LIMK2 is a serine/threonine/tyrosine kinase that promotes tumor cell invasion and metastasis by phosphorylating cell proteins and altering their functions. There is a need to find tumor-specific substrates for LIMK2 in order to understand the downstream pathway of these substrates, their function, and how they are regulated by LIMK2. Recently, our labrotory identified LIMK2 as an excellent target for curing castration-resistant prostate cancer (CRPC). In this study, we identify two novel substrates for LIMK2 in CRPC: speckle-type POZ protein (SPOP), and Y-box binding protein-1 (YBX1). While LIMK2 negatively regulates SPOP, it positively regulates YBX1 − both by phosphorylation using in-vitro kinase assays. A study in our labrotory also proved that LIMK2 regulates Aurora A kinase (AURKA), where AURKA directly phosphorylates LIMK2. AURKA is a serine/threonine kinase that regulates cell cycle during mitosis; it is known to be upregulated, with uncontrolled activity, in many types of cancer, including prostate cancer. It is therefore important to identify new substrates for AURKA, especially in light of reported lethality in early embryonic mice, in association with AURKA-knockout. In other words, targeting AURKA directly may cause severe toxicity, a finding that has prevented direct inhibitors from passing Phase II clinical trials. In this study, we also identified SPOP and YBX1 as direct substrates for AURKA. Our results confirm what we know about the LIMK2/AURKA relationship: that AURKA negatively regulates SPOP and positively regulates YBX1. Targeting LIMK2 and AURKA indirectly through SPOP, YBX1 and its other substrates holds tremendous therapeutic potential in treating prostate cancer. With this, we open the door for researches to investigate the direct phosphorylation of SPOP and YBX1 in other types of cancer cells known to have overexpression in SPOP and/or YBX1.

One of the most common types of cancer among women is breast cancer. It represents one of the diseases leading to a high number of mortalities among women. On the other hand, prostate cancer is the second most frequent malignancy in men worldwide. The early detection of prostate cancer is fundamental to reduce mortality and increase the survival rate. A comparison between six types of machine learning models as Logistic Regression, Decision Tree, Random Forest, Gradient Boosting, k Nearest Neighbors, and Naïve Bayes has been performed. This research aims to identify the most efficient machine learning algorithms for identifying the most significant risk factors of prostate and breast cancers. For this reason, National Health Interview Survey (NHIS) and Prostate, Lung, Colorectal, and Ovarian (PLCO) datasets are used. A comprehensive comparison of risk factors leading to these two crucial cancers can significantly impact early detection and progressive improvement in survival. / Includes bibliography. / Thesis (P.S.M.)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

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

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / The incidence of multiple primary neoplasms has been increasing over the years. Within this group, the coexistence of primary prostate cancer and primary colorectal cancer is one of the most frequent. The objective of this case report is to present the case of a 76-year-old male patient who presented the diagnosis of prostate cancer and synchronous rectal cancer. To this end, his clinical history in the oncological service of the Hospital Militar Central del Perú (tertiary hospital) has been reviewed. / Revisión por pares

MSc (Microbiology) / Department of Microbiology / Background: Prostate cancer (PCA) is a major health concern in males, particularly those above 40 years old. It is the most common form of cancer in males worldwide, including South Africa. In South Africa, the rate of histologically diagnosed prostate cancer is 40 per 100 000 in whites and 14 per 100 000 in blacks, and 1 in 8 men will develop PCA in their lifetime. Several reports have suggested the association of viruses in the pathogenesis of prostate cancer. Objectives: This study was aimed at identifying Hepatitis B virus (HBV), human papilloma virus (HPV) and human herpes virus type 8 (HHV-8), implicated in other forms of cancer, in a cohort of South African patients with either PCA or benign prostatic hyperplasia (BPH); and to seek possible associations thereof. Methods: The study group comprised 187 male patients recruited from Polokwane Hospital presenting with either PCA (staged by Gleason scores) or BPH. Enzyme-linked immunosorbent assay was used to detect antibodies to HHV-8 and HPV; and to detect hepatitis B surface antigen (HBsAg) in the plasma of the study subjects. Total DNA was extracted from plasma and targeted for the identification of HBV and HHV-8 DNA by nested PCR protocols. The HBV nested PCR protocol amplifies a 336bp fragment of the overlapping surface polymerase gene of HBV. The HHV-8 nested protocol amplifies a 233bp fragment of the ORF 26 gene of HHV-8. Amplified DNA products were purified, sequenced by the Sanger protocol and phylogenetically analysed for viral genotypes. The Chi-square test was used to infer statistically significant differences in the level of detection of viruses and the stage of prostate cancer development. Results: Of the 187 participants, a seroprevalence of 4.8% (9/187, HBsAg), 5.3% (10/187, HPV IgG antibody) and 27% (33/124, HHV-8 IgG antibody) were observed. HBsAg was detected more in individuals with BPH than those without and this was statistically significant at ( 2=6.0, p< 0.05). HHV-8 DNA was detected more in individuals in the 60-79 years age range and this was statistically significant at ( 2=61.1, p< 0.05). Occult HBV infection (that is the presence of HBV DNA in the absence of HBsAg) was detected in 23/178 (12.9%) of patients. Taking into account occult HBV infection, the overall prevalence of HBV was 17.7%. HBV genotype E was more prevalent (86.7%) followed by genotype A (13.3%). HHV-8 genotypes K and R were inferred. Apparently, this is the first report on the identification of HHV-8 genotypes K and R from South Africa. Conclusion: The current study has demonstrated for the first time, the presence of genotypes K and R of HHV-8 in South Africa. This study also suggests that there is a high level of occult genotype E HBV infection. Future studies will explore the virome in prostate cancer biopsies.

Orientador: Fábio Porto-Foresti / Resumo: Os pesticidas organofosforados, como por exemplo o diclorvós (DDVP), são amplamente utilizados na atualidade, apesar de existirem muitos estudos que comprovem a sua atuação como desreguladores endócrinos. Esses desreguladores são capazes de interferir na homeostase mantida pelos hormônios e podem estar ligados ao desenvolvimento de lesões neoplásicas no sistema genital masculino, como o câncer de próstata, que representa a segunda maior incidência de neoplasias no sexo masculino no mundo. A progressão dessas lesões pode se dar através do processo de angiogênese e depende do equilíbrio local nas atividades de fatores proangiogênicos e antiangiogênicos. Um dos fatores antiangiogênicos mais bem estudados é a endostatina, inibidor endógeno da angiogênese, enquanto que o fator proangiogênico mais importante é o VEGF, juntamente com o seu receptor Flk-1. A angiogênese pode ser induzida pela hipóxia que ocorre no ambiente tumoral devido à disponibilidade limitada de oxigênio entre as células proliferativas. Assim, o presente estudo teve como objetivo analisar a morfologia e os marcadores moleculares envolvidos no processo de angiogênese (HIF-1α, VEGF, Flk-1 e endostatina) na próstata de ratos para avaliar a influência do praguicida diclorvós, associado ou não à indução química por N-metil-N-nitrosoureia (MNU). Foram utilizados 32 ratos da linhagem Fischer 344, com idade de 90 dias. Os ratos foram separados em quatro grupos experimentais: Controle, DDVP, MNU, MNU+DDVP. Foram feitas a... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Orientador: WellersonRodrigo Scarano / Coorientador: Flávia Karina Dellela / Banca: Luis Antonio Justilin Junior / Banca: Silvana Gisele Pegorin de Campos / Resumo: A Iniciação e Progressão das neoplasias prostáticas apresentam base hormonal, onde se destacam as alterações envolvendo estrógenos e andrógenos inerentes ao processo de envelhecimento, com incremento dos níveis estrogênicos em relação aos androgênicos. O Bisfenol A (BPA) é o xenoestrógeno mais estudado na atualidade e sua atividade estrogênica tem despertado interesse devido à ampla dispersão do composto no meio ambiente. Assim sendo, o BPA poderia contribuir para o aumento da incidência, agressividade e capacidade metastática dos tumores prostáticos. Por outro lado, a quimioproteção com os fitoquímicos dietéticos está associada à redução na incidência e na progressão de diferentes neoplasias, diminuição de processos inflamatórios e estresse oxidativo ocasionados por substâncias potencialmente nocivas. Desta forma, este estudo objetivou avaliar os efeitos dos fitoquímicos 3,3'-Di-indolil-metano (DIM) e Genisteína (Gen) isolados e/ou associados em células tumorais prostáticas humanas expostas ao BPA. Para tanto, as linhagens LNCaP e PC-3 foram cultivadas e submetidas, por 96h, aos tratamentos C (controle), B (BPA 10nM/L), BD (BPA 10nM/L + DIM 25μM/L), BG (BPA 10nM/L + Gen 25μM/L) e BDG (BPA 10nM/L + DIM 25μM/L + Gen 25μM/L); cujas doses foram estabelecidas pelo ensaio de viabilidade celular. Posteriormente, foi realizado Western Blotting para estudo das proteínas envolvidas com processos de sobrevivência, proliferação, morte celular, modulação hormonal e estresse oxidativo. A análise dos resultados mostrou que os tratamentos BD, BG e BDG, na linhagem LNCaP, apresentaram capacidade de sub-regular a expressão de AR. Acerca das proteínas ERK1/2 em PC-3, B provocou um aumento de expressão, enquanto BDG ocasionou uma diminuição. Já na linhagem LNCaP, a redução da expressão desta MAPK ficou por conta do tratamento BG. Para as proteínas JNK1/2, verificou-se a capacidade de B sub-regular a... / Abstract: The prostate cancer initiation and progression present hormonal basis and this is mainly related to changes involving estrogens and androgens inherent aging process, where there is an increment of estrogens levels relative to androgens. Nowadays, Bisphenol A (BPA) is the most studied xenoestrogen and its estrogenic activity has attracted attention for its wide dispersion in the environment. Thus, this compound could contribute to the increased incidence, aggressiveness and metastatic ability of prostate tumors. Moreover, the chemoprotection with dietary phytochemicals is associated with a reduction in the incidence and progression of different cancers, decrease inflammatory processes and oxidative stress caused by potentially harmful substances. Therefore, this study aimed to evaluate the effects of phytochemicals 3,3 '-Di-indolyl-methane (DIM) and Genistein (Gen) isolated and/or associated to prostatic tumor cells exposed to BPA. For this purpose, LNCaP and PC-3 cells were cultured and exposed, for 96 hours, to the treatments C (control), B (BPA10nM/L), BD (BPA 10nM/L + DIM 25μM/L), BG (BPA 10nM/L + Gen 25μM/L) e BDG (BPA 10nM/L + DIM 25μM/L + Gen 25μM/L); which doses were established by cell viability assay. Subsequently, the cells were subjected to protein extraction for Western Blotting in order to analyze proteins involved in survival, proliferation, cell death, hormonal modulation and oxidative stress processes. The results showed that BD, BG and BDG treatments, in LNCaP cells, were able to down-regulate AR expression. About the ERK1/2 proteins in PC-3 lineage, B caused an increase of expression, while BDG was responsible for a decrease. However, in LNCaP, reducing the expression of MAPK was due to BG treatment. For the JNK1/2 protein, B had ability to down-regulate its expression and, on the other hand, phytochemicals from 3 treatments (BD, BG and BDG), increasing its expression in LNCaP. For the same cell lineage, the ERα ... / Mestre

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>