tbuckley/cabot-search huggingface dataset:
Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity.
Authors: P Rosenkranz-Weiss, W C Sessa, S Milstien, S Kaufman, C A Watson, J S Pober
Journal: Journal of Clinical Investigation (1994)

We have examined cytokine regulation of nitric oxide synthase (NOS) in human umbilical vein endothelial cells (HUVEC). 24-h treatment with IFN-gamma (200 U/ml) plus TNF (200 U/ml) or IL-1 beta (5 U/ml) increased NOS activity in HUVEC lysates, measured as conversion of [14C]L-arginine to [14C]L-citrulline. Essentially, all NOS activity in these cells was calcium dependent and membrane associated. Histamine-induced nitric oxide release, measured by chemiluminescence, was greater in cytokine-treated cells than in control cells. Paradoxically, steady-state mRNA levels of endothelial NOS fell by 94 +/- 2.0% after cytokine treatment. Supplementation of HUVEC lysates with exogenous tetrahydrobiopterin (3 microM) greatly increased total NOS activity, and under these assay conditions, cytokine treatment decreased maximal NOS activity. IFN-gamma plus TNF or IL-1 beta increased endogenous tetrahydrobiopterin levels and GTP cyclohydrolase I activity, the rate-limiting enzyme of tetrahydrobiopterin synthesis. Intracellular tetrahydrobiopterin levels were higher in freshly isolated HUVEC than in cultured cells, but were still limiting. We conclude that inflammatory cytokines increase NOS activity in cultured human endothelial cells by increasing tetrahydrobiopterin levels in the face of falling total enzyme; similar regulation appears possible in vivo.
Effect of ACAT Inhibition on the Progression of Coronary Atherosclerosis
Authors: Steven E. Nissen, E. Murat Tuzcu, H. Bryan Brewer, Ilke Sipahi, Stephen J. Nicholls, Peter Ganz, Paul Schoenhagen, David D. Waters, Carl J. Pepine, Tim D. Crowe, Michael H. Davidson, John E. Deanfield, Lisa M. Wisniewski, James J. Hanyok, Laurent M. Kassalow
Journal: New England Journal of Medicine (2006)

The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects.We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis.The primary efficacy variable analyzing the progression of atherosclerosis--the change in percent atheroma volume--was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (-5.6 mm3, P=0.001) but not in the pactimibe group (-1.3 mm3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53).For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515.).
Natural History of Asymptomatic Patients With Normally Functioning or Minimally Dysfunctional Bicuspid Aortic Valve in the Community
Authors: Hector I. Michelena, Valerie A. Desjardins, Jean-François Avierinos, Antonio Russo, Vuyisile T. Nkomo, Thoralf M. Sundt, Patricia A. Pellikka, A. Jamil Tajik, Maurice Enriquez-Sarano
Journal: Circulation (2008)

Bicuspid aortic valve is frequent and is reported to cause numerous complications, but the clinical outcome of patients diagnosed with normal or mildly dysfunctional valve is undefined.In 212 asymptomatic community residents from Olmsted County, Minn (age, 32+/-20 years; 65% male), bicuspid aortic valve was diagnosed between 1980 and 1999 with ejection fraction > or =50% and aortic regurgitation or stenosis, absent or mild. Aortic valve degeneration at diagnosis was scored echocardiographically for calcification, thickening, and mobility reduction (0 to 3 each), with scores ranging from 0 to 9. At diagnosis, ejection fraction was 63+/-5% and left ventricular diameter was 48+/-9 mm. Survival 20 years after diagnosis was 90+/-3%, identical to the general population (P=0.72). Twenty years after diagnosis, heart failure, new cardiac symptoms, and cardiovascular medical events occurred in 7+/-2%, 26+/-4%, and 33+/-5%, respectively. Twenty years after diagnosis, aortic valve surgery, ascending aortic surgery, or any cardiovascular surgery was required in 24+/-4%, 5+/-2%, and 27+/-4% at a younger age than the general population (P<0.0001). No aortic dissection occurred. Thus, cardiovascular medical or surgical events occurred in 42+/-5% 20 years after diagnosis. Independent predictors of cardiovascular events were age > or =50 years (risk ratio, 3.0; 95% confidence interval, 1.5 to 5.7; P<0.01) and valve degeneration at diagnosis (risk ratio, 2.4; 95% confidence interval, 1.2 to 4.5; P=0.016; >70% events at 20 years). Baseline ascending aorta > or =40 mm independently predicted surgery for aorta dilatation (risk ratio, 10.8; 95% confidence interval, 1.8 to 77.3; P<0.01).In the community, asymptomatic patients with bicuspid aortic valve and no or minimal hemodynamic abnormality enjoy excellent long-term survival but incur frequent cardiovascular events, particularly with progressive valve dysfunction. Echocardiographic valve degeneration at diagnosis separates higher-risk patients who require regular assessment from lower-risk patients who require only episodic follow-up.
Endothelial Nox2 Overexpression Potentiates Vascular Oxidative Stress and Hemodynamic Response to Angiotensin II
Authors: Jennifer K. Bendall, Ruth Rinze, David Adlam, Amy L. Tatham, Joe de Bono, Keith M. Channon
Journal: Circulation Research (2007)

Vascular disease states are associated with endothelial dysfunction and increased production of reactive oxygen species (ROS) derived from vascular NADPH oxidases in both vascular smooth muscle cells (VSMCs) and endothelial cells. Recent evidence suggests an important role for VSMC NADPH oxidases in vascular ROS production. However, it is unclear whether increased NADPH oxidase activity in endothelial cells alone is sufficient to alter overall vascular ROS production and hemodynamics. We sought to address these questions using transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NADPH oxidase, Nox2. Aortas of Nox2 transgenic (Nox2-Tg) mice had increased total Nox2 mRNA and protein levels compared with wild-type littermates. Both p22phox mRNA and protein levels were also significantly elevated in Nox2-Tg aortas. Aortic superoxide production was significantly increased in Nox2-Tg mice compared with wild-type, but this difference was abolished by endothelial removal. Superoxide dismutase inhibition increased superoxide release and levels of Mn superoxide dismutase protein were significantly elevated in aortas from Nox2-Tg mice compared with wild type. Increased ROS production from endothelial Nox2 overexpression led to increased endothelial nitric oxide synthase protein and extracellular signal-regulated kinase 1/2 phosphorylation in transgenic aortas. Basal blood pressure was similar, however the pressor responses to both acute and chronic angiotensin II administration were significantly increased in Nox2-Tg mice compared with wild type. These results demonstrate that endothelial-targeted Nox2 overexpression is sufficient to increase vascular NADPH oxidase activity, activate downstream signaling pathways, and potentiate the hemodynamic response to angiotensin II, despite compensatory increases in vascular antioxidant enzymes. Endothelial cell Nox2-containing NADPH oxidase plays an important functional role in vascular redox signaling.
Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Human Pancreatic Adenocarcinomas: Clinicopathologic and Prognostic Significance of Matrilysin Expression
Authors: Hiroyuki Yamamoto, Fumio Itoh, Shouhei Iku, Yasushi Adachi, Hiroshi Fukushima, Shigeru Sasaki, Mitsuhiro Mukaiya, Koichi Hirata, Kohzoh Imai
Journal: Journal of Clinical Oncology (2001)

PURPOSE: A disruption in the balance between the matrix metalloproteinases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been implicated in the progression of many types of cancer. The aim of this study was to determine whether a specific MMP or TIMP has clinicopathologic and prognostic significance in pancreatic carcinoma. PATIENTS AND METHODS: Using immunohistochemistry, we analyzed 70 pancreatic ductal adenocarcinoma tissues for expression of MMP-1, MMP-2, MMP-3, MMP-7 (matrilysin), MMP-9, MT1-MMP, TIMP-1, and TIMP-2. The results were matched with clinicopathologic characteristics and patients’ survival. The effects of the suppression of a specific MMP on in vitro invasiveness of pancreatic carcinoma cells were also examined. RESULTS: Expression of MMP-1, MMP-2, MMP-3, matrilysin, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was detected in either tumor cells or tumor stromal cells, or in both components, at varying frequencies. Among MMPs, matrilysin showed a unique distribution in the tumor nests; its expression was usually most pronounced at the invasive front of the tumors. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 40 cases (57%), were judged to be positive for matrilysin. Matrilysin positivity was significantly correlated with pT, pN, and pM categories and with more advanced pathologic tumor-node-metastasis stages. Patients with matrilysin-positive carcinoma had a significantly shorter overall survival time than did those with matrilysin-negative carcinoma. Matrilysin was a significant independent prognostic factor for overall survival in multivariate analysis. In contrast, there was no correlation between the presence of other MMPs or TIMPs and clinicopathologic characteristics, nor was the presence of individual MMPs or TIMPs related to survival. Antisense matrilysin-transfected CFPAC-1 cells expressed reduced levels of matrilysin and demonstrated a similar growth potential but were less invasive in vitro compared with neotransfected CFPAC-1 cells. CONCLUSION: Our results suggest that matrilysin may play a key role in progression of pancreatic carcinoma and thereby contribute to a poor prognosis. Because different synthetic MMP inhibitors affect different types of MMPs to a different degree, examination of the expression of MMPs, especially that of matrilysin, may serve as an indicator for selecting the most effective MMP inhibitor.
Surrogacy of Financial Conflicts of Interest
Authors: Ralph M. Meyer
Journal: Journal of Clinical Oncology (2013)

Conflict of interest occurs when meeting professional responsibilities is compromised by opportunities for secondary personal gain. 1,2Although benefits that comprise these gains may include prestige, power, or status, 1,2 since the 1980s, biomedical literature has more often emphasized that medical researchers and educators have opportunities for financial gains because of their interactions with the private sector. 3 These resulting risks for financial conflicts of interest could become apparent through bias in the conduct or reporting of research or in the provision of educational material.Advances in diagnostics and therapeutics resulting from new molecular understandings of disease processes have likely created greater opportunities for interaction and collaboration between the pharmaceutical and biotechnology sectors and the academic and health care provider communities, and have probably contributed to the need for medical journals, 4,5 academic institutions, 6,7 and professional societies 8,9 to each develop policies that require researchers and other professionals to disclose their relationships with commercial entities.These disclosures allow users of related research or educational material to be aware of potential risks of bias.The American Society of Clinical Oncology (ASCO) has an explicit disclosure policy in association with material to be reported at the annual ASCO meeting. 8 In the article that accompanies this editorial, Moy et al 10 describe associations with commercial entities that were disclosed by authors of abstracts submitted to the 2006 and 2008 to 2011 ASCO annual meetings.The authors observed several key findings.First, the large database permitted identification of an increasing trend of almost 1% per year in the proportion of abstracts associated with disclosures.As the authors note, this observation is likely explained by a combination of increased relations associated with a need for disclosure and increased compliance with disclosure policies.Second, the authors observed that abstracts associated with disclosures received more prominent positioning at the ASCO meeting; there was greater representation of these abstracts at oral sessions, and a gradient was observed across the spectrum of the higher profile plenary sessions to the lower profile poster discussions.This trend continued across posters unassociated with discussions to publication-only abstracts.Finally, the authors evaluated peer-review scoring of merit.Scores were graded from one to five, with lower numbers associated with higher merit.Abstracts associated with a financial disclosure received superior mean peer-review scores (2.76 v 3.01; P Ͻ .001), a finding that remained even after excluding publication-only abstracts (2.62 v 2.73; P Ͻ .001).As these latter mean scores each fell within the favorable end of the fourth-highest category ("Good," which extends from 2.6 to 3.5) and because the a very large database allows minor differences to
Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial
Authors: Richard M Bergenstal, Carol Wysham, Leigh MacConell, Jaret Malloy, Brandon Walsh, Ping Yan, Ken Wilhelm, Jim Malone, Lisa E Porter
Journal: The Lancet (2010)
Many LINE1 elements contribute to the transcriptome of human somatic cells
Authors: Sanjida H Rangwala, Lili Zhang, Haig H Kazazian
Journal: Genome biology (2009)

Abstract Background While LINE1 (L1) retroelements comprise nearly 20% of the human genome, the majority are thought to have been rendered transcriptionally inactive, due to either mutation or epigenetic suppression. How many L1 elements 'escape' these forms of repression and contribute to the transcriptome of human somatic cells? We have cloned out expressed sequence tags corresponding to the 5' and 3' flanks of L1 elements in order to characterize the population of elements that are being actively transcribed. We also examined expression of a select number of elements in different individuals. Results We isolated expressed sequence tags from human lymphoblastoid cell lines corresponding to 692 distinct L1 element sites, including 410 full-length elements. Four of the expression tagged sites corresponding to full-length elements from the human specific L1Hs subfamily were examined in European-American individuals and found to be differentially expressed in different family members. Conclusions A large number of different L1 element sites are expressed in human somatic tissues, and this expression varies among different individuals. Paradoxically, few elements were tagged at high frequency, indicating that the majority of expressed L1s are transcribed at low levels. Based on our preliminary expression studies of a limited number of elements in a single family, we predict a significant degree of inter-individual transcript-level polymorphism in this class of sequence.
Lurasidone as Adjunctive Therapy With Lithium or Valproate for the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study
Authors: Antony Loebel, Josephine Cucchiaro, Robert Silva, Hans Kroger, Kaushik Sarma, Jane Xu, Joseph R. Calabrese
Journal: American Journal of Psychiatry (2013)

OBJECTIVE Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. METHOD Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (-17.1 versus -13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (-1.96 versus -1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone. CONCLUSIONS In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.
Dietary Fat Intake Determines the Effect of a Common Polymorphism in the Hepatic Lipase Gene Promoter on High-Density Lipoprotein Metabolism
Authors: Jose M. Ordovas, Dolores Corella, Serkalem Demissie, L. Adrienne Cupples, Patrick Couture, Oscar Coltell, Peter W.F. Wilson, Ernst J. Schaefer, Katherine L. Tucker
Journal: Circulation (2002)

Background— Gene-nutrient interactions affecting high-density lipoprotein cholesterol (HDL-C) concentrations may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. Hepatic lipase (HL) is a key determinant of HDL metabolism. Four polymorphisms in linkage disequilibrium have been identified in the HL gene (LIPC), defining what is known as the −514T allele. This allele has been associated with decreased HL activity and increased HDL-C concentrations. However, the effect is variable among populations. Methods and Results— We have examined interaction effects between the −514(C/T) LIPC polymorphism, dietary fat, and HDL-related measures in 1020 men and 1110 women participating in the Framingham Study. We found a consistent and highly significant gene-nutrient interaction showing a strong dose-response effect. Thus, the T allele was associated with significantly greater HDL-C concentrations only in subjects consuming &lt;30% of energy from fat ( P &lt;0.001). When total fat intake was ≥30% of energy, mean HDL-C concentrations were lowest among those with the TT genotype, and no differences were observed between CC and CT individuals. We found similar gene-nutrient interactions when the outcome variables were HDL 2 -C ( P &lt;0.001), large HDL subfraction ( P &lt;0.001), or HDL size ( P =0.001). These interactions were seen for saturated and monounsaturated fat intakes (highly correlated with animal fat in this population), but not for polyunsaturated fat. Conclusions— Dietary fat intake modifies the effect of the −514(C/T) polymorphism on HDL-C concentrations and subclasses. Specifically, in the Framingham Study, TT subjects may have an impaired adaptation to higher animal fat diets that could result in higher cardiovascular risk.
Epithelial-to-Mesenchymal Transition Predicts Cyclosporine Nephrotoxicity in Renal Transplant Recipients
Authors: Marc Hazzan, Alexandre Hertig, David Buob, Marie-Christine Copin, Christian Noël, Eric Rondeau, Yi-Chun Dubois-Xu
Journal: Journal of the American Society of Nephrology (2011)

Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and β-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P=0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA.