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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.
1

Incidental prostate cancer in Chinese men

Lamsir, Seno., 藍海聰. January 2009 (has links)
published_or_final_version / Surgery / Master / Master of Medical Sciences
2

Identification and functional characterization of novel regulators of androgen receptor transcriptional activity

Lingadahalli, Shreyas Vaman January 2018 (has links)
University of Macau / Faculty of Health Sciences
3

The oncolytic adenoviral AdΔΔ mutant sensitizes prostate cancer cells to mitoxantrone by promoting apoptosis and attenuating autophagy

Aguirre, Hernandez Carmen January 2017 (has links)
Prostate cancer (PCa) is the second most common cause of cancer-related deaths in men in the Western world. Advanced PCa is initially managed by anti-androgen therapy however, resistance frequently develops resulting in progressive metastatic disease. The current standard of care for hormone-insensitive PCa includes the cytotoxic drugs docetaxel and mitoxantrone although resistance rapidly develops to all available therapies. We demonstrated that the replication-selective oncolytic adenoviral mutant AdΔΔ enhanced drug-induced cell killing in several preclinical cancer models. AdΔΔ is deleted in the viral E1ACR2 and E1B19K, to prevent pRb-binding and enhance drug-mediated apoptotic cell killing, respectively. In drug-insensitive PCa tumour-xenografts, in vivo administration of AdΔΔ greatly enhanced drug-mediated tumour regression. The aim of my thesis project was to investigate the role of apoptosis and pro-survival pathways, including drug-induced autophagy, in AdΔΔ-mediated drug-sensitisation. I have demonstrated that autophagy was activated in a dose-dependent manner in response to mitoxantrone in the human PCa cell lines PC3, PC3M and 22Rv1. Low doses of mitoxantrone (< EC50-values) caused initiation of autophagy, determined as increased conversion of LC3I to LC3II and increased number of acidic vesicles, indicating autophagosome formation. At higher doses degradation of p62 was also observed, suggesting autophagosome fusion with the lysosome. AdΔΔ attenuated the drug-induced activation of autophagy by restoring basal LC3II/I ratios, and increasing apoptosis, determined as increased PARP-cleavage and mitochondrial depolarization. The autophagyinducer rapamycin prevented AdΔΔ-mediated sensitization in PC3 cells increasing mitoxantrone EC50-values 3-fold and attenuating apoptosis induction. In contrast, the autophagy-inhibitor chloroquine further sensitized PC3 and 22Rv1 cells to the combinationtreatment, decreasing mitoxantrone EC50-values by 40% and increasing apoptotic cell death. Atg7 is a key-factor in the autophagy pathway and siRNA-mediated knockdown prevented increases in LC3II/I ratios. In siAtg7-transfected PC3 cells mitochondrial depolarization was further promoted in combination-treated cells, similar to the results with chloroquine. The cellular Bcl-2-protein has important roles as a mediator of both anti-apoptotic and antiautophagic functions. In cells transfected with siBcl-2 the LC3II/I ratios increased and AdΔΔ- mediated sensitization to mitoxantrone was prevented, indicating initiation of autophagy. In addition, mitoxantrone-induced degradation of Bcl-2 was attenuated by AdΔΔ infection, suggesting stabilization of the protein. The mechanisms for the AdΔΔ-mediated increases in cell killing were also demonstrated in 3-dimensional co-culture models of PC3 or 22Rv1 in combination with prostate stromal cells and extracellular matrix proteins using confocal microscopy. These data demonstrate that AdΔΔ attenuates drug-induced cell survival/rescue and promotes elimination of cancer cells through apoptosis and viral lysis, and that Bcl-2 was essential for the sensitisation.
4

Novel urinary and serological markers of prostate cancer using proteomics techniques: an important tool for early cancer diagnosis and treatment monitoring

Adeola, Henry Ademola January 2016 (has links)
In Africa, Prostate cancer (PCa) is the most frequently diagnosed solid organ tumour in males and use of prostate specific antigen (PSA) is presently fraught with diagnostic inaccuracies. Not least, in a multi-ethnic society like South Africa, proteome differences between African, Caucasian and Mixed-Ancestry PCa patients are largely unknown. Hence, discovery and validation of affordable, non-invasive and reliable diagnostic biomarkers of PCa would expand the frontiers of PCa management. We have employed two high-throughput proteomics technologies to identify novel urine- and blood-based biomarkers for early diagnosis and treatment monitoring of prostate cancer in a South African cohort as well as elucidate proteome differences in patients from our heterogeneous cohort. We compared the urinary proteomes of PCa, Benign Prostatic Hyperplasia (BPH), disease controls comprising patients with other uropathies (DC) and normal healthy controls (NC) both by pooling and individual discovery shotgun proteomic assessment on a nano-Liquid chromatography (nLC) coupled Hybrid Quadrupole-Orbitrap Mass Spectrometer platform. In-silico verification of identified biomarkers was performed using the Human Protein Atlas (HPA) as well as SRMAtlas; and verified potential biomarkers were experimentally prevalidated using a targeted parallel reaction monitoring (PRM) proteomics approach. Further, we employed the CT100+ antigen microarray platform to assess the differential humoral antibody response of PCa, DC and BPH patients in our cohort to a panel of 123 tumour-associated cancer antigens. Candidate antigen biomarkers were analyzed for ethnic group variation in our cohort and potential cancer diagnostic and immunotherapeutic inferences were drawn. Using these approaches, we identified 5595 and 9991 non-redundant peptides from the pooled and individual experiments respectively. While nine proteins demonstrated ethnic trend, 37 and 73 proteins were differentially expressed by pooled and individual analysis respectively. All 32 verified biomarkers were prevalidated with parallel reaction monitoring. Good PRM signals for 12 top ranking biomarker was observed, including PSA and prostatic acid phosphatase. We also identified 41 potential diagnostic and immunotherapeutic antigen biomarkers. Proteogenomic functional pathway analyses of differentially expressed antigens showed similar enrichments of biologic processes. We identified herein novel urinary and blood-based potential diagnostic biomarkers and immunotherapeutic targets of PCa in a South African PCa Cohort using multiple proteomics approaches.
5

EXAMINATION OF PROSTATE CANCER ASSOCIATED FACTORS FOR THEIR CONTRIBUTION TOWARDS THE DEVELOPMENT OF PROSTATE CANCER AND PROGRESSION INTO CASTRATION RESISTANT PROSTATE CANCER / PROSTATE CANCER ASSOCIATED FACTORS

Gu, Yan January 2021 (has links)
Although early detection and treatment of prostate cancer (PC) shows clinical benefit, advanced PCs that progress despite androgen deprivation therapy almost invariably result in castration resistance. This progression is lethal as castration-resistant prostate cancer (CRPC) are intimately associated with metastasis and remains the predominant cause of PC-related fatalities. Increasing evidence reveal a critical role of prostate cancer stem cells (PCSCs) in facilitatin g PC progression and acquisition of androgen independence. Taking advantage of our putative DU145 cell derived-PCSC population, we examined a number of candidate proteins for their contribution to PC progression and CRPC development. We identified three PCSC-specific proteins, BChE, CNTN1 and PCSK9. Butyrylcholinesterase (BChE) is a plasma enzyme known for its role in hydrolyzing ghrelin and bioactive esters, and is associated with altered metabolisms. Serum BChE is reduced in several cancer types. In this thesis we revealed a biphasic alteration of BChE and identified its downregulation at early stage of PC and upregulation at advanced stage PC. In a similar manner, we reported a functional role of CNTN1 in PC advancement. We demonstrate evidence for CNTN1-mediated enhancement of LNCaP cell proliferation in vitro and formation of CRPC in vivo, as well as its oncogenic potency in a prostate-specific CNTN1 transgenic model. Furthermore, we constructed a novel CNTN1-associated gene panel that predicts PC relapse risk with high robustness. IQGAP1 is critical in cytoskeletal dynamics which underlies cancer progression, metastasis, and PCSC biology. We showed IQGAP1 downregulation in both CRPCs and advanced PCs, and constructed a 27-gene signature using differentially expressed genes (DEGs) relative to this downregulation. This IQGAP1-relevant 27-gene panel robustly predicts PC relapse following radical prostatectomy and shows high translational value as a complementary panel to currently available commercial multigene panels. PCSK9 is an important protein in the regulation of cholesterol metabolism but its role in cancer is not known. We provide a comprehensive set of evidence supporting its role in the formation of CRPC, likely via mechanisms involving enhanced intratumoral uptake and sustained AR signalling under androgen-deprived conditions. Importantly, bigenic TRAMP mice deficient in PCSK9 have shown significantly prolonged survival and reduced metastasis. Collectively, we identified four factors with pivotal roles in PC development and progression into CRPC, albeit with different mechanisms. The altered expression of these factors in advanced PC and their widespread impact on a diverse range of mechanisms important in cell proliferation and survival underscores the importance of PCSCs in promoting advanced prostate cancer. Taken together, the findings of this thesis will advance our knowledge on PCSC-relevant pathways and their association with prostate cancer progression and metastasis. / Thesis / Doctor of Philosophy (Medical Science)
6

Daily Image Guided Radiation Therapy for Prostate Cancer: An assessment of treatment plan reproducibility.

Knight, Kellie Ann January 2006 (has links)
Doctor of Health Science / It is well documented that for prostate cancer patients undergoing radiation therapy there is a correlation between target volume displacement and changes in bladder and rectal volumes. However, these studies have used a methodology that has captured only a subset of all treatment positions. This research used daily Computer Tomography (CT) imaging to comprehensively assess organ volumes, organ motion and their effect on dose, something that has never been performed previously, thus adding considerably to the understanding of the topic. Daily CT images were obtained using a Siemens Primus Linear Accelerator equipped with an in-room Somatom CT unit in the accelerator suite, marketed as ‘Primatom’, to accurately position the patient prior to treatment delivery. The internal structures of interest were contoured on the planning workstation by the investigator. The daily volume and location of the organs were derived from the computer to assess and analyse internal organ motion. The planned dose distribution was then imported onto the treatment CT datasets and used to compare the planned dose to i) the actual isocentre, where the isocentre was actually placed for that fraction, ii) the uncorrected isocentre, by un-doing any on-line corrections performed by the treatment staff prior to treatment delivery, and iii) the future isocentre, by placing the isocentre relative to internal organ motion on a daily basis. The results of this study did not confirm a statistically significant decrease in rectum volumes over time (hypothesis 1), however large fluctuations in bladder volume were confirmed (hypothesis 2). Internal organ motion for the rectum and bladder was demonstrated to be related to organ filling. Ideal planning volumes for these organs have been reported to minimise systematic and random uncertainty in the treatment volumes. An observed decrease in prostate volume over time, a systematic uncertainty in the location of the prostate at the time of the planning CT scan and a significant relationship between prostate centre of volume and rectum and bladder volumes has resulted in a recommendation that patients should be re-scanned during treatment to ensure appropriate clinical target volume coverage. A significant relationship between rectal and bladder volumes and the dose delivered to these organs was found (hypothesis 3). The dose delivered to the planning target volume was not related to the rectal or bladder volumes, although it was related to the motion of these organs. Despite these results only minimal effects on the dose delivered to any of the three isocentres occurred, indicating that the planned dose was accurately delivered using the methodology presented here (hypothesis 4). However the results do indicate that the patient preparation instructions need to be improved if margins are to be reduced in the future. It is unrealistic to assume that Image Guided Radiation Therapy will ever become routine practice due to infrastructure costs and time limitations. This research will inform radiation therapy centres of the variables associated with prostate cancer treatment on a daily basis, something that has never before been realistically achievable. As a result centres will be able to devise protocols to improve treatment outcomes.
7

Daily Image Guided Radiation Therapy for Prostate Cancer: An assessment of treatment plan reproducibility.

Knight, Kellie Ann January 2006 (has links)
Doctor of Health Science / It is well documented that for prostate cancer patients undergoing radiation therapy there is a correlation between target volume displacement and changes in bladder and rectal volumes. However, these studies have used a methodology that has captured only a subset of all treatment positions. This research used daily Computer Tomography (CT) imaging to comprehensively assess organ volumes, organ motion and their effect on dose, something that has never been performed previously, thus adding considerably to the understanding of the topic. Daily CT images were obtained using a Siemens Primus Linear Accelerator equipped with an in-room Somatom CT unit in the accelerator suite, marketed as ‘Primatom’, to accurately position the patient prior to treatment delivery. The internal structures of interest were contoured on the planning workstation by the investigator. The daily volume and location of the organs were derived from the computer to assess and analyse internal organ motion. The planned dose distribution was then imported onto the treatment CT datasets and used to compare the planned dose to i) the actual isocentre, where the isocentre was actually placed for that fraction, ii) the uncorrected isocentre, by un-doing any on-line corrections performed by the treatment staff prior to treatment delivery, and iii) the future isocentre, by placing the isocentre relative to internal organ motion on a daily basis. The results of this study did not confirm a statistically significant decrease in rectum volumes over time (hypothesis 1), however large fluctuations in bladder volume were confirmed (hypothesis 2). Internal organ motion for the rectum and bladder was demonstrated to be related to organ filling. Ideal planning volumes for these organs have been reported to minimise systematic and random uncertainty in the treatment volumes. An observed decrease in prostate volume over time, a systematic uncertainty in the location of the prostate at the time of the planning CT scan and a significant relationship between prostate centre of volume and rectum and bladder volumes has resulted in a recommendation that patients should be re-scanned during treatment to ensure appropriate clinical target volume coverage. A significant relationship between rectal and bladder volumes and the dose delivered to these organs was found (hypothesis 3). The dose delivered to the planning target volume was not related to the rectal or bladder volumes, although it was related to the motion of these organs. Despite these results only minimal effects on the dose delivered to any of the three isocentres occurred, indicating that the planned dose was accurately delivered using the methodology presented here (hypothesis 4). However the results do indicate that the patient preparation instructions need to be improved if margins are to be reduced in the future. It is unrealistic to assume that Image Guided Radiation Therapy will ever become routine practice due to infrastructure costs and time limitations. This research will inform radiation therapy centres of the variables associated with prostate cancer treatment on a daily basis, something that has never before been realistically achievable. As a result centres will be able to devise protocols to improve treatment outcomes.
8

Inhibition of breast and prostate cancer cell growth by 3,3'-diindolylmethane and related compounds

Kotha, Leela 15 May 2009 (has links)
Selective receptor modulators have been developed for steroid hormone receptors as a new class of mechanism-based drugs for treatment of hormone related diseases. We investigated an alternative mechanism-based strategy for treating various cancers with selective aryl hydrocarbon receptor modulators (SAhRMs), such as diindolylmetane/(DIM), 2,3,7,8-tetrachlorodibenzo-pdioxin/( TCDD), and 6-6-methyl-1,3,8-trichlorodibenzofuran/(MCDF) that exhibit antiproliferative activity in several cancer cell lines. MDA-MB-453 and BT-474 are estrogen receptor/(ER) negative breast cancer cell lines that express a functional aryl hydrocarbon receptor/(AhR) and treatment with SAhRMs significantly inhibited MDA-MB-453/BT-474 cell proliferation but did not significantly affect the percent distribution of cells in G0/G1/S/G2/M phases of cell cycle. TCDD and the SAhRMs had minimal effects on the expression of various cellular kinases. These data coupled with results obtained for other activated kinase pathways demonstrate that TCDD and SAhRMs uniquely inhibit growth of ER-negative MDA-MB 453/BT-474 breast cancer cells through kinase independent pathways. However, the SAhRMs induced HES-1, an antiproliferative transcription factor, in both cell lines and this might represent a possible mechanism for the growth inhibitory effects observed with these compounds. We proved that ring substituted DIMs exhibit androgenic/antiandrogenic activities in androgen receptor/(AR)-positive LNCaP/22RV1 prostate cancer cell lines resulting in antiproliferative activities. These antiproliferative activities were accompanied by antiandrogenic activity and structure-dependent down regulation of AR. The ring-substituted DIMs also induced both non-steroidal anti-inflamatory drug-induced gene-1/(NAG-1) and activating transcription factor 3/(ATF-3), two anti-proliferative/apoptotic genes which are responsible in part for the inhibitory effects of these compounds on the proliferation of prostate cancer cells.
9

Perlecan regulation of sonic hedgehog signaling: from drosophila to humans

Hernandez, Ana Maria 15 May 2009 (has links)
Prostate cancer is the second leading cause of death from cancer in men in the United States. Most men will die of the advanced, metastatic form of the disease. Thus, treatment strategies targeting the metastatic form of the disease are especially needed. Emerging research on metastatic cancer highlights the importance of the microenvironment in cancer progression and metastasis, with an emphasis on deregulated developmental signaling in cancer progression. Research in model organisms has shown that developmental signaling pathways are regulated by various components of the extracellular matrix, including heparan sulfate proteoglycans. In the model system Drosophila, the heparan sulfate proteoglycan Trol is needed for Hhdependent proliferation in quiescent neural stem cells. In collaboration with others, I have shown that the human homolog of Trol, PERLECAN, regulates SONIC HEDGEHOG-dependent proliferation in advanced prostate cancer by two different mechanisms. This makes PERLECAN a potential drug target and biomarker for prostate cancer screening and treatment. My results also validate the discoveries made in Drosophila in the context of human disease. With this validation, I propose and describe the Drosophila Ejaculatory Bulb (EjB) as model for prostate cancer and prostate aging.
10

In Vitro Effects of Bisphenol A on Prostate Cells: Searching for Clues of Environmental Carcinogenesis

Sienkiewicz, Marta 30 April 2012 (has links)
Estrogens maintain the appropriate androgen-estrogen balance for normal regulation of the structure and function of the male reproductive tract, including the prostate gland. This research investigated viability of cells and expression of selected genes in prostate carcinoma cells (PC-3) exposed to bisphenol A (BPA), an estrogen-like substance present in a number of plastic materials. PC-3 cells are able to metabolize BPA at concentrations below 100 µM. BPA exposure at concentrations between 1nM and 100 µM does not increase or significantly reduce cell viability of these cells. Although the genes investigated in this study (GSTP1 and MGMT) did not show a significant change in expression following in vitro exposure to BPA, the positive control ethinyl estradiol (EE2) caused an increase in GSTP1 expression at mRNA level. These results indicate that BPA does not affect the viability of prostate cells, and motivate a need for further research to identify other genes that could be affected by BPA.

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