Prostate cancer (PCa) is the second most diagnosed cancer in men. The resistance of prostate cancer to chemotherapy has been linked to the ATP Binding Cassette (ABC)-Mediated Multidrug Resistance (MDR). This study investigated the combination of 3-Bromopyruvate (3-BPA) and the anti-inflammatory molecule SC-514 in reducing MDR in prostate cancer. The compounds were incorporated into a PLGA nanoparticles to increase delivery to target cells. To investigate the effectiveness of SC-514 and/3-BPA, cytoxicity assays including trypan blue dye exclusion, MTT tetrazolium reduction, NBT, LDH release poly caspase detection, cell titer glow assay, and ELISA were utilized. Both immunofluorescence and multidrug resistance efflux assays were utilized to estimate the number of drug resistant cells. SC-514 was encapsulated in PLGA nanoparticles via single-emulsion method. SC-514 nanoparticles were analyzed utilizing Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Liquid chromatography–mass spectrometry (LC–MS) was used to measure the amount of SC- 514 released from the nanoparticle. Alternative SC-514 drug release quantification methods such as colony forming assay, wound healing assay, and transwell and migration assay were explored. / Includes bibliography. / Dissertation (PhD)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

The oncogenic role of many of inflammatory genes in prostate cancer (PCa) remains unexplored despite the increasing association of chronic inflammation with PCa initiation, progression, and therapy resistance. The overarching goal of this project was to identify dysregulated inflammatory genes that correlate with PCa progression and seek to understand their molecular mechanisms and the therapeutic potential of targeting them. To achieve this, we utilized cutting-edge integrative (epi) genomic and transcriptomic techniques to identify and characterize inflammatory genes whose deregulation or (epi) genetic alterations correlate with PCa progression. Weighted Gene Co-expression Network Analysis and other multivariate analysis techniques identified IRAK1 as one of the inflammatory signatures found to be overexpressed in over 80% of prostate adenocarcinoma (PRAD) samples. We also explored the diagnostic and prognostic potential of IRAK1 as a biomarker using Kaplan Meier Survival Analysis and AUROC Analysis. DNA methylation analysis showed that IRAK1 is hypomethylated and found to negatively correlate with its overexpression in PRAD patients. We also found some missense and truncated mutations in some patients and reported a high level of IRAK1 gene amplification in castration-resistant and neuroendocrine PCa patients. / Includes bibliography. / Dissertation (PhD)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

archives@tulane.edu / The current system for evaluating prostate cancer architecture is the Gleason Grade system, which divides the morphology of cancer into five distinct architectural patterns, labeled numerically in increasing levels of cancer aggressiveness and generates a score by summing the labels of the two most dominant patterns. The Gleason score is currently the most powerful prognostic predictor of patient outcomes; however, it suffers from problems in reproducibility and consistency due to the high intra-observer and inter-observer variability among pathologists. In addition, the Gleason system lacks the granularity to address potentially prognostic architectural features beyond Gleason patterns. We look towards persistent homology, a tool from topological data analysis, to provide a means of evaluating prostate cancer glandular architecture. The objective of this work is to demonstrate the capacity of persistent homology to capture architectural features independently of Gleason patterns in a representation suitable for unsupervised and supervised machine learning. Specifically, using persistent homology, we compute topological representations of purely graded prostate cancer histopathology images of Gleason patterns and show that persistent homology is capable of clustering prostate cancer histology into architectural groups through discrete representations of persistent homology in both two-dimensional and three-dimensional histopathology. We then demonstrate the performance of persistent homology based features in common machine learning classifiers, indicating that persistent homology can both separate unique architectures in prostate cancer, but is also predictive of prostate cancer aggressiveness. Our results indicate the ability of persistent homology to cluster into unique groups with dominant architectural patterns consistent with the continuum of Gleason patterns. In addition, of particular interest, is the sensitivity of persistent homology to identify specific sub-architectural groups within single Gleason patterns, suggesting that persistent homology could represent a robust quantification method for prostate cancer architecture with higher granularity than the existing semi-quantitative measures. This work develops a framework for segregating prostate cancer aggressiveness by architectural subtype using topological representations, in a supervised machine learning setting, and lays the groundwork for augmenting traditional approaches with topological features for improved diagnosis and prognosis. / 1 / Peter Lawson

Prostate cancer is one of the most frequently diagnosed cancers and the second leading cause of cancer-related deaths in male population. While localized prostate cancer can be successfully treated with surgery or radiation therapy, the metastatic disease has no curable options. Metastasis can be developed as a result of failed therapy of localized cancer or present at initial diagnosis. As metastasis is the most common cause of prostate cancer-related death, developing novel approaches and improving the efficiency of existing therapies for the metastatic prostate cancer treatment will significantly improve patients’ survival. <div><br><div>The first-line treatment option for metastatic prostate cancer and localized prostate cancer with high risk of recurrence is androgen deprivation therapy (ADT) that decreases androgen receptor (AR) signaling. However, targeting AR signaling inevitably leads to AR reactivation and cancer progression to the castration-resistant prostate cancer (CRPC) that has no curable treatment options. Moreover, about 30% of CRPC cases progress to neuroendocrine prostate cancer (NEPC), highly aggressive and lethal type of prostate cancer. </div><div><br></div><div>Recently my group has shown that protein arginine methyltransferase 5 (PRMT5) functions as an activator of AR expression in hormone-naïve prostate cancer (HNPC). In this dissertation, I demonstrate that PRMT5 also functions as an epigenetic activator of AR transcription in CRPC via symmetric dimethylation of H4R3 at the AR promoter. This epigenetic activation is dependent on pICln, a PRMT5 interaction partner involved in spliceosome assembly, and independent of MEP50, the canonical cofactor of PRMT5. PRMT5 and pICln, but not MEP50, were required for the expression of AR signaling pathway genes. In clinical samples of both HNPC and CRPC, nuclear PRMT5 and pICln protein expressions were highly positively correlated with nuclear AR protein expression. In xenograft tumors, targeting PRMT5 or pICln significantly decreased tumor growth and AR expression. </div><div><br></div><div>Overall, this work identifies PRMT5/pICln as a therapeutic target for HNPC and CRPC treatment that needs to be further evaluated in clinical setting. </div></div>

Orientador: Wellerson Rodrigo Scarano / Coorientador: Luis Fernando Barbisan / Banca: Sebastião Roberto Taboga / Banca: Raquel Fantin Domeniconi / Resumo: Sabe-se que fatores ambientais e de estilo de vida, tais como a dieta, são capazes de induzir significativas mudanças na concentração e no metabolismo dos hormônios esteroides, o que pode contribuir para o desenvolvimento de doenças prostáticas. O Bisfenol A (BPA) é um componente dos produtos a base de resinas epóxi e plásticos policarbonato e tem sido investigado por sua provável atividade carcinogênica para a mama e próstata. O objetivo geral desse trabalho foi investigar se a exposição gestacional ao BPA suplementado ou não com Indol-3-Carbinol (I3C), um composto natural com propriedades quimioprotetoras, interfere no padrão de desenvolvimento da próstata, bem como na suscetibilidade ao desenvolvimento de lesões prostáticas. Fêmeas prenhes da linhagem Sprague-Dawley foram divididas em 5 grupos experimentais: G1: Controle (ração basal); G2: BPA25 (25μg/Kg); G3: BPA25 (25μg/Kg) + I3C; G4: BPA250 (250μg/Kg); G5: BPA250 (250μg/Kg) + I3C. Machos selecionados de diferentes ninhadas (2/ninhada) foram eutanasiados no DPN21 para avaliação imediata sobre a morfogênese prostática e no DPN180 para avaliação dos efeitos tardios.No DPN21 e DPN180 os animais foram eutanasiados por decapitação, o sangue foi coletado para análises hormonais e os hemilobos ventrais direitos separados para rotina histológica, análise estereológica e imuno-histoquímica, e os esquerdos congelados em nitrogênio líquido para o Western Blot. O lobo dorsolateral foi coletado no DPN180 para avaliação histopatológica. O peso do lobo ventral da próstata reduziu no grupo G5 em relação a G4, enquanto no DPN180 não houve diferença nesse parâmetro. Com relação à estereologia no DPN21 evidenciou-se aumento do compartimento epitelial e diminuição do compartimento luminal nos grupos G3 e G5. Quanto ao índice de proliferação celular no DPN21 observou-se aumento nos grupos... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Environmental factors and life style, such as diet, are able to induce significant changes in the concentration and metabolism of steroid hormones and can contribute with prostatic diseases development. Bisphenol A (BPA) is an organic compound used to make epoxy resins and polycarbonate plastics and has been investigated for its probable carcinogenic activity for breast and prostate. The aim of this study was to investigate if gestational exposure to BPA, supplemented or not with Indole-3-Carbinol (I3C), a natural compound with chemoprotective properties, can modify the prostate development pattern as well as the susceptibility to develop lesions in prostate. Sprague-Dawley pregnant females were divided into five experimental groups: G1: Control (basal chow); G2: BPA25 (25μg/Kg) G3: BPA25 (25μg/Kg) + I3C; G4: BPA250 (250μg/Kg); G5: BPA250 (250μg/Kg) + I3C. Selected males from different litters (2/litter) were euthanized in PND21, to study the early effects on prostate morphogenesis and in PND180 to evaluate the late effects. At PND21 and PND180 the animals were euthanized by decapitation, blood was collected to hormone assays and right ventral lobule was used for histopathological evaluation, stereological analysis, immunohistochemistry and TUNEL assay, and the left ventral lobule was frozen and stored in the -80oC freezer for Western Blot analysis. Dorsolateral lobe was collected for histopathologic evaluation at PND180 animals. Prostatic ventral lobe weight at PND21 decreased in the G5 group compared to G4, while at PND180 there was no significant difference in this parameter. At PND21 there was increase in epithelial compartment and decrease in the luminal compartment in G3 and G5 compared to G1. Epithelial cells proliferation index at PND21 was significant higher in G2 and G3 than G1, and apoptosis index in I3C groups (G3 e G5) was higher in relation... (Complete abstract click electronic access below) / Mestre

The mevalonate pathway plays an important role in cancer biology and has been targeted with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. Statins and bisphosphonates inhibit the mevalonate pathway at different steps, thus having negative effects at various levels on cancer cells. A combination of these drugs may result in an amplified cytotoxic effect and allow for use of significantly lower doses of the drugs involved. Statins inhibit the mevalonate pathway at 3-hydroxy-3-methylglutaryl coenzyme A reductase and bisphosphonates at farnesyl pyrophosphate synthase. Our results show that low-dose combinations of simvastatin and alendronate have a synergistic cytotoxic effect on androgen-independent prostate cancer PC-3 cells, but not on androgen-dependent LNCaP or DU 145 prostate cancer cells. These two drugs cause a sequential blockade of the mevalonate pathway and significantly affect survival and apoptotic pathways by down-regulating phospho-AKT and activating c-JUN and ERK.

Orientador: Marlus Chorilli / Resumo: O câncer de próstata (CP) é a neoplasia maligna urológica mais comum e a segunda principal causa de mortalidade de homens associada ao câncer no mundo. O tratamento é iniciado por meio de intervenções cirúrgicas que abrangem a prostatectomia radical, tratamentos radioterápicos, terapias envolvendo privação androgênica e as imunoterapias. A quimioterapia também é bastante utilizada e recentes estudos demonstraram um controle notável do crescimento do CP utilizando docetaxel (DTX). No entanto, o DTX apresenta efeitos colaterais associados à toxicidade, tanto do fármaco como da formulação, Taxotere®. Em consequência disso, o desenvolvimento de sistemas nanotecnológicos de liberação de fármacos, como lipossomas, tem sido promissor para o tratamento do CP, em virtude das múltiplas características favoráveis desses nanosistemas, como biocompatibilidade e biodegradabilidade. Uma abordagem atrativa é a modificação superficial dos lipossomas com ligantes específicos dos receptores regulados nas superfícies de células tumorais, como os receptores de transferrina, que podem ser superexpressos em células tumorais de próstata. O atual trabalho visou desenvolver, caracterizar e avaliar a citotoxicidade in vitro de lipossomas funcionalizados com transferrina para veiculação do DTX no tratamento do CP. Os lipossomas foram obtidos por meio da técnica clássica da hidratação do filme lipídico e foram constituídos pela mistura de fosfatidilcolina de soja (SPC): colesterol (Col) : DSPE-PEG (2000)... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Prostate cancer (PC) is the most common urological malignancy and the second leading cause of cancer-related mortality in men worldwide. Treatment is initiated through surgical interventions that include radical prostatectomy, radiotherapy treatments, androgen deprivation therapies and immunotherapies. Chemotherapy is also widely used and recent studies have shown remarkable control of CP growth using docetaxel (DTX). However, DTX has side effects associated with the toxicity of both the drug and the formulation Taxotere®. As a result, the development of nanotechnological drug delivery systems, such as liposomes, has been promising for the treatment of CP, due to the multiple favorable characteristics of these nanosystems, such as biocompatibility and biodegradability. An attractive approach is the superficial modification of liposomes with receptor-specific ligands regulated on tumor cell surfaces, such as transferrin receptors, which can be overexpressed in prostate tumor cells. The present work aimed to develop, characterize and evaluate the in vitro cytotoxicity of transferrinfunctionalized liposomes for DTX delivery in the treatment of CP. The liposomes were obtained by the classical technique of hydration of the lipid film and consisted of soybean phosphatidylcholine (SPC): cholesterol (Col): DSPE-PEG (2000) -Maleimide and SPC: Col: DSPE-PEG (2000) mixture. ) -Maleimide: DTX, in the molar ratios 10: 2: 0.78 and 10: 2: 0.78: 0.52, respectively. The characterizations were... (Complete abstract click electronic access below) / Mestre

Scholarly articles related to the physical and emotional effects of prostate cancer treatment and survivorship are abundant. However, few researchers have explored resiliency of prostate cancer survivors through their recovery and survivorship experience. There is a gap in the literature regarding resilience through the lived experiences of prostate cancer survivors. Counselor educators could be better prepared to teach counselors to promote the resilience needs of prostate cancer survivors. The purpose of this hermeneutic phenomenological qualitative study was to explore and describe the lived experiences of prostate cancer survivors. Coding analysis of data collected from interviews of 7 participants generated 3 major themes and 30 subthemes of experiences. Themes included experiences and feelings surrounding the cancer diagnosis, descriptions of resilience, and the personal growth the participants gained from their experiences. The results of this study give voice to their challenges and offer insight into how prostate cancer survivors find meaning while adapting constructively to adversity and resilience. A clearer understanding of these experiences may promote understanding of the prostate cancer experience for men, offer insight for promoting resilience among prostate cancer survivors, and give clues to the experiences of other populations responding to cancer.

Breast and prostate cancers are among the two most common forms of cancer. In addition to the symptoms caused by the tumor itself, there are several sequelae associated with breast and prostate cancer that can be caused by the psychological impact of the diagnosis or from cancer treatment. Many of these symptoms can persist during the survivorship phase, even after the cancer has been treated. As such, given the large clinical population affected by these diseases, there is a strong need to identify and treat the unique symptom burden that these patients experience. While diagnosis and management of breast and prostate cancer-specific mortality have markedly developed over the years, there are still gaps in managing symptoms of cancer-related morbidity. Additionally, conventional pharmacological treatments for symptom management can come with their associated side-effects. Mindfulness-based interventions are a relatively new symptom management modality that have come as a part of a wave of cognitive-based therapies for simultaneous treatment of multiple cancer-related symptoms. Given the relative infancy of this treatment modality, much of the research has focused on its efficacy and validity as a treatment option. Even with exponential interest in this field, much of the underlying physiology of mindfulness is still unknown. This will be an examination of physiological mechanisms implicated in mindfulness-based interventions as they relate to breast and prostate cancer patients.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第18478号 / 農博第2078号 / 新制||農||1026(附属図書館) / 学位論文||H26||N4862(農学部図書室) / 31356 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 植田 和光, 教授 小川 順, 教授 栗原 達夫 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM