Browsing by Subject "prostate cancer"
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Item Bioengineered Nanoparticles for Targeted Cancer Therapy(2018-05) Gdowski, Andrew S.; Vishwanatha, Jamboor K.; Ranjan, Amalendu P.; Cistola, David P.; Olivencia-Yurvati, Albert H.Despite improved overall survival in cancer patients over the past 50 years, limited advances have been made in treating patients with metastatic cancers. Multiple types of cancers demonstrate the unique ability to specifically metastasize to the bone. Among these, prostate cancer exhibits increased capacity to create bone specific lesions with high frequency. Once bone localization takes place, treatment regimens are limited and overall survival is poor. These bone metastases often cause debilitating and life threatening problems including: uncontrollable pain, hypercalcemia, broken bones, spinal cord compression, and the inability to perform activities of daily living. The overarching goal of this thesis was to develop novel bone targeted nanoparticle therapies. The first generation of nanoparticles we engineered and tested were designed to target the hydroxyapatite structure of the bone particularly in areas of high bone turnover with subsequent therapeutic release at the site of the tumor. Notably, this nanoparticle formulation was efficacious in decreasing prostate cancer bone metastatic tumors, improving bone structure, and reducing pain in a mouse model. The next generation of nanoparticles were developed to simultaneously target the bone endothelium and tumor cells using a programmable bioinspired approach with guidance from genomic information of prostate cancer patients. This novel bioinspired nanoparticle demonstrated enhanced ability to self-recognize cancer cells as well as improved bone homing and retention in our in vivo evaluation. Finally, we addressed the challenge of nanoparticle manufacturing scale up from lab size quantities to large scale batches using a microfluidic process. It is our sincere hope that concepts and publications derived from this thesis will help guide future efforts for targeted therapy and improve the lives of patients with cancer.Item Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model(MDPI, 2020-06-10) Merchenthaler, Istvan; Lane, Malcolm; Stennett, Christina; Zhan, Min; Nguyen, Vien; Prokai-Tatrai, Katalin; Prokai, LaszloHot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17beta-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10beta, 17beta-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.Item Cabazitaxel-Loaded Nanoparticles Reduce the Invasiveness in Metastatic Prostate Cancer Cells: Beyond the Classical Taxane Function(MDPI, 2023-02-26) Lampe, Jana B.; Desai, Priyanka P.; Tripathi, Amit K.; Sabnis, Nirupama A.; Chen, Zhe; Ranjan, Amalendu P.; Vishwanatha, Jamboor K.Bone-metastatic prostate cancer symbolizes the beginning of the later stages of the disease. We designed a cabazitaxel-loaded, poly (lactic-co-glycolic acid) (PLGA) nanoparticle using an emulsion-diffusion-evaporation technique. Bis (sulfosuccinimidyl) suberate (BS3) was non-covalently inserted into the nanoparticle as a linker for the conjugation of a bone-targeting moiety to the outside of the nanoparticle. We hypothesized that the nanoparticles would have the ability to inhibit the epithelial-to-mesenchymal transition (EMT), invasion, and migration in prostate cancer cells. Targeted, cabazitaxel-loaded nanoparticles attenuated the EMT marker, Vimentin, and led to an increased E-cadherin expression. These changes impart epithelial characteristics and inhibit invasive properties in cancer progression. Consequently, progression to distant sites is also mitigated. We observed the reduction of phosphorylated Src at tyrosine 416, along with increased expression of phosphorylated cofilin at serine 3. These changes could affect migration and invasion pathways in cancer cells. Both increased p-120 catenin and inhibition in IL-8 expression were seen in targeted, cabazitaxel-loaded nanoparticles. Overall, our data show that the targeted, cabazitaxel-loaded nanoparticles can act as a promising treatment for metastatic prostate cancer by inhibiting EMT, invasion, and migration, in prostate cancer cells.Item 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 EGCG and Its Role in Prostate Cancer Angiogenesis(2005-05-01) Thomas, Rusha; Porunelloor Mathew; Ming-Chi Wu; Dan DimitrijevichThomas, Rusha, EGCG and its role in prostate cancer angiogenesis. Master of Science (Biochemistry and Molecular Biology), May 2005, 47 pages, 14 illustrations, reference list, 44 titles. Hypoxia inducible factor-1 (HIF-1)-mediated upregulation of vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with malignancies. HIF-1 consists of a constitutively expressed HIF-1β subunit, and a hypoxia-inducible HIF-1α subunit. Hypoxic induction of HIF-1α correlates with increased transcriptional activation of its downstream target genes, including VEGF. Epidemiologic and laboratory studies indicate that green tea has cancer preventive activity which has been attributed to its polyphenol components, the major one being epigallocatechin gallate (EGCG). This study investigated the effect of EGCG on normoxic VEGF expression in PC-3ML human prostate cancer cells. In contrast to previous studies where EGCG inhibited VEGF expression in breast and colon cancer cell lines, our results demonstrated that EGCG has the ability to upregulate HIF-1α transcription factor via inhibition of prolyl hydroxylation and subsequent von Hippel-Lindau protein interaction. HIF-1α upregulation by EGCG led to increased VEGF promoter activity and protein expression.Item Genetic characterization of comorbidity patterns in aging associated diseases using integrative genomics(2019-08) Pathak, Gita A.; Phillips, Nicole R.; Planz, John V.; Barber, Robert C.; Zhou, Zhengyang; Gryczynski, IgnacyThe aging population in the US continues to grow at an exponential rate estimated to reach more than 90 million by 2060. The coexistence of two or more diseases (comorbidity) is prevalent in ages 65 years and above, and the number of comorbidities increases with age. The genetic factors underlying presence and absence of comorbidities is a severely understudied research domain. Alzheimer's disease (AD) is a type of dementia affecting 5.5 million people with an average age of diagnosis at 70 years. Hypertension is a coexisting condition in 60% AD individuals, also known as direct comorbidity. On the other hand, cancer is reported to be inversely comorbid with AD; individuals with cancer history have been reported to have lower risk of AD and vice versa. Furthermore, individuals with cancer history are diagnosed with long term side effects of radiation therapy — radiotoxicity. Twin-based studies have reported that certain gene variants are associated with radiotoxicity phenotypes with a heritability of 66%. This study proposes to investigate genetic factors associated with the direct and inverse comorbidity of AD with hypertension and cancer, and proctitis — a radiotoxicity phenotype observed in survivors of prostate cancer. The study aims to integrate gene variants, derived-gene expression and copy number variation (CNV), followed by functional and pathway-based prioritization of observed findings. We used genome-wide and cerebral spinal fluid profile to investigate presence of hypertension with AD to evaluate individual-level differences, followed by targeted investigation of neighboring gene expression profiles of identified variants. We found several novel genes associated with AD-hypertension comorbidity. The investigation between AD and cancer identified regions in chromosomes 4, 5 and 19 that are targeted by miRNA-17 family along with other miRNAs reported to be inversely expressed and play opposite role in pathogenicity of both diseases. The SNP-derived transcriptomic profile between AD and cancer highlighted involvement of sirtuin signaling. The findings together indicate involvement of mitochondrial and metabolic dysregulation which possibly contribute in differences of the epithelial-mesenchymal-transition. The SNP-derived expression and CNV association with proctitis highlighted genes involved in DNA-repair and mitochondrial ROS damage pathways.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 Lectin-like transcript 1 as a natural killer cell-mediated immunotherapeutic target for triple negative breast cancer and prostate cancer(OAE Publishing, Inc., 2019-12-17) Sun, Yuanhong; Malaer, Joseph D.; Mathew, Porunelloor A.Breast and prostate cancer are the leading causes of death in females and males, respectively. Triple negative breast cancer (TNBC) does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2, resulting in limited treatment options. Androgen deprivation therapy is the standard care for prostate cancer patients; however, metastasis and recurrence are seen in androgen-independent prostate cancer. Both prostate and breast cancer show higher resistance after recurrence and metastasis, which increases the difficulty of treatment. Natural killer (NK) cells play a critical role during innate immunity and tumor recognition and elimination. NK cell function is determined by a delicate balance of inhibitory signals and activation signals received through cell surface receptors. Lectin-like transcript 1 (LLT1, CLEC2D, OCIL) is a ligand of NK cell inhibitory receptor NKRP1A (CD161). Several studies have that reported higher expression of LLT1 is associated with the development of various tumors. Our studies revealed that TNBC and prostate cancer cells express higher levels of LLT1. In the presence of a monoclonal antibody against LLT1, NK cell-mediated killing of TNBC and prostate cancer cells were greatly enhanced. This review highlights the potential that using monoclonal antibodies to block LLT1 - NKRP1A interactions could be an effective immunotherapeutic approach to treat triple negative breast cancer and prostate cancer.Item Mitochondrial Genetics and Function among Men Screened for Prostate Cancer(2015-12-01) Sprouse, Marc L.; Arthur J. Eisenberg; Rhonda Roby; Robert C. BarberGenetic alterations are associated with sporadic cancer development, progression and metastasis. Until now, more was known about nuclear DNA (nDNA) mutations and their role in cancer than the types of genetic changes that occur in the mitochondrial genome (mtGenome). Changes to mitochondrial DNA (mtDNA) are frequent in prostate cancer (PCa). Further, these changes have been associated with enhanced tumorigenesis and progression to an aggressive phenotype. However, it is unclear whether changes to the mtGenome can delineate PCa progression from indolent cancer to an advanced metastatic disease. An exhaustive characterization of the mtGenome of men screened for PCa was performed to determine if genetic differences between varying PCa disease states can be measured. Two genetic techniques (copy number and genome sequencing) were used to perform a comprehensive characterization of the changes to mtDNA in whole blood extracts from three groups of men screened for prostate cancer: normal control (NC), no evidence of disease (NED), and, biochemical recurrence/metastasis (BCR/MET). Mitochondrial DNA copies per cell and mtGenome deletion ratio (whole mtGenomes:truncated mtGenomes) were measured using a multiplex real-time quantitative PCR (qPCR) assay. Whole mtGenome sequence data were generated using a massively parallel sequencing platform, the Ion Torrent Personal Genome Machine (PGM). Real-time qPCR revealed a higher dispersion of mtDNA copies per cell and mtGenomes harboring a large scale deletion in samples from men with advanced stages of PCa when compared to normal controls and indolent PCa. Whole mtGenome sequencing showed a higher number of genetic variants in men with PCa, some of which are predicted to be pathological. A significant positive correlation was observed between mutational load and PCa disease status. Further, three-dimensional comparative modeling evidenced the negative effect of a single mtDNA missense mutation on a protein’s structural integrity. Overall, the presented data suggest there are differences in the mtGenome between men with and without PCa that are measurable in peripheral blood and may be used as a potential risk assessment tool. Future analyses with a larger sample size may lead to more compelling evidence that supports the role of changes to the mtGenome with PCa progression.Item Overexpression of LLT1 (OCIL, CLEC2D) on prostate cancer cells inhibits NK cell-mediated killing through LLT1-NKRP1A (CD161) interaction(Impact Journals, LLC, 2016-09-08) Mathew, Stephen O.; Chaudhary, Pankaj; Powers, Sheila B.; Vishwanatha, Jamboor K.; Mathew, Porunelloor A.Prostate cancer is the most common type of cancer diagnosed and the second leading cause of cancer-related death in American men. Natural Killer (NK) cells are the first line of defense against cancer and infections. NK cell function is regulated by a delicate balance between signals received through activating and inhibitory receptors. Previously, we identified Lectin-like transcript-1 (LLT1/OCIL/CLEC2D) as a counter-receptor for the NK cell inhibitory receptor NKRP1A (CD161). Interaction of LLT1 expressed on target cells with NKRP1A inhibits NK cell activation. In this study, we have found that LLT1 was overexpressed on prostate cancer cell lines (DU145, LNCaP, 22Rv1 and PC3) and in primary prostate cancer tissues both at the mRNA and protein level. We further showed that LLT1 is retained intracellularly in normal prostate cells with minimal cell surface expression. Blocking LLT1 interaction with NKRP1A by anti-LLT1 mAb on prostate cancer cells increased the NK-mediated cytotoxicity of prostate cancer cells. The results indicate that prostate cancer cells may evade immune attack by NK cells by expressing LLT1 to inhibit NK cell-mediated cytolytic activity through LLT1-NKRP1A interaction. Blocking LLT1-NKRP1A interaction will make prostate cancer cells susceptible to killing by NK cells and therefore may be a new therapeutic option for treatment of prostate cancer.Item Patterns of Primary Surgical Procedures Among Men Admitted to Texas Hospitals with a Diagnosis of Prostate Cancer(2001-12-01) Galdiano, Rosemary; Antonio Rene; Doug A. Mains; Sue LurieGaldiano, Rosemary, Patterns of primary surgical procedures among men admitted to Texas hospitals with a diagnosis of prostate cancer. Master of Public Health (Epidemiology), December 2001, 28 pp., 3 tables, 4 illustrations, references, 21 titles. Data for the Texas Health Care Information Council was analyzed to identify the patterns of surgical procedures among men admitted to 114 Texas hospitals with a diagnosis of prostate cancer in 1999; and to determine whether these patterns varied by race and age. In all, 4,608 cases were compared for differences between age, race and type of surgical procedure using Pearson’s chi-square test. Frequencies were tabulated for age, race, length of stay, type of surgery, and type of insurance. Radical prostatectomy and transurethral resection of the prostate are the most common procedures performed. Black and Hispanic men less than 45 years old were more likely to receive radical prostatectomy than whites. Transurethral resection of the prostate (TURP) is most commonly performed in men 75 years and older with higher proportions among black and Hispanic men. Younger men (ageyears) who received TURP were more likely to be white. White men between the ages of 45 and 84 were more likely to receive perineal prostatectomy. These findings identified patterns of treatment with defined differences between age and race.Item Post-transcriptional and Epigenetic Regulation of MIEN1 in Prostate Cancer(2014-08-01) Rajendiran, Smrithi; Vishwanatha, Jamboor K.; Basu, Alakananda; Berg, Rance E.Migration and invasion enhancer 1 (MIEN1), a gene located in the 17q12 region of the human chromosome, enhances migratory and invasive potential of cancer cells via two mechanisms; activating the Akt dependent NF-κB downstream signaling and facilitating filopodia formation; thereby playing an important role in cancer progression. MIEN1 is highly expressed in many cancers including prostate and breast, but its expression is very basal to null in a variety of normal tissues making it a plausible target for cancer therapy. Though the functions of MIEN1 are known, the reasons for its increased expression in cancer is unknown. Determining the molecular gene regulatory mechanisms by which expression of MIEN1 is curtailed in normal cells will help in developing better targeting strategies. Among the different gene regulatory mechanisms including transcriptional regulation, post-transcriptional modifications and histone and DNA alterations, here we focus on post transcriptional and DNA methylation based regulation of MIEN1. We show that MIEN1 is downregulated post-transcriptionally by miRNA-940 which itself is present in low amounts in cancer cells and tissues compared to the normal counterparts. The miR-940 also contributes to inhibition of cancer progression by attenuating the migration, invasion, anchorage-independent growth and epithelial-to-mesenchymal transition, when ectopically re-introduced into cancer cells. The miR-940 can be detected in circulation and its elevated levels in serum from cancer patients than normal subjects, suggest its potential as a biomarker for prostate cancer diagnosis. MIEN1, like urokinase plasminogen activator, is also suppressed by DNA methylation in normal cells. On the contrary, hypomethylation in cancer, results in its overexpression. The current approach of using global demethylating agents to activate the expression of hypermethylated tumor suppressor genes may in the long run activate tumor promoting genes like MIEN1. Thus, our study supports the notion that gene-centric hypomethylating agents may be a better epigenetic targeting approach to treat cancer. In conclusion, our data confirm the role of post-transcriptional and DNA methylation mediated mechanisms in the regulation of MIEN1.Item Review of the Current Treatment Options for a Prostate Cancer, Evolution of Radiosurgery, and Initiation of a Cyberknife Prostate Cancer Trial(2007-03-01) Camarena, Julieanna Angel; Oglesby, Michael; Gwirtz, Patricia A.; Aschenbrenner, JohnCamarena, Julieanna, Angel. Review of the Current Treatment Options for Prostate Cancer, Evolution of Radiosurgery, and Initiation of Cyberknife Prostate Cancer Trial. Master of Science (Clinical Research Management), May 2008, 141 pp., 3 tables, 4 illustrations, bibliography, 73 titles. Prostate cancer is the uncontrolled growth of the prostate gland cells. It is the most common cancer found in American men other than non-melanoma skin cancer. This disease will affect 1 in 6 men during their lifetime. With early diagnosis and treatment, prostate cancer has a cure rate of 90%. Currently there are several treatment options available for prostate cancer. The most common forms of treatment for early and intermediate state prostate cancers are surgery, radiation therapy, hormone deprivation therapy, and active surveillance. New treatment modalities including CyberKnife radiosurgery are currently being tested to gather data on safety and efficacy. Although the CyberKnife system gained clearance from the Food and Drug Administration in 2001 to treat tumors anywhere in the body where radiation treatment is indicated, long term data has not accrued on this device to assess its safety and efficacy. Investigational new treatments such as the CyberKnife must undergo clinical trials even after it is approved to determine long term effects of the procedure. As an intern with a CyberKnife, prostate cancer clinical trial, the author assisted in initiating the clinical trial at a major institution and observed the many aspects of clinical research with a focus on the role of a clinical research coordinator. Through this experience, the author researched the key components in a protocol and the background information necessary to compose a clinical trial protocol in the area of prostate cancer.Item Targeted Delivery of [alpha]-Mangostin to Prostate Cancer Cells Utilizing Reconstituted High-Density Lipoprotein Nanoparticles(2022-08) Kapic, Ammar; Berg, Rance E.; Basha, Riyaz; Ranjan, Amalendu P.