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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Evaluation of high activity rhenium-186 HEDP with stem cell transplant in prostate cancer

O'Sullivan, Joseph Murtagh January 2003 (has links)
No description available.
22

Characterisation of deubiquitinase enzymes involved in androgen receptor regulation in prostate cancer

Ramsey, Hollie-Alexandra January 2012 (has links)
The androgen receptor (AR) is a key transcription factor in prostate cancer (CaP) growth and metastases, and is the main target for CaP treatment via the use of anti-hormonal therapies. Unfortunately, this treatment is only effective in the short-term and re-growth of the tumour results in most cases, termed castrate-resistant CaP (CRCaP), this is refractory to additional chemotherapies and hence fatal. Expression and reactivation of the AR is commonly seen in CRCaP and acts as a driver of advanced CaP growth suggesting the receptor remains a suitable target for next generation CaP therapies. Ubiquitination represents one of the numerous post-translational modifications that are vital for many cellular processes, including transcription and regulation of protein stability. The AR is a target for ubiquitination by several E3 ubiquitin ligase enzymes that can lead to either increased activity or degradation depending on the E3 ligase involved. Importantly, the persistence of the AR in CRCaP suggests that deciphering the mechanisms that regulate AR stability in this disease state may provide extremely useful and novel therapies. A major knowledge gap exists however, in our understanding of the reversal of ubiquitination by deubiquitinase enzymes (DUBs) within the AR signalling cascade that could be extremely important for the evidenced aberrant AR function in CRCaP. Therefore, the aim of this study was to characterise deubiquitinase enzymes (DUBs) involved in controlling AR activity and establishing potential roles of the enzymes in CaP development. A comprehensive siRNA library screen investigating the role of each DUB enzyme in AR signalling using the androgen-dependent LNCaP CaP cell line was undertaken and ubiquitin specific protease (USP) 12 (USP12) and USP10 were identified as regulators of AR activity. USP12 depletion resulted in reduced expression of androgen-responsive genes, suggesting USP12 is an activator of AR-mediated transcription, a notion confirmed in luciferase reporter assays. USP12 depletion failed to affect AR protein levels, but attenuated receptor recruitment to target gene promoters suggesting it is required to facilitate activated AR promoter binding. Studies of the phenotypic effects of USP12 knockdown revealed reduced LNCaP proliferation, increased cell cycle arrest and apoptosis, suggesting that USP12 inhibition could hold therapeutic potential in prostate cancer. In contrast, USP10 depletion resulted in increased expression of androgen-response genes, and repressed AR transcriptional activity in luciferase reporter assays. Unlike USP12, which interacted with AR when over-expressed in COS-7 cells, USP10 did not interact with the receptor, leading to the hypothesis that it may exert its effects through deubiquitination and stabilisation of the AR co-repressor, and E3 ubiquitin ligase, MDM2. A preliminary study to investigate the effects of MDM2 and USP10 co-transfection was unfortunately unsuccessful but further optimisation would assist in elucidating the role of the DUB in the AR signalling cascade. In conclusion, two DUB enzymes, USP12 and USP10, were identified to be important in modulation of AR activity. USP12 acts as co-activator of the AR and may be a potential therapeutic target in CaP. USP10, on the other hand, is a co-repressor of the AR and may act through MDM2.
23

An investigation into the role of the transcription factor ERG and its regulation of the members of the insulin-growth factor signalling pathway in prostate cancer

Adamo, Patricia Maria January 2013 (has links)
Recently the fusion gene TMPRSS2-ERG has been highlighted as a cancer-specific event in prostate carcinogenesis and is present in up to 800/0 of prostate carcinomas. Fusion a llows the androgen-driven TMPRSS2 promoter to control transcription of the oncogene, ERG, resulting in abhorrent ERG overexpression. In other cancer settings, ERG fusion genes are known to regulate members of the IGF signalling pathways and the IGF pathway has been highly implicated in prostate cancer development. The insulin-like growth factors and their binding proteins may provide good indicators of ERG status in prostate cancer and as they are secretory proteins they may act as easily accessible biomarkers. To address whether there is fun ctional relationship between ERG and the IGF pathway. expression profiltng of ERG, IGF·I, IGF binding proteins ( I to 6) and the tumour-suppressor protein , PTEN were carried in prostate cancer ce ll-lines. lnvestigation into ERG isoform expression was performed along with chromatin immunoprecipitation and dualluciferase assay to determine ERG's transcriptional action on the IOF targets. ERG knockdown and over expression and downstream effects on the IGF targets were also determined followed by ERG, IGF-f and fGFBP status in clinical samples. The androgen·dependent, fusion containing VCaP cell·line was the highest expresser of ERG and IGF-I was not found to be expressed in any of the cell-lines. ERG Isoform profiling revealed heterogeneous patteming across cell·lines, with LNCaP being a non·expresser. Chromatin immunoprecipitation detennined that ERG was able to bind to the promoters ofal! the target genes. Dual-Iuciferase promoter assay showed that ERO can directly regulate the transcription of IGFBP-3, IGFBP-5 and PTEN but not IGF-I. Here for the first time, I present evidence for the binding and regulation of the IGF binding proteins (lGFBP-3 and IGFBP-5), along with the tumour suppressor protein, PTEN by the transcription factor ERG. Full elucidation of the effect of ERG and ERG fusion genes on the IOF signalling pathway, in the prostate cancer scenario could lead to the development for novel biomarkers of prostate cancer progression.
24

Understanding lifestyle-related psychosocial processes after prostate cancer diagnosis

Kassianos, Angelos January 2013 (has links)
Prostate cancer diagnosis can result in patients losing control who then make efforts to cope by seeking information, social and medical support and changing their health behaviour. The objective of the Thesis is to investigate the psychosocial processes that influence prostate cancer patients’ coping process with an emphasis on dietary change. A mixed methods approach was used comprising of five studies. The first (Chapter 4) recruited 98 patients and significant others who completed an online survey. It found significant others to develop a need for treatment and interaction-specific information earlier than patients who were more in need for treatment and disease-specific information. Education predicted the time of information needs’ development. The second study (Chapter 5) recruited 126 GPs to an online survey and compared their responses to patients’ and significant others’. It found that GPs’ underestimate the time patients develop an interest in information whereas gender and years of practice can explain GPs’ perceptions of patients’ information needs. The third study (Chapter 6) systematically reviewed the literature to identify an association between dietary changes and quality of life identifying ten randomised-control trials and proposing that an association exists which needs further establishment on the pathways of the relationship. The fourth study (Chapter 7) recruited 95 patients on an online and paper survey and found that socio-demographic factors, cognitive functioning, external locus of control and cancer symptoms (dyspnea) can explain whether patients will change their diet after diagnosis but only cognitive functioning can explain changes after therapy has started. Finally, the fifth study (Chapter 8) used semi-structured interviews with eight patients and found that they develop an underlying mechanism that includes the determinants and the resulted evaluations of dietary change. Findings from the Thesis suggest that a holistic and patient-centred approach when targeting prostate cancer patients’ needs should be considered.
25

Evaluation of the functional role(s) of TIMP-3 in prostate cancer progression

Popoola, Olajumoke Oyinade January 2013 (has links)
Prostate cancer is the second highest cause of cancer death in men and its transformation to an untreatable state depends on the loss of the cells' requirement for androgen. Metalloproteinases such as matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are implicated in prostate cancer. Tissue inhibitor ofmetalloproteinase (TIMP) is a family of 4 inhibitors whose major functions are to regulate the activity of metalloproteinases. TIMP-3 inhibits ADAMTSs, MMPs and ADAMs, and independently inhibits angiogenesis. The aims of this research were to investigate the expression and modulation of TIMP-3 in prostate stromal and cancer cells in order to better understand its role(s) in prostate cancer. The effects of androgen, growth factors and cytokines on TIMP-3 expression in prostate stromal and cancer cells were analysed. Co-culture analyses were employed to investigate the effect of cell-cell contact on TIMP-3 expression. RNAi experiments were carried out to study the effects of TIMP-3 inhibition on biological functions. Tissue micro array analyses were carried out in order to investigate correlation of TIMP-3 expression with prostate cancer malignancy. TIMP-3 expression was higher in prostate stromal cells than cancer cells. Co-culture analyses showed up-regulation of TIMP-3 in stromal cells and down-regulation in cancer cells. Immuno-staining in prostate tissues demonstrated higher TIMP-3 staining normal and benign tissues compared to malignant tissue. The modulation of TIMP-3 expression observed by androgen was cancer-cell-specific and by growth factors/cytokines was stromal-cell-specific. RNAi-mediated down-regulation of TIMP-3 in cancer-associated stromal cells resulted in increased migration and invasion. ECM lysates from transfected stromal cells demonstrated reduced MMP-2 inhibition. Overall, these results show the interplay of the stromal and tumour compartments in modifying the activity of prostate tumour, and suggest that TIMP-3 is important in modulating the migration and invasive potential.
26

Non-myeloablative allotransplantation combined with tumour-specific vaccination for the treatment of prostate cancer

Michelini, Rodrigo Hess January 2008 (has links)
Mechanisms of tolerance induced by tumour cells hamper natural and vaccine-induced protective immune responses in cancer patients. Thus, strategies to overcome tolerance and restablish anti-tumour immunity have been attempted. Non-myeloablative haematopoietic cell transplantation can cure patients affected by haematological malignancies but has had limited success against solid tumours. This is possibly because of peripheral tolerance induction and/or suboptimal priming of tumour-specific T lymphocytes.
27

Assessing morbidity associated with standard transurethral resection of the prostate : a comparison between 1.5% glycine and 5% glucose irrigation during TURP

Collins, J. W. January 2007 (has links)
Despite the known complications of transurethral prostatectomy TURP remains the gold standard for benign prostatic hypertrophy causing bladder outflow obstruction. Standard TURP may predispose a patient to increased morbidity and mortality by several mechanisms including irrigating fluid absorption and blood loss as well as the standard risks from operating on an aged population. There is increasing evidence in the literature to support the hypotheses that glycine irrigation when absorbed is both cardiotoxic and neurotoxic. This prompted me to investigate whether two different irrigant fluids differ in terms of harmful effects and whether these differences can be measured in the perioperative period.
28

Caveolin-1 involvement in prostate cancer

Day, Elizabeth Helen January 2011 (has links)
Caveolin-l (Cav-l) is an important component of plasma membrane caveolae and orchestrates cell signalling in the regulation of proliferation and apoptosis. Unlike many cancers, prostate cancer cells demonstrate elevated levels of cav-l expression which has been linked to Gleason scoring and aggression. A loss of cav-l, with siRNA, in an advanced prostate cancer cell line (PC-3) caused a significant increase in PI positive cells combined with reduced proliferation. Both Akt and ERK signalling showed altered functioning under these conditions and may orchestrate these effects. Such an effect was not observed in benign prostate epithelial cells (PrEC) implicating cav-l as an important protein in the control of cellular viability in malignant but not benign prostate cells. To investigate possible causes of elevated cav-l expression in malignant prostate cells, miRNAs predicted to target the cav-l 3 'UTR were analyzed in both benign and malignant prostate cell lines. In PC-3 cells both miR-30a-3p and miR-203 expression was significantly reduced and miR-I06a and miR-93 increased when compared to benign PrEC cells. Over-expression ofmiR-30a-3p, miR-93, miR-203 but not miR-I06a in PC-3 cells caused significant reduction in cav-l protein expression. This points to a role for these miRNAs in the regulation of cav-l in prostate cancer cells. Interestingly cav-l knockdown in PC-3 cells increased expression of miR-124 and miR-124 up-regulation reduced cav-l protein and mRNA expression, suggesting that the two molecules are linked. Androgen stimulation of LNCaP cells implicate an androgen response element may be involved in the transcriptional regulation of miR-124. In summary, these results suggest changes in miRNA expression with oncogenic transformation may result in over- expression of cav-l which promotes cell survival and proliferation, hence promoting cancer progression. Whether the effects of these miRNAs on cav-l are direct and occur at an early or late stage in the development of the malignancy needs to be determined but it is clear that miRNA expression profiles are becoming increasingly important potential biomarkers in the early diagnosis of many cancers.
29

The differential expression of VEGFxxxb in prostate disease

Waine, Elizabeth Claire January 2012 (has links)
Vascular Endothelial Growth Factor-A are potent angiogenic factors that are up-regulated in tumours, and are a target for anti-angiogenic therapy. VEGF-A exists as two mutually exclusive families of isoforms generated by alternative splicing - the pro-angiogenic VEGFxxx isoforms, and the anti-angiogenic VEGFxxxb isoforms. The role of VEGFxxxb isoforms in prostate cancer is not known, and studies to date have not distinguished between the two families. The aim of this work is to determine whether VEGF splicing is regulated in prostate cancer. Expression of VEGFl65b and VEGFl65 protein in transurethral resections of the prostate from benign and malignant tissue was determined and attempts made to quantify the expression were made using ELISA. Expression of the anti-angiogenic isoforms were investigated in benign, malignant areas and in areas of prostatic intra-epithelial neoplasia of radical prostatectomy specimens by semi- quantitative PCR. In addition, assessment was made of the effect of over-expression ofVEGFl65b on the growth of prostate tumours in vivo.
30

Prostate cancer biomarkers : adiposity, adipokines and lifestyle factors

Burton, Anya J. G. January 2012 (has links)
Prostate cancer is a common cancer, particularly in Western countries. Increasing body mass index (BMI) has been associated with a modest increased risk of advanced and fatal prostate cancer (12-15% per 5 kg/m2 increase in BMI). Adipokines (adipose derived hormones) have been proposed as mediators of this association, but the results of several (mostly small) observational studies have been conflicting. The thesis describes investigations conducted into associations of adiposity, adipokines and lifestyle factors with prostate cancer; firstly, a systematic review and dose-response meta-analysis of the association of the adipokines adiponectin and leptin with prostate cancer incidence and progression. Secondly, a nested case-control study in men aged 50-69 with PSA-detected prostate cancer recruited during the case-finding stage of ProtecT (a population-based randomised trial of treatments for localised prostate cancer) compared BMI, WHR, adiponectin, leptin and leptin:adiponectin (L:A) ratio between 311 men with advanced (the cases) and 413 men with localised (the controls) prostate cancer. Finally, an exploration of associations of BMI, lifestyle factors and adipokines with age-related PSA change (,PSA growth') in men with localised prostate cancer undergoing active monitoring in ProtecT. The meta-analysis found adiponectin levels to be associated with a small reduced risk of total (OR 0.96, 95%CI 0.94-0.98, per 2.5~g/m1) and aggressive (OR 0.89, 95%CI 0.83-0.95) prostate cancer. The ProtecT case-control study indicated an inverse association of adiponectin with risk of advanced stage prostate cancer in overweight and obese men (p for interaction by BMI - 0.006; OR 0.62, 95% Cl 0.42- 0.90 per log(~g/ ml) in men ~25kg/m2}. The meta-analysis did not find a clear association between leptin and total (OR 1.01, 95% Cl 0.98-1.03 per 2.5 ng/ml) or aggressive (OR 1.01, 95%CT 0.99-1.06) prostate cancer and the ProtecT case-control study found little evidence of an association of leptin with prostate cancer stage or grade. There was weak evidence that L:A ratio was inversely associated with stage in normal weight men (OR 0.69, 95%CI 0.45-1.04) and positively associated with stage in overweight men (OR 1.22, 95%CI 0.97-1 .54) (p for interaction = 0.009). BMI was not associated with risk of advanced stage or high grade prostate cancer, or PSA growth, in ProtecT. In men undergoing active monitoring in ProtecT, exercise was inversely, and smoking was positively, associated with PSA at age 50 and yearly PSA growth; both of these factors have been linked to risk of aggressive or fatal prostate cancer. In conclusion, adiponectin appears protective against aggressive prostate cancer, particularly in overweight and obese men. Leptin and adiponectin (or L:A ratio) alone are unlikely to be major risk factors for overall prostate cancer and therefore their measurement at diagnosis would not aid prognostication. However, modification of adipokine levels through diet, exercise and weight loss is not likely to be harmful and may reduce the risk of other obesity-related cancers and diseases (e.g. cardiovascular disease). It is also unlikely that leptin is mediating the association of BMI with advanced or aggressive prostate cancer.

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