Browsing by Subject "Male Urogenital Diseases"
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Item Clinical Diagnosis(W.B. Saunders Company, 1981-01-01) Todd, JamesItem Detection of Androgen Receptors by Flow Cytometry(2008-05-01) Dutta, Mayurika; McClain, Robert; Singh, Meharvan; Hall, StanDutta, Mayurika, ‘Detection of androgen receptors by Flow Cytometry’. Internship Practicum report, Biotechnology, May 2008, 80 pp., 1 table, 18 figures. The use of androgen therapy is expanding given the documented potential benefits like increasing bone mineral density, muscle mass and strength. Androgen therapy also has potential risks including increasing the likelihood of prostate cancer and cardiovascular disease. So, we need a way to differentiate those who are likely to be benefitted by the therapy and those that are not. Data from Dr. Meharvan Singh’s lab has shown that activation of intracellular androgen receptors triggers cell survival pathways, while activation of the membrane androgen receptor suppresses cytoprotective pathways, and thus promotes cell death. We propose to develop a diagnostic kit that measures the relative ratio of intracellular androgen receptors and membrane androgen receptors, which is predicted to gauge relative risks or benefits associated with androgen therapy.Item Geographic Information System: A Targeted Approach to Syphilis Elimination(2000-08-01) Morrison-Jones, June; Urrutia-Rojas, Ximena; Lurie, Sue; Oppong, JosephMorrison-Jones, June, Geographic Information System: A Targeted Approach to Syphilis Elimination. Master of Public Health, August 2000, 55 pp., 3 tables, 3 appendices, reference list, 25 titles. Syphilis is a sexually transmitted disease that has long caused a heavy public health and economic burden in the United States. With syphilis rates reaching their lowest recorded levels in the United States, Health officials are calling for an increased effort to eliminate the disease. In the United States, syphilis is also now extremely concentrated geographically, facilitating effective intervention. Most syphilis cases disproportionately affect a small portion of the population. African Americans who live below the poverty level, have limited access to health care, and have a number of social problems are also affected. This study examines the geographic distribution of syphilis and factors associated with syphilis transmission in Dallas County. The study used the techniques of geographic information system, principles of epidemiology, sociocultural linkages (race, ethnicity, and gender) between demographic factors and syphilis, to gain insights into the geographic distribution of syphilis among the affected groups, and intervention strategies for syphilis elimination were developed. These suggestions should assist the Dallas County Health Department in launching an effective syphilis elimination program. Results showed that zip codes with high incidence of cases were generally adjacent to each other. In addition, statistically significant results confirmed that poverty, minority-race ethnicity and geographic core areas are factors associated with the transmission of syphilis.Item Health Risk, Behavior and Attitudes of Urban African American Men Toward Prostate Cancer Screening(2006-05-01) Samuel, Prattus; Sue Lurie; Kristine Lykens; Sejong BaeSamuel, Prauttus K., Health Risk, Behavior and Attitudes of Urban African American Men Toward Prostate Screening. Master of Public Health (Community Health), May 20, 2006, 84 pp., 10 tables, 1 illustration, 72 references. In Texas, prostate cancer is the second leading cause of cancer death among non-Hispanic whites and African American (AA) males. This thesis addresses the research questions: what psycho-social characteristics associated with men who participate in prostate screening? What psycho-social and clinical characteristics are associated with reported risk factors? Focus groups were conducted to identify attitudes, perceptions and health beliefs of African American men’s early detection behavior. Existing data from a prostate screening program in Dallas County, Texas was analyzed to determine associations of demographic variables, risk factors variables and screening participation for each subgroup with AA as the group of interest. Comparison of responses and data analysis provided the framework for a conceptual model.Item Hematologic malignancies following external beam radiation therapy for localized prostate cancer(2010-10-01) Ojha, Rohit P.; Felini, Martha J.; Singh, Karan P.; Thertulien, RaymondOjha, Rohit P. Hematologic malignancies following external beam radiation therapy for localized prostate cancer. Doctor of Public Health (Epidemiology), December 2010, 88 pp., 6 tables, 2 illustrations, references, 96 titles. The incidence of hematologic malignancies following external beam radiation therapy (EBRT) among prostate cancer patients has received limited attention despite evidence that radiation has a role in leukemogenesis and myelomagenesis. Therefore, we investigated the effect of external beam radiation therapy on acute myeloid leukemia and myeloma incidence among prostate cancer patients. We utilized the Surveillance, Epidemiology, and End Results database to identify a cohort of men (n=168,612) with newly diagnosed prostate adenocarcinoma between January 1988 and December 2003. Cox proportional hazard regression was used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of acute myeloid leukemia and myeloma incidence following definitive therapy with EBRT alone, brachytherapy alone, or surgery alone compared to no definitive therapy. The cohort yielded 184 incident acute myeloid leukemia cases and 344 incident myeloma cases during 1,064,820 person-years of follow-up after prostate adenocarcinoma diagnosis. Patients treated with EBRT had a higher adjusted relative hazard of developing acute myeloid leukemia than patients treated with brachytherapy or surgery when each therapy group was compared to patients who were not treated with definitive therapy (EBRT: HR=2.05, 95% CI 1.29, 3.26; brachytherapy: HR=1.22, 95% CI 0.46, 3.22; surgery: HR=1.24, 95% CI 0.77, 1.98). Patients treated with EBRT, brachytherapy, or surgery did not have increased adjusted relative hazards of developing myeloma when each therapy group was compared to patients who were not treated with definitive therapy (EBRT: HR=0.97, 95% CI: 0.70, 1.35; brachytherapy: HR=0.60, 95% CI: 0.28, 1.33; surgery: HR=1.02, 95% CI: 0.75, 1.39). Our findings suggest that acute myeloid leukemia incidence is a greater concern for patients treated with EBRT than brachytherapy for localized or locally advanced prostate adenocarcinoma. However, our results indicate that neither EBRT nor brachytherapy increases the relative hazard of myeloma incidence among patients with localized or locally advanced prostate adenocarcinoma. Ultimately, our findings may contribute to the collective evidence regarding the risks and benefits of external beam radiation therapy.Item HIF: A Key Survival Factor for Serum-Deprived Prostrate Cancer Cells(2008-05-01) Thomas, Rusha; Jamboor Vishwanatha; Harlan Jones; Raghu KrishnamoorthyThomas, Rusha, HIF: A key survival factor for serum-deprived prostate cancer cells. Doctor of Philosophy (Molecular Biology and Immunology), May 2008, 134 pages, 47 illustrations, reference list, 105 titles. The hypoxia-inducible factor (HIF) is central to hypoxic adaptation of tumors, and consists of an oxygen-labile HIF-1α and a constitutively expressed HIF-1β subunit. In specific aim 1, we report that prolonged serum deprivation is a potent inducer of HIF-1α in PC-3 and LNCaP prostate cancer (PCa) cells, despite normal oxygen conditions. In contrast, cells grown in the presence of serum did not upregulate HIF-1α protein levels. Moreover, HIF-1α protein increase during serum deprivation correlated with increased cell survival, while suppression of HIF-1α expression significantly decreased PCa cell viability. Our results further demonstrate that HIF-1α protein increase during serum deprivation is due to increased HIF-1α protein synthesis. First, there was no significant increase in HIF-1α mRNA. Secondly, cycloheximide, a protein synthesis inhibitor, prevented HIF-1α protein increase in serum-deprived PCa cells. Moreover, the expression of HIF-1α-target genes, VEGF and IGF-2, was concomitantly increased in serum-deprived PCa cells, while suppression of HIF-1α expression markedly inhibited their induction. Most interestingly, our study showed a significant decline in PCa cell survival following inhibitor of IGF-2 activity. Taken together, our study demonstrates for the first time that PCa cells counteract the stress of prolonged serum deprivation by upregulating HIF-1α protein which increases IGF-2 expression to promote cell survival. In specific aims 2 and 3, we investigated the molecular mechanism of autocrine regulation of HIF-1α, IGF-2 and cell survival in serum-deprived PC-3 and LNCaP PCa cells. We detected a time-dependent increase in Akt activation during serum deprivation, and inhibition of Akt activation attenuated the serum deprivation-mediated increase in HIF-1α and cell survival. Importantly, IGF-2 secretion significantly increased during serum deprivation, and was accompanied by increased activation of its receptor, insulin-like growth factor-I receptor (IGF-IR). Additionally, inhibition of IGF-2 activity markedly suppressed the serum deprivation-mediated increase in IGF-IR and Akt activation, HIF-1α expression, as well as its own transcription, suggesting autocrine regulation of HIF-1α expression via IGF-2. Reciprocal regulation of the IGF-2/IGF-IR system and P13K-Akt pathway was further demonstrated by findings wherein Akt activation was prevented following suppression of IGF-IR expression, and IGF-IR activation was inhibited following P13K inhibition. Lastly, HIF-1α suppression abolished the serum deprivation-mediated increase in Akt activation, and also resulted in higher IGF-IR protein levels indicating reduced IGF-IR activation. Collectively, our study demonstrates that a HIF-1α-dependent autocrine feedback loop upregulates HIF-1α, and thus promotes survival of normoxic, serum-deprived PCa cells.Item Intravenous Pyruvate to Prevent Renal Injury Following Cardiac Arrest and Resuscitation(2014-08-01) Hollrah, Roger A.; Robert T. Mallet; Myoung-Gwi Ryou; Rong MaIntroduction: Cardiac arrest followed by resuscitation and recovery of spontaneous circulation (ROSC) produces systemic ischemia reperfusion (I/R), affecting all internal organs, including the kidney. This type of stress generates both a robust increase in reactive oxygen and nitrogen species (RONS) and an intense inflammatory response, which can result in renal cell death. The glycoprotein erythropoietin (EPO) has been shown to combat renal I/R injury by offering cyto-protection against inflammation and oxidative damage, as well as inhibiting apoptosis. The endogenous intermediary metabolite pyruvate has been observed to stabilize specific genetic machinery responsible for the production of EPO. This study was conducted to test the efficacy of intravenous pyruvate in exploiting these endogenous mechanisms of EPO to protect the kidney from cardiac arrest-induced, I/R injury. Hypothesis: Pyruvate administration during cardiopulmonary resuscitation (CPR), defibrillation, and ROSC will protect the kidneys from I/R injury by suppressing oxidative stress and inflammation via increased EPO production at the renal corticomedullary border. Methods: Yorkshire swine underwent 10 minutes of cardiac arrest, CPR effected by precordial compressions, and defibrillation, and were recovered for either 4 hours (acute) or 3 days (chronic). The animals were randomly assigned to 1 of 4 groups. Two groups underwent the cardiac arrest protocol described above: one group received intravenous infusion of 2M sodium pyruvate at a rate of 0.1 mmol∙kg-1∙min-1 during CPR and the first 60 minutes of recovery; the other group received an equimolar infusion of NaCl. The other two groups were surgically prepared and infused with NaCl or sodium pyruvate, but were not subjected to cardiac arrest, CPR, or defibrillation. For the acute protocol (n=28), animals were sacrificed 4hr after cardiac arrest, while in the chronic protocol (n=18), animals recovered for 3d before sacrifice. To evaluate the impact of cardiac arrest and pyruvate treatment on renal metabolism and antioxidant defense, proteins were extracted from snap-frozen renal corticomedullary border tissue for spectrophotometric activity assays of a panel of 10 metabolic and antioxidant enzymes; myeloperoxidase (MPO), an enzyme marker of pro-inflammatory leukocytes, was analyzed to assess inflammation. Plasma was sampled before cardiac arrest and at the time of biopsy to measure creatinine concentration, an indirect measure of glomerular filtration rate (GFR). Enzyme-linked immunosorbent assay (ELISA) kits were used to measure EPO content and Kidney Injury Molecule-1 (KIM-1) content, a receptor expressed on renal tubular cells that plays an important role in apoptosis. Tissue sections were stained with hematoxylin and eosin (H&E) and examined under light microscopy to count neutrophils and monocytes and to compare structure integrity across the different treatment groups and protocols. Results: In this study global I/R stress imposed on the kidneys by reversible cardiac arrest did not appreciably alter the activity of the 10 panel enzymes. Despite having no histological evidence of neutrophil infiltration (H&E stained slides), an increase in renal MPO activity was evident at 4 h recovery in the NaCl group which was prevented by pyruvate treatment (P [less than] 0.05). There was no evidence of ultrastructural damage to renal cortical and outer medullary structures. There was a noticeable increase in renal EPO content at 4 h ROSC vs. the sham group. An apparent, albeit not statistically significant, increase in KIM-1 content was observed in the two CPR groups vs. the NaCl-infused sham group. Plasma creatinine concentrations did not change appreciably between pre-arrest baseline and 3 d recovery. Interpretation and Conclusion: The I/R stress produced by the present cardiac arrest-resuscitation failed to alter appreciably the activities of the 10 panel enzymes, suggesting the oxidative stress was not sufficient to overwhelm the kidney’s endogenous antioxidant defenses. Plasma creatinine concentrations were also stable, implying the GFR was maintained and the glomerular ultrastructures were unaffected by I/R. The increase in MPO activity at 4 h ROSC implied a transient infiltration of inflammatory leukocytes, although none were visible on histological examination. The increase in KIM-1 content, though not statistically significant, suggests modest renal apoptotic activity after cardiac arrest and reperfusion. The transient increase in renal EPO content in the NaCl-infused post-arrest vs. sham pigs supports the possibility that even a brief period of renal ischemia by cardiac arrest can evoke renal EPO production. Collectively, these results indicate the renal I/R imposed by cardiac arrest and resuscitation does not inflict appreciable damage on the kidneys or its enzyme systems, at least within the first 3 d of post-arrest recovery. Abbreviations: AKI: acute kidney injury; ARF: acute renal failure; CK: creatine kinase; CPR: cardiopulmonary resuscitation; CS: citrate synthase; EPO: erythropoietin; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; G6PDH: glucose 6-phosphate dehydrogenase; GFR: glomerular filtration rate; GP: glutathione peroxidase; GR: glutathione reductase; HIF-1: hypoxia-inducible factor 1; I/R: ischemia-reperfusion; KIM-1: kidney injury molecule 1; LDH: lactate dehydrogenase; MPO: myeloperoxidase; PFK: phosphofructokinase; PHD: prolyl hydroxylase; RONS: reactive oxygen and nitrogen species; ROSC: recovery of spontaneous circulation.Item Novel Gene C17ORF37 in Prostate Cancer Progression and Metastasis(2010-05-01) Dasgupta, Subhamoy; Vishwanatha, Jamboor K.C17orf37 also known as MGC14832, C35, Rdx12, a novel gene located on human chromosome 17q12 in the ERBB2 amplicon, is abundantly expressed in different forms of human cancer. C17orf37 expression has been reported to positively correlate with grade and stage of cancer progression; however the functional significance of C17orf37 overexpression in cancer biology is not known. Here, we show that C17orf37 is highly expressed in prostate cancer cell lines and tumors, compared to minimal expression in normal prostate cells and tissues. RNA interference mediated downregulation of C17orf37 resulted in decreased migration and invasion of DU-145 prostate cancer cells, and suppressed the DNA binding activity of NF-κB transcription factor resulting in reduced expression of downstream target genes MMP-9, uPA and VEGF. Phosphorylation of PKB/Akt was also reduced upon C17orf37 downregulation, suggesting C17orf37 acts as a signaling molecule that increases invasive potential of prostate cancer cells by NF-κB mediated downstream target genes. Cellular localization studies by confocal and total internal reflection (TIRF) microscopy revealed expression of C17orf37 protein in the cytosol predominantly surrounding the membrane of prostate cancer cells. We identified that C17orf37 has a functional prenylation motif and is posttranslationally modified by geranylgeranyl transferase-I (GGTase-I) enzyme. Prenylated proteins (often referred to as CAAX family of proteins) contain a CAAX motif (C denotes cysteine, A represents aliphatic amino acids, and X any amino acid) at the carboxyl terminal which serves as a substrate for a series of post-translational modifications converting otherwise hydrophilic to lipidated proteins with hydrophobic domain, facilitating membrane localization. Geranylgeranylation of C17orf37 at the ‘CVIL’ motif translocates the protein to the inner leaflet of plasma membrane, enhances migratory phenotype of cells by inducing increased filopodia formation and potentiates directional migration. The prenylation-deficient C17orf37 mutant is functionally inactive and fails to disseminate injected cells in the mouse model of metastasis. This implies that prenylation activates the C17orf37 protein in cancer cells and functionally regulates metastatic progression of the disease. Our data strongly suggest C17orf37 overexpression in prostate cancer functionally enhances migration and invasion facilitating metastatic dissemination of tumor cells, and is an important target for cancer therapy.Item STAT6 and Its Relationship with PSA and Annexin A2 in Human Prostate Cancer(2008-05-01) Roth, Cherice P.; Singh, Meharvan; Jones, Harlan P.; Sharma, RajendraRoth, Cherice, STAT6 and its relationship with PSA and Annexin A2 in Human Prostate Cancer. Master of Science (Biochemistry and Molecular Biology), May 2008, 49 pages, 13 illustrations, reference list, 54 titles. The increase of signal transducer and activator of transcription (STAT6) has been correlated with increased prostate tumor size as well as Gleason score. This molecule’s exact role in prostate cancer is still unknown. This research focused on the relationships of STAT6 in prostate specific antigen (PSA) expression as well as its novel interaction with annexin A2. These data show that STAT6 is involved in an alternate PSA expression pathway. It is also concluded that the interaction of STAT6 and annexin A2 increased the activated STAT6 (p-STAT) but not total STAT6. Chromatin immunoprecipitation also confirmed the novel protein-protein interaction between STAT6 and annexin A2 is nuclear.Item Store operated calcium entry in glomerular mesangial cells and diabetic nephropathy(2016-08-01) Chaudhari, Sarika; Rong Ma; J. Thomas Cunningham; Robert T. MalletGlomerular mesangial cells (MCs) are the major source of extracellular matrix (ECM). One of the early pathological changes in diabetic nephropathy (DN) is accumulation of ECM in glomeruli. Multifunctional store-operated Ca2+ entry (SOCE) regulates MC function. However, whether and how SOCE in MCs contributes to pathophysiology of DN remains unknown. The aim of the study was to investigate association of SOCE in MCs with ECM protein expression and the underlying mechanism using both in vitro and in vivo systems. Study I was to determine the effect of diabetes on SOCE. In cultured human MCs, we found that prolonged high glucose (HG) treatment (7 days) significantly increased SOCE and membrane currents through store-operated channels (SOC). These responses were abolished by SOC inhibitors. Consistently, prolonged HG treatment also increased the abundance of SOC proteins STIM1 and Orai1. HG also increased STIM1, but not Orai1 mRNA expression. Furthermore, both STIM1 and Orai1 proteins were also increased in the glomeruli/renal cortices of diabetic rats. Study II determined the influence of SOCE in MCs on ECM protein expression. We found that activation of SOC by thapsigargin reduced the abundance of fibronectin and collagen IV while inhibitors of SOC had opposite effects. Knockdown of Orai1 in human MCs increased fibronectin abundance. The HG induced increase in fibronectin was attenuated by SOCE. Using a nanoparticle siRNA delivery system, specific knockdown of Orai1 in MCs in mice increased glomerular fibronectin and collagen IV protein content and mesangial expansion. Study III determined the mechanism for inhibition of ECM protein expression by SOCE. We found that activation of SOC attenuated TGFβ1 mediated phosphorylation and translocation of Smad3, a known fibrotic pathway in MCs. However, there was no change in the production or secretion of TGFβ1 by MCs. Orai1 knockdown in MCs in mice increased the activation of Smad3. Taken together, our results indicate that SOCE in MCs may be increased in the late stage of diabetes, which suppresses ECM protein expression by inhibiting TGFβ1-smad3 pathway.