The purpose of this study was to determine the factors related to young black men’s intention to screen for prostate cancer as well as their engagement in prostate cancer risk-reduction behaviors. The study tested the significance of the constructs – age, attitude (direct and indirect), social influence, comfortability, cues to action, health screening experiences and knowledge – in predicting young black men’s intention to screen for prostate cancer; as well as the significance of the constructs – age, cues to action, exercise and knowledge – in predicting engagement in prostate cancer risk-reduction behaviors. Demographic/personal factors were also explored in related to the model predictors. Web-based and paper-pencil surveys were administered to 279 black men aged between 18 – 40 years from the Austin area. Three focus groups were conducted to collect information regarding young black men’s behavioral beliefs toward prostate cancer screening as well as their comfortability with prostate examinations. The number of usable surveys was 267. Using direct and indirect measures, the combination of attitude, social influence, comfortability (indirect model), and knowledge explained 41.0 and 43.0 percent of the variance in intention to screen for prostate cancer, respectively; with social influence being the strongest predictor ([Beta]=0.41; p <0.01 for the direct model and [Beta]=0.47 for the indirect model). For the model with prostate cancer risk-reduction as the outcome variable, the model accounted for 10.0 percent of the variance in behavior with only knowledge ([Beta]=0.19; p=0.03) as significant predictor. Interventions that address young black men’s attitude, social influence, comfortability, and knowledge may be necessary to increase young men’s intention to screen for prostate cancer when it is recommended by a physician. Additionally, factors surrounding exercise and knowledge may be important in increasing young men’s engagement in prostate cancer risk-reduction behaviors. Future studies using intention as a predictor of young men’s behavior are needed to assess the influence of intention on prostate cancer screening. / text

Les protéines de la Famille Ets sont des facteurs de transcription qui reconnaissent par l'intermédiaire d'un domaine de liaison à l'ADN, appelé le domaine ETS, une séquence nucléotidique centrée sur un core consensus 5'-GGAA/T-3'. Le gène fev, un membre de cette famille, a été isolé chez l'humain après avoir été identifié dans une tumeur de Ewing chez l'enfant comme le résultat d'une translocation chromosomique. Une étude préliminaire de 1997 indiquait que chez l'Homme, Fev possède une expression tissulaire restreinte au petit intestin et à la prostate "adulte". Dans la première partie de ce travail, nous avons observé une surexpression de l'ARNm de ce facteur de transcription dans une large série d'adénocarcinomes prostatiques de différenciation variable en comparaison au profil d'expression observé dans un groupe témoin de prostates hyperplasiées. En recherchant des lignées cellulaires qui expriment ce facteur, nous avons mis en évidence la présence de ce messager dans la lignée humaine d'origine prostatique LNCaP. De même, les lignées humaines d'origine hématopoïétiques Dami/HEL92.1.7, K-562, KU-812 F et U-937 expriment ce facteur. Parallèlement, nous avons réalisé l'étude de l'expression de Fev dans le cerveau humain. En effet, chez le rat et chez la souris, l'homologue de Fev (mPet-1/Pet-1) est exprimé spécifiquement dans les neurones sérotoninergiques. Nous avons ainsi montré sur le cerveau humain que l'ARNm de Fev est exclusivement exprimé dans les noyaux du raphé qui contiennent les neurones sérotoninergiques. Il est co-exprimé avec deux marqueurs de ces neurones, la SERT/5-HTT et la TPH2. Parallèlement, nos travaux de caractérisation fonctionnelle de la protéine Fev ont permis de définir ce facteur comme un répresseur transcriptionnel. En effet, ce facteur possède un domaine carboxy-terminal riche en résidus alanines qui lui confère, en partie, sa fonction de répresseur de la transcription (répression active); la délétion de cette région conduisant à une réduction drastique de l'effet répresseur. Parallèlement, nous avons montré que le domaine ETS de Fev est responsable d'une activité répressive passive par l'occupation des sites de liaison aux facteurs Ets. Néanmoins, nous ne connaissons pas, à l'heure actuelle, les gènes-cibles spécifiques qui sont directement réprimés par Fev dans les cellules dans lesquelles le gène est normalement exprimé. Nous avons tenté de développer, par établissement de clones stables, des modèles cellulaires où le gène d'intérêt est surexprimé, mais ces tentatives furent infructueuses. Cet effet drastique de Fev est conféré par la partie carboxy-terminale. Il est ainsi probable que la surexpression de ce répresseur transcriptionnel spécifique de certains gènes cibles de la famille Ets provoque des effets sur la survie des cellules en régulant des gènes indispensables à la croissance cellulaire, et ainsi empêchant la prolifération de clones cellulaires.

Prostate cancer is the most commonly diagnosed cancer and second leading cause of death in American men. Patients with localized prostate cancer may experience unique and multidimensional symptoms that are distressful from treatment and thereafter. This cross-sectional correlational study aimed to investigate the relationships among stress, symptoms, symptom distress, and symptom self-management and identify the effective strategies of symptom self-management in men with localized prostate cancer following prostatectomy or radiation therapy.Eight saliva samples and 3 questionnaires (Perceived Stress Scale, Symptom Indexes, and Strategy and Effectiveness of Symptom Self-Management) were obtained from each participant between 1 and 3 months following their first prostate cancer treatment. The sample consisted of 53 men with localized prostate cancer. Mean salivary cortisol concentrations for the entire sample ranged from 0.3 to 0.08 ug/dL. Cortisol was secreted in a circadian rhythm with heightened activity in the early morning and lowered activity late in the day. The circadian pattern of cortisol secretion was similar in both the prostatectomy and radiation therapy groups, although the values were slightly different. Two areas Under the Curve (AUC) of salivary cortisol were calculated. Three cortisol circadian rhythms were identified, but the majority of the sample had a typical negative consistent circadian rhythm.Patients with localized prostate cancer who underwent radical prostatectomy or radiation therapy had low perceived stress. Perceived stress was positively correlated with AUCg, noon salivary cortisol concentrations, and afternoon salivary cortisol concentrations. Subjects reported a moderate degree of symptoms and symptom distress on urinary, bowel, and sexual dysfunction 1-3 months following treatments. The most effective strategies of urinary symptom management were pad and kegel exercise; the most effective strategy of bowel symptom management was rest or endure; the most effective strategies of sexual dysfunction management included express their feelings or find alternative ways to express their affection. The symptom self-management strategies were significantly and positively correlated with symptom self-management effectiveness.Symptom distress and AUCg were significant and strong predictors of symptom self-management. Findings can help health care providers develop effective strategies for symptom self-management that enhance health related quality of life among men with localized prostate cancer.

No description available.

Vinclozolin (VCZ), an antiandrogenic fungicide, is an endocrine disrupting chemical that is known to possess high affinity for the androgen receptor (AR) and modulate expression of critical androgen-dependant genes in the prostate. In this study, viability and expression of AR, NKX3.1 and CYP3A4 genes were measured in androgen-sensitive prostate cells LNCaP after exposure to VCZ and VCZ treated with S9 microsomes in a time and dose dependent manner. NKX3.1 is an androgen regulated gene that plays a vital role in prostate development. CYP3A4 is involved in xenobiotic metabolism. VCZ decreased the viability at high doses after 48 hours which was slightly mitigated by treatment with S9 metabolites. Expression of NKX3.1 and CYP3A4 was upregulated while an initial downregulation of AR was observed. NKX3.1 upregulation corroborates with possibility of antiandrogens to act as androgens in LNCaP. The results illustrate that VCZ can interfere with the expression of critical prostate genes.

Tumour hypoxia has been demonstrated to cause development of an aggressive tumour phenotype and is associated with increased patient mortality and poorer response to treatments such as chemotherapy and radiotherapy. Previous studies have established that hypoxia exists within a nidus of prostate cancer. Based on the importance of the tumour microenvironment, especially hypoxia, in prostate cancer, the major aims of this thesis were to establish: (a) the role of a novel putative survival factor, dermcidin, in prostate cancer survival under hypoxia/oxidative stress; and (b) the effect of nitric oxide-donating non-steroidal anti-inflammatory drugs (NO-NSAIDS), a new class of drugs, on the killing of prostate cancer cells subjected to hypoxia. A wide-range of confirmatory, cellular and molecular biology techniques were employed in this thesis. The PC-3 hormone-insensitive prostate cancer cell line was used for the majority of studies as this cell line represents hormone-independent prostate cancer, treatment of which is currently palliative. Cell incubation at 0.2% oxygen for 48 hours was established as suitable conditions to stimulate the development of the hypoxia response. Upregulation of nuclear hypoxia-inducible factor-1α protein was the main marker used to assess the hypoxia response. Dermcidin messenger RNA production was found to occur in a range of prostate cancer cell lines; was upregulated in cell lines by both hypoxic and oxidative stress; and found to act as a proliferation, survival and pro-invasion factor under hypoxia and oxidative stress in immortalised prostate cancer cell lines. Furthermore, the portion of the dermcidin molecule responsible for the survival advantage was localised to the proteolysis-inducing factor core peptide subunit. However, subsequent analysis of primary cancer samples from prostate cancer patients revealed that dermcidin was not expressed in these tumours, although dermcidin mRNA was identified in analysis of other primary tumours. As such, the role of dermcidin in prostate cancer was not evaluated further in this thesis. Investigation of NO-sulindac (a NO-NSAID drug) in hypoxic PC-3 cells showed that these agents were significantly more pro-necrotic, pro-apoptotic and anti-invasive than traditional, unnitrated sulindac. NO-sulindac was found to downregulate the hypoxia response mounted by PC-3 cells under hypoxia via the Akt signalling pathway. Finally, analysis of the role of NO-sulindac in radiosensitising hypoxic PC-3 cells showed that NO-sulindac caused significant radiosensitisation under normoxia, but particularly in hypoxic conditions. As such, NO-NSAIDs show great promise as neoadjuvant, concurrent and adjuvant treatments for patients with hypoxic prostate cancer. The findings of this thesis illustrate several potential novel strategies for treatment of hormone-independent prostate cancer.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Background: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double-blind, placebo-controlled, prostate cancer prevention study funded by the National Cancer Institute and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo). At the time of the trial's development, NIH had invested substantial resources in evaluating the potential benefits of these antioxidants. To capitalize on the knowledge gained from following a large cohort of healthy, aging males on the effects of selenium and/or vitamin E, ancillary studies with other disease endpoints were solicited. Methods: Four ancillary studies were added. Each drew from the same population but had independent objectives and an endpoint other than prostate cancer. These studies fell into two categories: those prospectively enrolling and following participants (studies of Alzheimer's disease and respiratory function) and those requiring a retrospective medical record review after a reported event (cataracts/age-related macular degeneration and colorectal screening). An examination of the challenges and opportunities of adding ancillary studies is provided. The impact of the ancillary studies on adherence to SELECT was evaluated using a Cox proportional hazards model. Results: While the addition of ancillary studies appears to have improved participant adherence to the primary trial, this did not come without added complexity. Activation of the ancillary studies happened after the SELECT randomizations had begun resulting in accrual problems to some of the studies. Study site participation in the ancillary trials varied greatly and depended on the interest of the study site principal investigator. Procedures for each were integrated into the primary trial and all monitoring was done by the SELECT Data and Safety Monitoring Committee. The impact of the early closure of the primary trial was different for each of the ancillary trials. Conclusions: The ancillary studies allowed study sites to broaden the research opportunities for their participants. Their implementation was efficient because of the established infrastructure of the primary trial. Implementation of these ancillary trials took substantial planning and coordination but enriched the overall primary trial.

CTCs have emerged as a potential source of clinical significance. But with numerous isolating systems currently available, the numbers of captured CTCs vary widely. At this point, CellSearch remains the only FDA-approved system with clinical significance whereby the results could be used to monitor patients with metastatic colon, breast, or prostate cancer. However, its inability to isolate CTCs from non-high risk prostate cancer patients or CTCs that are EpCAM-negative has led to criticism. In this study, we have shown that size-based filtration successfully isolates CTCs from patients with localized and metastatic prostate cancer. We have also shown that CTCs can be successfully isolated from low and intermediate risk groups. Additionally, clusters of CTCs were preserved and isolated in all localized risk groups and metastatic patients. Furthermore, we enumerated the isolated CTCs using automated and manual methods in low risk, intermediate risk, high risk, and metastatic prostate cancer. The automated and manual counts were comparable. Moreover, the amounts of clusters and the size of clusters correlated with the status and stage of prostate cancer. / October 2016