A partir de um melhor entendimento sobre a radiossensibilidade do câncer de próstata, com a redefinição de parâmetros radiobiológicos, atualmente os esquemas hipofracionados de próstata tornaram-se um dos principais desafios da radioterapia moderna. Associado a este conhecimento, o emprego de técnicas precisas de radioterapia possibilitaram a entrega de maiores doses por fração, com manutenção da toxicidade e melhor controle de qualidade dos planos de tratamento. Pretendemos avaliar a implementação da radioterapia tridimensional computadorizada (3D-CRT) ou intensidade modulada do feixe (IMRT) utilizando o regime de hipofracionamento moderado (70 Gy em 28 frações) em pacientes com neoplasia localizada da próstata na rotina do departamento de radioterapia do Hospital das Clínicas da FMRP-USP. Avaliação da viabilidade técnica e do impacto financeiro na utilização da radioterapia hipofracionada na instituição. / Evaluate the implementation of computerized three-dimensional radiation therapy (3D-CRT) or intensity modulated beam (IMRT) using moderate hypofractionation schedule (70 Gy in 28 fractions) in patients with localized prostate cancer (no metastasis lymph node or distant metastasis) in routine of department of radiotherapy of the Hospital of FMRP-USP. Assessment of technical feasibility and financial impact on the use of hypofractionated radiotherapy in the institution.

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Cheung Chun Pan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 192-227). / Abstracts in English and Chinese. / Acknowledgements --- p.I / Abstract (English) --- p.II / Abstract (Chinese) --- p.VI / Contents --- p.VIII / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Nuclear hormone receptor: a general review --- p.1 / Chapter 1.1.1 --- Classification of nuclear hormone receptors --- p.1 / Chapter 1.1.2 --- Mechanism of action --- p.2 / Chapter 1.1.3 --- Domains structure and functions --- p.3 / Chapter 1.1.4 --- Orphan nuclear receptors --- p.4 / Chapter 1.2 --- Prostate gland - a male accessory reproductive organ --- p.6 / Chapter 1.2.1 --- "Anatomy, histology and physiology of the prostate gland" --- p.6 / Chapter 1.2.2 --- Endocrinology of the prostate gland --- p.8 / Chapter 1.2.3 --- Pathogenesis of the prostate gland --- p.8 / Chapter 1.3 --- The role of estrogen receptors in the prostate gland and prostate cancer --- p.9 / Chapter 1.3.1 --- Estrogens in male --- p.10 / Chapter 1.3.2 --- Effects of estrogens in the prostate gland --- p.11 / Chapter 1.3.3 --- Estrogen receptors - two isoforms --- p.13 / Chapter 1.3.4 --- Expression of ERs in the prostate gland --- p.14 / Chapter 1.3.5 --- Estrogen-modulated transgenic mice 226}0ؤ functional studies of ERs --- p.16 / Chapter 1.4 --- Estrogen receptor-related receptors: orphan receptors --- p.18 / Chapter 1.4.1 --- Estrogen receptor-related receptors: Three isoforms --- p.18 / Chapter 1.4.2 --- Expression of ERRs in different tissues --- p.20 / Chapter 1.4.3 --- Promoter binding and genes regulated by of ERRs --- p.22 / Chapter 1.4.4 --- Coregulators of ERRs --- p.24 / Chapter 1.4.5 --- Ligand of ERRs --- p.25 / Chapter 1.4.6 --- Functional roles of ERRs --- p.29 / Chapter 1.4.7 --- Cross talk between ERRs and ERs --- p.31 / Table 11 --- p.33 / Figure 1.1 - 15 --- p.35 / Chapter Chapter 2 --- Aims of the Study --- p.40 / Chapter Chapter 3 --- Methods and Materials / Chapter 3.1 --- "Expression patterns of ERRs and steroid hormone receptors in the human prostate cell lines, tumor xenografts and prostatic tissues" --- p.41 / Chapter 3.1.1 --- Human prostatic tissues --- p.41 / Chapter 3.1.2 --- Cell cultures --- p.41 / Chapter 3.1.3 --- Human prostate cancer xenografts --- p.42 / Chapter 3.1.4 --- Full length clones of ERR isoforms --- p.42 / Chapter 3.1.5 --- Reverse transcription-polymerase chain reactions (RT-PCR) --- p.43 / Chapter 3.1.6 --- Semi-quantitative RT-PCR analysis --- p.45 / Chapter 3.1.7 --- Southern blot analysis --- p.46 / Chapter 3.1.8 --- Generation and characterization of polyclonal antibodies --- p.49 / Chapter 3.1.9 --- Western blot analysis --- p.55 / Chapter 3.1.10 --- Immunohistochemistry --- p.56 / Chapter 3.2 --- Relationship of ERR and ER expressions in the prostatic cells --- p.57 / Chapter 3.2.1 --- "Expression vectors of ERRa, ERRγ and ERa" --- p.57 / Chapter 3.2.2 --- "Transient transfection of ERRa, ERRγ and ERa expression vectors in PC-3 cells" --- p.58 / Chapter 3.2.3 --- Semi-quantitative RT-PCR analysis --- p.59 / Chapter 3.3 --- Intracellular trafficking and transcriptional activity of GFP-tagged ERRs in the prostatic cells --- p.59 / Chapter 3.3.1 --- Construction of GFP-tagged ERR fusion plasmids --- p.59 / Chapter 3.3.2 --- Examination of transcriptional activity of GFP-tagged ERRs by luciferase assay --- p.61 / Chapter 3.3.3 --- Subcellular localization of GFP-tagged ERRs in the living prostatic cells --- p.63 / Chapter 3.3.4 --- Immunofluorescent staining GFP-tagged ERRs --- p.63 / Chapter 3.4 --- The Role of ERRs in the growth of the prostatic cells --- p.64 / Chapter 3.4.1 --- Evaluation the transfection efficiencies of PC-3 and PNT2 cells --- p.64 / Chapter 3.4.2 --- Cells proliferation assays in ERRs transient transfected prostatic cells --- p.66 / Chapter 3.4.3 --- Flow cytometry of ERRs transient transfected PC-3 cells --- p.66 / Chapter 3.4.4 --- RT-PCR of cell cycle-related genes in ERRs transient transfected PC-3 cells --- p.67 / Chapter 3.4.5 --- Generation of PNT2 and DU145 cells stably transfected with ERRy --- p.68 / Chapter 3.4.6 --- Cell proliferation assay of ERRy stable-transfected PNT2 and DU 145cells --- p.72 / Chapter 3. 4.7 --- Anchorage independent growth assay of ERRy stable-transfected PNT2 and DU 145 cells --- p.72 / Chapter 3.4.8 --- Flow cytometry of ERRγ stable-transfected PNT2 and DU145 cells --- p.74 / Chapter 3.4.9 --- RT-PCR of cell cycle-related genes in ERRγ stable-transfected PNT2 and DU 145 cells --- p.74 / Chapter 3.4.10 --- Western blot analysis of p21 in ERRγ stable-transfected PNT2 cells --- p.75 / Chapter 3.5 --- Statistical analysis --- p.75 / Table 3.1 - 3.2，Figure 3.1 - 35 --- p.76 / Chapter Chapter 4 --- Results / Chapter 4.1 --- "Expression patterns of ERRs and steroid hormone receptors in the human prostate cell lines, tumor xenografts and prostatic tissues" --- p.93 / Chapter 4.1.1 --- "mRNA expression patterns of ERR isoforms in the prostatic cell lines, prostate cancer xenografts and human prostatic tissues" --- p.93 / Chapter 4.1.2 --- mRNA expression patterns of steroid hormone receptors and prostatic differentiation markers in the prostatic cell lines and xenografts --- p.95 / Chapter 4.1.3 --- Characterization of antisera against human ERRs by ERR recombinant proteins --- p.97 / Chapter 4.1.4 --- Protein expression of ERR isoforms in the human prostatic cell lines --- p.98 / Chapter 4.1.5 --- "Immunolocalization of ERR isoforms in the normal, dysplastic and neoplastic prostates" --- p.98 / Chapter 4.2 --- Interrelationship of ERR and ER expression in PC-3 prostate cancer cells --- p.100 / Chapter 4.2.1 --- "Expressions of ERRγ, ERa and ERβ in the ERRa transient transfected PC-3 cells" --- p.100 / Chapter 4.2.2 --- Expression of ERRa in the ERRγ and ERa transient transfected PC-3 cells --- p.101 / Chapter 4.3 --- Intracellular trafficking and transcriptional activities of ERRs in the prostatic cells with fused green fluorescence protein 一 ERRs --- p.102 / Chapter 4.3.1 --- Trans activation of ERE response element 226}0ؤ driven reporter by ERR isoforms in the PC-3 cells in the presence or absence of serum --- p.102 / Chapter 4.3.2 --- Trans activation of SF-1 response element driven reporter by ERR isoforms in the PC-3 cells in the presence or absence of serum --- p.104 / Chapter 4.3.3 --- Subcellular localizations of three ERR isoforms in the PC-3 cells in the presence or absence of serum --- p.105 / Chapter 4.4 --- The role of ERRs in the growth of prostatic cells --- p.106 / Chapter 4.4.1 --- "The growth of ERRs transient transfected PC-3, PNT2 prostatic cells" --- p.107 / Chapter 4.4.2 --- Cell cycle analysis of ERRs transient transfected PC-3 cells --- p.108 / Chapter 4.4.3 --- Expression of cyclin-dependent kinase (CDK) inhibitors and p53 in the ERRs transient transfected PC-3 cells --- p.108 / Chapter 4.4.4 --- Establishment of ERRγ stable-transfected PNT2 and DU145 cells --- p.109 / Chapter 4.4.5 --- Transcriptional activation of ERE response element in ERRγ stable-transfected PNT2 cells --- p.111 / Chapter 4.4.6 --- Effect of over-expression of ERRγ on the growth of PNT2 and DU145 stable-transfected cells --- p.112 / Chapter 4.4.7 --- Efficiencies of colony formation of ERRγ stable-transfected PNT2 and DU145 cells --- p.113 / Chapter 4.4.8 --- Cell cycle analysis of ERRγ stable-transfected PNT2and DU 145 cells --- p.114 / Chapter 4.4.9 --- Expression of cell cycle-related genes in the ERRy stable-transfected PNT2 and DU 145 cells --- p.116 / Figure 4.1 - 4.38，Table 4.1 - 43 --- p.119 / Chapter Chapter 5 --- Discussion / Chapter 5.1 --- "Expression study in human prostatic cells, tumor xenografts" --- p.159 / Chapter 5.1.1 --- "Differential expression patterns of ERRs in prostatic cells, cancer xenografts and tissues" --- p.160 / Chapter 5.1.2 --- Co-localization of ERRs and ERβ in the human prostate --- p.166 / Chapter 5.1.3 --- Differential expression patterns of steroid hormone receptors and prostatic specific markers in prostatic cells and xenografts --- p.168 / Chapter 5.2 --- ERRα acts as a expression repressor of ERRγ and ERα in PC-3 cells --- p.173 / Chapter 5.3 --- ERRs are nuclear localized and constitutively active in PC-3 cells --- p.176 / Chapter 5.4 --- ERRs acts as the negative growth regulators in the prostatic cells --- p.179 / Chapter 5.4.1 --- Cell cycle control of mammalian cells --- p.180 / Chapter 5.4.2 --- The roles of AR and ERs in the cell cycle regulation --- p.181 / Chapter 5.4.3 --- Inhibition of cell proliferation in ERRs transient transfected PC-3 cells and ERRγ stable-transfected PNT2 and DU145 cells --- p.184 / Chapter 5.4.4 --- Inhibition of anchorage independent growth in ERRγ stable-transfected PNT2 and DU 145 cells --- p.188 / Chapter Chapter 6 --- Conclusion --- p.191 / Chapter Chapter 7 --- References --- p.192 / Chapter Chapter 8 --- Publications --- p.227

With ever increasing advancements in imaging, there is an increasing abundance of images being acquired in the clinical environment. However, this increase in information can be a burden as well as a blessing as it may require significant amounts of time to interpret the information contained in these images. Computer assisted evaluation is one way in which better use could be made of these images. This thesis presents the combination of texture analysis of images acquired during the treatment of cancer with machine learning in order to improve radiotherapy. The first application is to the prediction of radiation induced pneumonitis. In 13- 37% of cases, lung cancer patients treated with radiotherapy develop radiation induced lung disease, such as radiation induced pneumonitis. Three dimensional texture analysis, combined with patient-specific clinical parameters, were used to compute unique features. On radiotherapy planning CT data of 57 patients, (14 symptomatic, 43 asymptomatic), a Support Vector Machine (SVM) obtained an area under the receiver operator curve (AUROC) of 0.873 with sensitivity, specificity and accuracy of 92%, 72% and 87% respectively. Furthermore, it was demonstrated that a Decision Tree classifier was capable of a similar level of performance using sub-regions of the lung volume. The second application is related to prostate cancer identification. T2 MRI scans are used in the diagnosis of prostate cancer and in the identification of the primary cancer within the prostate gland. The manual identification of the cancer relies on the assessment of multiple scans and the integration of clinical information by a clinician. This requires considerable experience and time. As MRI becomes more integrated within the radiotherapy work flow and as adaptive radiotherapy (where the treatment plan is modified based on multi-modality image information acquired during or between RT fractions) develops it is timely to develop automatic segmentation techniques for reliably identifying cancerous regions. In this work a number of texture features were coupled with a supervised learning model for the automatic segmentation of the main cancerous focus in the prostate - the focal lesion. A mean AUROC of 0.713 was demonstrated with 10-fold stratified cross validation strategy on an aggregate data set. On a leave one case out basis a mean AUROC of 0.60 was achieved which resulted in a mean DICE coefficient of 0.710. These results showed that is was possible to delineate the focal lesion in the majority (11) of the 14 cases used in the study.

A partir de um melhor entendimento sobre a radiossensibilidade do câncer de próstata, com a redefinição de parâmetros radiobiológicos, atualmente os esquemas hipofracionados de próstata tornaram-se um dos principais desafios da radioterapia moderna. Associado a este conhecimento, o emprego de técnicas precisas de radioterapia possibilitaram a entrega de maiores doses por fração, com manutenção da toxicidade e melhor controle de qualidade dos planos de tratamento. Pretendemos avaliar a implementação da radioterapia tridimensional computadorizada (3D-CRT) ou intensidade modulada do feixe (IMRT) utilizando o regime de hipofracionamento moderado (70 Gy em 28 frações) em pacientes com neoplasia localizada da próstata na rotina do departamento de radioterapia do Hospital das Clínicas da FMRP-USP. Avaliação da viabilidade técnica e do impacto financeiro na utilização da radioterapia hipofracionada na instituição. / Evaluate the implementation of computerized three-dimensional radiation therapy (3D-CRT) or intensity modulated beam (IMRT) using moderate hypofractionation schedule (70 Gy in 28 fractions) in patients with localized prostate cancer (no metastasis lymph node or distant metastasis) in routine of department of radiotherapy of the Hospital of FMRP-USP. Assessment of technical feasibility and financial impact on the use of hypofractionated radiotherapy in the institution.

Thesis Portfolio Abstract Background Whilst the role of Psychological Flexibility on psychosocial outcomes has been assessed in some chronic health conditions and cancers, its role in psychosocial outcomes in men with prostate cancer has not been established. Fear of cancer recurrence has been shown to be associated with poorer psychosocial outcomes. The relationship of Psychological Flexibility on the impact of fear of cancer recurrence has not be evaluated. Research into the measurement of Psychological Flexibility in individuals with chronic ill health has not revealed a definitive measure. Methods A systematic review of the reliability and validity of measures of Psychological Flexibility in individuals with chronic health conditions was conducted. A quality assessment of the included studies was conducted and relevant results were synthesised. A cross-sectional study utilising a survey methodology was conducted to establish the role of Psychological Flexibility and fear of cancer recurrence in psychological distress and quality of life in men with prostate cancer. Regression analyses were used to establish whether fear of cancer recurrence or Psychological Flexibility significantly predicted any variance in distress or quality of life. Whether Psychological Flexibility mediated or moderated the relationship between fear of cancer recurrence and psychosocial outcomes was assessed with conditional process analysis. Results The systematic review revealed no single definitive measure of Psychological Flexibility, and that many measures currently in use within research and clinical settings have not been fully validated in individuals with chronic ill health conditions. The cross-sectional study found that Psychological Flexibility and fear of cancer recurrence each significantly predict variance in psychological distress and quality of life. Psychological Flexibility mediated and moderated the relationship between fear of cancer recurrence and psychological distress and mediated the relationship between fear of cancer recurrence and quality of life. Conclusions In the absence of a definitive measure of Psychological Flexibility, information on the measures identified were provided to allow clinicians and researchers to choose the most appropriate measure for their use. Future research might focus on further validation of existing measures of Psychological Flexibility rather than the development of additional measures. The challenges underlying using a psychometric approach to measure contextual science concepts was discussed. Due to the role of Psychological Flexibility within psychosocial outcomes in prostate cancer, it was suggested as a potential treatment target. The relevance of treatments such as Acceptance and Commitment Therapy, which aim to increase Psychological Flexibility, for men with prostate cancer was discussed. Future research avenues to further assess the role of Psychological Flexibility in psychosocial outcomes was discussed.

Cancer cell esterases are often overexpressed and some have chiral specificities different from those of corresponding normal cells. Carboxylesterases in particular are known to be overexpressed in several cancers. Additionally, cancer cells often exhibit high levels of intrinsic oxidative stress that is required for survival and an aggressive phenotype. We hypothesized that these 2 characteristics of cancer cells could be exploited to aid in the detection and treatment of prostate cancer. We have developed a fluorogenic ester probe that is activated by carboxylesterase to help distinguish tumorigenic cells from nontumorigenic prostate cells. Ester prodrugs have the same activation mechanism and have been thought to be a promising approach in cancer therapy. Prodrugs are inactive drugs that can be selectively activated by a specific enzyme. We have developed a chiral ester prodrug strategy using native polyacrylamide gel electrophoresis (n-PAGE) and proteomic methods to compare and identify the esterase profiles of several tumorigenic and nontumorigenic prostate cell lines. Our results showed that cell lysates from LNCaP, DU 145, and PC3 prostate cancer cell lines exhibit differential esterase activity compared with non-tumorigenic RWPE-1 prostate cell lysates when incubated with α- naphthyl acetate or α-naphthyl N-acetyl-alaninate ester substrates and a diazonium salt. We have identified oxidized protein hydrolase (OPH), a serine esterase/protease that catalyzes the removal of N-acylated residues from proteins, to be differentially expressed between some tumorigenic and nontumorigenic prostate cell lines. OPH was found to have high hydrolytic activity towards the S-isomer of α-naphthyl N-acetylalaninate (S-ANAA) chiral ester. LNCaP lysates incubated with N-acetyl-alanyl-p-nitroanilide, a known OPH substrate, had twofold higher OPH activity compared with RWPE-1 lysates. We have also developed and tested novel glutathione depleting prodrugs modeled after S-ANAA that increase oxidative stress and induced apoptosis in tumorigenic prostate cells with little effect on nontumorigenic RWPE-1 cells. These results suggest that ester molecular beacon probes and ester prodrugs may be effective in identifying and treating prostate cancer tumors that overexpress esterases with little effect on normal prostate cells.

No description available.

Prostate cancer represents a serious health concern as the most diagnosed form of cancer in men and the second leading cause of cancer death in the Western world. Current treatments for prostate cancer are non-targeted and result in a number of undesirable, non-specific effects, highlighting the need for novel, targeted therapeutics in the treatment of prostate cancer. Prostate Specific Membrane Antigen (PSMA) offers great promise in the targeting of prostate cancer for imaging and therapy. PSMA is a transmembrane carboxypeptidase with cell surface expression several orders of magnitude higher in cancerous prostatic epithelia than found in other tissue and PSMA is constitutively internalized into cells. The unique expression profile of PSMA and its constitutive internalization offer great value in the targeted delivery of therapeutics to prostate cancer cell. In 2002, two synthetic RNA ligands, aptamers, were selected for their ability to inhibit the enzymatic activity of PSMA. In 2006, the utility of these aptamers in the delivery of cytotoxic siRNA across the cell membrane was demonstrated in vivo using aptamer-siRNA chimeras. However, those experiments were performed by intratumoral injection, and systemic administration will be necessary for use in the clinic. In this thesis, we improve PSMA targeted chimeras to serve as more powerful therapeutics in the treatment of prostate cancer. We optimize existing aptamer-siRNA chimeras for increased potency and stability and improved pharmacokinetics to enable systemic administration. We truncate the PSMA binding aptamers for amenability to large-scale chemical synthesis. With emerging roles for PSMA enzymatic activity in the prostate cancer disease we identify aptamers that are suitable for chemical synthesis and retain inhibitory properties against PSMA. Finally, we assess the use of aptamers as synthetic ligands in the functional inhibition of PSMA mediated motility in prostate cancer. Our results demonstrate the ability of aptamer-siRNA chimeras to specifically kill PSMA-expressing cells with cytotoxic siRNA upon systemic injection. We confirm a newly reported role for PSMA in the promotion of cell motility and demonstrate the ability of aptamers to effectively neutralize PSMA-mediated motility. The results presented within argue strongly for the functional utility of aptamers in the treatment of prostate cancer.

Cancer screening is useful for improving survival rates and treatment outcomes, which is why there are screening recommendations for the most prevalent types of cancer. Despite gains in the reduction of cancer-related mortality rate worldwide in the past few years, the Haitian community continues to experience high mortality rates due to cancer. The prevalence of prostate cancer in the Haitian population is among the highest worldwide at 767 per 100,000, with a mortality rate of 403 per 100,000. One of the causes may be the low prostate cancer screening rate in the Haitian community; however, no studies have been focused on an association between demographic factors within this community and the low prostate cancer screening rate. This study's purpose was to address this gap through a cross-sectional quantitative design using the health belief model as a theoretical framework and a convenience sample of 282 Haitian males. The rate of prostate cancer screening among Haitian immigrants living in Brooklyn was examined based on the demographic variables of age, income, and education. Participants' perceptions regarding prostate cancer screening were also evaluated based on the same variables. Loglinear, and binary logistic regression were used for data analysis. Although education was found to be the strongest and only significant predictor variable for prostate cancer screening participation within the target population, no conclusion could be drawn regarding the effect of the select variables on the participants' perceptions on prostate cancer screening. The implications for this study include increased knowledge for public health promotion initiatives and for those in the Haitian community working to reduce the morbidity and mortality rates due to prostate cancer.