Veterans Affair Medical Center

Northport, NY, United States

Veterans Affair Medical Center

Northport, NY, United States
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Zaheer S.,University of Iowa | Thangavel R.,Veterans Affair Medical Center | Thangavel R.,University of Iowa | Sahu S.K.,Veterans Affair Medical Center | And 3 more authors.
Neuroscience | Year: 2011

We have previously demonstrated that glia maturation factor (GMF), a brain-specific protein, isolated, sequenced, and cloned in our laboratory, is a prominent mediator of inflammation in the CNS leading to the death of neurons. In the present study, we demonstrate, for the first time, a significant upregulation of the GMF protein in various regions of Alzheimer's disease (AD) brains compared with age-matched non-demented (ND) control brains. We analyzed AD and ND brain samples by quantitative enzyme-linked immunosorbent assay (ELISA) using a combination of highly specific monoclonal and polyclonal anti-GMF antibodies developed and characterized in our laboratory. For the comparison between ND controls and AD cases, we examined brain tissue from 12 ad cases (ages ranging from 78-92 years) and eight age-matched ND controls (ages ranging from 76-88 years). We observed a significant increase in GMF concentration in entorhinal cortex, parietal cortex, frontal cortex, occipital cortex, perirhinal cortex, and temporal cortex of AD patients. Our results clearly demonstrate that the GMF protein levels are significantly higher in all AD-affected brain regions than in ND controls. The immunohistochemistry analysis revealed co-localization of GMF with amyloid plaques (AP) and neurofibrillary tangles (NFTs) in AD brains. Our results imply that under conditions of neurodegeneration the expression of GMF is significantly upregulated. © 2011.


Leather H.,University of Florida | Walden E.O.,University of Florida | Laplant K.D.,Veterans Affair Medical Center
Journal of the National Cancer Institute | Year: 2010

Background: Randomized controlled trials (RCTs) improve clinical care through evidence-based results. Guidelines exist for RCT result reporting, but specific details of therapeutic administration promote clinical application and reproduction of the trial design. We assess the reporting methodology in RCTs published in major oncology journals. Methods: Ten essential elements of RCT reporting were identified and included drug name, dose, route, cycle length, maximum number of cycles, premedication, growth factor support, patient monitoring parameters, and dosing adjustments for hematologic and organ-specific toxicity. All therapy-based oncology RCTs published between 2005 and 2008 in the New England Journal of Medicine (NEJM), Journal of Clinical Oncology (JCO), Journal of the National Cancer Institute (JNCI), Blood, and Cancer were analyzed for inclusion of these 10 elements. Results: Of 339 identified articles, 262 were included in the final analysis (165 from JCO, 31 from NEJM, 27 from Cancer, 20 from JNCI, and 19 from Blood). Premedication, growth factor support, and dose adjustments for toxicities were each reported less than half of the time. Only 30 articles (11%) met the main objective of complete data reporting (ie, all 10 essential elements) and was highest in JNCI (5/20; 25%), followed by Cancer (5/27; 18%), JCO (18/165; 11%), Blood (1/19; 5%), and NEJM (1/31; 3%). The presence of an online appendix did not substantially improve complete reporting. Conclusions: RCTs published in major oncology journals do not consistently report essential therapeutic details necessary for translation of the trial findings to clinical practice. Potential solutions to improve reporting include modification of submission guidelines, use of online appendices, and providing open access to trial protocols. © The Author 2010. Published by Oxford University Press. All rights reserved.


Stanic B.,University of Iowa | Katsuyama M.,Kyoto Prefectural University of Medicine | Miller F.J.,University of Iowa | Miller F.J.,Veterans Affair Medical Center
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

OBJECTIVE-: To examine the effect of an oxidized extracellular oxidation-reduction (redox) state (Eh) on the expression of NADPH oxidases in vascular cells. METHODS AND RESULTS-: The generation of reactive oxygen species by NADPH oxidase (Nox)-based NADPH oxidases activates redox-dependent signaling pathways and contributes to the development of "oxidative stress" in vascular disease. An oxidized plasma redox state is associated with cardiovascular disease in humans; however, the cellular mechanisms by which the extracellular redox state may cause disease are not known. Aortic segments and cultured aortic smooth muscle cells were exposed to Eh between -150 mV (reduced) and 0 mV (oxidized) by altering the concentration of cysteine and its disulfide, cystine, the predominant redox couple in plasma. A more oxidized Eh increased the expression of Nox1 and resulted in Nox1-dependent proliferation of smooth muscle cells. Oxidized Eh rapidly induced epidermal growth factor receptor phosphorylation via shedding of epidermal growth factor-like ligands from the plasma membrane and caused extracellular signal-regulated kinase 1/2-dependent phosphorylation of the transcription factors activating transcription factor-1 and cAMP-response element-binding protein. Inhibition of epidermal growth factor receptor or extracellular signal-regulated kinase 1/2 activation, or addition of small interference RNA to activating transcription factor-1, prevented the increase in Nox1 expression. CONCLUSION-: Our results identify a novel mechanism by which extracellular oxidative stress increases expression and activity of Nox1 NADPH oxidase and contributes to vascular disease. © 2010 American Heart Association, Inc.


Steyers III C.M.,University of Iowa | Miller Jr. F.J.,University of Iowa | Miller Jr. F.J.,Veterans Affair Medical Center
International Journal of Molecular Sciences | Year: 2014

Chronic inflammatory diseases are associated with accelerated atherosclerosis and increased risk of cardiovascular diseases (CVD). As the pathogenesis of atherosclerosis is increasingly recognized as an inflammatory process, similarities between atherosclerosis and systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel diseases, lupus, psoriasis, spondyloarthritis and others have become a topic of interest. Endothelial dysfunction represents a key step in the initiation and maintenance of atherosclerosis and may serve as a marker for future risk of cardiovascular events. Patients with chronic inflammatory diseases manifest endothelial dysfunction, often early in the course of the disease. Therefore, mechanisms linking systemic inflammatory diseases and atherosclerosis may be best understood at the level of the endothelium. Multiple factors, including circulating inflammatory cytokines, TNF-α (tumor necrosis factor-α), reactive oxygen species, oxidized LDL (low density lipoprotein), autoantibodies and traditional risk factors directly and indirectly activate endothelial cells, leading to impaired vascular relaxation, increased leukocyte adhesion, increased endothelial permeability and generation of a pro-thrombotic state. Pharmacologic agents directed against TNF-α-mediated inflammation may decrease the risk of endothelial dysfunction and cardiovascular disease in these patients. Understanding the precise mechanisms driving endothelial dysfunction in patients with systemic inflammatory diseases may help elucidate the pathogenesis of atherosclerosis in the general population. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Stanic B.,University of Iowa | Pandey D.,University of Georgia | Fulton D.J.,University of Georgia | Miller Jr. F.J.,University of Iowa | Miller Jr. F.J.,Veterans Affair Medical Center
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

OBJECTIVE-: To characterize the relationship between the expression of epidermal growth factor (EGF)-like ligands and vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression and activity in a primate model of atherosclerosis. METHODS AND RESULTS-: Adult male Cynomolgus monkeys were fed a normal or atherogenic (AS) diet for 45 months, after which animals from the AS group were placed on a normal diet for 8 months (regression). The expression of membrane-associated EGF-like ligands was increased in arteries from animals on the AS diet and normalized in the regression group. EGF-like ligands were distributed throughout atherosclerotic vessels but predominantly colocalized with macrophages. Consistent with ligand shedding, circulating heparin-bound EGF was elevated in the plasma of AS monkeys but not in those on regression diet. Atherosclerosis was associated with the activation of EGF receptor signaling. Expression of NADPH oxidase subunits Nox1 and Nox2 but not Nox4 or Nox5 was increased in arteries from monkeys on the AS diet and returned to normal with regression. Levels of Nox1 and Nox2 positively correlated with EGF-like ligands. In cultured monkey smooth muscle cells, treatment with EGF-like ligands increased Nox1 expression and activity. CONCLUSION-: These data identify EGF-like ligands as potential modulators of atherogenesis, resulting in part from increased vascular NADPH oxidase activity. © 2012 American Heart Association, Inc.


Streeter J.,University of Iowa | Schickling B.M.,University of Iowa | Jiang S.,University of Iowa | Stanic B.,University of Iowa | And 5 more authors.
Circulation Research | Year: 2014

Rationale: Activation of Nox1 initiates redox-dependent signaling events crucial in the pathogenesis of vascular disease. Selective targeting of Nox1 is an attractive potential therapy, but requires a better understanding of the molecular modifications controlling its activation. Objective: To determine whether posttranslational modifications of Nox1 regulate its activity in vascular cells. Methods and Results: We first found evidence that Nox1 is phosphorylated in multiple models of vascular disease. Next, studies using mass spectroscopy and a pharmacological inhibitor demonstrated that protein kinase C-beta1 mediates phosphorylation of Nox1 in response to tumor necrosis factor-α. siRNA-mediated silencing of protein kinase C-beta1 abolished tumor necrosis factor-α-mediated reactive oxygen species production and vascular smooth muscle cell migration. Site-directed mutagenesis and isothermal titration calorimetry indicated that protein kinase C-beta1 phosphorylates Nox1 at threonine 429. Moreover, Nox1 threonine 429 phosphorylation facilitated the association of Nox1 with the NoxA1 activation domain and was necessary for NADPH oxidase complex assembly, reactive oxygen species production, and vascular smooth muscle cell migration. Conclusions: We conclude that protein kinase C-beta1 phosphorylation of threonine 429 regulates activation of Nox1 NADPH oxidase. (Circ Res. 2014;115:911-918.) © 2014 American Heart Association, Inc.


Deorah S.,University of Cincinnati | Rao M.B.,University of Cincinnati | Raman R.,University of Cincinnati | Gaitonde K.,University of Cincinnati | And 3 more authors.
BJU International | Year: 2012

OBJECTIVE To describe the survival of patients with primary small cell carcinoma (SCC) of the prostate and assess prognostic factors based on a large population sample. PATIENTS AND METHODS A total of 241 cases of SCC of the prostate were reported to the Surveillance, Epidemiology, and End Results (SEER) registries from 1973 to 2003 of which 191 cases were included in our study. We used the Kaplan-Meier method for estimating survival, and Cox proportional hazard regression modelling to evaluate prognostic variables. RESULTS The overall age-adjusted incidence rate was 0.278 per 1 000 000 (95% confidence interval, 0.239-0.323). In all, 60.5% presented as metastatic disease compared with 39.5% who presented as local/regional disease (P= 0.012). The 12, 24, 36, 48 and 60 months observed survival rates were 47.9%, 27.5%, 19%, 17% and 14.3% respectively. On univariate analyses, age <60, concomitant low-grade prostatic adenocarcinoma, absence of metastasis, prostatectomy and radiation therapy were favourable prognostic factors. In multivariate regression modelling, age, pathology and stage were strong predictors of survival. CONCLUSIONS Using the SEER database, we present the largest study describing the epidemiology of primary SCC of the prostate. We found age, concomitant low-grade prostatic adenocarcinoma, and stage of the disease to be the strongest predictors of survival for patients with prostatic SCC. Future studies evaluating a broader range of clinical and molecular markers are needed to refine the prognostic model of this relatively rare disease. © 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.


Sheehan A.L.,University of Iowa | Carrell S.,University of Iowa | Johnson B.,University of Iowa | Stanic B.,University of Iowa | And 3 more authors.
Atherosclerosis | Year: 2011

Objective: Examine the contribution of Nox1 NADPH oxidase to atherogenesis. Methods and results: Male apolipoprotein E deficient mice (ApoE-/-) and male mice deficient in both apolipoprotein E and Nox1 (ApoE-/- Nox1-/y) received an atherogenic diet for 18 weeks. Mean blood pressures, body weights, and serum cholesterol levels were similar between the two groups of mice. Deficiency of Nox1 decreased superoxide levels and reduced lesion area in the aortic arch from 43% (ApoE-/-) to 28% (ApoE-/- Nox1-/y). The reduction in lesion size at the level of the aortic valve in ApoE-/-/Nox1-/y was accompanied by a decrease in macrophage infiltration as compared to ApoE-/- mice. Carotid artery ligation in ApoE-/- mice induced accelerated intimal hyperplasia with decreased cellular proliferation and increased collagen content in the neointima of vessels deficient in Nox1. Conclusions: Nox1-derived ROS modify lesion composition and contribute to lesion size in a murine model of atherosclerosis. © 2011.


Jagadeesha D.K.,University of Iowa | Takapoo M.,Veterans Affair Medical Center | Banfi B.,University of Iowa | Bhalla R.C.,University of Iowa | And 2 more authors.
Cardiovascular Research | Year: 2012

Aims: In atherosclerosis and restenosis, vascular smooth muscle cells (SMCs) migrate into the subendothelial space and proliferate, contributing to neointimal formation. The goal of this study was to define the signalling pathway by which Nox1 NAPDH oxidase mediates SMC migration. Methods and results: SMCs were cultured from thoracic aorta from Nox1 -/y (Nox1 knockout, KO) and wild-type (WT) mice. In response to thrombin, WT but not Nox1 KO SMCs generated increased levels of reactive oxygen species (ROS). Deficiency of Nox1 prevented thrombin-induced phosphorylation of Src and the subsequent transactivation of the epidermal growth factor receptor (EGFR) at multiple tyrosine residues. Next, activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and matrix metalloproteinase-9 (MMP-9) by thrombin was inhibited by the EGFR inhibitor AG1478 and in Nox1 KO SMCs. Thrombin-induced shedding of N-cadherin from the plasma membrane was dependent on the presence of Nox1 and was blocked by AG1478 and an inhibitor of metalloproteinases. Migration of SMCs to thrombin was impaired in the Nox1 KO SMCs and was restored by expression of Nox1. Finally, treatment of WT SMCs with AG1478 abrogated Nox1-dependent SMC migration. Conclusions: The Nox1 NADPH oxidase signals through EGFR to activate MMP-9 and promote the shedding of N-cadherin, thereby contributing to SMC migration. © The Author 2011.


Jiang S.,University of Iowa | Streeter J.,University of Iowa | Schickling B.M.,University of Iowa | Zimmerman K.,University of Iowa | And 3 more authors.
Cardiovascular Research | Year: 2014

AimsIschaemic preconditioning (IPC) is an adaptive mechanism that renders the myocardium resistant to injury from subsequent hypoxia. Although reactive oxygen species (ROS) contribute to both the early and late phases of IPC, their enzymatic source and associated signalling events have not yet been understood completely. Our objective was to investigate the role of the Nox1 NADPH oxidase in cardioprotection provided by IPC.Methods and resultsWild-type (WT) and Nox1-deficient mice were treated with three cycles of brief coronary occlusion and reperfusion, followed by prolonged occlusion either immediately (early IPC) or after 24 h (late IPC). Nox1 deficiency had no impact on the cardioprotection afforded by early IPC. In contrast, deficiency of Nox1 during late IPC resulted in a larger infarct size, cardiac remodelling, and increased myocardial apoptosis compared with WT hearts. Furthermore, expression of Nox1 in WT hearts increased in response to late IPC. Deficiency of Nox1 abrogated late IPC-mediated activation of cardiac nuclear factor-κB (NF-κB) and induction of tumour necrosis factor-α (TNF-α) in the heart and circulation. Finally, knockdown of Nox1 in cultured cardiomyocytes prevented TNF-α induction of NF-κB and the protective effect of IPC on hypoxia-induced apoptosis.ConclusionsOur data identify a critical role for Nox1 in late IPC and define a previously unrecognized link between TNF-α and NF-κB in mediating tolerance to myocardial injury. These findings have clinical significance considering the emergence of Nox1 inhibitors for the treatment of cardiovascular disease. © 2014 The Author.

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