by Cheung Tak Chi. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 117-123). / Abstract also in Chinese. / Acknowledgeements --- p.i / Abbreviations --- p.ii / Abstract --- p.v / List of Figures --- p.viii / List of Tables --- p.xiv / Contents --- p.xv / Contents / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- Epidemiological Risk Factors --- p.1 / Chapter 1.1.1 --- Age --- p.1 / Chapter 1.1.2 --- Race --- p.2 / Chapter 1.1.3 --- Environmental or Migratory Factor --- p.2 / Chapter 1.1.4 --- Diet --- p.2 / Chapter 1.1.5 --- Genetics --- p.3 / Chapter 1.2 --- Regulation of Normal Prostate Development and Function --- p.4 / Chapter 1.3 --- Biochemistry and Development of Prostate Cancer --- p.6 / Chapter 1.3.1 --- Androgen-Dependent Prostate Cancer --- p.6 / Chapter 1.3.2 --- Androgen-Independent Prostate Cancer --- p.8 / Chapter 1.4 --- Classification of Prostate Cancer --- p.9 / Chapter 1.4.1 --- Stage A Prostate Cancer --- p.10 / Chapter 1.4.2 --- Stage B Prostate Cancer --- p.10 / Chapter 1.4.3 --- Stage C Prostate Cancer --- p.11 / Chapter 1.4.4 --- Stage D Prostate Cancer --- p.11 / Chapter 1.5 --- Methods for Early Detection of Prostate Cancer --- p.12 / Chapter 1.6 --- Clinical Treatment of Prostate Cancer --- p.12 / Chapter 1.6.1 --- Surgery --- p.12 / Chapter 1.6.2 --- Radiotherapy --- p.13 / Chapter 1.6.3 --- Chemotherapy --- p.13 / Chapter 1.6.4 --- Hormonal Therapy --- p.13 / Chapter 1.7 --- Objective --- p.14 / Chapter 1.8 --- Estrogen and Its Related Compounds --- p.16 / Chapter 1.8.1 --- 17β-Estradiol --- p.16 / Chapter 1.8.2 --- Tamoxifen --- p.18 / Chapter 1.8.3 --- Aromatase Inhibitor --- p.20 / Chapter 1.9 --- Anticancer Drugs --- p.23 / Chapter 1.9.1 --- Doxorubicin --- p.23 / Chapter 1.9.2 --- cis-Platinum --- p.24 / Chapter 1.10 --- Apoptotic Pathways --- p.25 / Chapter 1.10.1 --- BCL-2 /BAD Pathway --- p.26 / Chapter 1.10.2 --- FADD Pathway --- p.27 / Chapter 1.10.3 --- CAS Pathway --- p.27 / Chapter 2. --- Materials and Methods --- p.28 / Chapter 2.1 --- Materials --- p.28 / Chapter 2.2 --- Cell Lines --- p.32 / Chapter 2.3 --- Preparation of Drugs --- p.32 / Chapter 2.4 --- Drug Sensitivity Assay --- p.33 / Chapter 2.5 --- Cell Cycle Analysis --- p.35 / Chapter 2.6 --- DNA Fragmentation Assay --- p.36 / Chapter 2.7 --- Annexin Binding Assay --- p.37 / Chapter 2.8 --- Western Blot Analysis --- p.38 / Chapter 2.9 --- Data Analysis --- p.41 / Chapter 3. --- Results --- p.42 / Chapter 3.1 --- Response of Human Androgen-Independent Prostate Cancer Cells to Doxorubicin and cis-Platinum --- p.42 / Chapter 3.2 --- The Effect of 17p-Estradiol on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.45 / Chapter 3.2.1 --- 17β-Estradiol on Cell Growth --- p.45 / Chapter 3.2.2 --- 17β-Estradiol on Anticancer Drug Sensitivity --- p.45 / Chapter 3.2.3 --- 17β-Estradiol and Doxorubicin on Cell Cycle Progression --- p.51 / Chapter 3.2.4 --- 17β-Estradiol and Doxorubicin Induced DNA Fragmentation --- p.57 / Chapter 3.2.5 --- 17β-Estradiol and Doxorubicin on Annexin Staining --- p.59 / Chapter 3.2.6 --- 17β-Estradiol and Doxorubicin on Apoptotic Protein Expression --- p.62 / Chapter 3.3 --- The Effect of Tamoxifen on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.64 / Chapter 3.3.1 --- Tamoxifen on Cell Growth of Human --- p.65 / Chapter 3.3.2 --- Tamoxifen on Anticancer Drug Sensitivity --- p.65 / Chapter 3.3.3 --- Tamoxifen and Doxorubicin on Cell Cycle Progression --- p.71 / Chapter 3.3.4 --- Tamoxifen and Doxorubicin Induced DNA Fragmentation --- p.76 / Chapter 3.3.5 --- Tamoxifen and Doxorubicin on Annexin Staining --- p.78 / Chapter 3.3.6 --- Tamoxifen and Doxorubicin on Apoptotic Protein Expression --- p.79 / Chapter 3.4 --- The Effect of Aromatase Inhibtiors on the Growth and Anticancer Drug Sensitivity of Human Androgen-Independent Prostate Cancer Cells --- p.81 / Chapter 3.4.1 --- Aromatase Inhibitors on Cell Growth --- p.81 / Chapter 3.4.2 --- Aromatase Inhibitors on Anticancer Drug Sensitivity --- p.83 / Chapter 3.4.3 --- 4-AcA and Doxorubicin on Cell Cycle Progression --- p.93 / Chapter 3.4.4 --- 4-AcA and Doxorubicin Induced DNA Fragmentation --- p.99 / Chapter 3.4.5 --- 4-AcA and Doxorubicin on Annexin Staining --- p.100 / Chapter 3.4.6 --- 4-AcA and Doxorubicin on Apoptotic Protein Expression --- p.102 / Chapter 4. --- Discussion --- p.105 / Chapter 4.1 --- 17 β-Estradiol and Anticancer Drug Sensitivity --- p.106 / Chapter 4.2 --- Tamoxifen and Anticancer Drug Sensitivity --- p.109 / Chapter 4.3 --- Aromatase Inhibitors and Anticancer Drug Sensitivity --- p.112 / Chapter 4.4 --- DU145 Cells vs PC3 Cells --- p.115 / Chapter 5. --- Conclusion and Perspectives --- p.116 / Chapter 6. --- References --- p.117

Background and aims of the study. Prostate cancer (PCa) is one of the most common hormone-dependent cancers in men in Western and also Asian countries. The standard treatment options for localized PCa include surgery and androgen-deprivation therapy (ADT). However, most patients upon ADT therapy invariably relapse and progress to a more aggressive and metastatic stage termed as castration-resistant PCa (CRPC). Accumulating studies indicate that androgen receptor (AR) transcriptional activity is dysregulated during the advanced progression of CRPC. One important mechanism responsible for the growth of CRPC includes increased intra-tumoral androgen synthesis in PCa. Recently, a novel androgen-responsive fusion gene TMPRSS2:ERG formed by fusion between the transmembrane protein TMPRSS2 and transcription factor ERG, has been identified in approximately 50% PCa samples, which results in the aberrant expression of ERG function as oncogenic factor in PCa. Currently, TMPRSS2:ERG is regarded as a significant potential diagnostic and prognostic biomarker for PCa. Estrogen-related receptor alpha-ERRα, the first identified ligand-independent orphan nuclear receptor, is characterized to be up-regulated in advanced cancers, suggesting that ERRα might play important regulatory roles in the malignant progression of PCa. Previous studies showed that ERRα can functionally cross-talk with AR signaling via co-targeting to AR targets and regulate the expression of some steroidogenic enzymes in breast cancer. Based on this background, it is hypothesized that ERRα could functionally regulate the TMPRSS2:ERG fusion gene and play a regulatory role in the development and progression of CRPC through activation of the intracellular androgen synthesis pathway. / Results. 1) The results obtained in this study showed that suppression of ERRα by its specific inverse agonist XCT790 or shRNA-knockdown could induce down-regulation of TMPRSS2:ERG and also its target genes in AR-positive VCaP PCa cells. 2) Ectopic expression of ERRα and/or its coactivator PGC-1α could increase the expression of TMPRSS2:ERG in AR-negative NCI-H660 PCa cells. 3) Two ERRα-DNA binding elements were identified by ChIP assay and sequence analysis in the promoter of TMPRSS2:ERG and both of these two elements could be transactivated by ERRα and PGC-1α. 4) Ectopic expression of TMPRSS2:ERG under the regulation of ERRα enhanced the prostatic cell invasion capacity as shown in the TMPRSS2:ERG infectants of BPH-1 and PC-3 prostatic cells. 5) ERG expressed by the TMPRSS2:ERG fusion could directly transactivate the ERRα gene in prostatic cells. 6) A positive correlation on the expressions between TMPRSS2:ERG and ERRα was demonstrated in a xenograft model of CRPC (VCaP-CRPC). 7) The expression of TMPRSS2:ERG and ERRα showed significant up-regulation and the transactivation activity of ERRα was also enhanced in castration-resistant VCaP-CRPC cells. 8) Ectopic expression of ERRα could promote resistant growth capacity to androgen-deprivation condition in LNCaP PCa cells, whereas shRNA-mediated silence of ERRα could weaken this resistant capacity. Furthermore, ectopic expression of ERRα in LNCaP-ERRα infectants could promote their in vivo growth resistance to castration in SCID mice. 9) Expression of several androgenic enzyme genes, including CYP11A1, CYP17A1 and ARK1C3, were detected to be up-regulated in castration-resistant VCaP-CRPC cells. Moreover, ectopic expression of ERRα could induce the increased expression of these enzyme genes in LNCaP-ERRα infectants, whereas knockdown of ERRα by shRNA could decrease their expression. 10) ERRα could directly transactivate the gene promoters of CYP11A1, CYP17A1 and ARK1C3 which contain ERRE elements prediction by sequence analysis. These results suggested that ERRα could play a role in de novo or intra prostatic androgen synthesis in the PCa cells. / Conclusions. The results obtained in this study suggested that ERRα and TMPRSS2:ERG could form a positive reciprocal loop in PCa cells, and ERRα could also promote the resistant growth capacity of PCa cells resistant to the androgen-deprivation condition in vitro and also castration-resistant growth in vivo via a mechanism of up-regulation of androgenic enzyme genes. The results also suggested that ERRα might play a significant regulatory role in the development and progression of PCa, particularly the advanced CRPC, and also ERRα could be a potential therapeutic target for the treatment of PCa, particularly the advanced PCa-CRPC. / 研究背景與研究目的：前列腺癌作為激素依賴的一種癌症，經常出現在西方和亞洲國家的男性人群中。對於局限性前列腺癌多採用外科手術和去勢的治療。但是大多數病人經過去勢治療后會再次復發並且形成更加惡心幾轉移的前列腺癌，稱之為去勢難治性前列腺癌（CRPC）。越來越多的研究表明在去勢難治性前列腺癌發病過程中，雄激素受體轉錄活性異性增強。其中一個重要機理解釋為前列腺癌細胞自身合成的雄激素增多。進來，在大約50%的前列腺癌病人中新檢測到一個受雄激素受（AR）體調控的融合基因TMPRSS2:ERG，它是由稱為TMPRSS2的一個跨膜蛋白和一個稱為ERG的轉錄因子融合而成，它的出現導致了在前列腺癌中異常的稱為致癌因子的ERG蛋白的高表達。目前，TMPRSS2:ERG已經被作為一個重要的潛在的診斷和預測的標誌物應用在前列腺癌中。作為第一個鑒定的配體不依賴的孤兒受體-ERRα，被證明在晚期的癌症中有很高的表達，預示著ERRα可能在惡性的癌症中起到一個非常重要的調控作用。之前的研究表明通過共同調控AR的下游基因，ERRα同AR信號通路之間有功能性的交叉調控；除此之外，在乳腺癌中，ERRα還可以調控一些類固醇類化合物的合成相關的一些酶的合成。依據上述，我們推定ERRα可能功能性地調控TMPRSS2:ERG融合基因的表達並且通過調控細胞內的雄激素的合成進而在去勢難治性前列腺癌的發生和發展中起到一個非常重要的作用。 / 結果：本論文研究結果總結如下：1）在有AR表達的前列腺癌細胞-VCaP細胞中，通過ERRα特異性的抑制劑XCT790處理或者shRNA介入的干擾ERRα的mRNA的方法來抑制ERRα，下調了TMPRSS2:ERG和它的一些下游調控基因的表達。2）在沒有AR表達的前列腺癌細胞-NCI-H660細胞中，上調ERRα或者它的特異性的共激活因子PGC-1α表達可以提升TMPRSS2:ERG的表達。3）通過ChIP實驗，在TMPRSS2:ERG的啟動子上面，兩個ERRα的DNA結合位點被鑒定出來。並且這兩個位點可以被ERRα和PGC-1α轉錄激活。4）在兩個前列腺細胞BPH-1和PC-3細胞中，在ERRα的調控下高表達TMPRSS2:ERG融合基因可以增強細胞的侵襲能力。5）融合基因TMPRSS2:ERG導致的ERG蛋白的表達可以直接轉錄激活ERRα的表達。6）我們通過VCaP細胞的異種移植建立VCaP-CRPC的體內模型來模擬CRPC過程，在整個過程中，我們發現TMPRSS2:ERG和ERRα有一致性的表達相關性。除此之外，我們根據上述動物模型通建立了VCaP-CRPC細胞系，並且發現在VCaP-CRPC細胞細胞中，TMPRSS2:ERG和ERRα都有被上調並且ERRα的轉錄活性同樣也提升。7）在LNCaP細胞中高表達ERRα可以提升細胞在去除雄激素的環境中生長的能力。但是當在LNCaP細胞中用shRNA干擾掉ERRα可以明顯減弱這種生長的能力。用LNCaP-ERRα穩轉ERRα的細胞異種移植建立SCID老鼠體內腫瘤模型，我們發現和LNCaP-pBABE對照組相比，LNCaP-ERRα細胞生長的更快更大。並且在對老鼠進行睪丸切除術后，LNCaP-ERRα組細胞更快適應這種環境并繼續生長，相比之下，LNCaP-pBABE對照組則持續萎縮減小。8）在上述的VCaP-CRPC細胞中，我們發現一些和雄激素合成相關的關鍵的酶包括CYP11A1，CYP17A1和ARK1C3的表達量有顯著地提升。而且在LNCaP-ERRα細胞中同樣檢測到這些酶的表達量的提升。然而當在LNCaP細胞中用shRNA干擾掉ERRα可以明顯減降低上述酶的表達。9）我們在CYP11A1，CYP17A1和ARK1C3基因的啟動子區域發現有ERRα結合位點，並且發現這些位點可以被ERRα轉錄激活。 / 結論：本論文的研究結果提示在前列腺癌細胞中，ERRα和TMPRSS2:ERG可以形成一個相互正向調控的循環。除此之外，上調ERRα可以促進細胞在去除雄激素的環境中生長的能力，並且在動物體內可以提升細胞在睪丸去除的環境中的適應和生長能力。這種體內和體外的能力的提升是通過一種潛在的上調前列腺癌細胞的雄激素合成相關的關鍵的酶的表達，進而提升雄激素的含量而得以實現的。上述的結果預示著ERRα可能在前列腺癌發生機發展的過程中起到非常重要的調控作用，尤其在晚期的CRPC中。同時，ERRα也可能作為一個潛在的重要的前列腺癌尤其是晚期的CRPC的治療靶點，尤其是一些潛在ERRα的特異性抑制劑，比如XCT790，可能作為將來用以作為治療前列腺癌的特異性靶點藥物。 / Xu, Zhenyu. / Thesis Ph.D. Chinese University of Hong Kong 2014. / Includes bibliographical references (leaves 126-143). / Abstracts also in Chinese. / Title from PDF title page (viewed on 05, October, 2016). / Xu, Zhenyu. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

OBJETIVOS: Avaliar o tempo de internação hospitalar e fatores preditores de internação prolongada após PRR realizada em instituição de ensino de alto volume cirúrgico. Objetivos secundários incluíram avaliar taxa de visitas não planejadas ao ambulatório e ao pronto-atendimento, readmissões hospitalares e taxa de complicações perioperatórias utilizando método de classificação padronizado. MÉTODOS: Foi realizada análise retrospectiva de dados prospectivamente coletados em base de dados padronizada para doentes portadores de câncer de próstata localizado submetidos a PRR no ICESP. Os procedimentos foram realizados por residentes do último ano de Urologia sob supervisão de um médico assistente (com experiência superior a 300 PRRs). Internação prolongada foi definida com internação > 2 dias (quartil superior). Um modelo de regressão logística incluindo apenas variáveis pré-operatórias foi inicialmente construído para determinar os fatores que predizem internação prolongada antes do ato cirúrgico; subsequentemente um segundo modelo incluindo tanto variáveis pré como intra e pós-operatórias foi analisado. As variáveis pré-operatórias incluídas no modelo foram: Idade, raça, IMC, PSA, índice de comorbidade de Charlson ajustado e não ajustado por idade, escore de ASA, cirurgias abdominais prévias, estádio clínico, volume prostático, Gleason da biópsia e porcentagem de fragmentos positivos, estratificação de risco NCCN. Os fatores intra e pós-operatórios incluídos na análise foram: tipo de anestesia, tempo operatório, sangramento estimado, transfusão sanguínea, preservação do feixe neurovascular, dissecção linfonodal, peso da próstata, volume tumoral, escore de Gleason do espécime, status da margem cirúrgica, estádio patológico e, finalmente, presença de complicações pós-operatórias (de acordo com o sistema de Clavien). RESULTADOS: Entre janeiro de 2010 e janeiro de 2012, 1011 pacientes foram submetidos a PRR em nossa instituição. A mediana de tempo de internação foi de 2 dias, sendo que 217 (21,5%) pacientes apresentaram internação prolongada. Os fatores preditores de internação prolongada dentre as variáveis pré-operatórias foram ICCa (OR. 1,317, IC95% 1,106-1,568, p=0,002) ou ICC não ajustado e idade separadamente (OR. 1,401, IC95% 1,118-1,756, p=0,003 e OR 1,050, IC95% 1,023-1,078, p < 0,001, respectivamente), escore de ASA 3 (OR. 3,260, IC95% 1,646-6,455, p < 0,001), volume prostático no USG-TR (OR, 1,005, IC95% 1,001-1,011, p=0,038) e raça negra (OR. 2,235, IC95% 1291-3,869, p=0,004); considerando-se também fatores intra e pós-operatórios na regressão, o tempo operatório (OR 1,007, IC95% 1,001-1,013, p=0,022) e presença de complicações de qualquer grau (OR 2,013, IC95% 1,192-3,399, p=0,009) ou complicações maiores (OR 2,357, IC95% 1,228-4,521, p=0,01) também foram correlacionados de maneira independente com internação prolongada. A taxa de readmissão hospitalar nesta série foi de 2,7%; visitas não programadas ao pronto atendimento ocorreram em 7,3% dos casos. A taxa global de complicações (intra e pós-operatórias) foi de 14,5%; a incidência de complicações pós-operatórias menores (graus 1 e 2) e maiores (Grau 3 ou 4) foi de 8,5% e 5,4%, respectivamente. CONCLUSÃO: Os fatores preditores independentes de internação prolongada dentre as variáveis pré-operatórias foram ICCa (ou ICC não ajustado e idade separadamente), escore de ASA 3, volume prostático no USG-TR e raça negra; considerando-se também fatores intra e pós-operatórios, o tempo operatório e presença de complicações de qualquer grau e complicações maiores foram correlacionados de maneira independente com internação prolongada. A identificação destes fatores permite não só auxiliar no planejamento de gastos e aconselhamento de pacientes, mas potencialmente promover modificações de variáveis que possam reduzir o tempo de admissão dos pacientes após PRR / OBJECTIVES: To evaluate the length hospital stay and predictors of prolonged hospitalization after RRP performed in a high-surgical volume teaching institution. Secondary objectives were to analyze the rate of unplanned visits to the office and emergency care, hospital readmissions and perioperative complications rates using a standardized classification system. METHODS: Retrospective analysis of prospectively collected data in a standardized database for patients with localized prostate cancer undergoing RRP in our institution. The procedures were performed by senior residents under the supervision of a staff surgeon (with prior experience larger than 300 RRPs). Prolonged hospitalization was defined as hospital stay longer than 2 days (upper quartile). A logistic regression model including only preoperative variables was initially built to determine the factors that predict prolonged hospital stay before the surgical procedure; subsequently, a second model including both pre and intraoperative variables was analyzed. Preoperative variables included in the model were age, race, BMI, PSA, Charlson comorbidity index (adjusted and not adjusted for age), ASA score, previous abdominal surgery, clinical stage, prostate volume, biopsy Gleason and percentage of positive cores, NCCN risk stratification. Intra and postoperative factors included in the analysis were: type of anesthesia, operative time, estimated bleeding loss, transfusion, nerve-sparing approach, lymph node dissection, prostate weight, tumor volume, Gleason score specimen, positive margin rates, pathologic stage, and, finally, the presence of postoperative complications (according to Clavien grading system). RESULTS: Between January 2010 and January 2012, 1011 patients underwent RRP at our institution. The median hospital stay was 2 days, and 217 (21.5%) patients had prolonged hospitalization. Predictors of prolonged hospital stay among the preoperative variables were ICCa (OR. 1.317, 95% CI 1.106 to 1.568, p = 0.002) or unadjusted ICC and age separately (OR. 1.401, 95% CI 1.118 to 1.756, p = 0.003 and OR 1.050, 95% CI 1.023 to 1.078, p < 0.001, respectively), ASA score of 3 (OR. 3.260, 95% CI 1.646 to 6.455, p < 0.001), prostate volume on USG-TR (OR, 1.005; 95% CI 1.001 -1.011, p = 0.038) and African-American race (OR 2.235, 95% CI 1291 to 3.869, p = 0.004).; considering also intra and postoperative factors, operative time (OR 1.007, 95% CI 1.001 to 1.013, p = 0.022) and the presence of any complications (OR 2.013, 95% CI 1.192 to 3.399, p = 0.009) or major complications (OR 2.357, 95% CI 1.228 to 4.521, p = 0.01) were also correlated independently with prolonged hospital stay. Hospital readmission rate in this series was 2.7%; unscheduled visits to emergency care occurred in 7.3% of cases. The complication rate was 14.5%; the incidence of minor (grades 1 and 2) and major complications (Grade 3 or 4) was 8.5% and 5.4%, respectively. CONCLUSION: The independent predictors of prolonged hospitalization among the preoperative variables were ICCa (or unadjusted ICC and age separately), ASA score of 3, prostate volume on USG-TR and African-American race; considering also intra and postoperative factors, operative time, presence of any complications and major complications were correlated independently with prolonged hospital stay. The identification of these factors allows not only better planning the institutional costs related to RRP but also proper counseling of patients undergoing RRP; potentially modifiable risk factors can be optimized to shorter length of hospital stay after RRP

<p>När en man diagnostiseras med prostatacancer innebär det en psykisk påfrestning för mannen och hans kvinnliga partner. Reaktioner som chock, meningsförlust, ensamhet och ångest är vanligt förekommande. Syftet med denna litteraturstudie var att beskriva hur det vardagliga livet upplevs och påverkas hos par där mannen lever med diagnostiserad prostatacancer. Resultaten i studien baseras på tio vetenskapliga artiklar med fokus på parens erfarenheter av sjukdomen. Impotens, inkontinens och fatigue var symtom som drabbade mannen till följd av sjukdomen. Dessa förändringar inverkade på parets vardag och relation. Förändringarna var psykiskt påfrestande för parets hälsa och både mannens och kvinnans livskvalitet försämrades på grund av cancersjukdomen. Psykiska problem som depression, oro, ångest och skuld var dock mer förekommande hos kvinnan. Trots att paren var i stort behov av information upplevde de att hälso- och sjukvården inte uppmärksammade deras behov. Tydligare riktlinjer inom sjukvården för hur par som lever med prostatacancer ska bemötas efterlyses. På så sätt kan sjuksköterskan lättare tillgodose parets behov av information och stöd. Sjuksköterskan bör uppmärksamma och bemöta kvinnans individuella önskemål samt visa en öppenhet gentemot de sexuella problem som kan drabba paren. Mer forskning, speciellt i Skandinavien, efterlyses för att få en klarare bild över hur både en homosexuellt och heterosexuell relation påverkas av prostatacancer.  </p> / <p>When a man is diagnosed with prostate cancer it implies a psychological strain for the man and his female partner where reactions such as shock, loss of meaning, loneliness and anxiety are common. The purpose of this literature review was to describe how everyday life is perceived and influenced in couples where the man has been diagnosed with prostate cancer. The results of the study are based on ten scientific articles focused on exploring couple’s experiences of the disease and how they are affected by the situation. Symptoms such as impotence, incontinence and fatigue were changes that affected the couple’s everyday life and their relationship. These changes were psychologically trying for the couple’s health and their quality of life decreased because of the cancer.  Psychological problems like depression, anxiety and guilt were more common for the woman. Despite the fact that the couples were in great need of information, they felt that health care providers were not attentive to these needs. Clearer guidelines are needed within the health-care system for how couples living with prostate cancer should be treated. The nurse would thereafter be better equipped to meet the couple’s needs for information and support. The nurse should highlight and approach women’s individual needs and show openness towards the sexual problems that can befall couples. More research is needed, particularly in Scandinavia, in order to get a clearer picture of how a homosexual and heterosexual relationship is affected by prostate cancer.</p>

När en man diagnostiseras med prostatacancer innebär det en psykisk påfrestning för mannen och hans kvinnliga partner. Reaktioner som chock, meningsförlust, ensamhet och ångest är vanligt förekommande. Syftet med denna litteraturstudie var att beskriva hur det vardagliga livet upplevs och påverkas hos par där mannen lever med diagnostiserad prostatacancer. Resultaten i studien baseras på tio vetenskapliga artiklar med fokus på parens erfarenheter av sjukdomen. Impotens, inkontinens och fatigue var symtom som drabbade mannen till följd av sjukdomen. Dessa förändringar inverkade på parets vardag och relation. Förändringarna var psykiskt påfrestande för parets hälsa och både mannens och kvinnans livskvalitet försämrades på grund av cancersjukdomen. Psykiska problem som depression, oro, ångest och skuld var dock mer förekommande hos kvinnan. Trots att paren var i stort behov av information upplevde de att hälso- och sjukvården inte uppmärksammade deras behov. Tydligare riktlinjer inom sjukvården för hur par som lever med prostatacancer ska bemötas efterlyses. På så sätt kan sjuksköterskan lättare tillgodose parets behov av information och stöd. Sjuksköterskan bör uppmärksamma och bemöta kvinnans individuella önskemål samt visa en öppenhet gentemot de sexuella problem som kan drabba paren. Mer forskning, speciellt i Skandinavien, efterlyses för att få en klarare bild över hur både en homosexuellt och heterosexuell relation påverkas av prostatacancer. / When a man is diagnosed with prostate cancer it implies a psychological strain for the man and his female partner where reactions such as shock, loss of meaning, loneliness and anxiety are common. The purpose of this literature review was to describe how everyday life is perceived and influenced in couples where the man has been diagnosed with prostate cancer. The results of the study are based on ten scientific articles focused on exploring couple’s experiences of the disease and how they are affected by the situation. Symptoms such as impotence, incontinence and fatigue were changes that affected the couple’s everyday life and their relationship. These changes were psychologically trying for the couple’s health and their quality of life decreased because of the cancer.  Psychological problems like depression, anxiety and guilt were more common for the woman. Despite the fact that the couples were in great need of information, they felt that health care providers were not attentive to these needs. Clearer guidelines are needed within the health-care system for how couples living with prostate cancer should be treated. The nurse would thereafter be better equipped to meet the couple’s needs for information and support. The nurse should highlight and approach women’s individual needs and show openness towards the sexual problems that can befall couples. More research is needed, particularly in Scandinavia, in order to get a clearer picture of how a homosexual and heterosexual relationship is affected by prostate cancer.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2007. / Title from PDF title page (viewed on Feb. 4, 2010). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 24-28).

Overexpression of the epidermal growth factor receptor (EGFR), a member of the ErbB family, and its closest homologue HER2, have been associated with aggressive tumour progression and reduced sensitivity to DNA-damaging agents. In order to block the proliferation of refractory tumors overexpressing EGFR, a novel strategy has been developed that sought to design molecules capable of not only blocking EGFR-TK, but also damaging DNA. These molecules, termed combi-molecules (CMs), have been shown to degrade under physical conditions to release another inhibitor of EGFR, and to be potent against tumor cells of various origins including breast, prostate and carcinoma of the vulva. However, despite their potency, their growth inhibitory IC50 values were still in the high micromolar range. In order to augment the potency of the CMs, here they were re-designed to contain two quinazoline moieties and a central N,N-bis(2-aminoethyl)methylamine spacer which, following degradation, could yield higher concentrations of free inhibitors and a more cytotoxic bifunctional DNA damaging species. Here, we describe the mechanism of action of the first prototype of this approach, JDE52, which we now classify as a double-arm CM, in comparison with ZRBA1, its closest single-arm counterpart. The results indicated that JDE52 was capable of inducing significant blockade of EGFR, DNA single-strand breaks and inter-strand cross-links. ZRBA1, its single-arm counterpart, was capable of only forming DNA single-strand breaks. The fluorescent property of FD105, the secondary inhibitor that both JDE52 and ZRBA1 are capable of releasing, has permitted the analysis of its levels in tumor cells by UV flowcytometry. It was found that JDE52 was indeed capable of significantly releasing higher levels of fluorescence (p&lt;0.05) in human tumor cells, compared with levels of fluorescence released by ZRBA1. More importantly, JDE52 induced higher levels of apoptosis and cell killing than ZRBA1. Apoptosis was triggered by JDE52 at a faster rate than ZRBA1. The results in toto suggest that the superior potency of JDE52, when compared with ZRBA1, may be imputed to mechanisms associated with the generation of higher levels of FD105 intracellularly, and the induction of DNA cross-links, which are known to be more cytotoxic. These combined mechanisms (blockade of EGFR-TK and formation of cross-links) contributed to an accelerated rate of apoptosis in cells treated with JDE52. This study conclusively demonstrated that designing molecules as prodrugs of high levels of quinazoline inhibitors of EGFR and bifunctional DNA cross-linking species is a valid strategy to enhance the potency of CMs against refractory tumors.

The process of metastasis is initiated through the acquisition of inherent and autonomous motile and invasive properties by tumor cells. These phenomena are initiated through a balance between forward cancer cell membrane protrusion and tail retraction, and occur via cell cytoskeleton remodeling, actin reorganization, and coordinated focal adhesion assembly and disassembly events. Among the vast network of cytoskeletal proteins, the actin-bundling protein fascin plays a major function in cell cytoskeleton remodeling. It is a 55-kDa protein involved in the formation of filopodia and cell migration, and found to be upregulated in many cancers. We report herein key functions for fascin in the regulation of prostate and breast cancer progression. Fascin expression is upregulated in localized and hormone refractory prostate cancer, responsible for a more aggressive clinical course. In addition, functional dissection of fascin reveals a novel function in the regulation of focal adhesion turnover dynamics, by modulating the phosphorylation state of central focal adhesion proteins through a potential collaboration with the protein tyrosine phosphatase, PEST. Together, our data support the importance of fascin in cancer cell invasion and as a significant prognostic marker and a potential therapeutic target for aggressive cancers.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.