arshad, Marcin Kowalski, Atul Kukar, Valentin Suma, Margot Vloka, Frederick Ehlert, Bengt Herweg, Jacqueline Donnelly, Julie Philip, George Reed, Alan Rozanski
Journal: Journal of the American College of Cardiology (2004)
Diabetes and Nutrition
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2002)

This is the first in a series of articles covering the 2002 American Diabetes Association Annual Meeting, which was held San Francisco, 14–18 June 2002.

Marion Franz (Minneapolis, MN) discussed the process used for the “evidence basing” approach for current American Diabetes Association (ADA) nutrition recommendations (1). “We have made some progress,” she pointed out, comparing the starvation treatment used in 1917 (composed of whiskey mixed with black coffee) with our current approaches. “There are many ways of approaching medical nutrition therapy” for persons with diabetes, she stated, which requires assessment of the individual’s goals and her/his ability to comply with a given recommendation. “The gold standard of research in nutrition has generally been a study in which food is provided to the subjects so that you can know what is being consumed,” she stated, but such studies are necessarily short in duration, and therefore may not be completely applicable to the “real world,” and must be extended by studies implemented in free-living subjects. Also, many questions have not been addressed in persons with diabetes and must be extrapolated from studies in persons with other conditions.

Franz referred to the studies on fiber as examples. Early studies showed a great deal of benefit, but “there are many variables. People lost weight, they changed the percentage of macronutrients, medications were changed, and yet all the benefit was ascribed to fiber.” More recent studies of high-fiber load approaches show only equivocal evidence, with benefit at fiber levels exceeding 50 g daily, far above the level of ∼20 g daily that can be attained in realistic circumstances, that has not been shown to be associated with improvement in lipids, glycemia, or insulin resistance. With newly diagnosed type 2 diabetes, she stated, lifestyle change leads to a fall in HbA1c of ∼2%, and …