tbuckley/cabot-search huggingface dataset:
Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure
Authors: A El-Armouche
Journal: Cardiovascular Research (2003)

Heart failure is accompanied by stereotypic alterations in cardiac gene expression. These changes are most likely secondary in the pathogenesis and can be viewed as protective, e.g. as energy-saving mechanisms, but at the same time, they aggravate contractile dysfunction and the deficit of failing cardiac myocytes to respond to altered hemodynamic needs. One of the best-studied, paradigmatic examples of this dichotomy is heterologous desensitization of the cardiac adenylyl cyclase (AC) signaling pathway. It protects against detrimental consequences of the excessive adrenergic drive, but it also blunts the most powerful inotropic support of the heart. Desensitization is associated with downregulation of β-adrenergic receptors, increased β-adrenoceptor kinases and increased inhibitory G protein α-subunits, Gαi. Whereas a causative role of the former is generally accepted, the role of the increase in Gαi has remained controversial for many years. The present article summarizes early and novel findings that, in the view of the authors, provide solid evidence for Gαi to play an important role in the adaptation of cardiac AC to various pathophysiological conditions.
Crucial steps in photoreceptor adaptation: Regulation of phosphodiesterase and guanylate cyclase activities and Ca<sup>2+</sup>-buffering
Authors: Karl-Wilhelm Koch
Journal: Behavioral and Brain Sciences (1995)

Abstract This commentary discusses the balance of phosphodiesterase and guanylate cyclase activities in vertebrate photoreceptors at moderate light intensities. The rate of cGMP hydrolysis and synthesis seem to equal each other. Ca 2+ as regulator of both enzyme activities is also effectively buffered in photoreceptor cells by cytoplasmic buffer components.
Greater Interobserver Agreement by Endoscopic Mucosal Resection Than Biopsy Samples in Barrett's Dysplasia
Authors: Sachin Wani, Sharad C. Mathur, Wouter L. Curvers, Vikas Singh, Lorenza Alvarez Herrero, Sandy B. Hall, Ozlem Ulusarac, Rachel Cherian, Douglas H. McGregor, Ajay Bansal, Amit Rastogi, Basem Ahmed, Mandeep Singh, Srinivas Gaddam, Fiebo J. Ten Kate, Jacques Bergman, Prateek Sharma
Journal: Clinical Gastroenterology and Hepatology (2010)
Soft Tissue Sarcoma
Authors: George D. Demetri, Scott Antonia, Robert S. Benjamin, Marilyn M. Bui, Ephraim S. Casper, Ernest U. Conrad, Thomas F. DeLaney, Kristen N. Ganjoo, Martin J. Heslin, Raymond J. Hutchinson, John M. Kane, G. Douglas Letson, Sean V. McGarry, Richard J. O'Donnell, I. Benjamin Paz, John D. Pfeifer, Raphael E. Pollock, R. Lor Randall, Richard F. Riedel, Karen D. Schupak, Herbert S. Schwartz, Katherine Thornton, Margaret von Mehren, Jeffrey Wayne
Journal: Journal of the National Comprehensive Cancer Network (2010)

OverviewSarcomas constitute a heterogeneous group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathological features, and are usually divided into 2 broad categories: sarcomas of soft tissues (including fat, muscle, nerve and nerve sheath, blood vessels, and other connective tissues) and sarcomas of bone.Soft tissue sarcomas (STS) are the most frequent sarcomas; the annual incidence in the United States for 2009 is estimated to be approximately 10,660 cases, with an overall mortality rate of approximately 3820 cases per year, including adults and children. 1 The true incidence of sarcoma is underestimated, especially because a large proportion of patients with gastrointestinal stromal tumors (GIST) may not
Evaluation and relevance of skin sensitivity in animal models
Authors: A. LOMBARD
Journal: British Journal of Dermatology (1986)

Journal Article Evaluation and relevance of skin sensitivity in animal models Get access A. LOMBARD A. LOMBARD Centre International de Toxicologie, BP 563 ‐ Miserey, 27005 Evreux, France Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 115, Issue s31, 1 August 1986, Pages 24–32, https://doi.org/10.1111/j.1365-2133.1986.tb02103.x Published: 01 August 1986
Requirement for TRAF3 in Signaling by LMP1 But Not CD40 in B Lymphocytes
Authors: Ping Xie, Bruce S. Hostager, Gail A. Bishop
Journal: The Journal of Experimental Medicine (2004)

CD40, a member of the tumor necrosis factor receptor family, and the Epstein-Barr virus–encoded oncoprotein latent membrane protein 1 (LMP1) share several tumor necrosis factor receptor–associated factor (TRAF) adaptor proteins for signaling. Among these, TRAF3 was the first identified to directly bind both receptors, yet its role remains a mystery. To address this, we generated B cell lines deficient in TRAF3 by homologous recombination. We found that CD40 signals were normal in the absence of TRAF3, with the exception of moderately enhanced c-Jun NH2-terminal kinase (JNK) activation and antibody secretion. In sharp contrast, LMP1 signaling was markedly defective in TRAF3−/− B cells. LMP1-induced activation of JNK and nuclear factor κB, up-regulation of CD23 and CD80, and antibody secretion were substantially affected by TRAF3 deficiency. Reconstitution of TRAF3 expression decreased CD40-induced JNK activation and antibody secretion, and fully restored LMP1 signaling. Although TRAF2 is widely believed to be important for LMP1 function, LMP1 signaling was intact in TRAF2−/− B cells. Our data reveal that CD40 and LMP1 unexpectedly use TRAF3 in different ways, and that TRAF3 is required for LMP1-mediated activation of B cells.
MicroRNA-146a in autoimmunity and innate immune responses
Authors: Edward K L Chan, Angela Ceribelli, Minoru Satoh
Journal: Annals of the Rheumatic Diseases (2012)

MicroRNA (miRNA) are approximately 22 nucleotide single-stranded RNA that regulate the stability of target messenger RNA by selective binding to specific sites at the 3'-untranslated regions (UTR). This triggers repression in translation and mRNA degradation. It has been estimated that approximately 60% of all mRNA are under the control of miRNA. Among the known hundreds of miRNA, some are considered master regulators controlling either a single or multiple cellular pathways. Some miRNA are known to affect development and cell differentiation, while others are implicated in immunity and autoimmune diseases. A very interesting example is miR-146a, which has been reported to be downregulated in systemic lupus erythematosus and upregulated in rheumatoid arthritis (RA). Several groups have recently focused their attention on miRNA in the pathogenesis of RA. Interestingly, the expression of miR-146a is upregulated in different cell types and tissues in RA patients. miRNA in RA could also be considered as possible future targets for new therapeutic approaches. This discussion will focus on the current understanding in the function of miR-146a in endotoxin tolerance and cross-tolerance, and how it may contribute to modulate the overproduction of known pathogenic cytokines, such as tumour necrosis factor α.
Cognitive Substrates of Thought Disorder, I: The Semantic System
Authors: T E Goldberg, M S Aloia, M L Gourovitch, D Missar, D Pickar, D R Weinberger
Journal: American Journal of Psychiatry (1998)

Objective:Few studies have explored in detail the relation of cognitive deficits in attention, working memory, and semantics to thought disorder. The authors sought to determine whether thought disorder resides in the semantic system or elsewhere. Method:Twenty-three normal comparison subjects and 23 patients with schizophrenia participated in the study. All subjects received tests of executive function and working memory, including the Wisconsin Card Sorting Test and the Letter-Number Span test; a test of deployment of attentional resources; and tests of semantic processing and language comprehension, including the Peabody Picture Vocabulary Test, the Speed and Capacity of Language-Processing Test, the Boston Naming Test, and tests of semantic verbal fluency and phonologic verbal fluency, from which was derived a difference score. All patients were also administered the Scale for the Assessment of Thought, Language, and Communication to assess thought disorder. Results:The normal subjects were compared with the schizophrenic patients who were rated as having mild thought disorder (N=13) or moderate to severe thought disorder (N=10). While differences between the schizophrenic subgroups and the comparison subjects were observed on nearly all tests, a large difference in effect size between the two schizophrenic subgroups was apparent only in the verbal fluency difference score. In a series of multiple regression analyses, two variables made significant contributions to the prediction of positive thought disorder: the verbal fluency difference score and the Peabody Picture Vocabulary Test score. Conclusions:These results suggest that clinically rated thought disorder is associated with and may result from semantic processing abnormalities. In particular, patients with more severe thought disorder may have difficulty accessing semantic items because of disorganization of the semantic systems and, to a more limited degree, may also lack a semantic or conceptual knowledge base. Am J Psychiatry 1998; 155: 1671-1676
Lomeguatrib, a Potent Inhibitor of <i>O</i>6-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors
Authors: Malcolm Ranson, Mark R. Middleton, John Bridgewater, Siow Ming Lee, Martin Dawson, Debra Jowle, Gavin Halbert, Sue Waller, Helen McGrath, Lindsey Gumbrell, R. Stanley McElhinney, Dorothy Donnelly, T. Brian H. McMurry, Geoffrey P. Margison
Journal: Clinical Cancer Research (2006)

A major mechanism of resistance to temozolomide involves the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (ATase). The main aims of this phase I trial were to determine an ATase-depleting dose (ADD) of lomeguatrib, a potent pseudosubstrate inhibitor, and to define a suitable dose of temozolomide to be used in combination with lomeguatrib in patients with advanced cancer.Lomeguatrib was administered at dose levels of 10 to 40 mg/m2 days 1 to 5, as a single agent, and also in combination with temozolomide. Once the ADD of lomeguatrib was identified, the dose of temozolomide in combination was increased, in successive patient cohorts, from 50 to 175 mg/m2 on days 1 to 5 of a 28-day cycle to define the maximal tolerated dose and dose-limiting toxicity of the combination.Thirty-eight patients with advanced solid tumors were enrolled. More than 95% ATase depletion within 4 hours of the first dose was achieved in peripheral blood mononuclear cells at lomeguatrib doses of > or =10 mg/m2/d i.v. or > or =20 mg/m2/d orally, and tumor biopsies showed > or =92% ATase depletion. At the ADD of lomeguatrib i.v., the maximal tolerated dose of temozolomide in combination was 150 mg/m2 days 1 to 5. The dose limiting toxicity of the combination of lomeguatrib and temozolomide was myelosuppression. The toxicity of lomeguatrib alone was minimal. In 23 patients with measurable disease, one complete response was seen and 12 patients had stable disease for at least 3 months.This first administration of lomeguatrib to man successfully established an oral ADD of lomeguatrib and identified a combination regimen with temozolomide suitable for future clinical evaluation.
Lobbyists for the sports drink industry: an example of the rise of “contrarianism” in modern scientific debate
Authors: Timothy David Noakes, Dale B Speedy
Journal: British Journal of Sports Medicine (2007)

We welcome any discussion of our article which traces the emergence, especially in the United States of America, of exercise-associated hyponatraemia (EAH) as a novel disease, even though its aetiology had already been established by us. We appreciate that some may wish to distance themselves from involvement in this affair. But this is not a sound basis for an objective scientific debate. We choose to respond first to Dr Murray’s letter.

In his position as Director of the Gatorade Sports Science Institute (GSSI), Dr Murray is a full-time employee of PepsiCo, which is a publicly listed company in the USA. The principal accountability of a publicly listed company like PepsiCo and its subsidiary, Gatorade, is to increase the wealth of its shareholders. This follows from the landmark case of Ford versus the Dodge Brothers heard in the Michigan Supreme Court in 1916.1

In his otherwise uncritical review of the Gatorade phenomenon, Rovell2 touches on this legal accountability: “This lack of change (in the Gatorade formulation) has caused some people to be sceptical as to the true function of the Gatorade Sports Science Institute (GSSI) which has funded more than 120 studies in the past 17 years. Is GSSI there to develop the latest and greatest sports drink formula for the masses, or is it there to use science to best defend the status quo? Is it really possible that nothing substantial has come along in sports drink science in the past four decades that would make Gatorade a better drink? There are, after all, very few product categories that fail to evolve over four decades” (pp 194–195). “…..But it is undeniable that GSSI was also created to be part of Gatorade’s powerful marketing arm” (p 195). “…..Having the Gatorade Sports Science Institute does mean walking a fine line …
Transfusion-refractory anaemia in liver cirrhosis
Authors: J C C So, Y-Y Hwang, W-H Shek, C C K Lam, C-L Lai, Y-L Kwong, E. El-Omar
Journal: Gut (2009)

A 33-year-old-man with chronic alcoholism presented with anaemia. Investigations showed haemoglobin 7.5 g/dl (reticulocytes: 11.2%), leucocytes 4.7×109/l, platelets 61×109/l, direct bilirubin 221 (reference <6) μmol/l, aspartate transaminase 109 (reference 15–38) U/l, alanine transaminase 38 (reference 8–58) U/l, γ-glutamyltransferase 31 (reference 11–62) U/l, lactate dehydrogenase 319 (reference 118–221) U/l, haptoglobin <0.06 (reference 0.16–1.97) g/l, methaemalbumin 0.18 (reference <0.1) mg/dl and a negative direct antiglobulin test. The iron status, cholesterol and triglyceride profiles were unremarkable. On referral, physical examination showed pallor, jaundice, …
End-systolic pressure as a balance between opposing effects of ejection.
Authors: W C Hunter
Journal: Circulation Research (1989)

Ejection has previously been thought to exert only negative effects on end-systolic left ventricular pressure, via mechanisms like shortening deactivation and the force-velocity relation. Whether ejection also exerted a positive influence on pressure generation was tested by comparing two successive beats: 1) the last beat of steady-state ejection versus 2) a totally isovolumic contraction at the end-systolic volume. In 12 isolated, blood-perfused canine hearts loaded with a simulated arterial system, ejecting end-systolic pressure exceeded isovolumic pressure by approximately 10 mm Hg when ejection fraction was 0.3. With both higher and lower ejection fractions, the excess of ejecting end-systolic pressure was smaller; beyond an ejection fraction of roughly 0.5, the trend reversed so that ejecting end-systolic pressure fell below isovolumic pressure. The maximum excess in ejecting end-systolic pressure was quite variable (1-17 mm Hg), but the pattern of its variation with ejection fraction was consistent. A correlate of the positive effect of ejection on ventricular pressure was found in the timing of end systole. For an ejection fraction of 0.4, the systolic duration of ejecting beats was approximately 45% longer than in isovolumic beats (range, 23-67%). Potentially, a positive effect of ejection might be due to a residual influence of the stronger activation of cardiac myofilaments early in ejecting systole during which the sarcomeres were at longer lengths than in the isovolumic beat at end-systolic volume (length-dependent activation). A hypothetical model based on this mechanism reproduced both of the positive effects of ejection that were observed: excess end-systolic pressure and prolonged duration of systole. Thus, the approximate load independence of end-systolic pressure could result from the counter balance between opposing influences of ejection.
Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC)
Authors: G. Chen, J. Feng, C. Zhou, Y.-L. Wu, X.-Q. Liu, C. Wang, S. Zhang, J. Wang, S. Zhou, S. Ren, S. Lu, L. Zhang, C.-P. Hu, C. Hu, Y. Luo, L. Chen, M. Ye, J. Huang, X. Zhi, Y. Zhang, Q. Xiu, J. Ma, L. Zhang, C. You
Journal: Annals of Oncology (2013)
<i>In Vitro</i> Immune Toxicity of Depleted Uranium: Effects on Murine Macrophages, CD4 <sup>+</sup> T Cells, and Gene Expression Profiles
Authors: Bin Wan, James T. Fleming, Terry W. Schultz, Gary S. Sayler
Journal: Environmental Health Perspectives (2005)

Depleted uranium (DU) is a by-product of the uranium enrichment process and shares chemical properties with natural and enriched uranium. To investigate the toxic effects of environmental DU exposure on the immune system, we examined the influences of DU (in the form of uranyl nitrate) on viability and immune function as well as cytokine gene expression in murine peritoneal macrophages and splenic CD4+ T cells. Macrophages and CD4+ T cells were exposed to various concentrations of DU, and cell death via apoptosis and necrosis was analyzed using annexin-V/propidium iodide assay. DU cytotoxicity in both cell types was concentration dependent, with macrophage apoptosis and necrosis occurring within 24 hr at 100 microM DU exposure, whereas CD4+ T cells underwent cell death at 500 microM DU exposure. Noncytotoxic concentrations for macrophages and CD4+ T cells were determined as 50 and 100 microM, respectively. Lymphoproliferation analysis indicated that macrophage accessory cell function was altered with 200 microM DU after exposure times as short as 2 hr. Microarray and real-time reverse-transcriptase polymerase chain reaction analyses revealed that DU alters gene expression patterns in both cell types. The most differentially expressed genes were related to signal transduction, such as c-jun, NF- kappa Bp65, neurotrophic factors (e.g., Mdk), chemokine and chemokine receptors (e.g., TECK/CCL25), and interleukins such as IL-10 and IL-5, indicating a possible involvement of DU in cancer development, autoimmune diseases, and T helper 2 polarization of T cells. The results are a first step in identifying molecular targets for the toxicity of DU and the elucidation of the molecular mechanisms for the immune modulation ability of DU.
P167 Screening for viral upper respiratory tract infection in pulmonary exacerbations in cystic fibrosis
Authors: R. J. Jose, S. Hassan, M. Butler, D. Watson, L. Kuitert
Journal: Thorax (2011)

<h3>Introduction and objectives</h3> It is unclear if respiratory viruses are important in precipitating pulmonary exacerbations in adults. Respiratory viruses are considered important pathogens in children with cystic fibrosis (CF), as they may be associated with deterioration in lung function and bacterial infection.12 Following the “flu” pandemic in 2009 we have started screening CF patients for viral upper respiratory tract infection for infection control. Our aim was to determine if adult CF patients admitted with a pulmonary exacerbation had positive nasopharyngeal swabs suggesting a viral aetiology. <h3>Methods</h3> Retrospective review of admissions to an adult CF unit between May 2009 and May 2011 to identify those who had nasopharyngeal swabs (NPS) for the molecular detection (PCR) of viruses in the nasopharyngeal tract. Data were collected from the hospitals9 computer information system. Continuous variables are described as median averages (IQR), and categorical variables as counts. <h3>Results</h3> 365 admissions were identified during this period (93 patients). 299 admissions were due to pulmonary exacerbation. A NPS was performed on 211 admissions (174 due to pulmonary exacerbation). Characteristics of patients that had NPS on admission are listed in Abstract P167 table 1. Only 5 (2.9%) NPS detected upper respiratory tract viruses in patients with a pulmonary exacerbation. Influenza A [H1N1] and Parainfluenzae were detected in three and two NPS respectively. <h3>Conclusions</h3> Viral infection, detected by NPS, is not common in adult CF patients admitted to our hospital with or without pulmonary exacerbations. Screening all adult patients with CF admitted to hospital for the presence of viruses in the upper respiratory tract has a low yield and is not recommended.
Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial
Authors: Walter Taal, Hendrika M Oosterkamp, Annemiek M E Walenkamp, Hendrikus J Dubbink, Laurens V Beerepoot, Monique C J Hanse, Jan Buter, Aafke H Honkoop, Dolf Boerman, Filip Y F de Vos, Winand N M Dinjens, Roelien H Enting, Martin J B Taphoorn, Franchette W P J van den Berkmortel, Rob L H Jansen, Dieta Brandsma, Jacoline E C Bromberg, Irene van Heuvel, René M Vernhout, Bronno van der Holt, Martin J van den Bent
Journal: The Lancet Oncology (2014)
Evolutionary rates and centrality in the yeast gene regulatory network
Authors: Richard Jovelin, Patrick C Phillips
Journal: Genome biology (2009)

Abstract Background Transcription factors play a fundamental role in regulating physiological responses and developmental processes. Here we examine the evolution of the yeast transcription factors in the context of the structure of the gene regulatory network. Results In contrast to previous results for the protein-protein interaction and metabolic networks, we find that the position of a gene within the transcription network affects the rate of protein evolution such that more central transcription factors tend to evolve faster. Centrality is also positively correlated with expression variability, suggesting that the higher rate of divergence among central transcription factors may be due to their role in controlling information flow and may be the result of adaptation to changing environmental conditions. Alternatively, more central transcription factors could be more buffered against environmental perturbations and, therefore, less subject to strong purifying selection. Importantly, the relationship between centrality and evolutionary rates is independent of expression level, expression variability and gene essentiality. Conclusions Our analysis of the transcription network highlights the role of network structure on protein evolutionary rate. Further, the effect of network centrality on nucleotide divergence is different among the metabolic, protein-protein and transcriptional networks, suggesting that the effect of gene position is dependant on the function of the specific network under study. A better understanding of how these three cellular networks interact with one another may be needed to fully examine the impact of network structure on the function and evolution of biological systems.