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Ruiz M.,Stanley Scott Cancer Center | Johnson D.,Louisiana State University Health Sciences Center | Reske T.,Louisiana State University Health Sciences Center | Cefalu C.,Louisiana State University Health Sciences Center | Estrada J.,Stanley Scott Cancer Center
Journal of the International Association of Providers of AIDS Care | Year: 2013

Background: Non-AIDS-defining cancers in HIV-infected patients in the highly active antiretroviral therapy era have increased. To our knowledge a comprehensive review of non-AIDS-related malignancies in New Orleans has not yet been conducted. Methods:Databases frommain institutions inNewOrleanswere queried retrospectively for the years 2001 to 2011.The International Classification of Diseases, Ninth Revision codes were used to search for HIV infection and cancer comorbidity. Results: A total of 16 patients were diagnosedwith lung cancer (mean age 50 years)with 81%of the patients presenting with advanced stages. In all, 20 (mean age 47 years)were diagnosed with anal cancer, and 35% presented in late stages. In all, 14 patients (mean age 42 years)were diagnosed with Hodgkin Lymphoma, and 64% were diagnosed at late stage. A total of 5 women (mean age 44 years) were diagnosed with breast cancer with 40% of them presenting at late stage. Conclusion: Malignancies were diagnosed at late stages in the majority of the cases, presented with worse outcomes, and had higher recurrence rates. The role of HIV and other viruses (Epstein Barr virus, human papillomavirus) and the potential mechanisms or pathways of oncogene activation also need to be clarified. © 2013 The Author(s).

Rathinam R.,Stanley Scott Cancer Center | Berrier A.,Health Science Center | Alahari S.K.,Stanley Scott Cancer Center | Alahari S.K.,The New School
Frontiers in Bioscience | Year: 2011

Rho family of GTPases is an ubiquitiously expressed and evolutionarily conserved family of GTP binding proteins that regulate actin dynamics and intracellular signaling. Among the Rho family GTPases, three members RhoA, Rac1 and CDC42 have been well characterized. They each play pivotal roles in gene expression, cell proliferation, apoptosis and various cellular functions. They are driven by signaling from RhoGDIs, RhoGEFs, RhoGAPs and cell surface receptors. Abnormalities in Rho GTPase function have major consequences on cell behavior. Over expression of Rho GTPases is associated with reorganization of actin cytoskeleton, an increase in cell migration, invasion and metastasis which are important aspects of cancer progression. This review will explore these Rho GTPases and the function of their associated signaling pathways in different types of cancers.

Yun J.,Korea Research Institute of Bioscience and Biotechnology | Yun J.,Loyola University Chicago | Espinoza I.,University of Mississippi | Pannuti A.,Stanley Scott Cancer Center | And 16 more authors.
Journal of Cellular Physiology | Year: 2015

p53 and Notch-1 play important roles in breast cancer biology. Notch-1 inhibits p53 activity in cervical and breast cancer cells. Conversely, p53 inhibits Notch activity in T-cells but stimulates it in human keratinocytes. Notch co-activator MAML1 binds p53 and functions as a p53 co-activator. We studied the regulation of Notch signaling by p53 in MCF-7 cells and normal human mammary epithelial cells (HMEC). Results show that overexpression of p53 or activation of endogenous p53 with Nutlin-3 inhibits Notch-dependent transcriptional activity and Notch target expression in a dose-dependent manner. This effect could be partially rescued by transfection of MAML1 but not p300. Standard and quantitative co-immunoprecipitation experiments readily detected a complex containing p53 and Notch-1 in MCF-7 cells. Formation of this complex was inhibited by dominant negative MAML1 (DN-MAML1) and stimulated by wild-type MAML1. Standard and quantitative far-Western experiments showed a complex including p53, Notch-1, and MAML1. Chromatin immunoprecipitation (ChIP) experiments showed that p53 can associate with Notch-dependent HEY1 promoter and this association is inhibited by DN-MAML1 and stimulated by wild-type MAML1. Our data support a model in which p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. In our cellular models, the effect of this association is to inhibit Notch-dependent transcription. Our data suggest that p53-null breast cancers may lack this Notch-modulatory mechanism, and that therapeutic strategies that activate wild-type p53 can indirectly cause inhibition of Notch transcriptional activity. © 2015 Wiley Periodicals, Inc.

Datta R.,Stanley Scott Cancer Center | Naura A.S.,Stanley Scott Cancer Center | Zerfaoui M.,Stanley Scott Cancer Center | Errami Y.,Stanley Scott Cancer Center | And 7 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

Background: We recently showed that poly(ADP-ribose)polymerase-1 (PARP-1) may play a role in allergen (ovalbumin)-induced airway eosinophilia, potentially through a specific effect on IL-5 production. We also reported that while IL-5 replenishment promotes reversal of eosinophilia in lungs of PARP-1-/- mice, IL-4 or Immunoglobulin E replenishment do not, suggesting a potentially significant regulatory relationship between PARP-1 and IL-5. Objective: To explore the mechanism by which PARP-1 regulates IL-5 production and to determine how PARP-1 inhibition blocks allergen-induced eosinophilia. Methods: This study was conducted using a murine model of allergic airway inflammation and primary splenocytes. Results: PARP-1 knockout-associated reduction in IL-5 upon allergen exposure occurs at the mRNA level. Such an effect appears to take place after IL-4 receptor activation as PARP-1 inhibition exerted no effect on JAK1/JAK3 activation. Signal transducer and activator of transcription-6 (STAT-6) protein was severely downregulated in spleens of PARP-1-/- mice without any effect on mRNA levels, suggesting an effect on protein integrity rather than gene transcription. Interestingly, the degradation of STAT-6 in PARP-1 -/- mice required allergen stimulation. Additionally, PARP-1 enzymatic activity appears to be required for STAT-6 integrity. The downregulation of STAT-6 coincided with mRNA and protein reduction of GATA-binding protein-3 and occupancy of its binding site on the IL-5 gene promoter. IL-4 was sufficient to induce STAT-6 downregulation in both PARP-1-/- mice and isolated splenocytes. Such degradation may be mediated by calpain, but not by proteasomes. Conclusion: These results demonstrate a novel function of PARP-1 in regulating IL-5 expression during allergen-induced inflammation and explain the underlying mechanism by which PARP-1 inhibition results in IL-5 reduction. © 2011 John Wiley & Sons A/S.

Wang Y.,Stanley Scott Cancer Center | Shenouda S.,Stanley Scott Cancer Center | Baranwal S.,Stanley Scott Cancer Center | Rathinam R.,Stanley Scott Cancer Center | And 5 more authors.
Molecular Cancer | Year: 2011

Although integrins have been implicated in the progression of breast cancer, the exact mechanism whereby they exert this regulation is clearly not understood. To understand the role of integrins in breast cancer, we examined the expression levels of several integrins in mouse breast cancer cell lines by flow cytometry and the data were validated by Western and RT-PCR analysis. The importance of integrins in cell migration and cell invasion was examined by in vitro assays. Further the effect of integrins on metastasis was investigated by in vivo experimental metastasis assays using mouse models.Results: Integrin α5 subunit is highly expressed in the nonmetastatic cell line 67NR and is significantly low in the highly invasive cell line 4T1. In contrast, expression levels of integrin α6 subunit are high in 4T1 cells and low in 67NR cells. In vitro data indicated that overexpression of α5 subunit and knockdown of α6 integrin subunit inhibited cell proliferation, migration, and invasion. Our in vivo findings indicated that overexpression of integrin α5 subunit and knockdown of α6 subunit decreased the pulmonary metastasis property of 4T1 cells. Our data also indicated that overexpression of alpha 5 integrin subunit and suppression of alpha6 integrin subunit inhibited cells entering into S phase by up-regulating p27, which results in downregulation of cyclinE/CDK2 complexes, This suggests that these integrins regulate cell growth through their effects on cell-cycle-regulated proteins. We also found that modulation of these integrins upregulates E2F, which may induce the expression of chk1 to regulate cdc25A/cyclin E/CDK2/Rb in a feedback loop mechanism.Conclusion: This study indicates that Integrin α5 subunit functions as a potential metastasis suppressor, while α6 subunit functions as a metastasis promoter. The modulation of integrins reduces cdc25 A, another possible mechanism for downregulation of CDK2. Taken together we demonstrate a link between integrins and the chk1-cdc25-cyclin E/CDK2-Rb pathway. © 2011 Wang et al; licensee BioMed Central Ltd.

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