Com o aumento da expectativa de vida no Brasil e a possibilidade de detecção precoce através de programas de rastreamento, o câncer de próstata, tem sido considerado um problema de saúde pública. Em um programa de rastreamento voluntário realizado no Hospital de Clínicas de Porto Alegre entre os anos de 1996 e 2000, 3.056 pacientes foram submetidos a um estudo transversal com o objetivo de determinar a prevalência e características do câncer de próstata na amostra. Para a análise estatística foi utilizado o teste qui-quadrado com nível de significância de p < 0,05.A idade média da amostra foi de 60,4 anos e a prevalência do câncer de próstata foi de 2,61%, sendo crescente com o aumento da idade. A sensibilidade e especificidade do PSA foram, respectivamente, 93,8% (IC = 85,4% a 97,7%) e 82,5% (IC = 81,1% a 83,8%), utilizando como ponto de corte do PSA o valor de 4ng/ml. O toque retal apresentou sensibilidade de 60% (IC = 48,4% a 70,6%) e especificidade 83,3% (IC = 81,9% a 84,6%). O número de biópsias realizadas para se diagnosticar um paciente com câncer de próstata foi de 11,9 e variou conforme a faixa etária. No estadiamento clínico, 51,3% dos pacientes eram T1C e 83,75% dos tumores estavam clinicamente confinados ao órgão. Enquanto estudos prospectivos e randomizados que tenham como desfecho a mortalidade não definirem o real papel do diagnóstico precoce do câncer depróstata, os programas de rastreamento devem ser realizados. Este estudo vem ao encontro da necessidade de conhecer a distribuição e as características da doença nas diversas regiões do país. / With the increase in life expectancy in Brazil and the possibility of early detection through screening programs, prostate cancer is being considered a public health problem. In a voluntary screening program performed in Hospital de Clínicas de Porto Alegre between the years of 1996 and 2000, 3,056 patients participated in a cross sectional study with the objective of determining the prevalence and features of prostate cancer in the sample. For statistical analysis, qui square test was performed considering a significance level of p < 0.05. The mean age of the sample was 60.4 years, and the prevalence of prostate cancer was 2.61%, increasing with age. The sensitivity and specificity of PSA were, respectively, 93.8% (CI = 85.4% to 97.7%) and 82.5% (CI = 81.1% to 83.8%) considering 4 ng/ml as the cut-off point for PSA. Rectal examination had a sensitivity of 60% (CI = 48.4% to 70.6%) and a specificity of 83.3% (CI = 81.9% to 84.6%). The amount of biopsies performed for diagnosing a patient with prostate cancer was 11.9 and varied according to age. In clinical staging, 51.3% of patients were T1C and 83.75% of tumors were clinically confined to the organ. While prospective and randomized trials with mortality as the endpoint do not define the real role of early diagnosis in prostate cancer, screening programs should be performed. This study meets the need for knowing the distribution and characteristics of the disease in the different regions of the country.

Made available in DSpace on 2014-06-11T19:23:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-02-28Bitstream added on 2014-06-13T20:29:32Z : No. of bitstreams: 1 brandt_jz_me_botib.pdf: 1613115 bytes, checksum: 288debdd54eae1f42b00457d3bf95f1e (MD5) / 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... / 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)

Introduction : Rapporter le développement et les expérimentations d'un nouveau système robotisé destiné à la curiethérapie prostatique possédant un système de suivi de la prostate et une possibilité de fusion écho-IRM. Matériel et méthodes : Un robot d'implantation d'aiguilles transpérinéales guidé par échographie transrectale avec suivi peropératoire des mouvements et de la déformation de la prostate a été crée. Les expériences ont été conduites sur 90 cibles réalisées dans 9 fantômes conçus pour être mobiles et déformables. Les expériences ont été ensuite conduites chez 2 cadavres. Le robot a cherché à déposer des billes de verre simulant des grains de curiethérapie aussi près que possible des cibles dans des fantômes évaluables par différentes modalités d'imagerie dont le scanner et dans des prostates de cadavre. Les résultats étaient mesurés en segmentant les cibles et les billes de verre sur des volumes tomodensitométriques des fantômes et des cadavres. Résultats : Le robot était capable d'atteindre les cibles choisies dans les fantômes avec une précision médiane de 2.73 mm, avec un déplacement médian de la prostate de 5.46 mm. La précision était meilleure à la base qu'à l'apex (2.28 mm vs 3.83 mm, p<0.01) et n'était pas significativement différente pour les implantations horizontales et obliques (2.7 vs 2.82 mm, p=0.18). Les tests sur cadavre ont montré la faisabilité et l'ergonomie du robot en salle d'opération mais des expérimentations plus poussées sont nécessaires. Conclusion : Ce robot destiné à la curiethérapie prostatique est le premier système utilisant le suivi de la prostate intra-opératoire pour guider des aiguilles dans la prostate. Les expériences préliminaires montrent sa capacité à atteindre des cibles malgré les mouvements de la prostate. Les applications pourraient être élargies à la thérapie focale et aux biopsies guidées compte-tenu de sa possibilité à fusionner l'imagerie IRM et l'échographie. / Purpose: To report on the development and the initial experience with a new 3D ultrasound robotic system for prostate brachytherapy assistance and focal therapy. MRI-TRUS fusion as well as its ability to track prostate motion intra-operatively allows it to manage motions and guide needles to MRI enhanced tumor foci. Materials and methods: A robotic system for TRUS-guided needle implantation combined with intraoperative prostate tracking was created. Experiments were conducted on 90 targets embedded in 9 mobile and deformable synthetic prostate phantoms. A preliminary feasibility study on 2 cadavers was also carried out. The experiments involved trying to insert glass beads as close as possible to targets in multimodal imaging phantoms and in cadaver prostates. The results were measured by segmenting the inserted beads in CT scan volumes of the phantoms and of the cadaver's radical prostatectomy specimens. Results: The robot was able to reach the chosen targets in phantoms with a median accuracy of 2.73 mm, with a median prostate motion of 5.46 mm. Accuracy was better in apex than in base (2.28 vs 3.83 mm, p<0.001) and was similar for horizontal and angled needle inclinations (2.7 vs 2.82 mm, p=0.18). Cadaver tests showed the feasibility of the robot's ergonomics in the operating room but further in vivo assessments are needed. Conclusion: This robot for prostate focal therapy and brachytherapy is the first system using intraoperative prostate motion tracking to guide needles into the prostate. The preliminary experiments described show its ability to reach targets in spite of the motion of the prostate.

Objetivo: Analisar a casuística de prostatovesiculectomias radicais com linfadenectomia ilíaca avaliando a validade das Tabelas de Partin versão 2001. Estudar variáveis que possam interferir no confinamento ou não da neoplasia como retardo cirúrgico, peso prostático, resultados referentes à biópsia e ano da cirurgia. Material e Métodos: Avaliação retrospectiva de 568 prontuários de pacientes submetidos à cirurgia para câncer de próstata clinicamente localizado entre 1995 até agosto de 2005 no Hospital de Clínicas de Porto Alegre. Foram excluidos quem tivesse feito hormonioterapia neoadjuvante ou com diagnóstico feito por ressecção endoscópica da próstata e aqueles com insuficiência dos dados no prontuário. Estágio clínico pelo toque retal , valores de PSA e dados da biópsia que diagnosticou a neoplasia, assim como dos dados da peça da prostatectomia radical foram coletados. Os valores preditivos das Tabelas de Partin, versão 2001 foram comparados com os do espécime cirúrgico e analisados através de Curvas R.OC. Foram também avaliados tempo de espera para cirurgia, peso da próstata, ano da cirurgia, uni ou bilateralidade tumoral na biópsia e qual a biópsia que diagnosticou (primeira ou ulterior) e analisados como fatores preditivos para confinamento ou não da neoplasia. Resultados: A idade média do pacientes foi 63 (42-77). A percentagem de estágio T1c foi de 63 %. Pacientes com escore de Gleason 2-4 na biópsia constituiram 20,2 %, notadamente antes de 2000. O percentual de pacientes com níveis de PSA menores de 4,0 ng/ml foi de 8,3 % e acima de 10,0 ng/ml foi de 35 %. Os percentuais de doença confinada ao órgão, extensão extra-prostática, invasão de vesículas seminais e metástases linfonodais foram 48,2 %, 35,3%, 13,9% e 2,6% , respectivamente. A área sob a curva calculada para doença confinada ao órgão foi de 0,65 , enquanto as áreas sob as curvas para extensão extra-prostática, invasão de vesículas seminais e metástases linfonodais foi respectivamente 0,54; 063 e 0,77. Pacientes que tiveram o diagnóstico já na primeira biópsia, ou com biópsias bilateralmente comprometidas e aqueles operados antes de 2000 tinham tendência ao não confinamento. Biópsias realizadas a partir de 2000 que já foram positivas na primeira tentativa tiveram maior tendência ao confinamento do que até 1999. Conclusão: As Tabelas de Partin tiveram valor preditivo marginal para as características patológicas finais como doença confinada ao órgão e invasão de vesículas seminais e valor preditivo importante para metástases linfonodais. Não mostraram valor preditivo para extensão extra-prostática. Bilateralidade tumoral na biópsia, diagnóstico na primeira biópsia (especialmente até 1999) e cirurgia antes de 2000 configuraram situações com tendência a tumores não confinados. / Objective: The predictive value of current Partin tables (2001) has been not validated in most of the countries as well Brazil. Therefore, we evaluated the validity of 2001 Partin tables for the ability to predict the pathological stage in specimens of radical prostatectomy. Also, we analysed how biopsies can predict results for organ confinement or not and as well what the year of the surgery can make in organ confinement issue . Materials and methods: The clinical and pathological findings of 568 patients who have had radical prostatectomy and iliac lymphadenectomy from 1995 to 2005 at Hospital de Clínicas de Porto Alegre were assessed. Those with missing information, patients who had neoadjuvant endocrine treatment and those who had the diagnosis by transurethral ressection of prostate were excluded. Serum PSA, clinical stage, biopsy characteristics and the pathological features of the specimens were collected. The predictive value of Partin tables and pathological findings of prostatectomy specimens were compared and analyzed according to Receiver Operating Characteristics curves. The delay of the surgery, prostate weight, year of the surgery, bilaterality of the biopsies and if the diagnostic biopsy was the first or not were important for the organ confined disease were also tested. Results: Median age of the patients was 63(42-77). The percentage of patients with clinical stage T1c was 63%. Gleason score 2-4 in biopsy constituted 20,2 %, at mainly before 2000. The ratio of patients with serum PSA above 4,0 ng/ml was 8,3% and higher than 10,0 ng/ml was 35%.Organ confined disease, extra-prostatic extension, seminal vesicle involvement and lymph node metastasis were 48,2%; 35,3%; 13,9 % and 2,6% respectively. Area under curve (AUC) values for organ confined disease, extra-prostatic extension, seminal vesicle invasion and lymph node involvement were 0,65 ; 0,54; 0,63 and 0,77. Tumor bilaterallity at biopsy and positive biopsy at the first procedure (at least until 1999) as well radical prostatectomy before 2000 were predictors for non organ confined prostate cancer. Conclusion: Partin tables have a marginally predictive value for the pathological features like organ confined disease and seminal vesicle involvement and a good predictive value for lymph node metastasis prediction. They don’t have predictive value for extra-prostatic extension. Positive first biopsy, bilateral tumor at biopsy and radical prostatectomy before 2000 were predictive for non organ confined disease.

Com o aumento da expectativa de vida no Brasil e a possibilidade de detecção precoce através de programas de rastreamento, o câncer de próstata, tem sido considerado um problema de saúde pública. Em um programa de rastreamento voluntário realizado no Hospital de Clínicas de Porto Alegre entre os anos de 1996 e 2000, 3.056 pacientes foram submetidos a um estudo transversal com o objetivo de determinar a prevalência e características do câncer de próstata na amostra. Para a análise estatística foi utilizado o teste qui-quadrado com nível de significância de p < 0,05.A idade média da amostra foi de 60,4 anos e a prevalência do câncer de próstata foi de 2,61%, sendo crescente com o aumento da idade. A sensibilidade e especificidade do PSA foram, respectivamente, 93,8% (IC = 85,4% a 97,7%) e 82,5% (IC = 81,1% a 83,8%), utilizando como ponto de corte do PSA o valor de 4ng/ml. O toque retal apresentou sensibilidade de 60% (IC = 48,4% a 70,6%) e especificidade 83,3% (IC = 81,9% a 84,6%). O número de biópsias realizadas para se diagnosticar um paciente com câncer de próstata foi de 11,9 e variou conforme a faixa etária. No estadiamento clínico, 51,3% dos pacientes eram T1C e 83,75% dos tumores estavam clinicamente confinados ao órgão. Enquanto estudos prospectivos e randomizados que tenham como desfecho a mortalidade não definirem o real papel do diagnóstico precoce do câncer depróstata, os programas de rastreamento devem ser realizados. Este estudo vem ao encontro da necessidade de conhecer a distribuição e as características da doença nas diversas regiões do país. / With the increase in life expectancy in Brazil and the possibility of early detection through screening programs, prostate cancer is being considered a public health problem. In a voluntary screening program performed in Hospital de Clínicas de Porto Alegre between the years of 1996 and 2000, 3,056 patients participated in a cross sectional study with the objective of determining the prevalence and features of prostate cancer in the sample. For statistical analysis, qui square test was performed considering a significance level of p < 0.05. The mean age of the sample was 60.4 years, and the prevalence of prostate cancer was 2.61%, increasing with age. The sensitivity and specificity of PSA were, respectively, 93.8% (CI = 85.4% to 97.7%) and 82.5% (CI = 81.1% to 83.8%) considering 4 ng/ml as the cut-off point for PSA. Rectal examination had a sensitivity of 60% (CI = 48.4% to 70.6%) and a specificity of 83.3% (CI = 81.9% to 84.6%). The amount of biopsies performed for diagnosing a patient with prostate cancer was 11.9 and varied according to age. In clinical staging, 51.3% of patients were T1C and 83.75% of tumors were clinically confined to the organ. While prospective and randomized trials with mortality as the endpoint do not define the real role of early diagnosis in prostate cancer, screening programs should be performed. This study meets the need for knowing the distribution and characteristics of the disease in the different regions of the country.

Orientador: Sara Teresinha Olalla Saad / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-16T20:55:53Z (GMT). No. of bitstreams: 1 Lazarini_Mariana_D.pdf: 4089908 bytes, checksum: bf5ee8f74ac7dfe4c18c3e84bdeeecff (MD5) Previous issue date: 2010 / Resumo: Importante passo para a compreensão dos processos fisiopatológicos das neoplasias é a identificação de genes diferencialmente expressos e das funções biológicas de cada proteína codificada por estes genes. Rho GTPase activating protein 21 (ARHGAP21) é uma proteína pertencente à família RhoGAP, que interage com ARF-GTPases e com alfa-catenina, modulando a dinâmica da actina associada às membranas do Golgi e à integridade das junções aderentes. O objetivo geral do presente estudo foi investigar as funções da proteína ARHGAP21 em células endoteliais e de adenocarcinoma de próstata com relação à viabilidade celular, ciclo celular, migração, adesão e expressão gênica. Neste trabalho foi demonstrado que ARHGAP21 possui atividade RhoGAP para RhoA e RhoC. Em células HUVECs (Human Umbilical Vein Endothelial Cells), foi observada uma localização nuclear e citoplasmática de ARHGAP21 e sua depleção induziu alterações no ciclo celular. Além disso, ensaios de microarranjos de DNA em HUVECs demonstraram modulação de genes como PAI-1, BNIP3, staniocalcina 1 e podocalyxin. Em linhagens celulares de adenocarcinoma de próstata (LNCaP e PC-3), também foi observada uma localização nuclear e citoplasmática de ARHGAP21. A diminuição da expressão desta proteína em células PC-3 resultou em redução da viabilidade e da migração celular em fibronectina. Com relação à viabilidade celular, a inibição de ARHGAP21 tem efeito adicional ao agente quimioterápico cisplatina. Em células LNCaP, por sua vez, foi observada uma menor adesão em matrigel e fibronectina das células submetidas à inibição da expressão de ARHGAP21, em comparação às células controle. Experimentos de microarranjos de DNA e RT-PCR quantitativo em tempo real em células de adenocarcinoma de próstata submetidas à inibição de ARHGAP21 demonstraram expressão alterada dos genes TGF-beta induced e dos genes BNIP3, staniocalcina 1 e podocalyxin, que também foram modulados nas células HUVECs com inibição da expressão de ARHGAP21. Em conclusão, o presente estudo identificou ARHGAP21 como uma proteína com importantes funções em células endoteliais e de adenocarcinoma de próstata, através da regulação da viabilidade, adesão e migração celular. Os achados aqui descritos sugerem que ARHGAP21 pode ser uma molécula alvo para a terapia de neoplasias, provavelmente através da sua função como reguladora da atividade de RhoA e RhoC / Abstract: One step in the path towards building a comprehensive molecular portrait of human cancer is the definition of differentially expressed genes and the function of their coding proteins. Rho GTPase activating protein 21 (ARHGAP21) is a RhoGAP protein, which interacts with ARF-GTPases and alpha-catenin, controlling actin dynamics on Golgi membranes and the integrity of adherens junctions, respectively. The aim of the present study was to investigate ARHGAP21 functions on endothelial and prostate cancer cells regarding to cell viability, cell cycle, migration, adhesion and gene expression. This study demonstrated that ARHGAP21 has RhoGAP activity for RhoA and RhoC. ARHGAP21 localized in the nucleus and cytoplasm of HUVECs (Human Umbilical Vein Endothelial Cells) and its depletion alteres the cell cycle phases. Furthermore, microarrays assays in HUVECs ARHGAP21 knockdown demonstrated modulation of genes such as PAI-1, BNIP3, stanniocalcin 1 and podocalyxin. In the prostate adenocarcinoma cell lines (LNCaP and PC-3), ARHGAP21 is also located in the nucleus and cytoplasm. Depletion of this protein in PC-3 cells resulted in decrease of cell viability and migration in fibronectin. Regarding to cell viability, inhibition of ARHGAP21 has an additional effect on cisplatin chemotherapeutic agent. In LNCaP cells, a lower adhesion was observed in matrigel and fibronectin of cells subjected to inhibition of ARHGAP21 expression compared to control cells. DNA microarray and quantitative RT-PCR experiments on prostate adenocarcinoma cells ARHGAP21 knockdown showed modulation of TGF-beta induced gene expression. The expression of BNIP3, stanniocalcin 1 and podocalyxin was also altered in HUVECs cells ARHGAP21 knockdown. In conclusion, this study identified ARHGAP21 as a protein with important functions in endothelial cells and prostate adenocarcinoma, by regulating cell viability, adhesion and migration. The findings described here suggest that ARHGAP21 may be a molecule target for cancer therapy, probably due to its GAP activity for RhoA and RhoC / Doutorado / Doutor em Fisiopatologia Medica

Orientadores: Akebo Yamakami, Laecio Carvalho de Barros, Laercio Luis Vendite / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação / Made available in DSpace on 2018-08-04T04:11:06Z (GMT). No. of bitstreams: 1 Castanho_MariaJosedePaula_D.pdf: 5605275 bytes, checksum: 589180e36f1eeebf2b8fa1ced3a0a4db (MD5) Previous issue date: 2005 / Resumo: O câncer de próstata é, atualmente, o segundo tipo de câncer com maior incidência entre a população masculina, no Brasil. Estimar o seu estágio, com as informações clínicas disponíveis para decidir a terapia a ser aplicada, é uma tarefa árdua. Neste trabalho, um modelo matemático é elaborado para auxiliar o médico na tomada de decisão. A teoria dos conjuntosfuzzy, por sua capacidade em lidar com incertezas, inerentes aos conceitos médicos, é a ferramenta utilizada, não só para desenvolver o modelo, como também para desenvolver a metodologia para sua avaliação, baseada na análise ROC (Receiver Operating Characteristic). A avaliação foi feita utilizando-se dados obtidos junto ao Instituto Americano do Câncer e permite afinnar que o sistema especialista construí do discrimina pacientes com câncer confinado à próstata daqueles com câncer não-confinado. Considerando a taxa de crescimento como um parâmetro incerto e variável na população, também é apresentado um modelo para descrever o crescimento do tumor / Abstract: Nowadays, prostate cancer is the second most common man cancer diagnosed in Brazil. Predicting the cancer stage from available clinical information to decide the therapy to be used is hard work. ln this study a mathematical model is developed to assist the physician in this task. The fuzzy sets theory provides effective tools to handle and manipulate imprecise data and to make decisions based on such data. As imprecision is a characteristic of medical concepts, this theory is utilized not oniy to develop the model as to develop the methodology for its evaluation, based on ROC (Receiver Operating Characteristic) analysis. To evaluate its performance, data from the American Cancer lnstitute were used. The results indicate that the model is able to discriminate patients with organ-confined disease from those with non-confined cancer. In addition, considering the growth rate as an uncertain, changeable parameter in the population, a model to describe the tumor growth is suggested. / Doutorado / Automação / Doutor em Engenharia Elétrica

As the most frequently diagnosed cancer in North American men, prostate cancer can progress to the androgen independent stage after initial response to androgen ablation therapy. The molecular mechanisms involved in the hormonal progression of prostate cancer are not completely understood. Here, we analyze changes in the transcriptome of prostate cancer cells at different stages of progression to reveal potential mechanisms. Applying Affymetrix GeneChip technology, we identified the transcriptomes in response to stimulation of androgen and PKA pathways in human prostate cancer cells. In addition to PSA, other common target genes were identified. Genes differentially expressed in response to androgen and stimulation of the PKA pathway in vitro were also differentially expressed during hormonal progression in vivo. Upon androgen stimulation, androgen receptor binds to a functional androgen response element within the promoter region of SESN1, a p53 targeted gene, and represses its expression. The expression of SESN1 was induced by castration in LNCaP xenografts, but the expression was eventually suppressed again in the androgen independent stage of prostate cancer. Knockdown of SESN1 promoted the proliferation of prostate cancer cells. Expression patterns of androgen-regulated genes in androgen independent tumours were revealed to be more similar to that from before castration than to the tumors under androgen ablation. The β-catenin, a potent coactivator of the androgen receptor, and Wnt pathway was deregulated in androgen-independent tumours. There was increased nuclear colocalization and interaction of androgen receptor and β-catenin with hormonal progression of prostate cancer. This study provides insight into hormonal effects on prostate cancer and possible pathways involved in the development of androgen independent disease, as well as potential therapeutic targets. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

The mechanism by which prostate cancer progresses from androgen dependence (AD) to androgen independence/castration resistance (AI/CR) is currently a major focus of prostate cancer-related research. Prostate cancers that progress to a state of AI/CR are typically resistant to most standard types of treatments. Due to its primary role in driving normal prostate cell growth and proliferation, the androgen receptor (AR) is believed to play a key role in progression. Coregulators, or any proteins which may either enhance or abrogate AR activity, are considered to be one of the potential mechanisms by which AR function may become impaired. Cyclin G-associated kinase (GAK) was initially identified as a potential coregulator of AR in a Tup 1 repressed transactivation system. A LNCaP cDNA library was screened for proteins which interacted with the NH2-terminus of AR. GAK was isolated from three independent library clones using two different AR baits (AR 1-549 and AR 1-646). This interaction was confirmed via GST pulldown and coimmunoprecipitation experiments, and preliminary luciferase assays suggested that GAK activates AR in a hormone dependent manner. In this study, my objectives were to validate GAK’s role as a coregulator of AR and to determine if overexpressing GAK affects progression to AI. In vitro luciferase assays whereby GAK was either overexpressed or knocked down in both LNCaP and PC3 cells did not significantly affect AR activity. Xenograft experiments utilizing a doxycycline (DOX) inducible lentiviral LNCaP-GAK overexpressing stable cell line demonstrated that while GAK may not play a significant role in modulating AR activity, it may adopt a more subtle role enhancing tumour take and tumour volume growth rate in vivo. While these results could not confirm GAK to be a direct coregulator of AR, it is entirely possible that GAK may influence prostate cancer progression, albeit indirectly. Recent publications report a growing amount of evidence suggesting GAK’s involvement in the critical cellular process of clathrin coated vesicle endocytosis, the dysregulation of which could potentially indirectly affect AR regulated genes. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Le cancer de la prostate est le cancer le plus fréquent chez les hommes dans la plupart des pays développés. C'est le cancer le plus fréquent chez les hommes en France (73.609 cas en 2014) et en Colombie (9564 cas en 2014). En outre, c'est la troisième cause de décès par cancer chez les hommes dans les deux pays (9,3 % en France et 7,1 % en Colombie en 2014). L'une des techniques de traitement est la radiothérapie externe, qui consiste à délivrer un rayonnement ionisant à une cible clinique, à savoir la prostate et les vésicules séminales. En raison des variations anatomiques au cours du traitement, qui consiste en environ 40 fractions de rayonnement délivrant une dose totale allant de 70 à 80Gy, des marges de sécurité sont définies autour de la cible tumorale lors de la planification du traitement. Ceci entraîne des portions d'organes sains voisins de la prostate - la vessie et le rectum - à être inclus dans le volume cible, pouvant conduire à des événements indésirables affectant les fonctions urinaires (hématurie et cystite, entre autres) ou rectale (saignement rectal, incontinence fécale, Etc.). La vessie présente les plus grandes variations de forme entre fractions de traitement, provoquées par des changements continus de volume. Ces variations de forme introduisent des incertitudes géométriques qui rendent difficile l'évaluation de la dose réellement délivrée à la vessie pendant le traitement. Ces incertitudes limitent la possibilité de modéliser une relation dose-volume pour la toxicité génito-urinaire tardive (GU). Le projet QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) a déclaré que la relation dose-réponse pour la toxicité gastro-intestinale tardive (GI) était loin d'être établie. Les variables dosimétriques obtenues à partir de la tomodensitométrie de planification peuvent être faiblement représentative de la dose effectivement administrée. En conséquence, il est crucial de quantifier les incertitudes produites par les variations inter-fraction de la vessie afin de déterminer les facteurs dosimétriques qui affectent les complications GU tardives. Le but de cette thèse était donc de caractériser et de prédire les incertitudes produites par les variations géométriques de la vessie entre les fractions de traitement, en utilisant uniquement la tomodensitométrie de planification comme information d'entrée. En pratique clinique, une seule tomodensitométrie est disponible au moment de la planification du traitement pour un patient typique, alors que des images supplémentaires peuvent être acquises en cours de traitement. Dans cette thèse une approche population a été utilisée pour obtenir suffisamment de données pour apprendre les directions les plus importantes du mouvement et de la déformation de la vessie en utilisant l'analyse en composante principales (ACP). Comme dans les travaux de référence, ces directions ont ensuite été utilisées pour développer des modèles basés population pour prédire et quantifier les incertitudes géométriques de la vessie. Cependant, nous avons utilisé une analyse longitudinale afin de caractériser correctement la variance du patient et les modes spécifiques du patient à partir de la population. Nous avons proposé d'utiliser un modèle à effets mixtes (ME) et une ACP hiérarchique pour séparer la variabilité intra et inter-patients afin de contrôler les effets de cohorte confondus. Finalement, nous avons présenté des modèles sur l'APC comme un outil pour quantifier des incertitudes de la dose produit par le mouvement et déformation de la vessie entre fractions. / Prostate cancer is the most common cancer amongst the male population in most developed countries. It is the most common cancer amongst the male population in France (73.609 cases in 2014) and in Colombia (9564 cases in 2014). It is also the third most common cause of cancer deaths in males in both countries (9.3% and 7.1% in France and in Colombia in 2014, respectively). One of the standard treatment methods is external radiotherapy, which involves delivering ionizing radiation to a clinical target, namely the prostate and seminal vesicles. Due to the uncertain location of organs during treatment, which involves around forty (40) radiation fractions delivering a total dose ranging from 70 to 80Gy, safety margins are defined around the tumor target upon treatment planning. This leads to portions of healthy organs neighboring the prostate or organs at risk — the bladder and rectum — to be included in the target volume, potentially resulting in adverse events affecting patients’ urinary (hematuria and cystitis, among others) or rectal (rectal bleeding, fecal incontinence, etc.) functions. The bladder is notorious for presenting the largest inter-fraction shape variations during treatment, caused by continuous changes in volume. These variations in shape introduce geometric uncertainties that render assessment of the actual dose delivered to the bladder during treatment difficult, thereby leading to dose uncertainties that limit the possibility of modeling dose-volume response for late genitourinary (GU) toxicity. The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) project has stated that a similar dose-response to that of late gastrointestinal (GI) toxicity is far from being established. The dosimetric variables obtained from the planning CT prove to be very poor surrogates for the real delivered dose. As a result, it appears crucial to quantify uncertainties produced by inter-fraction bladder variations in order to determine dosimetric factors that affect late GU complications. The aim of this thesis was thus to characterize and predict uncertainties produced by geometric variations of the bladder between fractions, using solely the planning CT as input information. In clinical practice, a single CT scan is only available for a typical patient during the treatment planning while on-treatment CTs/CBCTs are seldom available. In this thesis, we thereby used a population approach to obtain enough data to learn the most important directions of bladder motion and deformation using principal components analysis (PCA). As in groundwork, these directions were then used to develop population-based models in order to predict and quantify geometrical uncertainties of the bladder. However, we use a longitudinal analysis in order to properly characterize both patient-specific variance and modes from the population. We proposed to use mixed-effects (ME) models and hierarchical PCA to separate intra and inter-patient variability to control confounding cohort effects. . Subsequently, we presented PCA models as a tool to quantify dose uncertainties produced by bladder motion and deformation between fractions.