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Little Rock, AR, United States

Todorova V.K.,University of Arkansas for Medical Sciences | Kaufmann Y.,Central Arkansas Veterans Healthcare System | Luo S.,University of Arkansas for Medical Sciences | Klimberg V.S.,University of Arkansas for Medical Sciences
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: Modulation of estrogen receptor (ER) plays a central role in selective estrogen receptor modulators (SERMs) molecular mechanism of action, although studies have indicated that additional, non-ER-mediated mechanisms exist. It has been suggested that the induction of oxidative stress by SERM could be one of the non-ER-mediated mechanisms held responsible for their pro-apoptotic role in ER-negative cells. Tumor cells are known for their high requirement of glutamine (Gln) that serves multiple functions within the cells, including nutritional and energy source, as well as one of the precursors for the synthesis of natural antioxidant glutathione (GSH). We hypothesized that one of the mechanisms responsible for ER-independent anti-neoplastic properties of SERMs and also for their adverse side effects could be dependent on the inhibition of Gln uptake. Methods: Human ER-negative MDA-MB231 breast cancer cells were treated with different doses of Tam and Ral. Gln uptake was monitored by using [ 3H]Gln assay. The effect of Tam and Ral on Gln transporter ASCT2 expression, glutathione (GSH) levels and cellular proliferation was determined. Results: Tam and Ral inhibited Gln uptake in a dosedependent manner through inhibition of ASCT2 Gln transporter. This effect of the anti-estrogens was associated with inhibition of GSH production and apoptosis. Treatment of cells with N-acetyl L-cysteine and 17 beta-estradiol 2 reversed the effects of Ral and Tam. Conclusions: Our results indicate that one of the mechanisms of action (and possibly some of the side effects) of TAM and RAL is associated with inhibition of cellular Gln uptake, oxidative stress and induction of apoptosis. © Springer-Verlag 2010. Source


Wellen M.,Central Arkansas Veterans Healthcare System
Current Psychiatry Reports | Year: 2010

Demoralization is a phenomenon in which a patient reaches a state of subjective incompetence, hopelessness, and helplessness that can lead to that devastating moment in which he or she feels the only recourse left is to give up. This article reviews the medical literature regarding the current understanding, importance, and impact of demoralization. In addition, using the key characteristics of demoralization, this article attempts to compare and contrast demoralization with anhedonia and grief. © Springer Science+Business Media, LLC 2010. Source


Kaushal G.P.,Central Arkansas Veterans Healthcare System | Kaushal G.P.,University of Arkansas for Medical Sciences
Kidney International | Year: 2012

Autophagy is upregulated during ischemia-reperfusion (IR)-induced and cisplatin-induced acute kidney injury (AKI). Proximal tubule-specific Atg7 knockout mice exhibited increased renal injury compared with wild-type mice following cisplatin- and IR-induced AKI. Inhibition of autophagy by chloroquine aggravated AKI, whereas upregulation of autophagy by rapamycin recovered lost renal function and histology, further indicating a protective role of autophagy in AKI. These findings reported by Jiang et al. will provide stimulus to further examine the role and mechanism of the enhancement of autophagy in AKI. © 2012 International Society of Nephrology. Source


Todorova V.K.,University of Arkansas for Medical Sciences | Kaufmann Y.,Central Arkansas Veterans Healthcare System | Hennings L.,University of Arkansas for Medical Sciences | Suzanne Klimberg V.,University of Arkansas for Medical Sciences
Journal of Nutrition | Year: 2010

Doxorubicin (DOX), a widely used anticancer drug, has a dose-dependent cardiotoxicity, attributed mainly to free radical formation. The cardiomyocyte oxidative stress occurs rapidly after DOX treatment, resulting in harmful modifications to proteins, lipids, and DNA. Previous data showed that oral L-glutamine (Gln) prevented cardiac lipid peroxidation and maintained normal cardiac glutathione (GSH) levels in DOX-treated rats. Our aim in this study was to examine the effect of Gln on DOX-induced cardiac oxidative stress in a tumor-bearing host. Female Fisher344 rats with implanted MatBIII mammary tumors were randomized into 2 groups: a Gln group that received L-Gln (1 g.kg -1.d-1) (n = 10) via a Gln-enriched diet and/or gavage with 50% Gln suspension during the whole experiment and a control group that was fed the same diet formulation without Gln and/or were gavaged with water. All rats received a single injection of 12 mg/kg DOX and were killed 3 d later. GSH levels of hearts, livers, tumors, and blood, as well as cardiac histological alterations, lipid peroxidation, peroxinitrite levels, and caspase-3 activation were determined. Cardiac physiologic alterations were assessed by ultrasound imaging before and 3 d after DOX administration. The Gln supplementation resulted in lower cardiac lipid peroxidation and peroxintrite levels and elevated cardiac catalase enzyme activity and GSH compared with the controls, without affecting those of the tumors. DOX-induced alterations of the echocardiographic parameters were significantly reduced in the Gln-supplemented rats. These data indicate that Gln is able to reduce the oxidative damage of cardiomyocytes that occurs soon after DOX administration and thus protects the heart of a tumor-bearing host from DOX-induced cardiomyopathy. © 2010 American Society for Nutrition. Source


Joshi M.,University of Arkansas for Medical Sciences | Monson T.P.,Central Arkansas Veterans Healthcare System | Woods G.L.,Central Arkansas Veterans Healthcare System
Canadian Respiratory Journal | Year: 2012

Background: Interferon-gamma release assays including the QuantiFERON-TB Gold In-Tube test (QFT-GIT [Cellestis Ltd, Australia]) may be used in place of the tuberculin skin test (TST) in surveillance programs for Mycobacterium tuberculosis infection control. However, data on performance and practicality of the QFT-GIT in such programs for health care workers (HCWs) are limited. Objectives: To assess the performance, practicality and reversion rate of the QFT-GIT among HCWs at a tertiary health care institution in the United States. Methods: Retrospective chart review of HCWs at Central Arkansas Veterans Healthcare System (Arkansas, USA) who underwent QFT-GIT testing as a part of their employee screening between November 1, 2008 and October 31, 2009. Results : QFT-GIT was used to screen 3290 HCWs. The initial QFT-GIT was interpreted as positive for 129 (3.9%) HCWs, negative for 3155 (95.9%) and indeterminate for six (0.2%). Testing with QFTGIT was repeated in 45 HCWs who had positive results on the initial test. The QFT-GIT reverted to negative in 18 (40.0%) HCWs, all of whom had negative TST status and initial interferon-gamma values of 0.35 IU/mL to 2.0 IU/mL. Conclusions: The QFT-GIT test is feasible in large health care setting as an alternative to TST for M tuberculosis infection screening in HCWs but is not free from challenges. The major concerns are the high number of positive test results and high reversion rates on repeat testing, illustrating poor short-term reproducibility of positive QFT-GIT test results. These results suggest adopting a borderline zone between interferon-gamma values of 0.35 IU/mL to 2.0 IU/mL, and cautious clinical interpretation of values in this range. ©2012 Pulsus Group Inc. All rights reserved. Source

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