Orientador: Athanase Billis / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T11:31:23Z (GMT). No. of bitstreams: 1 Paes_ThaisRuanoLazzarini_M.pdf: 5175009 bytes, checksum: 3318a93ff18fb95a508582450435e1a6 (MD5) Previous issue date: 2008 / Resumo: Carcinoma da próstata é uma neoplasia maligna constituída por células que se originam de ácinos e/ou ductos prostáticos, com arranjo, graus de diferenciação e comportamento biológico variáveis. A prostatectomia radical como tratamento primário para câncer prostático clinicamente localizado tem aumentado dramaticamente nesta última década devido ao PSA. A identificação de margens cirúrgicas positivas é um fator adverso no prognóstico dos pacientes submetidos à prostatectomia radical por câncer prostático. Muitos autores relatam que margens cirúrgicas positivas são fatores preditivos significantes na progressão da doença. Já outros, afirmam que a sobrevida não é afetada pelas margens cirúrgicas. O significado do envolvimento somente microscópico do colo vesical é controverso na literatura. Para alguns autores há um menor risco de progressão quando comparado ao comprometimento das vesículas seminais e para outros o risco de recorrência é maior. Os objetivos deste trabalho foram: correlacionar margens cirúrgicas comprometidas e invasão do colo vesical em espécimes de prostatectomias radicais com variáveis clínico-patológicas. Foram estudados 230 pacientes submetidos consecutivamente a prostatectomia radical no Hospital de Clínicas da Universidade Estadual de Campinas (UNICAMP), no período de janeiro de 1997 a julho de 2005. Todo o espécime cirúrgico obtido foi previamente processado por inteiro para exame histopatológico. Cada peça cirúrgica foi pesada e medida, e a superfície foi totalmente coberta por tinta Nankim. O colo vesical e a margem apical foram amputados. Os valores séricos de PSA = 0,2 ng/mL foram considerados como progressão bioquímica. Os dados foram analisados estatisticamente utilizando-se o teste de Mann-Whitney para comparação de amostras independentes e o teste exato de Fisher para avaliação de diferenças entre proporções. O tempo de sobrevida livre de progressão bioquímica foi baseado na análise do produto-limite de Kaplan-Meier e a comparação entre os grupos foi feita usando o teste do long-rank, sendo considerado significante o valor de p =0,05. Os resultados obtidos mostraram que as margens cirúrgicas comprometidas têm relação significante com PSA pré-operatório, contagem final de Gleason (no espécime cirúrgico), extensão tumoral, estádio patológico, e tempo de progressão bioquímica (PSA) pós-prostatectomia radical. Pacientes com invasão do colo vesical apresentaram relação significante com PSA pré-operatório; contagem final de Gleason tanto no espécime cirúrgico quanto na biópsia prostática de agulha correspondente; extensão tumoral; estádio patológico e margens cirúrgicas uretral e circunferencial, porém sem relação estatística com tempo de progressão bioquímica (PSA) pós-prostatectomia radical. Ao compararmos a evolução livre de progressão bioquímica (PSA) pós-prostatectomia radical entre pacientes com invasão do colo vesical, e pacientes com invasão da vesícula seminal, os achados não apóiam considerar invasão microscópica do colo vesical como sendo pT4 / Abstract: Prostate cancer is a malignant neoplasia composed by cells with origin in prostatic acini and/or ducts that present variable arrangement, biologic behavior and differentiation. Radical prostatectomy as primary treatment for localized prostate cancer has been increased dramatically in the last years due to PSA. Positive surgical margin identification is an adverse prognostic factor in patients submitted to radical prostatectomy. Many authors mention that positive surgical margins are a significant predictive factor for disease progression. Others affirm that positive surgical margins or other variables do not affect prognosis. The significance of microscopic involvement of bladder neck is controversial in the literature. For some authors biochemical progression in patients with bladder neck invasion is less important than seminal vesicle involvement but not for others. The purpose of the study was to find any possible relationship of surgical margins and bladder neck invasion in radical prostatectomies to several clinicopathological variables. This study consisted in 230 patients submitted consecutively to radical prostatectomy in the University Hospital, School of Medicine, State University of Campinas (Unicamp), between January 1997 and July 2005. All specimens were whole processed for pathological examination. Each surgical fragment was weighted, measured, and painted with Nankim's ink. Bladder neck and apex were separately processed. Biochemical (PSA) progression following radical prostatectomy was considered as being = 0,2 ng/mL. The data were statistically analysed using Mann-Whitney test to compare independent samples and exact Fisher test to evaluate differences between proportions. The time to biochemical (PSA) progression was analysed by the Kaplan-Meier product-limit analysis and the comparison between groups was done using the log-rank test. A p value of <0.05 was considered statistically significant. The results showed that patients with positive surgical margins had higher preoperative PSA, higher Gleason score on the specimen, and more extensive tumors and pathologic stage. Patients with bladder neck invasion had higher preoperative PSA, higher Gleason score in biopsies and specimens, higher number of apical and circumferential positive surgical margins, and more extensive tumors and pathological stage. The time to biochemical (PSA) progression following radical prostatectomy was not statistically significant comparing patients with and without bladder neck invasion, but statistically significant when comparing patients with and without vesicle seminal invasion. This latter finding do not support considering bladder neck invasion as stage pT4 / Mestrado / Anatomia Patologica / Mestre em Ciências Médicas

No description available.

Understanding the factors that affect c-Myc in prostate cancer is critical to developing an effective means of treatment for aggressive, castration-resistant forms of the disease. Myc is an oncogene known to be overexpressed and stabilized in many types of cancer, prostate included. Recent insights into breast cancer have revealed that Myc protein retains a longer half-life in cancer cells, but the cause for this has yet to be deduced. Due to its close proximity and proven interaction with Myc, I propose that the lncRNA PVT1 is stabilizing Myc and facilitating its activation of target genes in castration-resistant prostate cancer. To explore this hypothesis, metastatic prostate cancer DU145 cells were transfected with both siRNAs and ASOs targeting PVT1. Cells were analyzed for changes in different protein levels, as well as binding partners, through the use of immunoprecipitation and western blot. These results were verified with RT-qPCR data to confirm knockdown levels of PVT1. Proliferation assays were also conducted to explore the proliferative abilities of cells when PVT1 levels were decreased. Transfection of PVT1 with siRNA yielded about a 50% knockdown, while ASO targeting brought PVT1 levels down 80%. PVT1 inhibition had different effects on the level of c-Myc in cells depending on the method of transfection used--while transfection with anti-PVT1 siRNAs slightly decrease the amount of c-Myc protein in the cell, transfection using ASOs significantly increases c-Myc. Most importantly, proliferation of DU145 cells decreased with PVT1 knockdown by ASOs. Removal of this lncRNA, therefore, hinders that oncogenic potential for growth of prostate cancer cells. Since Myc poses a difficult target for cancer therapy, any new method to mitigate its oncogenic signaling would be invaluable. Targeting lncRNA PVT1 may be a successful method of doing just that, but more work needs to be done to explore the effects of different knockdown strategies. It is clear, however, that the relationship between Myc and PVT1 is a convoluted interaction that warrants further research. A breakthrough in this area could lead to huge improvements in the way prostate cancer is diagnosed and treated.

The research goal was to document differences in the epidemiology of prostate cancer among multicultural men [non-Hispanic White (NHW), Hispanic (H), non-Hispanic Black (NHB)], and Black subgroups, particularly among NHB subgroups [US-born (USB) and Caribbean-born (CBB)]. Study findings will be useful in supporting further research into Black subgroups. Aim 1 explored changes over time in reported prostate cancer prevalence, by race/ethnicity and by birthplace (within the Black subgroups). Aim 2 investigated relationships between observed and latent variables. The analytical approaches included confirmatory factor analysis (CFA for measurement models) and structural equation modeling (SEM for regression models). National Center for Health Statistics, National Health Interview Survey (NHIS) data from 1999 – 2008 were used. The study sample included men aged 18 and older, grouped by race/ethnicity. Among the CBB group, survey respondents were limited to the English-speaking Caribbean. Prostate cancer prevalence, by race showed a higher trend among NHB men than NHW men overall, however differences over time were not significant. CBB men reported a higher proportion of prostate cancer among cancers diagnosed than USB men overall. Due to small sample sizes, stable prostate cancer prevalence trends could not be assessed over time nor could trends in the receipt of a PSA exam among NHB men when stratified by birthplace. USB and CBB men differ significantly in their screening behavior. The effect of SES on PSA screening adjusted for risk factors was statistically significant while latent variable lifestyle was not. Among risk factors, family history of cancer exhibited a consistent positive effect on PSA screening for both USB and CBB men. Among the CBB men, the number of years lived in the US did not significantly affect PSA screening behavior. When NHB men are stratified by birthplace, CBB men had a higher overall prevalence of prostate cancer diagnoses than USB men although not statistically significant. USB men were 2 to 3 times more likely to have had a PSA exam compared to CBB men, but among CBB men birthplace did not make a significant difference in screening behavior. Latent variable SES, but not lifestyle, significantly affected the likelihood of a PSA exam.

No description available.

Estrogens maintain the appropriate androgen-estrogen balance for normal regulation of the structure and function of the male reproductive tract, including the prostate gland. This research investigated viability of cells and expression of selected genes in prostate carcinoma cells (PC-3) exposed to bisphenol A (BPA), an estrogen-like substance present in a number of plastic materials. PC-3 cells are able to metabolize BPA at concentrations below 100 µM. BPA exposure at concentrations between 1nM and 100 µM does not increase or significantly reduce cell viability of these cells. Although the genes investigated in this study (GSTP1 and MGMT) did not show a significant change in expression following in vitro exposure to BPA, the positive control ethinyl estradiol (EE2) caused an increase in GSTP1 expression at mRNA level. These results indicate that BPA does not affect the viability of prostate cells, and motivate a need for further research to identify other genes that could be affected by BPA.

The potential of using FTIR imaging as analytical technique combined with pre-processing and multivariate analysis methods was investigated. FTIR spectroscopy has been used in the past to investigate aspects of prostate cancer cells and tissues, successfully showing the separation of spectral data taken from benign prostate samples and cancerous prostate samples of varying Gleason grade. This work was ground-breaking, diagnosing different grades of cancer in the same way to the original histopathologist-assigned grades of the tissue. The advent of FTIR imaging and its recent commercial availability has allowed the much more specific collection of FTIR spectra in the form of infrared images corresponding to hyperspectral cubes of data. Optimised protocols for FTIR imaging were developed for the collection of such images from prostate cancer tissue samples, so that the highest quality data could be obtained as time efficiently as possible. With the recent development of a resonant Mie scattering correction algorithm, the pre-processing of data could be done rigorously, eliminating all physical effects from spectral data for the first time. Hierarchical cluster analysis and K-means cluster analysis were employed as image clustering methods to classify the tissue based on morphology. Imaging data that had RMieS-EMSC, vector normalisation and a second derivative applied showed the best cluster assignment as advised by an experienced histopathologist.A large scale study was devised based on the author’s previous work to try and classify metastatic from non-metastatic prostate cancer epithelium using FTIR images. A method for the isolation of epithelial spectra was devised by the immunohistochemical staining of the tissue sample after data collection to highlight the epithelium, and overlaying the optical image of the stained tissue with the FTIR image. Resulting epithelial spectra were extracted from the FTIR images of the two tissue classes. Principal component analysis was applied to the data, and artificial neural network were constructed using training and test sets of patient-associated spectra. Experiments were done investigating whether non-metastatic cancer epithelium classified differently to non-cancerous epithelium, and whether epithelial spectra from patients with metastatic cancer would classify differently to patients with non-metastatic cancer. The non-metastatic data did not separate well from the non-cancer data. PCA results showed the metastatic data separated from the non-metastatic data very well, and seemingly robust ANNs were also developed to classify the data.

No description available.

The purpose of this paper is to characterize the glucocorticoid receptor (GR) signaling and relevance in the context of enzalutamide resistant prostate cancer cells. Enzalutamide is a drug that functions to dampen androgen receptor (AR) signaling, thus inhibiting cancer dependency on the receptor protein. Although the application of the drug reduces AR signaling in these cancer cells, an alternate pathway involving GR signaling may be upregulated as a compensatory bypass mechanism. Therefore, it possible that GR assumes the role of AR and facilitates tumor growth by promoting the expression of genes regulated by AR. To analyze how GR operates, we analyzed GR signaling in enzalutamide resistant metastatic prostate cancer cell lines. We assessed protein levels of AR and GR as well as mRNA expression of various AR targets. Our results illustrate the expected downregulation of AR and upregulation of GR in enzalutamide resistant cells. Furthermore, some canonical AR targets like prostate specific antigen (PSA), Prostate Specific Membrane Antigen (PSMA) and Prostatic Acid Phosphatase (PAP) were inhibited by a novel GR inhibitor. Thus, this GR inhibitor could be used in combination with enzalutamide and create a more potent AR signaling blockade. Prostate cancer is a very problematic disease in men and becomes especially challenging to treat during the metastatic stage as they are non-sensitive to anti-androgens. The significance of understanding how GR functions, as well as the potential benefit of blocking GR signaling, may provide insight into novel drugs and agents that could specifically target these pathways, control and mitigate cancer growth, and prolong the lives of patients.

Prostate cancer (PCa) is one of the most common cancer in men and affecting hundreds of thousands of men worldwide. The early detection of PCa have been proven to be advantageous for more efficient treatment against PCa. However, the conventional screening methods towards PCa are lack of selectivity and sensitivity, which leading to high false positive rate and overdiagnosis of PCa. The objective of this study is to (1) identify more sensitive and accurate diagnostic biomarkers towards PCa; (2) followed by developing new chemosensor towards the newly found biomarkers. In the first part of this study, based on the previously findings on urinary spermine as useful biomarker for PCa, a more comprehensive study on urinary polyamine levels was carried out and the important role of urinary spermine as biomarker for PCa detection was consolidated. In the second part of this work, molecularly imprinted polymer (MIP) towards the target analyte of urinary spermine was prepared for the capturing and extraction of spermine. The specific adsorption and selectivity towards spermine of the MIP were discussed and reported. In the third part of this study, a rapid detection method of spermine was developed via the use of aggregation-induced emission (AIE) active molecules. The presence of spermine would cause aggregation of this chemosensor for a "turn-on" detection of spermine under ultra-violet (UV) excitation, which would be useful in PCa diagnosis in the future.