tbuckley/cabot-search huggingface dataset:
Endocannabinoids and cannabinoid analogues block cardiac hKv1.5 channels in a cannabinoid receptor-independent manner
Authors: Adriana Barana, Irene Amorós, Ricardo Caballero, Ricardo Gómez, Lourdes Osuna, M. Pilar Lillo, Cristina Blázquez, Manuel Guzmán, Eva Delpón, Juan Tamargo
Journal: Cardiovascular Research (2009)

Endocannabinoids are synthesized from lipid precursors at the plasma membranes of virtually all cell types, including cardiac myocytes. Endocannabinoids can modulate neuronal and vascular ion channels through receptor-independent actions; however, their effects on cardiac K+ channels are unknown. This study was undertaken to determine the receptor-independent effects of endocannabinoids such as anandamide (N-arachidonoylethanolamine, AEA), 2-arachidonoylglycerol (2-AG), and endocannabinoid-related compounds such as N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), the endogenous lipid lysophosphatidylinositol (LPI), and the fatty acids from which some of these compounds are endogenously synthesized, on human cardiac Kv1.5 channels, which generate the ultrarapid delayed rectifier current (IKur). hKv1.5 currents (IhKv1.5) were recorded in mouse fibroblasts (Ltk− cells) by using the whole-cell patch-clamp technique. Most of these compounds inhibited IhKv1.5 in a concentration-dependent manner, the potency being determined by the number of C atoms in the fatty acyl chain. Indeed, AEA and 2-AG, which are arachidonic acid (20:4) derivatives, exhibited the highest potency (IC50∼0.9–2.5 µM), whereas PEA, a palmitic acid (PA-16:0) derivative, exhibited the lowest potency. The inhibition was independent of cannabinoid receptor engagement and of changes in the order and microviscosity of the membrane. Furthermore, blockade induced by AEA and 2-AG was abolished upon mutation of the R487 residue, which determines the external tetraethylammonium sensitivity and is located in the external entryway of the pore. AEA significantly prolonged the duration of action potentials (APs) recorded in mouse left atria. These results indicate that endocannabinoids block human cardiac Kv1.5 channels by interacting with an extracellular binding site, a mechanism by which these compounds regulate atrial AP shape.
Off-hours admission and mortality in two pediatric intensive care units without 24-h in-house senior staff attendance
Authors: Babette Peeters, Nicolaas J. G. Jansen, Casper W. Bollen, Adrianus J. van Vught, Douwe van der Heide, Marcel J. I. J. Albers
Journal: Intensive Care Medicine (2010)

To compare risk-adjusted mortality of children non-electively admitted during off-hours with risk-adjusted mortality of children admitted during office hours to two pediatric intensive care units (PICUs) without 24-h in-house attendance of senior staff.Prospective observational study, performed between January 2003 and December 2007, in two PICUs without 24-h in-house attendance of senior staff, located in tertiary referral children's hospitals in the Netherlands.Standardized mortality rates (SMRs) of patients admitted during off-hours were compared to SMRs of patients admitted during office hours using Pediatric Index of Mortality (PIM1) and Pediatric Risk of Mortality (PRISM2) scores. Office hours were defined as week days between 8:00 a.m. and 6:00 p.m., with in-house attendance of senior staff, and off-hours as week days between 6:00 p.m. and 8:00 a.m., Saturdays, Sundays and public holidays, with one resident covering the PICU and senior staff directly available on-call.Of 3,212 non-elective patients admitted to the PICUs, 2,122 (66%) were admitted during off-hours. SMRs calculated according to PIM1 and PRISM2 did not show a significant difference with those of patients admitted during office hours. There was no significant effect of admission time on mortality in multivariate logistic regression with odds ratios of death in off-hours of 0.95 (PIM1, 95% CI 0.71-1.27, p = 0.73) and 1.03 (PRISM2, 95% CI 0.76-1.39, p = 0.82).Off-hours admission to our PICUs without 24-h in-house attendance of senior staff was not associated with higher SMRs than admission during office hours when senior staff were available in-house.
Metabolic Consequences of Hepatic Steatosis in Overweight and Obese Adolescents
Authors: Brandy A. Wicklow, Kristy D.M. Wittmeier, Andrea C. MacIntosh, Elizabeth A.C. Sellers, Lawrence Ryner, Hacene Serrai, Heather J. Dean, Jonathan M. McGavock
Journal: Diabetes Care (2012)

To test the hypothesis that hepatic steatosis is associated with risk factors for type 2 diabetes in overweight and obese youth, mediated by cardiorespiratory fitness.This was a cross-sectional study comparing insulin sensitivity between 30 overweight and obese adolescents with hepatic steatosis, 68 overweight and obese adolescents without hepatic steatosis, and 11 healthy weight adolescents without hepatic steatosis. Cardiorespiratory fitness was determined by a graded maximal exercise test on a cycle ergometer. Secondary outcomes included presence of metabolic syndrome and glucose response to a 75-g oral glucose challenge.The presence of hepatic steatosis was associated with 55% lower insulin sensitivity (P = 0.02) and a twofold greater prevalence of metabolic syndrome (P = 0.001). Differences in insulin sensitivity (3.5 vs. 4.5 mU ⋅ kg(-1) ⋅ min(-1), P = 0.03), prevalence of metabolic syndrome (48 vs. 20%, P = 0.03), and glucose area under the curve (816 vs. 710, P = 0.04) remained between groups after matching for age, sex, and visceral fat. The association between hepatic steatosis and insulin sensitivity (β = -0.24, t = -2.29, P < 0.025), metabolic syndrome (β = -0.54, t = -5.8, P < 0.001), and glucose area under the curve (β = 0.33, t = 3.3, P < 0.001) was independent of visceral and whole-body adiposity. Cardiorespiratory fitness was not associated with hepatic steatosis, insulin sensitivity, or presence of metabolic syndrome.Hepatic steatosis is associated with type 2 diabetes risk factors independent of cardiorespiratory fitness, whole-body adiposity, and visceral fat mass.
Opposite Roles of Human Pancreatitis-Associated Protein and REG1A Expression in Hepatocellular Carcinoma: Association of Pancreatitis-Associated Protein Expression with Low-Stage Hepatocellular Carcinoma, β-Catenin Mutation, and Favorable Prognosis
Authors: Ray-Hwang Yuan, Yung-Ming Jeng, Hui-Ling Chen, Fon-Jou Hsieh, Ching-Yao Yang, Po-Huang Lee, Hey-Chi Hsu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Pancreatitis-associated protein (PAP) and regenerating protein 1 α (Reg1A) are up-regulated during the pancreas regeneration. This study is to investigate the clinicopathologic denotation of their expression in hepatocellular carcinoma (HCC). Experimental Design: PAP and REG1A mRNA levels were measured in 265 surgically removed unifocal primary HCCs using reverse transcription-PCR. Results: PAP and REG1A mRNAs were detected in 97 (36.6%) and 55 (20.8%) HCCs, respectively, including 46 with coexpression but in none of the 219 nontumorous livers. HCCs with PAP expression correlated with low-stage tumors without evidence of vascular invasion (P = 0.013) but the REG1A expression did not. By a combination analysis, HCCs with PAP expression alone showed the lowest frequency of p53 mutation (P &amp;lt; 0.036), the highest rates of grade 1 and low-stage tumors (P &amp;lt; 0.007 and P &amp;lt; 0.001, respectively), less frequent early tumor recurrence (P = 0.051), and hence a better 5-year survival (P = 0.044) than groups expressing PAP and REG1A, REG1A alone, and neither PAP or REG1A. Besides, PAP expressing HCCs had significantly frequent β-catenin mutation, regardless of REG1A expression, P &amp;lt; 0.00001. In the subset of HCCs that has no mutations of p53 and β-catenin but showed PAP expression, coexpression of REG1A and PAP was associated with more frequent vascular invasion than PAP expression alone (P &amp;lt; 0.005). Conclusions: These data suggest that PAP expression designate a subset of low-grade, low-stage HCC with frequent β-catenin mutation and hence more favorable prognosis, whereas further genetic or epigenetic alterations, such as p53 mutation and REG1A expression, lead to more advanced HCCs.
Collapse of the CD27+ B-Cell Compartment Associated with Systemic Plasmacytosis in Patients with Advanced Melanoma and Other Cancers
Authors: Erica L. Carpenter, Rosemarie Mick, Andrew J. Rech, Gregory L. Beatty, Theresa A. Colligon, Myrna R. Rosenfeld, David E. Kaplan, Kyong-Mi Chang, Susan M. Domchek, Peter A. Kanetsky, Leslie A. Fecher, Keith T. Flaherty, Lynn M. Schuchter, Robert H. Vonderheide
Journal: Clinical Cancer Research (2009)

Disturbed peripheral blood B-cell homeostasis complicates certain infections and autoimmune diseases, such as HIV and systemic lupus erythematosus, but has not been reported in cancer. This study aimed to investigate whether B-cell physiology was altered in the presence of melanoma and other cancers.
Differences in Prevalence, Extent, Severity, and Prognosis of Coronary Artery Disease Among Patients With and Without Diabetes Undergoing Coronary Computed Tomography Angiography
Authors: Jamal S. Rana, Allison Dunning, Stephan Achenbach, Mouaz Al-Mallah, Matthew J. Budoff, Filippo Cademartiri, Tracy Q. Callister, Hyuk-Jae Chang, Victor Y. Cheng, Kavitha Chinnaiyan, Benjamin J.W. Chow, Ricardo Cury, Augustin Delago, Gudrun Feuchtner, Martin Hadamitzky, Jörg Hausleiter, Philipp Kaufmann, Ronald P. Karlsberg, Yong-Jin Kim, Jonathon Leipsic, Troy M. Labounty, Fay Y. Lin, Erica Maffei, Gilbert Raff, Todd C. Villines, Leslee J. Shaw, Daniel S. Berman, James K. Min
Journal: Diabetes Care (2012)

We examined the prevalence, extent, severity, and prognosis of coronary artery disease (CAD) in individuals with and without diabetes (DM) who are similar in CAD risk factors.We identified 23,643 consecutive individuals without known CAD undergoing coronary computed tomography angiography. A total of 3,370 DM individuals were propensity matched in a 1-to-2 fashion to 6,740 unique non-DM individuals. CAD was defined as none, nonobstructive (1-49% stenosis), or obstructive (≥ 50% stenosis). All-cause mortality was assessed by risk-adjusted Cox proportional hazards models.At a 2.2-year follow-up, 108 (3.2%) and 115 (1.7%) deaths occurred among DM and non-DM individuals, respectively. Compared with non-DM individuals, DM individuals possessed higher rates of obstructive CAD (37 vs. 27%) and lower rates of having normal arteries (28 vs. 36%) (P < 0.0001). CAD extent was higher for DM versus non-DM individuals for obstructive one-vessel disease (19 vs. 14%), two-vessel disease (9 vs. 7%), and three-vessel disease (9 vs. 5%) (P < 0.0001 for comparison), with higher per-segment stenosis in the proximal and mid-segments of every coronary artery (P < 0.001 for all). Compared with non-DM individuals with no CAD, risk of mortality for DM individuals was higher for those with no CAD (hazard ratio 3.63 [95% CI 1.67-7.91]; P = 0.001), nonobstructive CAD (5.25 [2.56-10.8]; P < 0.001), one-vessel disease (6.39 [2.98-13.7]; P < 0.0001), two-vessel disease (12.33 [5.622-27.1]; P < 0.0001), and three-vessel disease (13.25 [6.15-28.6]; P < 0.0001).Compared with matched non-DM individuals, DM individuals possess higher prevalence, extent, and severity of CAD. At comparable levels of CAD, DM individuals experience higher risk of mortality compared with non-DM individuals.
Integration of tumour and viral genomic characterisations in HBV-related hepatocellular carcinomas
Authors: Giuliana Amaddeo, Qian Cao, Yannick Ladeiro, Sandrine Imbeaud, Jean-Charles Nault, Daphne Jaoui, Yann Gaston Mathe, Christophe Laurent, Alexis Laurent, Paulette Bioulac-Sage, Julien Calderaro, Jessica Zucman-Rossi
Journal: Gut (2014)

<h3>Background and aim</h3> Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV-related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features. <h3>Methods</h3> Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing <i>HBS</i> and <i>HBX</i> genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied. <h3>Results</h3> <i>HBX</i> revealed frequent non-sense, frameshift and deletions in tumours, suggesting an <i>HBX</i> inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, <i>TP53</i> mutations were associated with shorter survival only in HBV-related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (<i>HBX</i>, <i>TP53</i>, <i>IRF2</i>, <i>AXIN1</i> and <i>CTNNB1</i>). <h3>Conclusions</h3> Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients.
Atriopeptin III induces early relaxation of isolated mammalian papillary muscle.
Authors: A L Meulemans, K R Sipido, S U Sys, D L Brutsaert
Journal: Circulation Research (1988)

Atrial natriuretic peptide, released by mammalian atria in response to volume overload, induces vasodilation and natriuresis. In this study, a direct effect on cardiac mechanical performance was demonstrated. Atriopeptin III (10(-9)-10(-7) M) induced early relaxation and decreased peak twitch of isometric and isotonic twitches of isolated papillary muscles of cat and rat, without affecting maximal unloaded velocity of shortening. This effect resembled the effects of dibutyryl cyclic GMP and of sodium nitroprusside on cardiac muscle. The action of atriopeptin III, but not of dibutyryl cyclic GMP or sodium nitroprusside, was abolished by mechanically or chemically damaging the endocardial endothelial surface. Thus, the early relaxation of cardiac muscle induced by atrial natriuretic peptide may be mediated through receptors on the endocardial endothelium.
Biomarkers in COPD: the search continues!
Authors: David M. Mannino
Journal: European Respiratory Journal (2015)

In a working group of the National Institutes of Health focusing on biomarkers and surrogate end-points, a biomarker was defined as a "characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention" [1]. In the same document, the National Institutes of Health defined a clinical end-point as "a characteristic or variable that reflects how a patient feels, functions, or survives" and a surrogate end-point as a "biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence" [1]. Biomarkers accurately assessing disease activity and response to therapy are needed to develop better COPD treatment <http://ow.ly/HHPKl>
CTLA-4 Blockade: Autoimmunity As Treatment
Authors: Dilnawaz Kapadia, Lawrence Fong
Journal: Journal of Clinical Oncology (2005)

The immune system can recognize and respond to an incredible diversity of targets or antigens. With the evolution of this adaptive capability, the immune system has also co-evolved multiple layers of regulation to prevent autoimmunity, unwanted responses to self-antigens. Unfortunately, many tumor antigens represent self-antigens, and therefore tumors are usually not effectively eliminated by the immune system. Several different mechanisms are in place to maintain this tolerance to self-antigens. In the case of T-cell immunity, one important layer of regulation is the interplay between enhancement and inhibition of T-cell responses by costimulatory molecules. It is thought that, in most cases, signals from the T-cell receptor (TCR) alone are insufficient to result in optimal immune responses, 1 and a second, costimulatory signal is required to overcome a threshold for T cells to respond. This enhancement of TCR signals is provided primarily by CD28 on the T cells, which can be triggered by B7 expressed on the antigen-bearing cells. 2-7 Once activated, T cells express a second receptor, cytotoxic T lymphocyte– associated antigen 4 (CTLA-4), that can also bind the same B7 molecules. In contrast to CD28, CTLA-4 actually inhibits T-cell responses, thereby applying the brakes to an ongoing immune response. 8-13 Evidence that this receptor is, in fact, crucial to the maintenance of tolerance was demonstrated by CTLA-4 knockout mice that develop a lethal lymphoproliferative disease with infiltration of multiple organs by activated T cells. 14,15 In contrast, transient blockade of CTLA-4 triggering with antibody can lead to enhancement of T-cell responses but also can induce autoimmunity that can include encephalomyelitis, colitis and diabetes in some mouse models. 16-18 Nevertheless, these observations have led to therapeutic approaches targeting this inhibitory pathway for tumor immunotherapy. Allison et al 19 have demonstrated that CTLA-4 blockade
Relationships Between Medicine and Industry: Approaches to the Problem of Conflicts of Interest
Authors: Raymond Raad, Paul S. Appelbaum
Journal: Annual Review of Medicine (2011)

Relationships between physicians and industry are prevalent in medical education, clinical practice, and research, as well as at the level of medical institutions. These relationships can be valuable for the advancement of medicine but have also received increased scrutiny in recent years because they create conflicts of interest that pose a risk of biasing the judgments of physicians. Responses to these conflicts of interest by medical institutions, journals, and governments have utilized four main tools: education, disclosure, management, and prohibition. Each of the four has its advantages and drawbacks. Medicine faces the challenge of tailoring the use of these tools to minimize the risk of bias while allowing useful medical-industry collaborations to proceed. Viewing the dilemmas created by physicians' relationships with industry as a version of the principal-agent problem, which is much discussed by economists, may help in developing creative approaches to these issues.
A Prospective Study of Periodontal Disease and Pancreatic Cancer in US Male Health Professionals
Authors: Dominique S. Michaud, Kaumudi Joshipura, Edward Giovannucci, Charles S. Fuchs
Journal: JNCI Journal of the National Cancer Institute (2007)

Two previous cohort studies reported positive associations between tooth loss or periodontitis and pancreatic cancer risk. Data on periodontal disease were obtained at baseline and every other year thereafter in a cohort of 51,529 male health professionals aged 40-75 years. A total of 216 patients were diagnosed with incident pancreatic cancer during 16 years of follow-up. Multivariable relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models controlling for potential confounders, including detailed smoking history. All statistical tests were two-sided. Compared with no periodontal disease, history of periodontal disease was associated with increased pancreatic cancer risk (overall, multivariable RR = 1.64, 95% CI = 1.19 to 2.26; P = .002; crude incidence rates: 61 versus 25 per 100,000 person-years; among never smokers, multivariable RR = 2.09, 95% CI = 1.18 to 3.71; P = .01; crude incidence rates: 61 versus 19 per 100,000 person-years). In contrast, baseline number of natural teeth and cumulative tooth loss during follow-up were not strongly associated with pancreatic cancer. The association between periodontal disease and increased risk of pancreatic cancer may occur through plausible biologic mechanisms, but confirmation of this association is necessary.
FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix
Authors: M. N. Price, P. S. Dehal, A. P. Arkin
Journal: Molecular Biology and Evolution (2009)

Gene families are growing rapidly, but standard methods for inferring phylogenies do not scale to alignments with over 10,000 sequences. We present FastTree, a method for constructing large phylogenies and for estimating their reliability. Instead of storing a distance matrix, FastTree stores sequence profiles of internal nodes in the tree. FastTree uses these profiles to implement Neighbor-Joining and uses heuristics to quickly identify candidate joins. FastTree then uses nearest neighbor interchanges to reduce the length of the tree. For an alignment with N sequences, L sites, and a different characters, a distance matrix requires O(N(2)) space and O(N(2)L) time, but FastTree requires just O(NLa + N ) memory and O(N log (N)La) time. To estimate the tree's reliability, FastTree uses local bootstrapping, which gives another 100-fold speedup over a distance matrix. For example, FastTree computed a tree and support values for 158,022 distinct 16S ribosomal RNAs in 17 h and 2.4 GB of memory. Just computing pairwise Jukes-Cantor distances and storing them, without inferring a tree or bootstrapping, would require 17 h and 50 GB of memory. In simulations, FastTree was slightly more accurate than Neighbor-Joining, BIONJ, or FastME; on genuine alignments, FastTree's topologies had higher likelihoods. FastTree is available at http://microbesonline.org/fasttree.
PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure
Authors: Haishan Huang, Xiaofu Pan, Honglei Jin, Yang Li, Lin Zhang, Caili Yang, Pei Liu, Ya Liu, Lili Chen, Jingxia Li, Junlan Zhu, Xingruo Zeng, Kai Fu, Guorong Chen, Jimin Gao, Chuanshu Huang
Journal: Clinical Cancer Research (2015)

The carcinogenic capacity of B[a]P/B[a]PDE is supported by epidemiologic studies. However, the molecular mechanisms responsible for B[a]P/B[a]PDE-caused lung cancer have not been well investigated. We evaluated here the role of novel target PHLPP2 in lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure.We used the Western blotting, RT-PCR, [(35)S]methionine pulse and immunohistochemistry staining to determine PHLPP2 downregulation following B[a]P/B[a]PDE exposure. Both B[a]PDE-induced Beas-2B cell transformation model and B[a]P-caused mouse lung cancer model were used to elucidate the mechanisms leading to PHLPP2 downregulation and lung carcinogenesis. The important findings were also extended to in vivo human studies.We found that B[a]P/B[a]PDE exposure downregulated PHLPP2 expression in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The ectopic expression of PHLPP2 dramatically inhibited cell transformation upon B[a]PDE exposure. Mechanistic studies showed that miR-205 induction was crucial for inhibition of PHLPP2 protein translation by targeting PHLPP2-3'-UTR. Interestingly, PHLPP2 expression was inversely associated with tumor necrosis factor alpha (TNFα) expression, with low PHLPP2 and high TNFα expression in lung cancer tissues compared with the paired adjacent normal lung tissues. Additional studies revealed that PHLPP2 exhibited its antitumorigenic effect of B[a]P/B[a]PDE through the repression of inflammatory TNFα transcription.Our studies not only first time identify PHLPP2 downregulation by lung carcinogen B[a]P/B[a]PDE, but also elucidate a novel molecular mechanisms underlying lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure.