Prostate cancer is the most common form of non-skin cancer and the second leading cause of cancer deaths within the United States. The five year survival rate has increased from 69% to 99% over the last 25 years for the local and regional disease, but has remained fairly low (approximately 34%) for the advanced disease. Therefore, current research is aimed at finding complementary or alternative treatments that will specifically target components of the signal transduction, cell-cycle and apoptosis pathways to induce cell death, with little or no toxic side effects to the patient. In this study we investigated the effect of genistein on expression levels of genes involved in these pathways. Genistein is a (4 , 5 , 7-trihydroxyisoflavone) is a major isoflavone constituent of soy that has been shown to inhibit growth proliferation and induce apoptosis in cancer cells. The mechanism of genistein-induced cell death and potential molecular targets for genistein in LNCaP prostate cancer c ells was investigated using several techniques. The chemosensitivity of genistein towards the prostate cancer cells was investigated using the ATP and MTS assays and apoptosis induction was determined using apoptosis and caspase assays. Several molecular targets were also identified using cDNA microarray and RT-PCR analysis. Our results revealed that genistein induces cell death in a time and dose-dependent manner and regulates expression levels of several genes involved in carcinogenesis and immunogenicity. Several cell cycle genes were down-regulated, including the mitotic kinesins, cyclins and cyclin dependent kinases, indicating that genistein is able to halt cell cycle progression through the regulation of genes involved in this process. / Several members of the Bcl-2 family which are involved in apoptosis were also affected and a number of genes involved in immunogenicity were up-regulated including the DefB1 and HLA membrane receptors. The results of this study provide evidence of genistein's ability to inhibit growth proliferation and induce apoptosis and indicates its potential as an adjuvant in chemotherapy and immunotherapy. / by Kendra Merchant. / Thesis (Ph.D.)--Florida Atlantic University, 2009. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2009. Mode of access: World Wide Web.

Made available in DSpace on 2016-03-22T17:26:57Z (GMT). No. of bitstreams: 1 Neivo.pdf: 343535 bytes, checksum: e65c41380c8ceabe9bc780ffcc1c99f1 (MD5) Previous issue date: 2005-02-14 / Objective: The objective of this study is to describe the reproducibility of the sentinel lymph node technique in patients with prostate cancer and verify if there is improved accuracy over modified lymphadenectomy. Material and methods: Twenty-three patients with biopsy proven prostate cancer were enrolled in this study. Lymphoscintigraphy was performed after the transrectal administration of 99mTc-Sulphur Colloid guided by ultrasound, with one injection in each prostate lobe. Images were obtained 15 and 180 minutes after injection. Sentinel lymph node was harvested during surgery using a gamma probe, followed by extended lymphadenectomy. Results: The mean age of the patients in this study was 66 years old. An average of 3.36 sentinel lymph nodes was found for each patient. Radioactive lymph nodes were identified by the gamma probe in 21 out of 23 patients. In one of the patients there was no radiopharmaceutical migration from the injection site and in another the sentinel lymph node was visualized by lymphoscintigraphy but was not found during surgery. Three patients had lymph node metastasis; in one of these patients the sentinel lymph node was the only positive node and was found outside the modified lymphadenectomy region (dissection of the lymph nodes from the obturator fossa and the external iliac). Conclusion: Sentinel lymph node biopsy in prostate cancer adds important information to the staging of patients, not always attained through the lymphadenectomy restricted to the obturator fossa and external iliac. Such information is essencial for the choice of the best treatment to be applied. / n

Prostate cancer is the most commonly occurring cancer and the second leading cause of cancer death for men in the United States. Because early prostate cancer is frequently without symptoms and data on how to prevent prostate cancer is lacking, early detection has the greatest potential for decreasing mortality. Studies have shown Hispanics/Latinos to be less likely than whites or African-Americans to utilize prostate cancer screening exams. The purpose of this descriptive study was to design a social marketing plan which could be used as a model to promote Hispanic/Latino participation at prostate cancer screenings. Information obtained through medical and marketing literature review, the author's experiences serving on the promotion committee of a community-sponsored prostate cancer screening project, and interviews with 51 Hispanic/Latino prostate cancer screening participants is described and incorporated into a guide with recommendations for future program planners.

Androgens are critical for the development and maintenance of adult male characteristics such as muscle mass and sexual function. Consequently, the established decline with age of serum testosterone (T) in males has major health implications. While the androgen receptor (AR) is the major mediator of genomic androgen action and is required for the development of the male phenotype, reproductive organs and the maintenance of male secondary sexual characteristics, it is the entrance of androgens into the cell that mediates the activation of the AR and the subsequent modulation of expression of androgen regulated genes. Testosterone, biologically the most important androgen in male serum, circulates either free, loosely bound to albumin or tightly bound to sex hormone binding globulin (SHBG). Each of these forms of serum T have different abilities to enter cells, and which proportion of serum T is capable of entering cells and initiating the androgen signalling cascade, thereby leading to the activation of the AR has not been precisely defined. The AR amino terminal domain (NTD) is responsible for the majority of the ability of the AR to activate genes but the relative roles of the two activation functions in the AR NTD (activation functions 1 and 5; AF1 and 5) have not been precisely defined while the role of the AF2 surface which forms in the ligand binding domain upon agonist binding is responsible for interactions with key coregulators and also with the NTD in the amino-carboxyl (N/C) interaction. Our laboratory has recently identified a region within AF5 between amino acids 500-535 to which somatic mutations in castrate resistant prostate tumour samples collocate. Due to the lack of functional information on the AF5 region and the NTD in general, the function of this region and the functional consequences of the mutations remain to be defined. The objectives of this thesis were to develop a specific mammalian cell based bioassay capable of reliable measuring T in serum and to determine the ability of this bioassay to measure a physiologically relevant fraction of T in serum. Additionally, this thesis aimed to determine the relative contributions and roles of the activation functions of the AR to overall AR transcriptional activity along with the functional consequences for AR signalling of prostate cancer mutations which have previously been identified in the AF5 region of the AR NTD. The mammalian-cell based bioassay developed in this thesis is capable of sensitively and reliably measuring serum T. However, evaluation of this bioassay utilising approximately 1000 serum samples from the Florey Adelaide Male Aging Study reveals that this bioassay measures a fraction of T in serum that most closely relates to serum T. Furthermore, this measure does not correlate more strongly with grip strength, sexual function or waist circumference than the existing immunoassay-based measures of serum T, highlighting the limitations of utilising a static mammalian cell-based androgen bioassay to measure physiological levels of serum T in males. The investigation of the roles of the activation functions in the AR in this thesis have revealed that while the AF1 domain is responsible for the majority of the transactivation activity of the AR, AF5 and AF2 govern the sensitivity and cellular response of the AR to androgens by providing protein and interdomain interaction interfaces. Furthermore, the evidence in this thesis demonstrates that the AR requires interdomain communication for sensitive AR signalling. Finally, the findings in this thesis demonstrate that the AF5 surface is required for the N/C interaction and coregulator interactions while advanced prostate cancer mutations identified within this region confer increased transactivation activity of the AR in the presence of high cellular levels of coregulators. Collectively, the findings in this thesis provide several novel insights into the mechanism of action of serum androgens and challenges several long held assumptions of androgenic action in males. These findings also delineate a mechanism of treatment failure in advanced prostate cancer, provide a novel model for the events leading to sensitive AR transactivation and contribute to the understanding of physiologically relevant levels of serum T. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Ο καρκίνος του προστάτη αποτελεί σημαντικό πρόβλημα της δημόσιας υγείας ιδιαίτερα στο δυτικό κόσμο. Είναι ο πιο συχνός σπλαχνικός καρκίνος και ο δεύτερος πιο θανατηφόρος μετά τον καρκίνο του πνεύμονα. Η εισαγωγή και χρήση του PSA από τα τέλη της δεκαετίας του ’80 προσέθεσε ένα ισχυρό διαγνωστικό εργαλείο στα χέρια των κλινικών, το οποίο αναχαίτισε τη μέχρι τότε αυξητική τάση του αριθμού των θανάτων οφειλομένων στον καρκίνο του προστάτη. Το PSA ωστόσο χαρακτηρίζεται από χαμηλή ειδικότητα αλλά και ευαισθησία, χαρακτηριστικά που επιβάλλουν περιορισμούς στη χρήση του. Εξάλλου δεν προβλέπει το βαθμό της επιθετικότητας ενός αδενοκαρκινώματος του προστάτη, συμβάλοντας στο φαινόμενο της υπερδιάγνωσης αλλά κυρίως της υπερθεραπείας του καρκίνου του προστάτη. Κατά συνέπεια είναι απαραίτητη η ανάπτυξη μοριακών εργαλείων (δεικτών) οι οποίοι θα διαγιγνώσκουν τη νόσο με μεγαλύτερη ασφάλεια αλλά κυρίως θα μας δίνουν προγνωστικές πληροφορίες για τη βιολογική συμπεριφορά του όγκου, προλαμβάνοντας μια άσκοπη θεραπευτική παρέμβαση. Ενδιαφέρον πεδίο αναζήτησης τέτοιων δεικτών αποτελεί η χρωμοσωμική περιοχή 8q24. Ο μικροδορυφόρος DG8S737 εδράζεται στην περιοχή 8q24 και έχει δειχθεί, σε διαφορετικούς πληθυσμούς, ότι συγκεκριμένο αλληλόμορφό του σχετίζεται με επιθετικό, κλινικά σημαντικό καρκίνο του προστάτη. Στη συγκεκριμένη μελέτη ανιχνεύονται οι συχνότητας των αλληλομόρφων του μικροδορυφόρου DG8S737 σε μια ομάδα γενικού πληθυσμού (control) και σε μια ομάδα ασθενών οι οποίοι πάσχουν από επιθετικό καρκίνο του προστάτη. Τα αποτελέσματα επιβεβαιώνουν την τάση του αλληλομόρφου -8 να ανιχνεύεται συχνότερα σε ασθενείς παρά σε υγιείς. Εξάλλου παρατηρήθηκε για πρώτη φορά η ίδια τάση και για το αλληλόμορφο -10. Αυτά τα αποτελέσματα ενισχύουν το δυναμικό χρήσης του DG8S737 ως δείκτη για το μέτρο της επιθετικότητας του καρκίνου του προστάτη. / Prostate cancer represents a major public health issue in western world. It is the most frequently diagnosed visceral cancer whereas it is second in mortality. The use of PSA since the late 80s restrained the rising tendency of mortality of prostate cancer. PSA though, lacks in specificity. Besides it contributes to the phenomenon of overdiagnosis which leads to overtreatment of prostate cancer. Consequently it is necessary for novel biomarkers to emerge in order to diagnose more accurately and predict the aggressiveness of prostate cancer. The 8q24 region of chromosome 8 is a region which could harbor potential biomarkers for prostate cancer. The microsatellite DG8S737 in that region has a number of alleles, one of which has the tendency to be more often detected in patients with aggressive prostate cancer. We have studied the frequencies of alleles of DG8S737 in a group of patients with aggressive prostate cancer as well as in a group of control volunteers. The results confirm the findings of previous studies. The allele -8 of DG8S737 has been detected more often in patients than in healthy volunteers. A new finding is that allele -10 also is more frequently detected in the patients group rather than the control group. The results confirm previous findings and enforce the potential use of DG8S737 as novel biomarker for the aggressive prostate cancer.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23081号 / 医博第4708号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中本 裕士, 教授 小川 誠司, 教授 武田 俊一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

1 ABSTRACT Introduction and aim of the study Circulating tumor cells (CTCs) are a promising tool of identifying patients with castration- resistant prostate cancer (CRPC) who will benefit from often demanding cytotoxic therapy. The aim of this work was to evaluate the prognostic significance of CTC in docetaxel-treated CRPC patients. During the project, we also tested the various methods of CTC cultivation and studied their genetic profile as well as the genetic profile of histological specimen at the time of diagnosis. Patients and methods A total of 39 patients who met the CRPC criteria and were indicated for docetaxel chemotherapy were included in the prospective study. Blood collection for CTC analysis was done in all patients before chemotherapy and on the first day of the fourth or fifth cycle of docetaxel. In parallel, CTCs were cultivated. Isolation and detection of CTC was done using the AdnaTest system, which consists of immunomagnetic separation and subsequent detection of mRNA from the CTC lysate. The primary objective of the study was to evaluate the overall survival (OS) of patients. Survival analysis was performed using the Kaplan-Meier method of estimating the survival distribution function. The impact of individual factors was tested using the Log-rank test, the Wilcoxon test and the Cox...

Thèse ou mémoire avec insertion d'articles / Contexte: Aucune étude n'a décrit la qualité de vie (QdV) des hommes à risque de cancer de la prostate (CaP) au Canada. Notre objectif visait à faire une analyse descriptive complète de la QdV dans une cohorte canadienne d'hommes à haut risque de développer un CaP, et à évaluer l'impact des problèmes urinaires et érectiles sur la QdV générale. Méthodes: La QdV a été récoltée chez 2053 hommes à risque de CaP participant à une étude observationnelle prospective multicentrique appelée BIOmarqueurs, Cancer de la Prostate, Prévention et Environnement (BIOCaPPE). Les participants ont rempli plusieurs questionnaires validés afin d'évaluer leur QdV générale(Échelle d'anxiété et de dépression [HADS] et Inventaire de 36 items forme courte [SF-36]), et celle spécifique au CaP (Score international des symptômes de la prostate [IPSS] et Inventaire de la santé sexuelle pour hommes [SHIM]). Résultats: Parmi tous les participants, 122 (6,1%) représentent des cas définitifs d'anxiété et 40 (2,0%) des cas définitifs de dépression; 1068 (53,9%) ont des symptômes urinaires modérés à sévères et 154 (7,8%) ont des symptômes de dysfonction érectile sévères. Les participants ont une QdV similaire à celle des hommes de la population générale, à l'exception de la fonction urinaire. Plus les symptômes urinaires et de dysfonction érectile sont sévères, moins bonne est la QdV générale. Les symptômes urinaires ont un plus grand impact sur la QdV générale que les symptômes de dysfonction érectile. Conclusions: Nos résultats suggèrent que la majorité des participants perçoivent leur QdV comme étant satisfaisante, bien que la majorité présentent des symptômes urinaires modérés à sévères. Les symptômes anxieux, dépressifs et érectiles sont moins fréquents. Les symptômes urinaires et de dysfonction érectile ont un impact négatif sur la QdV générale. Il s'agit de la première analyse de la QdV d'une cohorte canadienne d'hommes à risque de CaP / Background: No study has described the quality of life (QoL) of men at risk for prostate cancer (PCa) in Canada. Our objective was to conduct a comprehensive descriptive analysis of QoL in a Canadian cohort of men at risk of developing PCa, and to assess the impact of urinary and erectile symptoms on general QoL. Methods: QoL was collected in 2053 men at risk for PCa participating in a prospective multicenter observational study called BIOmarkers, Prostate Cancer, Prevention and Environment (BIOCaPPE). Participants completed several validated questionnaires to assess their general QoL (Anxiety and Depression Scale [HADS] and 36-item Short Form Survey [SF-36]), and PCa-specific QoL (International Prostate Symptom Score [IPSS] and Sexual Health Inventory for Men [SHIM]). Results: Of all participants, 122 (6.1%) are definite cases of anxiety and 40 (2.0%) definite cases of depression; 1068 (53.9%) have moderate to severe urinary symptoms and 154 (7.8%) have severe erectile dysfunction symptoms. Participants have a QoL similar to that of men in the general population, except for urinary function. More severe the urinary and erectile dysfunction symptoms are, worse the general QoL is. Urinary symptoms have a larger impact on general QoL than erectile dysfunction symptoms. Conclusions: Our results suggest the majority of participants perceived their QoL as satisfactory, although the majority have moderate to severe urinary symptoms. Anxiety, depressive, and erectile symptoms are less common. Urinary and erectile dysfunction symptoms have a negative impact on general QoL. This is the first analysis of the QoL of a Canadian cohort of men at risk of PCa

L'hormonothérapie (HTX) est un traitement couramment administré chez les hommes atteints d'un cancer de la prostate et qui peut avoir des répercussions sur leur bien-être émotionnel, en incluant une occurrence possible de dépression. Les études qui ont évalué la relation entre l'HTX et le développement de la dépression chez ces patients ont tantôt démontré une telle association et tantôt non. Une explication avancée serait que le cancer de la prostate et ses traitements puissent mener à des altérations dans les niveaux de testosterone et de Cortisol pouvant être associées à la dépression. Cependant, ces études comportaient plusieurs limites méthodologiques dont l'utilisation d'un devis de recherche transversal et l'absence d'un groupe contrôle approprié. La présente thèse compte deux articles empiriques issus de la même étude longitudinale menée auprès de 60 participants traités par radiothérapie seule (n = 32) ou combinée à de l'HTX (n = 28) évalués avant le début des traitements et à sept autres reprises sur une période de 16 mois. Cette thèse visait à répondre aux objectifs principaux suivants : (1) vérifier si l'introduction de l'HTX (et le retrait) de l'HTX étaient associés à une augmentation (et une diminution) des troubles dépressifs et de la sévérité de la dépression; (2) documenter l'évolution des niveaux sanguins de testosterone et de Cortisol dans chacun des groupes; et (3) évaluer la relation entre les niveaux hormonaux de testosterone et de Cortisol et la dépression. Globalement, les résultats obtenus suggèrent que l'HTX a eu un impact mineur sur le développement et la résolution de la dépression chez ces hommes. Par ailleurs, les niveaux de testosterone et de Cortisol ont diminué de façon significative dans les deux groupes de traitement. Néanmoins, la baisse de testosterone dans le groupe qui recevait de l'HTX n'était pas associée significativement à la dépression alors que des scores plus élevés de Cortisol étaient significativement reliés à des niveaux plus importants de dépression, et ce, dans les deux groupes de traitement. Ces résultats contribuent au développement d'une meilleure compréhension de la relation entre les traitements oncologiques, les changements hormonaux et la dépression. Il apparaît maintenant important d'investiguer davantage les différents mécanismes hormonaux et psychologiques sous-jacents au développement de la dépression chez cette population.

This study determined the impact of vitamin C dose on genistein-induced apoptosis in LNCaP cancer cells at various treatment regimens in vitro. Although the linear regression of viability assay (MTT) indicated a p-value = 0.11; NBT assay reveal a declining SOD activity during cell death. Apoptosis induction was the main mode of treatment induced cell death. The overall data showed the trend of treatment efficacy as;(Gen 10uM + Vit C 40uM) > (Gen 30uM + Vit C 40uM) > (Gen 70uM + Vit C 40uM) > 10uM genistein > 70uM genistein. The chi-square test for comparing necrosis, apoptosis and life cells showed that Vitamin C could impact genistein-induced apoptosis in LNCaP cells (p = 0.0003). This study forms the basis for in vivo studies of the impact of vitamin C on genistein-induced apoptosis in LNCaP prostate cancer cells. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2015. / FAU Electronic Theses and Dissertations Collection