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Union City, NJ, United States

Davis H.R.,Merck Research Labs | Lowe R.S.,Sharp Corporation | Neff D.R.,Sharp Corporation
Atherosclerosis | Year: 2011

Ezetimibe (Zetia®, Ezetrol®, Merck, Whitehouse Station, NJ) is a potent inhibitor of sterol absorption, which selectively blocks the uptake of biliary and dietary cholesterol in the small intestine. Clinical trials have demonstrated the beneficial effects of ezetimibe on the reduction of atherogenic lipoproteins and the attainment of guideline-recommended lipid levels. Direct evidence that these improvements translate to a reduction in atherosclerosis or cardiovascular events is limited, although reductions in major atherosclerotic events that are consistent with the LDL-C lowering achieved have recently been presented for patients with chronic kidney disease treated with ezetimibe/simvastatin 10/20mg in the SHARP trial. Animal models of atherosclerosis have played a central role in defining the mechanisms involved in initiation and development of disease and have been used in drug development to evaluate potential therapeutic efficacy. The effect of ezetimibe on atherosclerosis has been examined in several of these animal model systems. ApoE knockout mice develop severe hypercholesterolemia and premature atherosclerosis with features similar to that seen in humans and techniques ranging from gross visualization of plaque to high-resolution MRI have demonstrated the consistent ability of ezetimibe to significantly inhibit atherosclerosis. sr-b1-/-/apoE-/- double knockout mice exhibit additional characteristics common to human coronary heart disease (CHD), and the one study of ezetimibe in sr-b1-/-/apoE-/- mice showed a significant reduction in aortic sinus plaque (57%), coronary arterial occlusion (68%), myocardial fibrosis (57%), and cardiomegaly (12%) compared with untreated controls. The effects of ezetimibe have also been evaluated in ldlr-/-/apoE-/- double knockout mice, demonstrating that functional LDL receptors were not required for ezetimibe-mediated reduction of plasma cholesterol or atherosclerosis. For the few studies that have been conducted in rabbits, ezetimibe has been shown to significantly inhibit diet and vascular-injury-induced atherosclerosis as measured by intima/media thickness, atherosclerotic lesion composition, and thrombosis. The current body of preclinical evidence consistently demonstrates that ezetimibe reduces atherosclerosis in animals, presumably due primarily to the decrease in circulating levels of atherogenic lipoproteins that the drug produces. Demonstration that ezetimibe-mediated lowering of atherogenic lipoproteins in humans has a similar effect on atherosclerosis and cardiovascular risk awaits additional results from recently completed and ongoing outcomes trials. © 2011 Elsevier Ireland Ltd. Source


Liu F.,University of Notre Dame | Li Q.,Merck Research Labs
Computational Statistics and Data Analysis | Year: 2014

A critical step in group sequential designs is computation of the appropriate critical values for rejecting H0 at the interim look to keep the overall type I error rate at a prespecified level. When applying the sequential test in a study with an equivalence hypothesis, calculation of the critical values is complicated by the dependency between the dual test statistics at each interim look. Current methods for calculating critical values apply two primary approximations: z-statistics assuming a large sample size, and ignorance of the contribution to the overall type I error rate from rejecting one out of the two one-sided hypotheses under a null value. In the sequential testing, with smaller stagewise sample size and type I error rate, the first approximation would result in unsatisfactory inflation of the type I error rate, and the second approximation could lead to excessive conservatism. We establish a mathematical and computational framework of the exact sequential test based on bivariate non-central t statistics and propose several numerical approaches for computing the exact equivalence boundaries and futility boundaries. Examples and simulation studies are used to compare the operating characteristics between the exact test procedure and three other approximate test procedures. © 2014 Elsevier B.V. All rights reserved. Source


Katwa P.,East Carolina University | Wang X.,East Carolina University | Urankar R.N.,East Carolina University | Podila R.,East Carolina University | And 6 more authors.
Small | Year: 2012

Concern about the use of nanomaterials has increased significantly in recent years due to potentially hazardous impacts on human health. Mast cells are critical for innate and adaptive immune responses, often modulating allergic and pathogenic conditions. Mast cells are well known to act in response to danger signals through a variety of receptors and pathways including IL-33 and the IL-1-like receptor ST2. Here, the involvement of mast cells and the IL-33/ST2 axis in pulmonary and cardiovascular responses to multi-walled carbon nanotube (MWCNT) exposure are examined. Toxicological effects of MWCNTs are observed only in mice with a sufficient population of mast cells and are not observed when mast cells are absent or incapable of responding to IL-33. Our findings establish for the first time that mast cells and the IL-33/ST2 axis orchestrates adverse pulmonary and cardiovascular responses to an engineered nanomaterial, giving insight into a previously unknown mechanism of toxicity. This novel mechanism of toxicity could be used for assessing the safety of engineered nanomaterials and provides a realistic therapeutic target for potential nanoparticle induced toxicities. The adverse pulmonary and cardiovascular responses elicited by multi-walled carbon nanotubes (MWCNTs) are mediated by IL-33 activation of mast cells via the ST2 receptor. MWCNT-induced toxicity is significantly decreased in the absence of mast cells, thus providing a potential therapeutic target for the adverse effects of nanoparticles. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Flach C.-F.,Gothenburg University | Ostberg A.K.,Gothenburg University | Nilsson A.-T.,Gothenburg University | Malefyt R.D.W.,Merck Research Labs | Raghavan S.,Gothenburg University
Infection and Immunity | Year: 2011

CD4 + T cells have been shown to be essential for vaccine-induced protection against Helicobacter pylori infection in mice. Less is known about the relative contributions of individual cell subpopulations, such as T h1 and T h17 cells, and their associated cytokines. The aim of the present study was to find immune correlates to vaccine-induced protection and further study their role in protection against H. pylori infection. Immunized and unimmunized mice were challenged with H. pylori, and immune responses were compared. Vaccine-induced protection was assessed by measuring H. pylori colonization in the stomach. Gastric gene expression of T h1- and/or T h17-associated cytokines was analyzed by quantitative PCR, and contributions of individual cytokines to protection were evaluated by antibody-mediated in vivo neutralization. By analyzing immunized and unimmunized mice, a significant inverse correlation between the levels of interleukin-12p40 (IL-12p40), tumor necrosis factor alpha (TNF), gamma interferon (IFN-γ), and IL-17 gene expression and the number of H. pylori bacteria in the stomachs of individual animals after challenge could be demonstrated. In a kinetic study, upregulation of TNF, IFN-γ, and IL-17 coincided with vaccine-induced protection at 7 days after H. pylori challenge and was sustained for at least 21 days. In vivo neutralization of these cytokines during the effector phase of the immune response revealed a significant role for IL-17, but not for IFN-γ or TNF, in vaccine-induced protection. In conclusion, although both T h1- and T h17-associated gene expression in the stomach correlate with vaccine-induced protection against H. pylori infection, our study indicates that mainly T h17 effector mechanisms are of critical importance to protection. Copyright © 2011, American Society for Microbiology. All Rights Reserved. Source


Mazura M.T.,26 E. Lincoln Avenue | Mazura M.T.,Imclone Systems | Cardasis H.L.,26 E. Lincoln Avenue | Spellman D.S.,26 E. Lincoln Avenue | And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Top-down mass spectrometry holds tremendous potential for the characterization and quantification of intact proteins, including individual protein isoforms and specific posttranslationally modified forms. This technique does not require antibody reagents and thus offers a rapid path for assay development with increased specificity based on the amino acid sequence. Top-down MS is efficient whereby intact protein mass measurement, purification by mass separation, dissociation, and measurement of product ions with ppm mass accuracy occurs on the seconds to minutes time scale. Moreover, as the analysis is based on the accurate measurement of an intact protein, top-down mass spectrometry opens a research paradigm to perform quantitative analysis of "unknown" proteins that differ in accurate mass. As a proof of concept, we have applied differential mass spectrometry (dMS) to the top-down analysis of apolipoproteins isolated from human HDL3. The protein species at 9415.45 Da demonstrates an average fold change of 4.7 (p-value 0.017) and was identified as an O-glycosylated form of apolipoprotein C-III [NANA-(2 → 3)-Gal-β(1 → 3)-GalNAc, +656.2037 Da], a protein associated with coronary artery disease. This work demonstrates the utility of top-down dMS for quantitative analysis of intact protein mixtures and holds potential for facilitating a better understanding of HDL biology and complex biological systems at the protein level. Source

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