Abstract not available

ABSTRACT The morphological premalignant changes in prostate epithelium such as high grade prostatic intraepithelial neoplasia (HGPIN) precede invasive prostate cancer (PC) by several decades. The overall aim of this project was to identify patterns of gene expression in HGPIN and early PC which increase our understanding of the early biology of PC and identify genes and pathways that correlate with an aggressive phenotype. A comprehensive tissue cohort of premalignant prostate lesions was collected in a tissue microarray (TMA) platform that was utilised for high-throughput validation of target genes. Using this unique resource, the expression of the tumour suppressor gene PTEN was assessed using immunohistochemistry in an initial candidate gene approach based on mouse models implicating PTEN in carcinogenesis. No significant difference in expression of PTEN was detected in premalignant and benign epithelium. A transcript profiling approach was undertaken by integrating laser capture microdissection, linear RNA amplification and oligonucleotide microarrays to perform a screen of matched patient samples of normal, HGPIN and PC cells. The expression patterns of two genes encoding secreted proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine (MIC-1) were validated using immunohistochemistry on TMAs representing the progression model of early PC. Increased expression of these proteins in PC was confirmed to occur early in the disease process and altered expression of NPY and MIC-1 was associated with worse clinical outcome. Further analysis of global gene expression patterns using a structured network knowledge base identified a notable aberration in the expression of extracellular matrix and extracellular matrix associated proteins in HGPIN and provided novel evidence for the role of this class of molecules in the development of PC. In summary, contrary to current dogma based on work in animal models, altered PTEN expression is unlikely to represent an important event in the development of malignancy in the human prostate. In contrast, the expression patterns and prognostic value of NPY and MIC-1 in HGPIN support their further evaluation as biomarkers for the development and progression of PC. The aberrant expression of genes and networks of genes detected in HGPIN will assist in further identification of biological pathways which may be targeted in therapeutic strategies against the development and progression of PC.

The most common and enduring explanation for the way research is used (or abused or not used) in policy is the ‘two communities’ theory. According to this theory, the problematic relationship between research and policy is caused by the different ‘cultures’ inhabited by policy makers and researchers. The most common and enduring types of strategies that are put forward to increase research use in policy involve bridging or linking these ‘two communities’. This study challenges this way of thinking about the relationship between research and policy. Four case studies of national public health policy in Australia—breast cancer screening, prostate cancer screening, needle and syringe programs in the community, and needle and syringe programs in prisons—are used to present the context, events, processes, research, and actors involved in policy making. Three theories are deployed to explore the relationship between research and policy in each of the cases individually and across the cases as a whole. These theories bring different determinants and dynamics of the relationship to light and each is at least partially successful in increasing our understanding of the relationship between research and policy. The Advocacy Coalition Framework (ACF) understands the relationship in terms of a power struggle between competing coalitions that use research as a political resource in the policy process. The Policy Making Organisation Framework (PMOF) understands the relationship in terms of institutional and political factors that determine the way data is selected or rejected from the policy process. The Governmentality Framework (GF) understands the relationship in terms of the Foucauldian construct of power/knowledge that is created through discourse, ‘regimes of truth’ and ‘regimes of practices’ found in public health policy and research. This study has found that in three of the four case studies, public health policy was strongly influenced by research, the exception being NSP in prisons. In all cases, however, it is not possible to construct a robust and coherent account of the policy process or the policy outcome without considering the multifaceted role of research. When these theories are explored at a more fundamental level they support the argument that when research influences policy it is transformed into knowledge-for-policy by being invested with meaning and power. This process of transformation occurs through social and political action that mobilises ideal structures (such as harm minimisation and the World Health Organisation’s principles for evaluating screening programs) and material structures (such as medical journals and government advisory bodies) to resolve meta-policy problems (such as how to define complex public health problems in a way that makes them amenable to empirical research and practical action). This study provides good evidence that the notion of ‘research transfer’ between ‘two communities’ is a flawed way of understanding the research–policy relationship. Rethinking the relationship between research and policy involves building an enhanced theoretical repertoire for understanding this complex social interaction. This step is essential to the success of future efforts to make public health policy that is effective, just and emancipatory. This study makes a contribution to this task.

<p><strong>Bakgrund- </strong>Prostatacancer är en av de vanligaste cancerformerna i Sverige och nästan 34 % av alla fall av cancer hos män är prostatacancer. Radikal prostatektomi är en behandling som innebär att hela prostatan och intilliggande körtlar tas bort. Prostatektomi kan ha negativ påverkan på livskvaliteten p.g.a. ingreppets komplikationer.</p><p><strong>Syfte- </strong>att belysa hur män upplever sin livskvalitet efter att ha genomgått en prostatektomi.</p><p><strong>Metod- </strong>En systematisk litteraturstudie. Artiklar har sökts fram i elektroniska databaser. Tio artiklar har granskats enligt kriterier för kvalitetsgranskning där nio kvalificerats och används i resultatet. Inspireras av kvalitativ analys och identifierat olika teman i texten. Vi kom fram till fyra kategorier som vi redovisar resultaten ifrån: fysiska, psykiska, sociala och omvårdnadsaspekter.</p><p><strong>Resultat- </strong>Sexualitet, relationer, männens upplevelse av självkänsla och kontroll över sin kropp samt informationsbrist var de viktigaste områdena där livskvaliteten påverkades negativt.</p><p><strong>Slutsats</strong>- Radikal prostatektomi innebar en stor förändrig för männens livskvalitet och deras liv. Vi tror att mer forskning behövs inom ämnesområdet för att få en djupare förståelse för hur männen upplever sin livskvalitet efter operationen.</p>

<p>The natural history of localized prostate cancer is not fully understood. In most patients the tumor will never progress to a lethal disease, while a subset of patients will ultimately die of the disease. Efficient tools to separate indolent from lethal disease is currently lacking which means that many patients will be offered treatment without any benefit, but still be at risk of experiencing treatment related side effects.</p><p>The aims of these studies were to get more insight into the natural history of untreated localized prostate cancer, to assess the prognostic value of established clinical parameters such as Gleason score, nuclear grade and tumor volume and, moreover, some new prognostic markers Ki-67, AMACR and MUC-1. We also aimed to study time trends in the detection of incidental tumors in Sweden.</p><p>Patients with localized disease (n=223) and no initial treatment were followed for 21 years. Most patients had a favorable outcome. However, a subset of patients developed lethal disease even beyond 15 years of follow-up and these patients define the group that may benefit most from treatment with curative intent. Patients with poorly differentiated tumors experienced a 9 time higher risk of dying in prostate cancer.</p><p>The studies on prognostic markers are based on a cohort of patients (n=253) with incidental prostate cancer detected by transurethral resection for presumed benign hyperplasia. All patients were left without initial treatment. Gleason grade, nuclear grade and tumor volume turned all out to be independent prognostic factors. MUC-1, AMACR and Ki-67 also carried prognostic information. However, after adjustment for Gleason grade, nuclear grade and tumor volume only MUC-1 and AMACR remained as statistically significant prognostic factors. When tested for sensitivity and specificity they all failed and, consequently, they seem to be of less value in daily practice for cancelling an individual patient regarding the choice of treatment.</p><p>Time trends in incidental prostate tumors in Sweden were analyzed in a cohort of patients with prostate tumors detected by transurethral resection (TUR-P). Through linkage of the national registration number (NRN) with several registers, e.g. the Swedish Cancer Registry, the National Inpatient registry and the Cause of Death Registry we identified, during the period 1970 through 2003, in total 23288 patients with incidental prostate cancer, who constituted the study group. As comparison group we choose all patients diagnosed with prostate cancer between 1970-2003 excluding those with incidental cancer, in total 112204 patients. Our result confirms earlier findings that there has been a dramatic change over time in incidence of incidental prostate cancers in Sweden, which parallels the introduction of prostate specific antigen. We also found that the cumulative incidence of prostate cancer death is high in the incidental group, opposing earlier findings that incidental tumours are a non-lethal disease.</p> / issn 1642-4063

<p>The main focus of my thesis has been to develop protocols for generating antigen-specific cytotoxic T lymphocytes (CTLs) and T helper cells (T_H) for adoptive transfer to treat cytomegalovirus (CMV) disease and prostate cancer. CMV viremia is a severe complication in immunocompromised stem cell transplanted patients. Prostate cancer is a leading cause of death for men in Western countries. Although different in nature, CMV-infected cells and prostate cancer cells can both be eliminated through specific activation of the adaptive immune system. </p><p>To generate CMV pp65-specific T cells, I utilized dendritic cells (DCs) modified with an HLA-A*0201/pp65_495-503 peptide, a recombinant adenovirus coding for pp65, <i>in vitro</i> transcribed pp65 mRNA and a recombinant pp65 protein. Peptide stimulation yielded large numbers of peptide-specific CD8⁺ T cells with high lytic activity while adenovirus or mRNA stimulation resulted in the expansion of CTLs against multiple pp65 epitopes. The recombinant protein activated primarily CD4⁺ T_H cells. Stimulation with DCs co-modified with pp65 mRNA and pp65 protein simultaneously generated both pp65-specific CTLs and T_H cells. Such T cells would cover all pp65 epitopes while avoiding potential virus related biohazards. The mRNA/protein combinatory approach can be used to stimulate T cells <i>ex vivo</i> from virtually all stem cell donors for adoptive T cell transfer. </p><p>I have identified two immunogenic HLA-A*0201-restricted peptide epitopes from the prostate tissue antigen TARP. Repeated stimulations with TARP peptide-pulsed DCs yielded up to 20% TARP-directed CD8⁺ T cells even when starting from undetectable frequencies (<0.01%). The T cells could be sorted to 99% purity and expanded 1000-fold with retained specificity and activity. We also detected TARP-directed CD8⁺ T cells in the blood of prostate cancer patients. Therefore, TARP seems to have potential as antigen in DC vaccination or adoptive T cell therapy of prostate cancer. </p>

There is an ever increasing need of new technologies for identification of molecular markers for early diagnosis of fatal diseases to allow efficient treatment. In addition, there is great value in finding patterns of metabolites, proteins or genes altered in relation to specific disease conditions to gain a deeper understanding of the underlying mechanisms of disease development. If successful, scientific achievements in this field could apart from early diagnosis lead to development of new drugs, treatments or preventions for many serious diseases.  Metabolites are low molecular weight compounds involved in the chemical reactions taking place in the cells of living organisms to uphold life, i.e. metabolism. The research field of metabolomics investigates the relationship between metabolite alterations and biochemical mechanisms, e.g. disease processes. To understand these associations hundreds of metabolites present in a sample are quantified using sensitive bioanalytical techniques. In this way a unique chemical fingerprint is obtained for each sample, providing an instant picture of the current state of the studied system. This fingerprint or picture can then be utilized for the discovery of biomarkers or biomarker patterns of biological and clinical relevance. In this thesis the focus is set on evaluation and application of strategies for studying metabolic alterations in human tissues associated with disease. A chemometric methodology for processing and modeling of gas chromatography-mass spectrometry (GC-MS) based metabolomics data, is designed for developing predictive systems for generation of representative data, validation and result verification, diagnosis and screening of large sample sets. The developed strategies were specifically applied for identification of metabolite markers and metabolic pathways associated with prostate cancer disease progression. The long-term goal was to detect new sensitive diagnostic/prognostic markers, which ultimately could be used to differentiate between indolent and aggressive tumors at diagnosis and thus aid in the development of personalized treatments. Our main finding so far is the detection of high levels of cholesterol in prostate cancer bone metastases. This in combination with previously presented results suggests cholesterol as a potentially interesting therapeutic target for advanced prostate cancer. Furthermore we detected metabolic alterations in plasma associated with metastasis development. These results were further explored in prospective samples attempting to verify some of the identified metabolites as potential prognostic markers.

The main focus of my thesis has been to develop protocols for generating antigen-specific cytotoxic T lymphocytes (CTLs) and T helper cells (TH) for adoptive transfer to treat cytomegalovirus (CMV) disease and prostate cancer. CMV viremia is a severe complication in immunocompromised stem cell transplanted patients. Prostate cancer is a leading cause of death for men in Western countries. Although different in nature, CMV-infected cells and prostate cancer cells can both be eliminated through specific activation of the adaptive immune system. To generate CMV pp65-specific T cells, I utilized dendritic cells (DCs) modified with an HLA-A*0201/pp65495-503 peptide, a recombinant adenovirus coding for pp65, in vitro transcribed pp65 mRNA and a recombinant pp65 protein. Peptide stimulation yielded large numbers of peptide-specific CD8+ T cells with high lytic activity while adenovirus or mRNA stimulation resulted in the expansion of CTLs against multiple pp65 epitopes. The recombinant protein activated primarily CD4+ TH cells. Stimulation with DCs co-modified with pp65 mRNA and pp65 protein simultaneously generated both pp65-specific CTLs and TH cells. Such T cells would cover all pp65 epitopes while avoiding potential virus related biohazards. The mRNA/protein combinatory approach can be used to stimulate T cells ex vivo from virtually all stem cell donors for adoptive T cell transfer. I have identified two immunogenic HLA-A*0201-restricted peptide epitopes from the prostate tissue antigen TARP. Repeated stimulations with TARP peptide-pulsed DCs yielded up to 20% TARP-directed CD8+ T cells even when starting from undetectable frequencies (&lt;0.01%). The T cells could be sorted to 99% purity and expanded 1000-fold with retained specificity and activity. We also detected TARP-directed CD8+ T cells in the blood of prostate cancer patients. Therefore, TARP seems to have potential as antigen in DC vaccination or adoptive T cell therapy of prostate cancer.

Background: The secretory epithelial cells of the prostate gland use sophisticated vehicles named prostasomes to relay important information to sperm cells in semen. This prostasome-forming and secretory ability of the epithelial cells is also preserved in poorly differentiated prostate cancer cells. Aim: The aim of this thesis was to examine different characteristics of prostasomes, especially those derived from malignant prostate cells, linked to their potential role in diagnosis and prognostication of prostate cancer. Results: Serum samples of prostate cancer patients contained autoantibodies against seminal prostasomes in a higher concentration than did control sera. These autoantibodies were most frequently directed against 25 prostasome-associated proteins, but no one was prostate specific. Clusterin was one of the most frequently occurring prostasomal proteins. Elevated titers were however seen in both patients´ and control sera. Clusterin turned out to be a major antigen of seminal prostasomes. No prostate specific or prostate cancer specific protein was discovered upon proteomic analysis of prostasomes deriving from malignant cells of vertebral metastases of prostate cancer patients. Human chromosomal DNA was identified in both seminal prostasomes and PC-3 cell prostasomes and strong evidence existed that the DNA was localized inside the prostasomes. Four out of 13 DNA clones of seminal prostasomes featured gene sequences (31%). The corresponding figures for PC-3 cell prostasomes were 4 out of 16 clones (25%). Conclusions: Prostasomes are immunogenic and give rise to serum autoantibodies. The most frequently occurring autoantibodies were directed against 25 prostasomal proteins but none of these was exclusively prostate specific. Thirty different proteins were identified in prostate cancer metastasis-derived prostasomes but none of these proteins was prostate cancer specific. Human chromosomal DNA was identified in prostasomes of both normal and malignant cell origin.

The purpose of this thesis is to explore how men experience living with localized prostate cancer. It includes four substudies carried out between 1997 and 2005. To gather data, the men were interviewed at home and the interviews were recorded. The men (n=27; ages 60-70) who participated in the substudies had a PSA ≤10 ng/ml at the time of diagnosis, and had what is known as low-risk prostate cancer. Seven of the men chose to “wait and see” how the disease would progress after receiving the diagnosis. Twenty men chose curative treatment (10 men external radiation therapy, 10 men radical surgery). The interviews were analyzed using a phenomenological hermeneutical method inspired by the philosophy of Paul Ricoeur, and qualitative content analysis. Men who live with localized prostate cancer perceive the disease as life-threatening, unpredictable, and without early symptoms, which creates a sense of uncertainty, worry, anxiety, despair, and fear of death. Men primarily share perceptions of the disease and treatment with their wives and relatives, as well as with other men in the same situation. They avoid talking about their illness, and keep their innermost thoughts about their disease, prognosis, and the future to themselves. The choice to share their thoughts and feelings only sparingly with others is related in part to the perceived stigmatization of the diagnosis, as well as to consideration for friends and family. The men report that external radiation therapy and radical surgery have negative side effects such as erectile dysfunction, urinary incontinence, and intestinal leakage. They describe the side effects as socially isolating; for example, urinary leakage can require a change of incontinence pads and clothing, and they feel that they smell bad. Men with erectile dysfunction describe themselves as maimed, and their sex lives have changed or disappeared. They report a change in their self-esteem and identity as men and they long for life as it was before the diagnosis, when they felt they had control over their bodily functions. A few men describe a sense of being literally and figuratively “exposed” when they are undressed for examinations or participate in discussions with female doctors and nurses about their erectile dysfunction. They do not describe this perception in the same way with respect to contact with male personnel. In the new situation after treatment, men try to regain a perceived sense of control in their daily lives, over the disease and the effects of treatment. They experience a sense of control over the disease through regular PSA tests; the implications of regular PSA tests can be interpreted as a life preserver in an uncertain world, considering that at the time they were diagnosed they had no symptoms and only had a PSA elevation. The PSA is important for this sense of control, and each PSA test is preceded by tense expectation. The PSA level is described as a reliable expression of the medical condition. The men cannot trust that their own perception of feeling healthy means that the disease is under control. Low and stable PSA levels over a long period of time give a sense of safety, security, and control over the situation. If the PSA climbs, the men feel that despite everything, they have caught it in time for further treatment. Discussions with other men with prostate cancer are also described as a way of having control over the situation. The men's endeavor to reconcile themselves to the new situation can be understood as a process, where they describe various strategies which can be used to forget the “cancer perspective” and achieve a perception of safety and security. Reconciliation with a new situation can be interpreted as a reorientation after the trauma of the cancer diagnosis. The study results show that the men are restrained in communicating their needs to others, which can be interpreted as their having a greater need for support and information than indicated by their signals. Having an internal image of what a man should be like can be an obstacle to showing these needs.