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Koul H.K.,Health science Center | Koul H.K.,Feist Weiller Cancer Center | Koul H.K.,Veterans Administration Medical Center | Pal M.,Health science Center | And 3 more authors.
Genes and Cancer | Year: 2013

Mitogen-activated protein kinases (MAPKs) mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the main subgroups, the p38 MAP kinases, has been implicated in a wide range of complex biologic processes, such as cell proliferation, cell differentiation, cell death, cell migration, and invasion. Dysregulation of p38 MAPK levels in patients are associated with advanced stages and short survival in cancer patients (e.g., prostate, breast, bladder, liver, and lung cancer). p38 MAPK plays a dual role as a regulator of cell death, and it can either mediate cell survival or cell death depending not only on the type of stimulus but also in a cell type specific manner. In addition to modulating cell survival, an essential role of p38 MAPK in modulation of cell migration and invasion offers a distinct opportunity to target this pathway with respect to tumor metastasis. The specific function of p38 MAPK appears to depend not only on the cell type but also on the stimuli and/or the isoform that is activated. p38 MAPK signaling pathway is activated in response to diverse stimuli and mediates its function by components downstream of p38. Extrapolation of the knowledge gained from laboratory findings is essential to address the clinical significance of p38 MAPK signaling pathways. The goal of this review is to provide an overview on recent progress made in defining the functions of p38 MAPK pathways with respect to solid tumor biology and generate testable hypothesis with respect to the role of p38 MAPK as an attractive target for intervention of solid tumors. © The Author(s) 2013.


Li W.,Health science Center in Shreveport | Li W.,Hebei University | Liu J.,Health science Center in Shreveport | Jackson K.,Health science Center in Shreveport | And 2 more authors.
PLoS ONE | Year: 2014

Shikonin, a small-molecule natural product which inhibits the activity of pyruvate kinase M2 (PKM2), has been studied as an anti-cancer drug candidate in human cancer models. Here, our results demonstrate that shikonin is able to sensitize human breast cancer cells to chemotherapy by paclitaxel (taxol). Human breast adenocarcinoma MBA-MD-231 cells, which have higher levels of PKM2 expression and activity compared with MCF-7 cells, were selected to study further. The concentrations of shikonin and taxol were first selected at which they did not significantly induce cytotoxicity when treated alone, whereas the combination induced apoptosis. Surprisingly, PKM2 activity was decreased by shikonin, but not by the combination treatment. To identify the potential targets of this combination, human phospho-kinase antibody array analysis was performed and results indicated that the combination treatment inhibited the activation of ERK, Akt, and p70S6 kinases, which are known to contribute to breast cancer progression. Finally, how the combination affects breast cancer cell growth in vivo was tested using a xenograft tumor model. The results indicated that shikonin plus taxol prolonged animal survival and reduced tumor size than the vehicle treatment group. In summary, our results suggest that shikonin has a potential as an adjuvant for breast cancer therapy. © 2014 Li et al.


Schumacher J.R.,University of Wisconsin - Madison | Hall A.G.,University of Florida | Davis T.C.,Feist Weiller Cancer Center | Davis T.C.,Louisiana State University Health Sciences Center | And 2 more authors.
Medical Care | Year: 2013

BACKGROUND:: Limited health literacy is a barrier for understanding health information and has been identified as a risk factor for overuse of the emergency department (ED). The association of health literacy with access to primary care services in patients presenting to the ED has not been fully explored. OBJECTIVE:: To examine the relationship between health literacy, access to primary care, and reasons for ED use among adults presenting for emergency care. METHODS:: Structured interviews that included health literacy assessment were performed involving 492 ED patients at one Southern academic medical center. Unadjusted and multivariable logistic regression models assessed the relationship between health literacy and (1) access to a personal physician; (2) doctor office visits; (3) ED visits; (4) hospitalizations; and (5) potentially preventable hospital admissions. RESULTS:: After adjusting for sociodemographic and health status, those with limited health literacy reported fewer doctor office visits [odds ratio (OR)=0.6; 95% confidence interval (CI), 0.4-1.0], greater ED use, (OR=1.6; 95% CI, 1.0-2.4), and had more potentially preventable hospital admissions (OR=1.7; 95% CI, 1.0-2.7) than those with adequate health literacy. After further controlling for insurance and employment status, fewer doctor office visits remained significantly associated with patient health literacy (OR=0.5; 95% CI, 0.3-0.9). Patients with limited health literacy reported a preference for emergency care, as the services were perceived as better. CONCLUSIONS:: Among ED patients, limited health literacy was independently associated with fewer doctor office visits and a preference for emergency care. Policies to reduce ED use should consider steps to limit barriers and improve attitudes toward primary care services. Copyright © 2013 by Lippincott Williams & Wilkins.


Shi R.,LSU Health Shreveport | Taylor H.,Feist Weiller Cancer Center | McLarty J.,LSU Health Shreveport | Liu L.,LSU Health Shreveport | And 2 more authors.
BMC Cancer | Year: 2015

Background: Breast cancer outcomes are influenced by multiple factors including access to care, and payer status is a recognized barrier to treatment access. To further define the influence of payer status on outcome, the National Cancer Data Base data from 1998-2006 was analyzed. Method: Data was analyzed from 976,178 female patients diagnosed with breast cancer registered in the National Cancer Data Base. Overall survival was the primary outcome variable while payer status was the primary predictor variable. Secondary predictor variables included stage, age, race, Charlson Comorbidity index, income, education, distance travelled, cancer program, diagnosing/treating facility, and treatment delay. Multivariate Cox regression was used to investigate the effect of payer status on overall survival while adjusting for secondary predictive factors. Results: Uninsured (28.68%) and Medicaid (28.0%) patients had a higher percentage of patients presenting with stage III and stage IV cancer at diagnosis. In multivariate analysis, after adjusting for secondary predictor variables, payer status was a statistically significant predictor of survival. Patients with private, unknown, or Medicare status showed a decreased risk of dying compared to uninsured, with a decrease of 36%, 22%, and 15% respectively. However, Medicaid patients had an increased risk of 11% compared to uninsured. The direct adjusted median overall survival was 14.92, 14.76, 14.56, 13.64, and 12.84 years for payer status of private, unknown, Medicare, uninsured, and Medicaid respectively. Conclusion: We observed that patients with no insurance or Medicaid were most likely to be diagnosed at stage III and IV. Payer status showed a statistically significant relationship with overall survival. This remained true after adjusting for other predictive factors. Patients with no insurance or Medicaid had higher mortality. © Shi et al.


Saxena M.,LSU Health Shreveport | Dykes S.S.,LSU Health Shreveport | Malyarchuk S.,LSU Health Shreveport | Wang A.E.,LSU Health Shreveport | And 2 more authors.
Oncogene | Year: 2013

Rac1-GTPases serve as intermediary cellular switches, which conduct transient and constitutive signals from upstream cues, including those from Ras oncoproteins. Although the sirtuin1 (SIRT1) deacetylase is overexpressed in several human cancers and has recently been linked to cancer cell motility as a context-dependent regulator of multiple pathways, its role in Rac1 activation has not been reported. Similarly, SIRT2 has been demonstrated to be upregulated in some cancers; however, studies have also reported its role in tumor suppression. Here, we demonstrate that SIRT1 and SIRT2 positively regulate the levels of Rac1-GTP and the activity of T-cell lymphoma invasion and metastasis 1 (TIAM1), a Rac guanine nucleotide exchange factor (GEF). Transient inhibition of SIRT1 and SIRT2 resulted in increased acetylation of TIAM1, whereas chronic SIRT2 knockdown resulted in enhanced acetylation of TIAM1. SIRT1 regulates Dishevelled (DVL) protein levels in cancer cells, and DVL along with TIAM1 are known to augment Rac activation; however, SIRT1 or 2 has not been previously linked with TIAM1. We found that diminished sirtuin activity led to the disruption of the DVL1-TIAM1 interaction. We hence propose a model for Rac activation where SIRT1/2 positively modulates the DVL/TIAM1/Rac axis and promotes sustained pathway activation.Oncogene advance online publication, 23 December 2013; doi:10.1038/onc.2013.549.


Hildebrandt G.C.,University of Regensburg | Hildebrandt G.C.,Feist Weiller Cancer Center | Fazekas T.,St Anna Childrens Hospital | Lawitschka A.,St Anna Childrens Hospital | And 6 more authors.
Bone Marrow Transplantation | Year: 2011

This consensus statement established under the auspices of the German working group on BM and blood stem cell transplantation (DAG-KBT), the German Society of Hematology and Oncology (DGHO), the Austrian Stem Cell Transplant Working Group, the Swiss Blood Stem Cell Transplantation Group (SBST) and the German-Austrian Pediatric Working Group on SCT (Päd-Ag-KBT) summarizes current evidence for diagnosis, immunosuppressive and supportive therapy to provide practical guidelines for the care and treatment of patients with pulmonary manifestations of chronic GVHD (cGVHD). Pulmonary cGVHD can present with obstructive and/or restrictive changes. Disease severity ranges from subclinical pulmonary function test (PFT) impairment to respiratory insufficiency with bronchiolitis obliterans being the only pulmonary complication currently considered diagnostic of cGVHD. Early diagnosis may improve clinical outcome, and regular post-transplant follow-up PFTs are recommended. Diagnostic work-up includes high-resolution computed tomography, bronchoalveolar lavage and histology. Topical treatment is based on inhalative steroids plus beta-agonists. Early addition of azithromycin is suggested. Systemic first-line treatment consists of corticosteroids plus, if any, continuation of other immunosuppressive therapy. Second-line therapy and beyond includes extracorporeal photopheresis, mammalian target of rapamycin inhibitors, mycophenolate, etanercept, imatinib and TLI, but efficacy is limited. Clinical trials are urgently needed to improve understanding and treatment of this deleterious complication. © 2011 Macmillan Publishers Limited. All rights reserved.


Jafri S.H.,Louisiana State University | Jafri S.H.,Feist Weiller Cancer Center | Shi R.,Louisiana State University | Shi R.,Feist Weiller Cancer Center | And 2 more authors.
BMC Cancer | Year: 2013

Background: Systemic inflammation has been linked with cancer development, cancer cachexia and poor outcome. Advanced lung cancer inflammation index (ALI) was developed to assess degree of systemic inflammation at the time of diagnosis in metastatic non-small cell lung (NSCLC) cancer patients. Methods: In a single institution retrospective review 173 patients with metastatic NSCLC diagnosed between Jan 1 2000 and June 30 2011 were included. ALI was calculated as (BMI x Alb/NLR) where BMI = body mass index, Alb = serum albumin, NLR (neutrophil lymphocyte ratio, a marker of systemic inflammation). Patients were divided into low inflammation (ALI ≥ 18) and high inflammation (ALI < 18) groups. Kaplan-Meier method was used to estimate progression free survival and overall survival. Log-rank test were used to compare the survivals among various factors. Multivariate Cox regression was used to perform survival analysis in order to estimate the hazards ratio for various factors. Results: Among 173 patients median age was 57 years, 67% were male, 52% had adenocarcinoma. Patients with an ALI score of < 18 suggesting high systemic inflammation were significantly more likely to have more than 2 sites of metastatic disease, have poor performance status and less likely to receive any chemotherapy. Their median progression free survival and overall survival was 2.4 months and 3.4 months as opposed to 5.1 months and 8.3 months in patients with ALI >18 (P < 0.001). On multi-variate analysis ALI score of <18 (1.42, 95% CI 1.003-2.01) remained significantly associated with worse outcome. Conclusion: ALI (<18) at diagnosis is an independent marker of poor outcome in patients with advanced NSCLC. © 2013 Jafri et al.; licensee BioMed Central Ltd.


Zhang K.,Feist Weiller Cancer Center | Fowler M.,U.S. Army | Glass J.,Feist Weiller Cancer Center | Yin H.,Feist Weiller Cancer Center
Prostate | Year: 2014

INTRODUCTION: NANOGP8 is a retrogene which encodes a full-length protein similar to the NANOG1 gene. The expression of NANOGP8 has been documented in several cancers and is related to cell proliferation and tumor development. However, the regulation of NANOGP8 expression has not been investigated. Therefore, the role of NANOGP8 in cell proliferation has not been completely understood. METHODS: We evaluate the expression of NANOG1 and NANOGP8 in prostate cancer cell lines and primary cultures of prostate tissues. We investigate clonogenicity, sphere formation, and xenograft tumor growth of prostate cancer cells with an activated 5'flanking region of NANOGP8. We examine the role of NANOGP8 in cell cycle progression. RESULTS: In the prostate cells the NANOG RNA was transcribed from NANOGP8 and not from NANOG1. Cells with the activated 5'flanking region of NANOGP8 exhibited enhanced clonogenicity, sphere formation, and xenograft tumor growth. The sphere culture and tumor initiation mouse mode promoted the activation of the 5' flanking region of NANOGP8. Forced expression of NANOGP8 increased the entry into the cell cycle. DISCUSSION: In prostate cells NANOGP8 is a predominant molecule of NANOG. The activation of 5'flanking sequence of NANOGP8 could play a role in the regulation of the stemlike properties of cancer stem cells and prostate tumor initiation and development. The microenvironment favoring cancer stem cells could promote the activation of the 5'flanking region of NANOGP8. Prostate 74:381-394, 2014. © 2013 Wiley Periodicals, Inc.


Li Z.,Feist Weiller Cancer Center | Tanaka H.,Feist Weiller Cancer Center | Galiano F.,Feist Weiller Cancer Center | Glass J.,Feist Weiller Cancer Center
Journal of Experimental and Clinical Cancer Research | Year: 2011

Background: Cancer cells have increased levels of transferrin receptor and lower levels of ferritin, an iron deficient phenotype that has led to the use of iron chelators to further deplete cells of iron and limit cancer cell growth. As cancer cells also have increased reactive oxygen species (ROS) we hypothesized that a contrarian approach of enhancing iron entry would allow for further increased generation of ROS causing oxidative damage and cell death. Methods. A small molecule library consisting of ∼11,000 compounds was screened to identify compounds that stimulated iron-induced quenching of intracellular calcein fluorescence. We verified the iron facilitating properties of the lead compound, LS081, through 55Fe uptake and the expression of the iron storage protein, ferritin. LS081-induced iron facilitation was correlated with rates of cancer cell growth inhibition, ROS production, clonogenicity, and hypoxia induced factor (HIF) levels. Results: Compound LS081 increased 55Fe uptake in various cancer cell lines and Caco2 cells, a model system for studying intestinal iron uptake. LS081 also increased the uptake of Fe from transferrin (Tf). LS081 decreased proliferation of the PC-3 prostate cancer cell line in the presence of iron with a lesser effect on normal prostate 267B1 cells. In addition, LS081 markedly decreased HIF-1α and -2α levels in DU-145 prostate cancer cell line and the MDA-MB-231 breast cancer cell lines, stimulated ROS production, and decreased clonogenicity. Conclusions: We have developed a high through-put screening technique and identified small molecules that stimulate iron uptake both from ferriTf and non-Tf bound iron. These iron facilitator compounds displayed properties suggesting that they may serve as anti-cancer agents. © 2011 Li et al; licensee BioMed Central Ltd.


Florin L.,Johannes Gutenberg University Mainz | Sapp M.,Feist Weiller Cancer Center | Spoden G.A.,Johannes Gutenberg University Mainz
Medical Microbiology and Immunology | Year: 2012

Papillomaviruses infect skin and mucosa where they induce warts and cancers. For entry to occur, they sequentially engage numerous host proteins, allowing them to deliver their genetic information into target cells. This multistep process starts with initial binding via its L1 major capsid protein, followed by structural changes of the capsid on the cell surface, engagement of different receptors, and endocytosis. The post-entry phase includes capsid disassembly, endosomal escape of a complex of the minor capsid protein L2 and the viral genome, its transport into the nucleus, and accumulation at nuclear substructures. This review summarizes the current knowledge of the papillomavirus entry pathway and the role of cellular proteins involved in this course of events. © Springer-Verlag 2012.

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