Indiana University-Purdue University Indianapolis (IUPUI) / In this thesis, I investigated the preclinical utility and antitumor efficacy of TRAIL delivered by Ad-IU2, a prostate-specific replication-competent adenovirus (PSRCA), against androgen-independent prostate cancer. Through transcriptional control of adenoviral early genes E1a, E1b and E4, as well as TRAIL by two bidirectional prostate-specific enhancing sequences (PSES), expression of TRAIL as well as adenoviral replication was limited to prostate-specific antigen and prostate-specific membrane antigen (PSA/PSMA)-expressing cells. Ad-IU2 replicated efficiently in and was restricted to PSA/PSMA-positive prostate cancer cells and induced 5-fold greater apoptosis in androgen-independent CWR22rv and C4-2 prostate cancer cells than the PSRCA control not expressing TRAIL. Ad-IU2 exhibited superior killing efficiency in PSA/PSMA-positive prostate cancer cells at doses 5 to 8-fold lower than that required by a non-TRAIL expressing PSRCA to produce a similar effect. This enhanced cytotoxic effect was not observed in non-prostatic cells, however. As an enhancement of its therapeutic efficacy, Ad-IU2 exerted a bystander effect through either direct cell-to-cell contact or soluble factors present in conditioned media from Ad-IU2-infected cells. In vivo, Ad-IU2, as compared to a control PSRCA, markedly suppressed the growth of subcutaneous CWR22rv xenografts at six weeks post-treatment (3.1 vs. 17.1-fold growth of tumor). The treatment of androgen-independent prostate cancer with Ad-IU2 prior to external beam radiation therapy (EBRT) significantly reduced clonogenic survival with dose reduction factors of 4.91 and 2.43 for CWR22rv and C4-2 cells, respectively. Radio-sensitization by Ad-IU2 was restricted to PSA/PSMA-positive cells. Combinatorial radio-gene therapy resulted in accumulation of cells in G1 phase and a perturbation of the radiation-induced G2 phase arrest. This multi-modal approach combining viral lysis, apoptosis-inducing gene therapy, and radiation therapy could have great impact in achieving complete local tumor control while reducing radiation dose and associated treatment morbidities. This would result in improvement of the clinical outcome of patients with high risk prostate cancer.

<p>Benign prostatic hyperplasia (BPH) is a common urologic condition among older men, affecting approximately half of men by age 50 and nearly 80% by age 80. Lower urinary tract symptoms (LUTS) associated with BPH may significantly impact quality of life for many of these men. Inflammation has been associated with the development and progression of BPH however, the precise impact and role(s) of immune cells in these conditions remains unclear. Many previous studies over the decades have explored the roles of immune cells in prostate disease in animal models and prostate tissues from human patients, and, more recently, through transcriptomic analyses of bulk cell populations and of single cells. These and other emerging technologies continue to add to the body of knowledge related to this area.</p> <p>The prostate is a complex organ composed of multiple epithelial and mesenchymal cell types and subtypes. The growth, morphology, and function of these cells is influenced by autocrine and paracrine cell-cell interactions in ways that are largely not yet understood. A better understanding of the composition, heterogeneity, morphology, interactions, and functional features of various prostate cell types, particularly involving immune cells in the context of inflammatory processes, is expected to improve our understanding of the impact of altered cellular composition and communication on prostate homeostasis and disease.</p> <p>Inflammation has been shown to impact the growth, morphology, and function of various prostate cell types. It is hypothesized that inflammation promotes epithelial cell proliferation and differentiation in BPH despite androgen-targeted therapy. It is hypothesized that communications between and within various immune cell populations perpetuate the non-resolving inflammatory microenvironment that promotes prostate cell expansion. In this research, the POET-3 mouse model of inducible autoimmune inflammation is used to evaluate the impact of autoimmune-type inflammation on basal epithelial cell progenitor growth and differentiation in the absence of androgens mimicking the conditions of androgen deprivation therapy (ADT), and to demonstrate the enhanced growth and differentiation potential conferred on basal progenitors by inflammation. </p> <p>Additionally, this research evaluates the morphology, gene expression, and cell-cell interaction predictions of BPH prostate immune cells to explore the role of immune cells and their interactions in driving BPH inflammation. </p> <p>Overall, inflammation induced epithelial and stromal expansion and basal progenitor cell proliferation in vivo and promoted basal progenitor cell growth and differentiation in vitro under androgen-deficient conditions mimicking androgen-targeted therapy. Histologic evaluation of BPH specimens reveals the composition and distribution of immune cells, including organizing lymphoid structures resembling tertiary lymphoid structures (TLS). Also, analyses of single cell RNA sequencing data of gene expression patterns and signaling pathways reveal a mixed inflammatory microenvironment in BPH. Furthermore, predicted ligand-receptor interactions indicate mixed inflammatory signaling between and among immune cell populations, including T cells, macrophages, and mast cells, that likely to the unresolving nature of BPH inflammation.</p> <p>In all, the results of these studies demonstrate inflammation-induced epithelial and stromal expansion in a mouse model of resolving prostatitis and indicate potential roles for multiple immune cell populations and their interactions in driving the ongoing inflammation of BPH, suggesting that this ongoing inflammation may impact the progressive stromal and epithelial expansion characteristic of BPH. </p>

Bakgrund: Prostatacancer är den vanligaste cancerformen som drabbar män i Sverige. Prostatakörteln är lokaliserad strax under urinblåsan och vid prostatacancer växer en tumör i prostatakörteln. Inkontinens, erektil dysfunktion och värmevallningar är vanligt förekommande biverkningar från behandlingen av prostatacancern. Syfte: Syftet med litteraturstudien var att beskriva mäns upplevelser av att leva med prostatacancer efter påbörjad behandling. Metod: Studien genomfördes som en allmän litteraturstudie och från två olika databaser framkom nio resultatartiklar. Resultatartiklarna granskades, bearbetades och sammanställdes till fem teman. Resultat: De teman som framkom var: brist på information, upplevelse av stöd, känslomässigt lidande, sexuell dysfunktion och behandlingspåverkan. Resultatet visade att män med prostatacancer upplevde brist på information från vårdpersonal samt att stöd från familj, vänner och vårdpersonal var en viktig del i hanteringen av prostatacancern. Männen upplevde både fysiskt samt psykiskt lidande. Konklusion: Män med prostatacancer är i behov av adekvat information och stöd. Sjuksköterskan bör även öka sin kunskap om mäns upplevelser av att leva med prostatacancer för att ha mer insikt vid tillämpning av personcentrerad omvårdnad. / Background: Prostate cancer is the most common form of cancer that afflicts men in Sweden. The prostate gland is located below the bladder and in case of prostate cancer a tumor grows inside the prostate gland. Incontinence, erectile dysfunction and hot flashes are common side effects from prostate cancer treatment. Aim: The aim of the literature study was to describe men's experiences of living with prostate cancer after initiated cancer treatment. Method: The study was implemented as a general literature study and nine result articles emerged from two different databases. The resulting articles were reviewed, processed and compiled into five themes. Result: Five main themes were identified: lack of information, experience of support, emotional suffering, sexual dysfunction and treatment impact. It appeared from the results that men with prostate cancer experienced lack of information from healthcare providers and that support from family, friends and healthcare providers was an important part of managing prostate cancer. The men experienced both physical and psychological suffering. Conclusion: Men with prostate cancer are in need of adequate information and support. Nurses should also increase their knowledge of men’s experiences of living with prostate cancer in order to have more insight when applying a person-centered care.

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La curiethérapie prostatique se fait en implantant des grains radioactifs dans une zone tumorale. À cause des soucis temporaux, la planification considère ces grains comme des sources ponctuelles dans un monde uniforme d’eau. Ce mémoire présente une évaluation de l’impact de deux effets perturbant la dosimétrie, avec des méthodes Monte Carlo, en curiethérapie prostatique. L’orientation des sources, négligée actuellement, risque d’altérer la dosimétrie calculée. Cet impact est évalué sur une cohorte de patients (n=287). Aucun impact n’est calculé sur la prostate et l’urètre mais un impact de -2% est calculé sur la vessie et le rectum. La présence de calcifications dans la zone tumorale est négligée par la planification actuelle. Une cohorte de patients (n=43) possédant des calcifications permet d’évaluer cet impact. Il ressort du calcul MC une différence de -13% sur le D90 du CTV et de -16% sur le D10 de l’urètre, en comparaison avec l’algorithme de planification actuel. / Prostatic brachytherapy is performed by inserting radioactive seeds in a tumoral zone. Because of time constraint, clinical planning considers those seeds as point sources in a water medium. This thesis presents the quantification of the impact of two perturbing effects on the dosimetry, evaluated through a Monte Carlo algorithm, in prostatic brachytherapy. Seeds orientation, actually neglected, may alter the clinical dosimetry. The impact of this effect is evaluated on a cohort (n=287) of patients. No effect is calculated on the prostate or the urethra but a difference of -2%, when compared to the clinical algorithm, is calculated on the OARs. Calcifications are actually neglected in the clinical planning. A cohort of patients (n=43) with visible calcifications is used to measure the effect of this approximation. MC calculations yield a difference of -13% on the CTV D90 and -16% on the urethra D10, when compared to the clinical algorithm.

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2010-2011 / Le cancer de la prostate (CaP) représente le cancer le plus fréquemment diagnostiqué chez les hommes de plus de 50 ans au Canada. Considérant l'hétérogénéité clinique du CaP, sa dépendance hormonale et une forte suspicion d'une contribution génétique à son étiologie, il apparaît crucial d'examiner si des polymorphismes au niveau des gènes reliés au métabolisme des androgènes et des oestrogènes seraient associés à une évolution clinique plus ou moins agressive du CaP. La glucuronidation est un processus majeur d'inactivation des hormones stéroïdiennes sexuelles. Cinq polymorphismes fonctionnels des enzymes UDP-glucuronosyltransférases (UGT) ont donc été étudiés. Une déficience en UGT2B17 et UGT2B28 a été associée à un risque accru de récidive biochimique post-prostatectomie chez les patients atteints d'un CaP cliniquement localisé. Ces résultats supportent l'hypothèse que des polymorphismes des UGT associés à une activité moindre conduisent potentiellement à des concentrations intracellulaires en androgènes actifs plus élevées, le tout se traduisant par une prolifération cellulaire accélérée et un pronostic moins favorable.