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Kong Z.,University of Texas Southwestern Medical Center | Kong Z.,Fudan University | Boike T.,University of Texas Southwestern Medical Center | Raghavan P.,University of Texas Southwestern Medical Center | And 11 more authors.
Cancer Research | Year: 2010

DAB2IP (DOC-2/DAB2 interactive protein) is a member of the RAS-GTPase-activating protein family. It is often downregulated in metastatic prostate cancer and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer. In this study, we furnish several lines of evidence indicating that metastatic human prostate cancer PC3 cells deficient in DAB2IP (shDAB2IP) exhibit increased clonogenic survival in response to ionizing radiation (IR) compared with control cells expressing an endogenous level of DAB2IP (shVector). Radioresistance was also observed in normal prostate cells that are deficient in DAB2IP. This enhanced resistance to IR in DAB2IP-deficient prostate cancer cells is primarily due to faster DNA double-strand break (DSB) repair kinetics. More than 90% of DSBs were repaired in shDAB2IP cells by 8 hours after 2 Gy radiation, whereas only 60% of DSB repair were completed in shVector cells at the same time. Second, upon irradiation, DAB2IP-deficient cells enforced a robust G2-M cell cycle checkpoint compared with control cells. Finally, shDAB2IP cells showed resistance to IR-induced apoptosis that could result from a striking decrease in the expression levels of proapoptotic proteins caspase-3, caspase-8, and caspase-9, and significantly higher levels of antiapoptotic proteins Bcl-2 and STAT3 than those in shVector cells. In summary, DAB2IP plays a significant role in prostate cell survival following IR exposure due to enhanced DSB repair, robust G2-M checkpoint control, and resistance to IR-induced apoptosis. Therefore, it is important to identify patients with dysregulated DAB2IP for (a) assessing prostate cancer risk and (b) alternative treatment regimens. © 2010 American Association for Cancer Research.


Adams-Haduch J.M.,University of Pittsburgh | Onuoha E.O.,University of Pittsburgh | Bogdanovich T.,University of Pittsburgh | Tian G.-B.,University of Pittsburgh | And 8 more authors.
Journal of Clinical Microbiology | Year: 2011

Acinetobacter baumannii is emerging as an important nosocomial pathogen worldwide. We report molecular epidemiology of 65 carbapenem-nonsusceptible A. baumannii isolates identified from hospitals in New York, Pennsylvania, Florida, Missouri, Nevada, and California between 2008 and 2009. All isolates were subjected to pulsed-field gel electrophoresis (PFGE). Select isolates then underwent multilocus sequence typing (MLST). While the PFGE patterns tended to cluster within each hospital, sequence types (STs) belonging to the clonal complex 92 (CC92) and the pan-European clonal lineage II (EUII; worldwide clonal lineage 2) were predominant in all hospitals. Of them, ST122 and ST208 were the most common and were found in four of the six hospitals. Isolates belonging to the pan-European clonal lineages I and III were identified in one hospital each. Carbapenemase-encoding genes bla OXA-23 and/or ISAba1-bla OXA-51-like were present among the majority of isolates. These findings suggest that carbapenem-nonsusceptible A. baumannii isolates found in U.S. hospitals constitute part of the global epidemic driven by CC92, but have unique STs other than ST92, which may be spreading by means of patient transfer between health care facilities within the United States. Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Hurlbut J.M.,University of Southern Nevada | Robbins L.K.,University of Texas at El Paso | Hoke M.M.,New Mexico State University
Journal of Community Health Nursing | Year: 2011

This study examined the relationship between spirituality and health-promoting behaviors in a convenience sample of 90 sheltered homeless women using the Health Promotion Lifestyle Profile II, the Spiritual Well-Being Scale, and a demographic questionnaire. A moderate positive correlation was found between spiritual well-being and overall health promoting lifestyle (r =.426). Moderate to strong positive correlations were found between the Spiritual Well-Being Scale and the Health Promotion Lifestyle Profile II dimension subscales (physical activity, nutrition, spiritual growth, interpersonal relations, and stress management). The results support the importance of spirituality in relation to health-promoting behaviors among sheltered homeless women. © Taylor & Francis Group, LLC.


Scott M.A.,University of Southern Nevada | Nguyen V.T.,University of California at Los Angeles | Levi B.,Stanford University | James A.W.,University of California at Los Angeles
Stem Cells and Development | Year: 2011

There has been a recent increase in our understanding in the isolation, culture, and differentiation of mesenchymal stem cells (MSCs). Concomitantly, the availability of MSCs has increased, with cells now commercially available, including human MSCs from adipose tissue and bone marrow. Despite an increased understanding of MSC biology and an increase in their availability, standardization of techniques for adipogenic differentiation of MSCs is lacking. The following review will explore the variability in adipogenic differentiation in vitro, specifically in 3T3-L1 and primary MSCs derived from both adipose tissue and bone marrow. A review of alternative methods of adipogenic induction is also presented, including the use of specific peroxisome proliferator- activated receptor-gamma agonists as well as bone morphogenetic proteins. Finally, we define a standard, commonly used adipogenic differentiation medium in the hopes that this will be adopted for the future standardization of laboratory techniques-however, we also highlight the essentially arbitrary nature of this decision. With the current, rapid pace of electronic publications, it becomes imperative for standardization of such basic techniques so that interlaboratory results may be easily compared and interpreted. © Copyright 2011, Mary Ann Liebert, Inc.


Leung E.L.-H.,University of Hong Kong | Fiscus R.R.,Nevada Cancer Institute | Fiscus R.R.,University of Southern Nevada | Tung J.W.,Nevada Cancer Institute | And 7 more authors.
PLoS ONE | Year: 2010

Background: The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. Methodology/Principal Finding: The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44+ cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44+ cells consisted of mixed CD44+ and CD44- cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44+ and CD44+ cells derived from CD44+-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44- cells. Furthermore, freshly sorted CD44+ cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44- cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. Conclusion/Significance: Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify the role of CD44 in tumor cell renewal and cancer propagation in the in vivo environment.© 2010 Leung et al.


Nadimi H.,Boston University | Wesamaa H.,University of Helsinki | Janket S.-J.,Boston University | Bollu P.,University of Southern Nevada | Meurman J.H.,University of Helsinki
British Dental Journal | Year: 2011

Background Various sugar substitutes have been introduced and are widely used in confections and beverages to avoid tooth decay from sugar and other fermentable carbohydrates. One group of sugar substitutes are sugar alcohols or polyols. They have been specifically used in foods for diabetic patients because polyols are not readily absorbed in the intestine and blood stream, preventing post-prandial elevation of glucose level. Additionally they may lower caloric intake. Methods We searched PubMed, Cochrane Controlled Trials Registry, Cochrane Oral Health Review, Centre for Reviews and Dissemination in the UK, National Library for Public Health and a Centre for Evidence Based Dentistry website up to the end of October 2010, using the search terms 'sugar alcohol' or 'sugar-free' or 'polyols' and combined with a search with terms 'dental caries' or 'dental erosion'. Results Xylitol, a polyol, has been approved by the US Food and Drug Administration for its non-cariogenic properties that actually reduce the risk of dental decay and recently, the European Union also officially approved a health claim about xylitol as a 'tooth friendly' component in chewing gums. Although the presence of acidic flavourings and preservatives in sugar-free products has received less attention, these additives may have adverse dental health effects, such as dental erosion. Furthermore, the term sugar-free may generate false security because people may automatically believe that sugar-free products are safe on teeth.Conclusion We concluded that polyol-based sugar-free products may decrease dental caries incidence but they may bring another dental health risk, dental erosion, if they contain acidic flavouring. There is a need for properly conducted clinical studies in this area. © 2011 Macmillan Publishers Limited. All rights reserved.


Leung E.L.,University of Nevada, Las Vegas | Leung E.L.,Chinese University of Hong Kong | Wong J.C.,University of Nevada, Las Vegas | Johlfs M.G.,University of Nevada, Las Vegas | And 6 more authors.
Molecular Cancer Research | Year: 2010

Previously, we showed that basal activity of nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG) signaling pathway protects against spontaneous apoptosis and confers resistance to cisplatin-induced apoptosis in human ovarian cancer cells. The present study determines whether basal PKG kinase activity regulates Src family kinase (SFK) activity and proliferation in these cells. PKG-Iα was identified as predominant isoform in both OV2008 (cisplatin-sensitive, wild-type p53) and A2780cp (cisplatin-resistant, mutated p53) ovarian cancer cells. In both cell lines, ODQ (inhibitor of endogenous NO-induced cGMP biosynthesis), DT-2 (highly specific inhibitor of PKG-Iα kinase activity), and PKG-Iα knockdown (using small interfering RNA) caused concentration-dependent inhibition of DNA synthesis (assessed by bromodeoxyuridine incorporation), indicating an important role of basal cGMP/PKG-Iα kinase activity in promoting cell proliferation. DNA synthesis in OV2008 cells was dependent on SFK activity, determined using highly selective SFK inhibitor, 4-(4′-phenoxyanilino)-6,7-dimethoxyquinazoline (SKI-1). Studies using DT-2 and PKG-Iα small interfering RNA revealed that SFK activity was dependent on PKG-Iα kinase activity. Furthermore, SFK activity contributed to endogenous tyrosine phosphorylation of PKG-Iα in OV2008 and A2780cp cells. In vitro coincubation of recombinant human c-Src and PKG-Iα resulted in c-Src-mediated tyrosine phosphorylation of PKG-Iα and enhanced c-Src autophosphorylation/activation, suggesting that human c-Src directly tyrosine phosphorylates PKG-Iα and the c-Src/PKG-Iα interaction enhances Src kinase activity. Epidermal growth factor-induced stimulation of SFK activity in OV2008 cells increased PKG-Iα kinase activity (indicated by Ser239 phosphorylation of the PKG substrate vasodilator-stimulated phosphoprotein), which was blocked by both SKI-1 and SU6656. The data suggest an important role of Src/PKG-Iα interaction in promoting DNA synthesis/cell proliferation in human ovarian cancer cells. The NO/cGMP/PKG-Iα signaling pathway may provide a novel therapeutic target for disrupting ovarian cancer cell proliferation. ©2010 AACR.


Wong J.C.,Nevada Cancer Institute | Wong J.C.,University of Nevada, Las Vegas | Fiscus R.R.,Nevada Cancer Institute | Fiscus R.R.,University of Nevada, Las Vegas | Fiscus R.R.,University of Southern Nevada
Journal of Cellular Biochemistry | Year: 2011

Inappropriate signaling conditions within bone marrow stromal cells (BMSCs) can lead to loss of BMSC survival, contributing to the loss of a proper micro-environmental niche for hematopoietic stem cells (HSCs), ultimately causing bone marrow failure. In the present study, we investigated the novel role of endogenous atrial natriuretic peptide (ANP) and the nitric oxide (NO)/cGMP/protein kinase G type-Iα (PKG-Iα) signaling pathway in regulating BMSC survival and proliferation, using the OP9 BMSC cell line commonly used for facilitating the differentiation of HSCs. Using an ANP-receptor blocker, endogenously produced ANP was found to promote cell proliferation and prevent apoptosis. NO donor SNAP (S-nitroso-N- acetylpenicillamine) at low concentrations (10 and 50 μM), which would moderately stimulate PKG activity, protected these BMSCs against spontaneous apoptosis. YC-1, a soluble guanylyl cyclase (sGC) activator, decreased the levels of apoptosis, similar to the cytoprotective effects of low-level NO. ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one), which blocks endogenous NO-induced activation of sGC and thus lowers endogenous cGMP/PKG activity, significantly elevated apoptotic levels by 2.5- and three-fold. Pre-incubation with 8-Bromo-cGMP or ANP, which bypass the ODQ block, almost completely prevented the ODQ-induced apoptosis. A highly-specific PKG inhibitor, DT-3, at 20, and 30 mM, caused 1.5- and two-fold increases in apoptosis, respectively. ODQ and DT-3 also decreased BMSCs proliferation and colony formation. Small Interfering RNA gene knockdown of PKG-Iα increased apoptosis and decreased proliferation in BMSCs. The data suggest that basal NO/cGMP/PKG-Iα activity and autocrine ANP/cGMP/PKG-Iα are necessary for preserving OP9 cell survival and promoting cell proliferation and migration. © 2010 Wiley-Liss, Inc.


Bachmeier C.J.,Roskamp Institute | Beaulieu-Abdelahad D.,Roskamp Institute | Ganey N.J.,Roskamp Institute | Mullan M.J.,Roskamp Institute | And 2 more authors.
Biopharmaceutics and Drug Disposition | Year: 2011

Venlafaxine and its metabolite desvenlafaxine are serotonin-norepinephrine reuptake inhibitors currently prescribed for the treatment of depression. Previously, it was reported that venlafaxine is an inducer of MDR1, the gene responsible for P-glycoprotein (P-gp). The present study expanded upon these findings by examining the effect of venlafaxine and desvenlafaxine on the expression of both P-gp and the breast cancer resistance protein (BCRP) in human brain endothelial cells (HBMEC), an in vitro model of the blood-brain barrier (BBB). The HBMEC were treated for 1 h with various concentrations (500 nM to 50 μM) of venlafaxine and desvenlafaxine. Western blot analysis revealed treatment with venlafaxine significantly induced the expression of P-gp (2-fold) and BCRP (1.75-fold) in a dose-dependent manner, while treatment with desvenlafaxine had no effect on drug efflux transporter expression. To determine the functional significance of this effect, the permeability of a known drug efflux probe, rhodamine 123, across the BBB model and Caco-2 cells, a model of intestinal absorption, were examined. Treatment with venlafaxine (1-50 μM) for 1 h significantly reduced the apical-to-basolateral permeability of R123 across the BBB model (30%) and Caco-2 cell monolayers (25%), indicative of increased drug efflux transporter expression at the apical membrane. Conversely, desvenlafaxine had no effect on R123 permeability in either cellular model. These studies indicate that venlafaxine, but not desvenlafaxine is an inducer of drug efflux transporter expression, which consequently increases the potential for clinical drug-drug interactions. Therefore, based on these preliminary results, caution should be taken when prescribing venlafaxine with other P-gp substrates. Copyright © 2011 John Wiley & Sons, Ltd.


Hatcher D.C.,University of Southern Nevada
Sleep Medicine Clinics | Year: 2010

Imaging plays a role in the anatomic assessment of the airway and adjacent structures. This article discusses the use of 3-dimensional (3D) imaging (cone beam computed tomography [CBCT]) to evaluate the airway and selected regional anatomic variables that may contribute to obstructive sleep-disordered breathing (OSDB) in patients. CBCT technology uses a cone-shaped x-ray beam with a special image intensifier and a solid-state sensor or an amorphous silicon plate for capturing the image. Incorporation of 3D imaging into daily practice will allow practitioners to readily evaluate and screen patients for phenotypes associated with OSDB. © 2010 Elsevier Inc. All rights reserved.

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