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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.

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.

Functional analysis of TSPY and its role in prostate carcinogenesis

Omar, Mahmoud Mustafa January 2005 (has links)
Testis specific protein Y chromosome encoded (TSPY) is a multicopy gene located on the human Y chromosome. It has been reported that the human genome harbours between 20 to 40 copies of the gene. Mammalian homologues of human TSPY were also found to be repetitive. The gene is expressed in human foetal and adult testis. The precise function of the expressed TSPY gene product is not fully defined, but it has been postulated to regulate proliferation of testicular spermatogonia. Up-regulation of TSPY expression has been detected in gonadoblastoma, testicular cancer and prostate cancer. The contribution of abnormal expression of TSPY to prostate carcinogenesis has not been investigated. Prostate cancer (CaP) and benign prostate hyperplasia (BPH) are the most common diseases of the human prostate. Prostate cancer is a disease of the elderly and is the second most common cancer and second most common cause of death from cancer among men in UK. In this thesis, the role of TSPY in prostate carcinogenesis was studied in four related aspects. First, TSPY protein and transcript expression pattern in CaP compared to Benign Prostate Hyperplasia (BPH) was studied using a combination of immunohistochemistry and mRNA in situ hybridisation. Second, the ability of TSPY to regulate cellular proliferation was investigated by transfection experiments of the prostate cancer LNCaP cell line. Third, TSPY genomic copy number in prostate cancer was characterised and compared to BPH. Finally, the downstream genes regulated by TSPY were investigated using high density microarray gene profiling method. An anti-human TSPY polyclonal antibody was developed for immunodetection of TSPY expression level in resected prostate tissues. In total, 72 cases of patients with prostate cancer and 20 cases of patients affected with BPH were studied by immunohistochemistry. TSPY was predominantly detected in the prostatic epithelium. In the benign gland, TSPY expression was limited to the basal cells compartment. TSPY expression was significantly up-regulated in prostate cancer when compared to BPH (P<0.0001). Furthermore, increased TSPY expression level was associated with aggressive disease (tumour with high Gleason score; P<0.02) and the presence of bone metastasis at the time of diagnosis (P<0.028). To address the functional role of 3 TSPY in prostate cancer, FLAG-TSPY was cloned and stably transfected into LNCaP cells. The presence of transfected TSPY increased LNCaP proliferation by two fold compared to empty vector control, consistent with a mitogenic function in CaP (P<0.0001). An absolute quantitative real time PCR based on Taqman assay was established and validated. TSPY genomic copy number was determined from comparing 161 samples: CaP-serum (n=47), resected tumour (n=31); BPH-serum (n=27), resected prostate (n=13) and control-serum (n=45). Of the clinical samples analysed, interpersonal variability of TSPY copy numbers was observed with the majority of cases containing between 20 to 50 TSPY copies per genome. Although, there were variability in TSPY copy numbers among individuals, there was no statistically significant correlation between TSPY copy number (serum and prostatic tissue) and the development of prostate cancer. Studying LNCaP stably transfected with TSPY and empty vector control, the key genes mediating the functional effect of TSPY were identified using Affymetrix oligonucleotide microarray method. In total, 332 genes have been altered 1.5 to 90 fold due to the effect of TSPY over-expression. Ten genes were selected and the gene expression levels were confirmed using semi-quantitative RT-PCR method. Gene clustering analysis has indicated changes in genes that regulate cellular differentiation (NRDG1, NF2, C-MAF and BMP11), apoptotic gene (BAX), cell cycle gene (cyclin G), detoxification gene (GST-2A) and genes linked to adhesion (PCDH7a, PLOD2 and IRS 1). In summary, TSPY is over-expressed in prostate cancer. This abnormal expression is linked to prostate cancer progression and metastasis. The up-regulation of TSPY expression is unlikely to be due to increased copy number. Expression of exogenous TSPY in prostate cancer cells enhanced cellular proliferation. The gene meditates its effect by down-regulating the expression pattern of selected differentiation, apoptosis and adhesion genes. Hence, over-expression of TSPY contributes to prostate carcinogenesis.

A randomised controlled trial of a diet and physical activity intervention in prostate cancer patients and related studies

O'Neill, Roisin Frances January 2013 (has links)
The utilisation of Androgen Deprivation Therapy (ADT) in prostate cancer patients is associated with a number of adverse side effects including: changes in body composition; an increase in fat mass and a decrease in muscle mass, increased fatigue and a reduced Quality of Life (QoL). Existing literature suggests that physical activity plays a key role in alleviating some of the associated side effects of ADT; however studies in this area are based on supervised facility-based exercise programs without dietary modification. The aim of this thesis is to present the rationale and methodology of a Randomised Controlled Trial (RCT) to test the efficacy of a 6 month combined dietary and walking intervention on alleviating the Health-Related QoL (HRQoL) issues associated with ADT treatment. Ninety-four men were recruited and randomised to the intervention arm or a standard care control arm. The trial had a significant impact on reducing the adverse body composition changes as well as improving the functional capacity of intervention patients compared to control patients. A systematic review was also completed to determine if expression of the lipogenic enzyme Fatty Acid Synthase (FAS) differs in prostate cancer tissue compared with normal prostate tissue. and if F AS expression in cancer tissue has a role in prostate cancer progression. The number of studies in the area was limited, however 6 of the 7 studies included in the review reported elevated F AS expression in prostate cancer tissue when compared to normal tissue. Additionally. using data from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. the association between body composition measurements (body mass index, height, waist circumference and waist-hip ratio). physical activity. smoking status and prostate cancer risk was explored using Cox Proportional Hazard analysis. None of the included' lifestyle behaviours or body composition measurements had a statistically significant effect on prostate cancer risk .

Selenium and prostate cancer

Hendrickx, Wouter R. L. January 2012 (has links)
Prostate cancer is the second most common diagnosed cancer and the third most common cause of death related to cancer among men in developed countries. Several epidemiological studies, prospective cohort studies and animal tumour models state an inverse relationship between selenium status and cancer incidence. Se- methylselenocysteine (SeMSC), present in garlic, onions, leeks and broccoli, has been shown to be the most effective anti-carcinogenic selenium form in animal models. The aim of the work presented in this thesis was to investigate the influence of selenium compounds (Se-methylselenocysteine and selenomethionine) on prostate cancer progression and metastasis using various human cell lines (LNCaP, OU145 and PC3). Standard 20 gel and SILAC (stable isotope labelling with amino acids in cell culture) proteomics were used, in combination with mass spectrometry, to identify selenium- responsive proteins. IMPOH2, GPI, EZR and RGS10 were validated by western blot, while POIA3 and 00X5 showed a selenium response under serum depleted conditions. Some proteins require more scrutinizing (galectin-1, XRCC5, TAGLN2, 00X5 and FLT) as conflicting results were obtained during validation. Preliminary analysis using 20 gel proteomics revealed galectin-1 to be selenium-responsive in PNT1A cells, although this could not be confirmed by Western blot or an in-house ELlSA. Previously, it has been shown that SeMSC decreased the expression of collagen I and increased that of collagen IV and collagen VI. A LNCaP 3D gel suspension model was developed to allow further investigation of extracellular matrix components using fluorescence microscopy. In addition, the effect of selenium exposure on the migration and invasion of PC3 cells was investigated using a transwell kinetic assay and revealed a dose response increase, especially under low baseline selenium concentrations. In order to optimize future selenium in vitro projects the dynamics of several selenium biomarkers were investigated using different conditions, enabling better comparison between cell lines and/or selenium compounds.

Potential chemo-prophylactics effect of green tea catechins in pre-malignant and malignant prostate

Jiang, Dian Dong January 2011 (has links)
Green tea catechins have been recognized as a potential chemopreventive agent for prostate. Prostatic intraepithelial neoplasia (PIN) lesion is widely accepted as the pre-invasive stage of adenocarcinoma and a predictive marker of prostate cancer development. This study confirmed that novel catechin-derivatives showed a greater inhibitory effect on proliferation in PIN cells than in PCa cells. In addition, two minor existing catechins, (-)-epigallocatechin (EGC) and (-)- epicatechin (EC) showed a synergistic inhibitory effect on PIN cell growth, invasion, migration and progression of PIN to a mesenchymal-like invasive phenotype by inhibition of Epithelial Mesenchymal Transition (EMT)-associated transcriptional factors such as Twist, Snail, Slug and Zeb-l. In this study, a carcinoma-associated fibroblast (CAF)-like human bone marrow- derived mesenchymal stem cells (hMSCs) was established via exposing hMSCs to human prostate tumour-conditioned medium (TCM). TCM-exposed hMSCs exhibited the ability to promote tumour cell growth of prostate and colon cancer and PIN cell invasion. Green tea catechin treatment inhibited PIN cell invasion by reversal of EMT. A chemo-resistant (CR) prostate cell line (CR-PC3M) was established and exhibited a greater resistance to several chemotherapeutic drugs such as 5- fluorouacil, Taxotere and Doxorubicin, and expressed a high level of a drug resistance-associated transporter ABCG2 and the cancer stem cell (CSC) marker

The proto-oncoprotein PRAME associates with the Cullin-2E3 ubiquitin ligase complex and is upregulated in response to bacterial pathogen associated molecual patterns

Wadelin, Frances Roswyn January 2012 (has links)
PRAME (preferentially expressed antigen in melanoma) is a cancer-testis antigen that is expressed in normal testis tissue and is detected at high levels in a number of haematological and solid organ malignancies. Little is known about the physiological function of PRAME, although a role in the repression of retinoic acid receptor signalling and modulation of cell proliferation has been proposed. PRAME has been shown to promote leukaemogenesis; therefore it is important to understand its expression is regulated in normal and cancerous cells. The aim of this thesis was to investigate PRAME gene regulation and to discover clues to its function by affinity purification of interacting proteins. Using sequence similarity searches, PRAME is defined here as a leucine-rich repeat protein, and it is shown to undergo both nuclear and cytoplasmic localisation. Transcription of the PRAME gene is shown to be induced by exposure of malignant cell lines to bacterial pathogen-associated molecular patterns (PAMPs) in combination with interferon-y. Evidence is presented that PAMP/interferon-y treatment also upregulates the translation of PRAME, and alters the subcellular localisation of PRAME protein, resulting in its association with the Golgi apparatus. These results suggest that PRAME may have a role in the innate immune response. Using affinity purification and mass spectrometry, novel PRAME- interacting proteins were identified. PRAME is shown to associate with the Cullin-2-E3 ubiquitin ligase complex via interaction with elongin C, as validated by in vitro binding studies, co-immunoprecipitation and immunofluorescence staining. Cytoplasmic PRAME is shown to colocalise with elongins in Golgi-like vesicles. In addition, PRAME is shown to interact with histones. Based on these results, it is proposed that PRAME is a BC-box protein that may function as a substrate targeting component of Cullin-2-E3 ubiquitin ligase complexes, which may aid in trafficking of intracellular proteins to endosomes and Golgi for degradation or modification. The interaction with histones suggests that nuclear PRAME may perform some role in gene regulation, and future studies will explore its potential role in histone ubiquitination.

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.

The rapid measurement of LNCAP intracellular PSA as a model for a novel cell based diagnostic exploiting magneto immunoassay

Sharif, Elham Abdullatif Modh January 2009 (has links)
A novel magneto immunoassay was developed to detect intracellular PSA in LNCAP cells. This project was conducted to investigate methods of rapid intracellular protein measurement using a magneto-immuno assay. Cell cultures were established using Jurkat and ECV304 cells and were used as a continuous source of intracellular proteins. As the project progressed LNCAP cells were used as a model for intracellular PSA. To release intracellular protein, experiments were performed to develop a novel method of cell lysis using paramagnetic particles (PMPs). To accomplish this, eight different lysis methods were initially evaluated using a quantitative approach measuring total protein and lactate dehydrogenase LDH activity. A qualitative approach was adapted to study the protein by western blotting and environmental scanning electron microscopy (ESEM). A novel method utilizing a sonicator probe in conjunction with paramagnetic particles to lyse Jurkat cells was investigated; two types of particles were investigated (1 urn and 2.8 urn Dynabeads). This method was compared with other traditional lysing methods such as freeze-thawing, detergent, heat treatment and a sonicator water bath. The results showed that chemical lysis method was the most efficient for releasing protein and yielded the highest LDH activity. But chemical lysis method was not able to release measurable PSA from LNCAP cells. A higher amount of PSA was released when sonicating LNCAP cells with super paramagnetic particles energised with a sonicator probe. Two sizes of paramagnetic particles (2.8 and 1 urn) and particles of the same size with different coating were evaluated. The size of the paramagnetic particles had a significant effect on the sonication process. ESEM studies showed that the cells tend to lose their shape and integrity when sonicated by the sonicator alone. Moreover comparing the micrographs obtained when sonicating the cells with 1 urn particles a membranous structures was observed while a coagualtive structures were observed when sonicating the cells with 2.8 urn particles. The second part of the thesis describes an investigation into a novel magneto immunoassay, using paramagnetic particles as a label for PSA detection, using a prototype devices developed at UWE. The method developed relies on the specificity of antibody-antigen interaction between antigen and antibody on PMPs and the surface of specifically designed reaction vessel containing the PMP to be captured on the surface. The captured PMP was then detected using magnetometer which has a resonant coil situated below the reaction surface. Using this approach a faster and cheaper detection of PSA could be achieved. A disposable reaction chamber, using low sample volume is added advantages in this method. Two detection systems were evaluated, a resonant coil magnetometer (RCM) detection system and a fixed frequency magnetometer (FFM), both developed at UWE. The latter system was used to investigate the effect of testosterone on LNCAP cells and the release of intracellular PSA. The results show that androgens cause a positively enhanced LNCAP cell growth rate, which consecutively leads to an increase in LNCAP intracellular PSA production. Correlation of serum samples using patient's samples from the Bristol Royal Infirmary was performed. The FFM system gave 90 % sensitivity and specificity.

Development and evaluation of a "molecular biopsy" for improved diagnosis of prostate cancer

Nair, Sabarinath Balachandran January 2013 (has links)
Prostate cancer is the most commonly diagnosed cancer in men in United Kingdom. Current diagnosis involves measurement of serum PSA levels and prostate biopsy. However, these tests can give false positive or negative results. Furthermore, they do not indicate disease staging, the behaviour and development of the cancer and hence do not lend to optimal management. Using blood samples, quantitative, real-time RT-PCR (LightCycler™) was used to evaluate molecular markers for inclusion in an alternative minimally invasive diagnostic and prognostic test. Expression levels of Clusterin, Caveolin-1 (Cav-1), E-cadherin (ECAD), Alpha-Methylacyl-CoenzymeA Racemase (AMACR), Enhance of zeste homologue 2 (EZH2) and Matrix metalloproteinases 2 and 24 (MMP2, MMP24) were measured in patient groups and correlated with known clinical details collected on a prostate cancer database. Normal males and patients with negative biopsy results were used as control groups. GAPDH was chosen as the housekeeping gene to normalize gene expression levels. Results and subsequent statistical analysis indicate that Clusterin, Cav-1, and ECAD are potentially strong markers for prostate cancer diagnosis and staging of the disease, and therefore in patient management. The strength of these markers can be increased by combining the results with other similarly evaluated markers. In this way, a combination of diagnostically and prognostically strong markers may be identified forming a panel of biomarkers for inclusion in a potential test. The development of further products now allows transportation of blood at ambient temperature with guaranteed mRNA stability. This will allow blood samples to be taken in a local surgery and transported to a routine laboratory for testing. This would help encourage men to seek prostate disease screening, enabling early diagnosis and intervention while avoiding unnecessary prostate biopsies and treatment.

The functional role of ADAMTS-1 and -15 in prostate cancer progression

Molokwu, Chidiebele N. January 2011 (has links)
Introduction: Prostate cancer is a leading cause of cancer death in men. Death is usually a consequence of castration resistant tumour progression. Some metalloproteinases are implicated in the process of cancer progression. ADAMTS proteinases (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) are metalloproteinases that play diverse roles in tissues. Prostate cancer cells express ADAMTS-l and -15 but the role played by these proteinases in prostate cancer progression is unknown. This study was designed to determine the role of ADAMTS-l and 15 in prostate cancer progression. Materials & Methods: Prostate cancer and stromal cell tumour spheroids were grown in 3-dimensional culture in ECM gel containing a quenched-fluorescent substrate. The tumour spheroids were observed for evidence of proteolytic activity. Prostate cancer cells were treated with DHT and TNF. Changes in expression of ADAMTS-I and -15 were analysed. ADAMTS-l and -15 expression was knocked-down in PC3 prostate cancer cells and the effect of knock-down on proliferation, migration and invasion was analysed. Results: Tumour spheroids emitted fluorescence after approximately 24 hours in culture, indicating proteolytic activity. DHT and TNF down-regulated ADAMTS-15 expression in LNCaP cells and stromal cells respectively. The validated anti-ADAMTS- 15 antibody detected 50kDa bands, suggesting a novel cleavage site within the disintegrin-like domain of ADAMTS-15. ADAMTS-l and 15 knock-down had no effect on proliferation, migration or invasion ofPC3 prostate cancer cells. Conclusions: Prostate cancer and stromal cells degrade components of the surrounding ECM. ADAMTS-15 but not ADAMTS-I expression is androgen and TNF-regulated. ADAMTS-l and 15 expression do not affect the proliferation, migration or invasive potential of PC3 cells in vitro. Cleavage of ADAMTS-15 in the disintegrin-like domain results in the release of a C-terminal fragment with potential anti-angiogenic properties. Down-regulation by DHT in prostate cancer cells suggests that ADAMTS-15 could be playing an anti-tumour role in prostate cancer progression.

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