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Nicolle, Rémy. "Regulatory networks driving bladder cancer." Thesis, Evry-Val d'Essonne, 2015. http://www.theses.fr/2015EVRY0009/document.
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La carcinogénèse est une conséquence de la continuelle activation de la prolifération cellulaire. Dans les cellules normales, les signaux mitogéniques sont traités par un réseau complexe d’interactions protéiques et de réactions enzymatiques, appelées voies de signalisation. Dans certains cas, le signal peut induire l’activation de nouveaux gènes et ainsi déclencher la mitose. Lors du développement ou de la cicatrisation, cette régulation du phénotype cellulaire contrôle étroitement le nombre et le comportement des cellules contribuant ainsi au maintien d’un tissu fonctionnel sain. A partir de profils génomiques, transcriptomiques et protéomiques de tumeurs de la vessie ainsi que des transcriptomes de cellules urothéliales normales dans différents états de prolifération et de différenciation, j’ai mis au point de nouvelles méthodologies pour caractériser les voies de signalisation et de régulation responsables des cancers de la vessie. Dans un premier temps, j’ai développé des outils pour l’identification et la visualisation des programmes transcriptionnels spécifiques à une tumeur ou à un sous-type tumoral et ce, par l’inférence d’un réseau de co-régulation et la prédiction de l’activité des facteurs de transcription. Ces méthodes sont disponibles dans un package Bioconductor, CoRegNet (bioconductor.org). La mesure de l’activité transcriptionnelle est basée sur l’influence d’un facteur de transcription sur l’expression de ses gènes cibles. Cette mesure a été utilisée pour identifier les régulateurs les plus actifs de chaque sous-type de cancer de la vessie. L’intégration de profils génomiques a mis en avant deux facteurs de transcription génétiquement altérés et ayant des rôles oncogènes dans les tumeurs luminales et basales. L’un d’entre eux a été validé expérimentalement dans ce travail.L’utilisation de CoRegNet a mis en évidence une large utilisation dans les tumeurs,des réseaux normaux de la différenciation et de la prolifération des cellules normales. Un régulateur de la prolifération normale est identifié comme étant activé de fa¸con constitutive par des altérations génétiques dans les tumeurs. Son impact sur la prolifération des cellules tumorales de la vessie a été expérimentalement validé. Par ailleurs, il a été constaté que l’un des régulateurs de la différenciation urothéliale présentant une baisse d’activité dans la quasi-totalité des tumeurs, est fréquemment muté. De plus amples analyses ont mis en avant son rôle majeur dans les tumeurs différenciées. Dans le but de caractériser les voies de signalisation à partir de données protéomiques d’expériences d’immunoprécipitations, j’ai développé un nouvel algorithme visant à construire un réseau dense à partir d’une liste de protéines d’intérêt et d’un ensemble d’interactions protéiques connues. L’algorithme est proposé sous la forme d’une application Cytoscape et s’intitule Pepper: Protein Complex Expansion using Protein-Proteininteraction networks (apps.cytoscape.org) Enfin, en utilisant à la fois le profil protéomique d’une expérience d’immunoprécipitation de FGFR3 ainsi que le profil transcriptomique des gènes qu’il régule en aval, j’ai appliqué Pepper pour caractériser la voie de signalisation de FGFR3 depuis ses partenaires protéiques jusqu’aux facteurs de transcription en aval. Enfin, ce travail a plus particulièrement permis d’identifier un lien de régulation entre FGFR3 et le gène suppresseur de tumeurs TP53Carcinogenesis is a consequence of the unceasing activation of cell proliferation. In normal cells, mito-genic stimuli are processed by a complex network of protein interactions and enzymatic reactions, often referred to as pathways, which can eventually trigger the activation of new genes to engage the cell into mitosis. During developmental or wound healing processes, this complex regulation of cellular phenotypes results in a tight control of the number and behavior of cells and therefore contributes to the maintenance of a functional and healthy tissue architecture. Based on genomic, transcriptomic and proteomic profiles of bladder tumors and transcriptomes of nor-mal urothelial cells at various states of proliferation and differentiation, I devised novel methodologies to characterize the pathways driving bladder cancer. I first developed a set of tools to identify and visualize sample and subtype-specific transcriptional pro-grams through the inference of a co-regulatory network and the prediction of transcription factor activity. These methods were embedded in a Bioconductor package entitled CoRegNet (bioconductor.org). The measure of transcriptional activity is based on the influence of a transcription factor on the expression of its target genes and was used to characterize the most active regulators of each bladder cancer subtypes. The integration of genomic profiles highlighted two altered transcription factors with driver roles in lumi-nal-like and basal-like bladder cancer, one of which was experimentally validated. The use of CoRegNet to model the contribution of regulatory programs of normal proliferation and diffe-rentiation in bladder cancers underlined a strong preservation of normal networks during tumorigenesis. Furthermore, a regulator of normal proliferation was found to be constitutively activated by genetic al-terations and its influence on bladder cancer cell proliferation was experimentally validated. In addition, a master regulator of urothelial differentiation was found to have a loss of activity in nearly all tumors. This was then associated to the discovery of frequent inactivating mutations and further analysis unco-vered a major role in differentiated tumors. In order to characterize signaling pathways from proteomic pull-down assays, I then designed a novel algorithm to grow a densely connected network from a set of proteins and a repository of protein interac-tions. The proposed algorithm was made available as a Cytoscape application named Pepper for Protein Complex Expansion using Protein- Protein interaction networks (apps.cytoscape.org). Finally, using both a proteomic pull-down assay of the bladder cancer oncogene FGFR3 and a transcrip-tomic profiling of its downstream regulated genes, I applied Pepper to characterize the full FGFR3 signa-ling pathway from its protein partners to the downstream transcriptional regulators. In particular, this uncovered a regulatory link between FGFR3 and the tumor suppressor TP53
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O'Brien, Timothy Stephen. "Angiogenesis in bladder cancer." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388846.
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PEDERZOLI, FILIPPO. "Microbiome and bladder cancer." Doctoral thesis, Università Vita-Salute San Raffaele, 2021. http://hdl.handle.net/20.500.11768/121778.
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The microbiome has gained increasing momentum in cancer research, as it has become clear that microorganisms residing within our body are involved in mediating the cellular and tissue metabolism in health and disease. In bladder cancer research, there are different microbial communities that may mediate cancer pathobiology and response to therapy: the gut microbiome, the urinary microbiome, the urothelium-bound microbiome. These bacterial communities may mediate the processes of carcinogenesis or recurrence, modify the response to local intravesical therapies or influence the activity of systemic anticancer protocols.
Based on these premises, my research project aimed to unveil the urinary and urothelium-bound microbiome in therapy-naïve bladder cancer patients, describing the differently enriched bacterial communities using a sex-based stratification. Compared to healthy controls, I found that the urine of men affected by bladder cancer were enriched in the order Opitutales and subordinate family Opitutaceae, together with the isolated class Acidobacteria-6, while in female patients I found enriched the genus Klebsiella. Notably, the bladder cancer tissue was enriched in the genus Burkholderia in both men and women, when compared to non-neoplastic, paired urothelium biopsies. Then, I also characterized the gut microbiome of bladder cancer patients undergoing neoadjuvant pembrolizumab to understand if the intestinal bacteria may influence the immune-mediated anticancer activity. In this set, I have reported that antibiotic therapy has a negative effect on immunotherapy efficacy. Second, the gut microbiome of patients not responding to neoadjuvant pembrolizumab was characterized by a higher abundance of Ruminococcus bromii, while patients who showed a response were enriched in the genus Sutterella. Lastly, I started the implementation of in vivo and in vitro systems to test the mechanistic role of the bacteria identified in human samples.
This thesis work reported innovative data on the role of different microbial communities (urinary/urothelium-bound/fecal) in bladder cancer and bladder cancer therapy, and provided novel in vivo and in vitro models to validate those finding and uncover the complex microbiome-host cells crosstalk in bladder cancer patients.The microbiome has gained increasing momentum in cancer research, as it has become clear that microorganisms residing within our body are involved in mediating the cellular and tissue metabolism in health and disease. In bladder cancer research, there are different microbial communities that may mediate cancer pathobiology and response to therapy: the gut microbiome, the urinary microbiome, the urothelium-bound microbiome. These bacterial communities may mediate the processes of carcinogenesis or recurrence, modify the response to local intravesical therapies or influence the activity of systemic anticancer protocols. Based on these premises, my research project aimed to unveil the urinary and urothelium-bound microbiome in therapy-naïve bladder cancer patients, describing the differently enriched bacterial communities using a sex-based stratification. Compared to healthy controls, I found that the urine of men affected by bladder cancer were enriched in the order Opitutales and subordinate family Opitutaceae, together with the isolated class Acidobacteria-6, while in female patients I found enriched the genus Klebsiella. Notably, the bladder cancer tissue was enriched in the genus Burkholderia in both men and women, when compared to non-neoplastic, paired urothelium biopsies. Then, I also characterized the gut microbiome of bladder cancer patients undergoing neoadjuvant pembrolizumab to understand if the intestinal bacteria may influence the immune-mediated anticancer activity. In this set, I have reported that antibiotic therapy has a negative effect on immunotherapy efficacy. Second, the gut microbiome of patients not responding to neoadjuvant pembrolizumab was characterized by a higher abundance of Ruminococcus bromii, while patients who showed a response were enriched in the genus Sutterella. Lastly, I started the implementation of in vivo and in vitro systems to test the mechanistic role of the bacteria identified in human samples. This thesis work reported innovative data on the role of different microbial communities (urinary/urothelium-bound/fecal) in bladder cancer and bladder cancer therapy, and provided novel in vivo and in vitro models to validate those finding and uncover the complex microbiome-host cells crosstalk in bladder cancer patients.
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Hung, Tzong Tyng Clinical School Prince of Wales Hospital Faculty of Medicine UNSW. "Studies of bladder cancer progression." Awarded by:University of New South Wales, 2009. http://handle.unsw.edu.au/1959.4/39786.
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Bladder cancer (BlCa) is the second most common genitourinary cancer, affecting both men and women. Most (70%) cases present at the superficial stage; 20% of these recur with muscle-invasive disease. Major genetic alterations associated with BlCa include: loss/gain in expression or mutations in Retinoblastoma (RB) gene, human epidermal growth factor receptors (HERs), H-ras, p53 and FGFR3. Only p53 mutations are well correlated with invasive BlCa; other changes show variable correlations with disease status. To understand the progression of BlCa, a model of nine human BlCa cell sublines derived from a single parent but differing in in vivo characteristics, has been developed previously. These cells represent a heterogenous population from a single tumour and a model of different stages of BlCa progression, from non-tumourigenic to invasive. Two sublines were selected for further investigation: C3 (non-tumourigenic) and B8 (invasive). These were transfected with green (C3-GSP-2) and red fluorescent reporters (B8-RSP-gck) respectively to investigate the effects of their co-injection in vivo, specifically, promotion of C3 tumour growth by B8 cells. Surprisingly, B8 tumour growth was inhibited by C3 cells in vivo at different cell numbers and proportions of cells injected. Microarray analysis of C3 and B8 cells revealed differential expression of 1367 genes with dramatic differences in the transforming growth factor-?? and integrin-mediated pathways. Gene expression of BMP2, INHBB, FST, NOG, ID4 and TGF- ??1, in the TGF- ?? pathway was further analysed with qRT-PCR in all nine sublines. Expression of BMP2 was significantly related to tumourigenic potential (p=0.0238, Mann-Whitney) and INHBB to invasive ability (p=0.0476, Mann-Whitney). The BlCa model did not include a metastatic component. To broaden the model, cell lines were established from an invaded lymph-node (B8-RSP-LN) and a bone-metastasis (B8-RSP-BN) after subcutaneous and intra-cardiac injection of B8-RSP-gck cells. No significant differences were observed in the migratory capability and anchorage-independent colony formation of these metastatic cells compared with B8 cells. Evaluation of expression of the panel of TGF-beta genes (BMP2, INHBB, FST, NOG, ID4 and TGF- ??1) and metastasis-related genes (MMP9, MMP2 and KAI1) indicated that expression of BMP2, FST, ID4 and MMP9 was decreased or lost in the metastatic sublines.
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Hung, Tzong-Tyng Clinical School Prince of Wales Hospital Faculty of Medicine UNSW. "Studies of bladder cancer progression." Awarded by:University of New South Wales. Clinical School - Prince of Wales Hospital, 2007. http://handle.unsw.edu.au/1959.4/40450.
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Bladder cancer (BICa) is the second most common genitourinary cancer, affecting both men and women. Most (70%) cases present at the superficial stage; 20% of these recur with muscle-invasive disease. Major genetic alterations associated with BICa include: loss/gain in expression or mutations in Retinoblastoma (RB) gene, human epidermal growth factor receptors (HERs), H-ras, p53 and FGFR3. Only p53 mutations are well correlated with invasive BICa; other changes show variable correlations with disease status. To understand the progression of BICa, a model of nine human BICa cell sublines derived from a single parent but differing in in vivo characteristics, has been developed previously. These cells represent a heterogenous population from a single tumour and a model of different stages of BICa progression, from non-tumourigenic to invasive. Two sublines were selected for further investigation: C3 (non-tumourigenic) and B8 (invasive). These were transfected with green (C3-GSP-2) and red fluorescent reporters (B8-RSP-gck) respectively to investigate the effects of their co-injection in vivo, specifically, promotion of C3 tumour growth by B8 cells. Surprisingly, B8 tumour growth was inhibited by C3 cells in vivo at different cell numbers and proportions of cells injected. Microarray analysis of C3 and B8 cells revealed differential expression of 1367 genes with dramatic differences in the transforming growth factor- ?? and integrin-mediated pathways. Gene expression of BMP2,INHBB, FST, NOG, ID4 and TGF- ??1, in the TGF- ?? pathway was further analysed with qRT-PCR in all nine sublines. Expression of BMP2 was significantly related to tumourigenic potential (p=0.0238, Mann-Whitney) and INHBB to invasive ability (p=0.0476, Mann-Whitney). The BICa model did not include a metastatic component. To broaden the model, cell lines were established from an invaded lymph-node (B8-RSP-LN) and a bonemetastasis (B8-RSP-BN) after subcutaneous and intra-cardiac injection of B8- RSP-gck cells. No significant differences were observed in the migratory capability and anchorage-independent colony formation of these metastatic cells compared with B8 cells. Evaluation of expression of the panel of TGF-beta genes (BMP2, INHBB, FST, NOG, /04 and TGF- (31) and metastasis-related genes (MMP9, MMP2 and KAI1) indicated that expression of BMP2, FST, /04 and MMP9 was decreased or lost in the metastatic sublines.
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Yong, Sze Ming. "Mucin expression in bladder cancer." Thesis, University of Aberdeen, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440597.
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Certain membrane bound mucins such as MUC1, MUC4, and MUC12 were expressed in normal bladder urothelium. MUC1 expression was the highest in normal bladder urothelium and was present in almost all samples. In superficial bladder cancer, MUC1 demonstrated a pattern of expression that increased in proportion to the increase in tumour grade from Grade 1 to Grade 3 and carcinoma in situ. Utilising TMAs, membrane-bound mucins such as MUC1, MUC3, MUC4, MUC12 and MUC 16 were shown to have increased incidence of expression with tumour stage progression to muscle-invasive bladder cancer (stage T2 and above). Secretory mucins showed a more varied pattern of expression. MUC2 mRNA was up-regulated in progressive muscle-invasive bladder cancer. MUC5AC and MUC5B displayed a low incidence of expression in superficial tumours and muscle invasive bladder cancer. MUC7 mRNA expression, however, was limited to only muscle-invasive disease similar to the membrane-bound mucins described above. In a small proportion of patients in the recurrent progressive TMA, expression of MUC4, MUC5AC and MUC5B in penultimate superficial tumours prior to tumour progression allowed prediction of impending disease progression to muscle invasive disease. MUC5B, MUC12 and MUC13 were expressed at higher incidence in the single non-recurrent TMA, compared with the incidence of expression in the recurrent non-progressive TMA. The expression of these mucins in newly diagnosed superficial bladder tumours may thus favour better prognosis, with a subsequent reduced risk of tumour recurrence.
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Sherwood, Benedict T. "Radiosensitivity in bladder cancer cells." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29874.
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Potentially curative treatment options for patients with organ-confined transitional cell carcinoma (TCC) of the bladder (T1-4a/N0/M0) are radical cystectomy or radiotherapy (RT)-based 'bladder-preserving' regimens. A substantial number of patients who receive RT fail to respond (approximately 50%). Consequently, a greater understanding of the mechanisms of radioresistence is required, together with predictive information regarding the response of tumours to RT. Hypoxia and intrinsic cellular Radiosensitivity (IRS) are examined here, a factors that may influence the outcome of RT.;An immunohistochemical assay using hypoxia-related carbonic anhydrase IX (CA IX) was undertaken to determine the prognostic significance of hypoxia in bladder tumours treated with RT. A modified version of the alkaline comet assay (ACA) was used to examine differences in IRS between cells derived from TCC specimens. Nuclear factors that influence comet formation (and therefore radiosensitivity) were also examined, such as DNA double strand break (DSB) rates and differences in nuclear matrix protein (NMP) composition.;CA IX immunostaining did not provide prognostic information with respect to response to radical RT. ACA analysis indicated a wide range of responses between tumours. In TCC cell lines, DSB rates are not demonstrably different in cells of differentiated radiosensitivity, however, comparative analysis of nuclear proteins identified differences in their constitutive NMPs and repair enzymes.;These results do not provide evidence that hypoxia influences outcome after RT, but support the contention that ICR is important in dictating the response of bladder tumours to RT. Furthermore, in bladder cancer cell lines of differing radiosensitivity, differences in NMP and repair enzymes are identified. Further work is required to determine whether these are of prognostic importance.
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Hemelt, Marjolein. "Risk factors for bladder cancer : The South and East China case-control study on bladder cancer." Thesis, University of Birmingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.532307.
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Marsh, Howard Piers. "Genetic polymorphisms in bladder cancer angiogenesis." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428513.
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Beatty, John David. "Characterisation of Bladder Cancer Dentritic Cells." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487987.
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Bacillus Calmette-Guerin (BCG) is the most effective intravesical therapy for superficial bladder cancer. It is hypothesised that BCG therapy has a local and systemic effect on antigen-presenting dendritic cells (DC) and that characteristics and variations in DC may reflect those of DC in cancer tissue. Blood, urine and tissue samples were taken from patients with bladder cancer before and during treatment with intravesical BCG. In blood the percentages and numbers of DC expressing maturation, co-stimulatory and intracellular cytokine markers were measured using flow cytometry. Immune responses in bladder cancer were monitored by the identification and characterisation of DC from the urine and tissue of patients with bladder cancer using flow cytometry, immunohistochemistry and electron microscopy. Significantly increased numbers of blood plasmacytoid DC in patients with T1 G3 bladder cancer decreased during BCG therapy so that after 6 treatments there were no differences in the number of blood DC in patients with stages of superficial bladder cancer. DC numbers expressing CD40 increased in the blood of patients treated with BCG. Numbers of DC expressing T helper 1 (Th1) cytokine increased in patients who did not develop an early recurrence of bladder cancer. Immature DC were identified in tissue and urine from patients with superficial bladder cancer and confirmed in samples of urine by immunohistochemistry and electron microscopy. BCG therapy decreased the percentage of DC in the urine of patients who subsequently had recurrent bladder cancer. The therapeutic effect of BCG may be mediated by normalising circulating numbers of plasmacytoid DC and by increasing numbers of DC expressing the costimulatory molecule CD40. In response to BCG therapy increased numbers of circulating Th1 cytokine (IL-12) expressing DC and increased percentages of urine DC may be crucial in preventing recurrent bladder cancer.
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Hussain, Syed Anwer. "Non-surgical management of bladder cancer." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288651.
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Ninalga, Christina. "Cancer Immunotherapy : A Preclinical Study of Urinary Bladder Cancer." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6761.
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Dolin, Paul John. "Epidemiological investigations of cancer of the bladder." Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670292.
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Maddineni, Satish B. "Novel treatments in muscle invasive bladder cancer." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.514438.
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Bladder cancer is the second commonest malignancy of the urinary tract accounting for 145,000 directly related deaths world-wide per annum. TCC accounts for the majority of bladder cancer presenting in Europe. Approximately 70-80% of all TCC is superficial at presentation. Superficial TCC presents a major healthcare issue as it is a highly recurrent and progressive disease with recurrence rates of up to 70% and pathological progression rates up to 30% depending on grade and stage of disease. Intravesical chemotherapy and immunotherapy are established adjuvant treatments in superficial TCC with the objective of reducing recurrence with chemotherapy and reducing both recurrence and progression with immunotherapy. Muscle invasive bladder cancer requires radical treatment with radiotherapy or cystectomy. Despite significant advances in surgical techniques and perioperative management, cystectomy remains a morbid procedure with the rate of cure having reached a plateau. Radical radiotherapy has undergone significant improvements in targeting and effective dose delivery over the past 3 decades. Experiments in this thesis investigate whether further improvements in radiation induced cell kill can be achieved by manipulating the epidermal growth factor receptor and its down-stream signalling cascades using the tyrosine kinase inhibitor ZD1839. In this thesis the effects of combination treatment with ZD1839 and radiotherapy in the established bladder cancer cell lines MGHU-1 and its mutant radiosensitive clone, S40b are studied. The optimisation schedule for treatment with ZD1839 was established using colony forming assays. The mechanism of action of ZD1839 was investigated using flow cytometry for analysis of cell cycle perturbations and effects on apoptosis. Further experiments were conducted to ascertain whether there was an additive or synergistic effect between ZD1839 and the established radiosensitiser Gemcitabine at the optimum treatment schedules established for both drugs using colony forming assays.
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Pettit, Stephen James. "Bladder cancer : an examination of immunotherapeutic strategies." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394678.
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Davies, Claire Louise. "Multidrug resistance in bladder and breast cancer." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299289.
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Babalghith, Ahmad Omar. "Genetic events involved in bladder cancer progression." Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445140.
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Bladder cancer is one of the most common cancers of the genitourinary tract. Transitional cell carcinoma (TCC) of the bladder includes two disease categories. Approximately, 85% of TCC are superficial tumours and the remaining percentage is invasive at presentation. Transurethral resection of the superficial tumours is the standard treatment. High recurrence rate was reported in these tumours and approximately 30% developed invasive tumours. Thus, it is essential to establish and identify molecular markers, which predict recurrence and progression status of bladder cancer patients. This study was divided into three main parts. The first part of this study was to optimise the CGH technique for DNA, extracted from bladder cancer cell lines and tissues. Since the origin of DNA used in CGH is crucial, different optimisation steps were investigated. Labelling of DNA by nick translation was determined to be 45 minutes for cell lines, while 20 minutes was sufficient for DNA extracted from tissues. Then probe mix preparation from cell lines was determined to be 800 ng of green probe and 400 ng of red probe, while in tissue 1600 ng of both probes were shown to have the best hybridisation signals. Denaturation time was the target in optimisation of CGH; denaturation of the human metaphase chromosome for 7 minutes produced the best fluorescent signals. Hybridisation for 6 days showed identical results between cell lines and tissues. In addition, washing the metaphase chromosomes to remove unbounded probes was determined to be 10 seconds for both cell lines and tissues. Furthermore, CGH was tested using DNA with known genetic aberrations and CGH was able to detect these aberrations.
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Lyrakos, Nikolaos. "Molecular evaluation of radiosensitivity in bladder cancer." Thesis, Cranfield University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420682.
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Anderson, Jane Ann. "Autotaxin expression in bladder and renal cancer." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6946/.
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Autotaxin is an extracellular enzyme that generates lysophosphatidic acid (LPA). LPA binds up to six different cell surface G protein-coupled receptors to initiate signaling resulting in cell survival, invasion and angiogenesis. For this reason autotaxin has emerged as a therapeutic target in several different malignancies. I have used immunohistochemistry to explore the expression of autotaxin and its correlation with clinico-pathological variables in bladder and renal cancer. I show that in bladder cancer, tumours from patients with muscle invasive disease were significantly more likely to show strong autotaxin expression than were those tumours from patients without evidence of muscle involvement (p=0.009). This observation is not only consistent with the known functions of autotaxin/LPA in promoting tumour invasion, but suggests that the potential use autotaxin inhibitors in preventing bladder cancer progression warrants further investigation. Although I failed to detect autotaxin expression in the tumour cells of patients with renal cancer, I did observe high-level expression of autotaxin on the tumour-associated vasculature, which in many cases was not apparent in blood vessels of matched normal renal tissues. This points to an important role for autotaxin in renal cancer-associated angiogenesis and suggests a potential role for autotaxin inhibition as an anti-angiogenesis therapy.
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Hemdan, Tammer. "Prognostic and Predictive Factors in Bladder Cancer." Doctoral thesis, Uppsala universitet, Urologkirurgi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282607.
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Bladder cancer is a potentially curable malignancy; however in regards to the state of current therapy regimens, a plateau has been reached in both the non-muscle and muscle invasive types. To obtain effective treatment, and consequently a decreased mortality, it has become imperative to test and understand aspects affecting therapy response. The aim of this thesis is to illustrate a better understanding of clinical factors affecting therapy response using new drug combinations and new tumor markers alongside established risk criteria. In Paper I we reported the 5 year follow up from a multicenter, prospectively randomized study and we evaluated the 5-year outcomes of BCG alone compared to a combination of epirubicin and interferon-a2b in the treatment of patients with T1 bladder cancer. Treatment, tumor size and tumor status at second resection were independent variables associated with recurrence. Concomitant Cis was not predictive of failure of BCG therapy. Independent factor for treatment failure was remaining T1 stage at second resection. In Paper II &III we investigated the validity of emmprin, survivin and CCTα proteins as biomarkers for response and survival before neoadjuvant cisplatin chemotherapy. Bladder tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry (IHC). Patients in the chemotherapy cohort with negative emmprin and CCTα expression had significantly better overall survival (OS) than those with positive expression. In Paper IV primary end point was examining STMN1 as prognostic factor in bladder cancer. Analysis was performed on three bladder cancer patient cohorts using IHC, western blot and a bladder cancer cell line. High levels of STMN1, expression correlated to shorter disease-specific survival and the growth and migration of the cells were significantly reduced when transfecting the cells with STMN1 siRNA. Conclusion Risk assessment and predictors of outcomes could help in individualized treatment and follow up. Biomarkers will become more important for treatment choices in bladder cancer management.
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Mariappan, Paramananthan. "Quality of bladder cancer surgery : improving outcomes." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31261.
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Background: At the time of diagnosis, approximately 75% of all bladder cancers are Non-Muscle Invasive Bladder Cancers (NMIBC) - the standard treatment for these cancers is a Transurethral Resection of the Bladder Tumour (TURBT). Although, the vast majority of these cancers are not life-threatening, they have a high risk of recurrence (and progression, particularly in higher risk NMIBC), despite the use of adjuvant intravesical chemotherapy. Consequently, patients are kept on long term cystoscopic surveillance with endoscopic removal if recurrences are detected - this impacts on patients' quality of life and contributes to the high cost for the healthcare provider. Aims: The fundamental aim of this series of clinical studies, spanning 12 years, was to identify and implement, means of improving the efficiency in both processing and operating on patients with NMIBC to not only reduce recurrence, but also to reduce the duration of follow up and repeat operations. It was an evolutionary process where the findings in the preceding studies formed the basis of the subsequent one - while the aim of the individual studies were different, there was a clear link to the essential principles, thus forming a coherent collection of studies. Methods and results: The project was carried out in 3 phases (with 2 or 3 main studies in each phase, augmented by 1 to 2 linked studies - making the entire submission for PhD by publications a series of 12 studies, to date): Phase 1 (5 studies in this phase): The aim was to demonstrate the natural history of non-invasive bladder cancer and identify sub-categories of patients who could be discharged from surveillance at 5 years. This was initially achieved by evaluating a prospectively maintained cohort of non-invasive bladder cancer patients diagnosed between 1978 and 1984 at the Western General Hospital, Edinburgh. This study identified the importance of the recurrence rate at the first follow up cystoscopy (RRFFC) as an essential prognostic marker. This finding was further validated using 2 separate cohorts from a different Centre (the Royal Infirmary, Edinburgh) managed in the 80s and the 90s, respectively. The data confirmed that over the decades, recurrence patterns do change, possibly as a result of differing techniques and improvements in optics and instruments; however, what remained the same was the prognostic value of the RRFFC. Phase 2 (3 studies in this phase): The early recurrence was deemed to be the result of missed and tumours left behind at the initial TURBT, i.e. a marker of quality. However, RRFFC was only known 3 months after the initial surgery. Since the RRFFC was such an important prognostic factor, the aim of this phase was to determine the surgical factors contributing to the quality of TURBT and subsequently implement changes to the principles in carrying out the surgery to improve this quality. This was achieved by prospective collection of information regarding all patients undergoing TURBT for new bladder cancers, recording the tumour features, surgeon experience, if the resection was deemed to have been complete or not, and the pathological results. We identified that the detrusor muscle in the resected specimen and the experience of the surgeon were independent determinants of TURBT quality. This finding was validated in a further study using cohorts from another time period and another Centre - this allowed me to develop the concept of Good Quality White Light TURBT (GQWLTURBT) as the benchmark for the white light TURBT. Phase 3 (4 studies in this phase): Photodynamic Diagnosis assisted TURBT (PDDTURBT) was demonstrated in randomised controlled trials as a technique that reduces the recurrences in NMIBC. In the absence of evidence with this technique in the 'real life' setting nor comparisons with standardised, benchmarked white light TURBT technique, we performed a prospective controlled study comparing PDD-TURBT and GQ-WLTURBT, evaluating early and delayed recurrence rates in 2 separate studies. I also performed a multicentre UK study on the outcomes with PDD-TURBT and collaborated with other experts in Europe in producing a review article around Photodynamic Diagnosis and the cost effectiveness of this technique. Summary: This coherent series of studies has contributed to knowledge in bladder cancer surgery by, among others: (a) mapping the individual patient natural history of non-invasive bladder cancer; (b) confirming the importance of early recurrence as a strong prognostic indicator; (c) identifying predictors of this early recurrence and the quality of TURBT; (d) introducing the concept of the benchmark Good Quality White Light TURBT and (e) demonstrating the benefits of photodynamic diagnosis within a 'real life' setting.
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Jevons, Sarah J. "Clinically relevant MRE11 variants in bladder cancer." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:8b304d5c-3970-4d8f-b554-dbd5d8fe7bca.
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Personalised medicine aims to empower patients and clinicians to make informed choices in order to enhance treatment outcomes. Currently, muscle-invasive bladder cancer (MIBC) is treated with cystectomy or radiotherapy/chemoradiation with no clear survival advantage for either option. Identification of predictive biomarkers could facilitate choice between treatments and potentially improve overall survival rates. MRE11 is a damage signaling protein whose function is crucial for in the DNA damage response. Intriguingly, expression of MRE11 by immunohistochemistry (IHC) is a promising predictive biomarker of radiotherapy response in MIBC patients. Paradoxically in terms of DNA repair, patients with low expression of MRE11, have a significantly worse survival rate following radiotherapy than those expressing high levels of MRE11 (Choudhury et al. 2010; Laurberg et al. 2012). The aim of the project was to investigate the underlying mechanisms of MRE11 expression in bladder cancer. A novel C-terminally truncated MRE11 variant was detected in bladder cancer cell lines and patient samples. The variant was the result of a post-translational cleavage of wild type MRE11 by caspase activity. Although caspases were responsible for the cleavage of MRE11, expression of the variant did not increase following the induction of apoptosis, implying that non-apoptotic caspases were involved. The variant was found to be less stable than wild type MRE11 and degraded by the proteasome. Functional aspects of the variant were investigated and it was found that the variant was located in the nucleus, can complex with NBS1 and RAD50 and co-localised with yH2AX at double-strand break sites. However, expression of the truncated variant led to a reduction in the efficiency of homologous recombination. The truncated variant is therefore likely to have a functional impact on DNA repair, potentially in a dominant negative manner. This might explain why high MRE11 expression was associated with increased survival following radiotherapy in bladder cancer patients. The high expression of MRE11 could include detection of high levels of the variant, associated with defective DNA repair and hence increased radiosensitivity. An underlying mechanistic explanation further supports the use of MRE11 immunohistochemistry as a predictive biomarker. These findings could also contribute towards the development of novel treatment strategies for patients with bladder cancer.
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Bispo, Mafalda Alves Fernandes. "Galacto-silicon phthalocyanines for bladder cancer treatment." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/19029.
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Mestrado em Bioquímica - Bioquímica ClínicaA terapia fotodinâmica (PhotodynamicTherapy, PDT) é uma metodologia emergente no tratamento de diversas doenças oncológicas e tem por base o uso de oxigénio molecular, luz e um fotossensibilizador (FS) para seletivamente destruir as células tumorais. Em oncologia, a PDT leva à indução de espécies reativas de oxigénio (reactive oxygen species, ROS) no tecido tumoral, no qual ocorreu previamente o uptake preferencial e/ou a retenção de um FS. As ftalocianinas têm-se vindo a revelar FSs promissores na PDT devido às suas propriedades foto-físicas. Contudo, estes compostos para além de pouco solúveis em água, têm problemas de agregação e de especificidade para os tecidos tumorais. Assim, o trabalho apresentado nesta tese teve como objetivo principal conjugar co-axialmente ftalocianinas de silício (silicon phthalocyanines, SiPcs) com duas moléculas de galactose (SiPcGal2) e com duas unidades dendríticas de galactose (SiPcGal4) para que estes FSs fossem reconhecidos por galectinas (e.g. galectina-1) sobrexpressas em células tumorais. Contudo, os compostos desejados finais não foram obtidos, uma vez que a remoção dos grupos isopropilideno, protetores dos grupos hidroxilo das unidades de galactose, não foi conseguida. Assim, foram avaliadas as propriedades foto-físicas e foto-químicas das SiPcs com as galactoses protegidas, comparando com a SiPc dihidróxido (SiPc(OH)2), de forma a estudar a influência da conjugação co-axial de biomoléculas no core destes tipo de FSs. Infelizmente, a solubilidade das SiPcs em solventes aquosos não foi conseguida, contudo o seu espectro de absorção UV-visível evidenciou elevada absorção a altos comprimentos de onda (650-700 nm), janela espectrofotométrica onde ocorre uma penetração mais profunda da luz nos tecidos. Para além disso, estes FSs demonstraram-se excelentes marcadores fluorescentes, estáveis após irradiação e bons geradores de 1O2. Foram ainda realizados estudos in vitro com o objetivo de validar o seu potencial fotodinâmico no tratamento do cancro da bexiga, sendo que a SiPcGal4 e a SiPcGal2 agregaram nas células, tendo assim um baixo uptake, baixa toxicidade após foto-ativação e baixa produção de ROS. No geral, as SiPcs demonstraram um grande potencial como futuros FSs para a PDT, dado as suas excelentes propriedades foto-físicas, o que nos incentiva na descoberta de novas técnicas que diminuam a sua agregação nas células, como a utilização de bio-formulações estáveis e a desproteção das moléculas de galactose, que também irá aumentar a sua especificidade para células tumorais.
Photodynamic Therapy (PDT) relies on the combination of a photosensitizer (PS), light and molecular oxygen (O2) to generate reactive oxygen species (ROS), which can trigger cell death pathways. In oncology, the PS needs to be preferentially accumulated in cancer cells and a good generator of ROS (especially singlet oxygen, 1O2). Phthalocyanines (Pcs) are promising PSs in PDT due to their photochemical and photophysical properties. However, Pcs present solubility and aggregation problems, as well as low selectivity to the cancer tissue. Therefore, it will be conjugated a silicon phthalocyanine (SiPc) with two galactose molecules (SiPcGal2) and another with two galacto-dendritic units (SiPcGal4), both in axial positions. The aim of that conjugation is to promote the binding of the PS with galactose-binding proteins such as galectins (e.g. galectin-1) which are found to be overexpressed in cancer cells. Nevertheless, the desired compound were not obtained, once the hydrolysis of the isopropylidene galactose-protective groups didn’t work. Thereby, the photophysical and photochemical properties of those two SiPcs with the galactose-protective groups were studied in comparison with the SiPc dihydroxide (SiPc(OH)2), in order to study the SiPc core properties as well as the influence of an axial conjugation of biomolecules. The PSs solubility was compromised in an aqueous solution, however their absorption UV-Visible spectra showed high absorption peaks at a high wavelengths range (650–700 nm), which is the ideal therapeutical window where there is a higher penetration of light into the tissues. Furthermore, these SiPcs demonstrated to be good fluorescence labels, photostable and good 1O2 generators. In vitro studies were performed with the aim of validating them as photodynamic therapeutic agents against bladder cancer cells, however SiPcGal4 and SiPcGal2 aggregated on cells, having a low uptake, phototoxicity and ROS production. Overall, SiPcs have demonstrated a great potential as future PSs for PDT, thanks to their excellent photophysical properties, which prompt us in the discovery of different approaches that diminished their aggregation on cells, such as the incorporation of PSs into bio-stable formulations and the deprotection of the galactose molecules, which will also increase their specificity to tumoral cells.
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Rutherford, Noah P., William Stone, Tesha E. Blair, Bel Krishna Thakuri, and Marianne Brannon. "Expression of Oxidized Protein Hydrolase in Bladder Cancers." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/223.
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The National Cancer Institution reported over 80,000 diagnoses of bladder cancer (BCa) in the United States in 2018. Despite these numbers, minimal research toward developing new diagnostic techniques and treatment options are underway. Evidence suggests a significant increase in non-specific a-naphthyl acetateesterase levels in BCa patient’s urine. There has been little research focused on identification of the esterase present. It is also suggested that elevated oxidative stress resulting in production of reactive oxygen species (ROS) is common in tumorigenic bladder cells as a result of increased metabolic activity. Oxidized protein hydrolase (OPH) is an 80kD serine protease, previously found to be elevated in many other types of cancer. OPH degrades proteins damaged by ROS and also exhibits a highly specific esterase activity toward (AcApNA) N-acetyl-alanyl-p-nitroanilide and ANAA (α-naphthyl N-acetylalaninate) containing substrate. Investigation of OPH expression in BCa could result in development of new diagnostic techniques and possible application toward prodrugs targeting cells with elevated ROS and/or OPH. Due to lack of commercial OPH, a positive control for this protein is needed for testing. To do this E. coli(BL-21 DE-3) were cultured and inserted with pET-21a (+) plasmids containing a human OPH gene insert prior to a His7 tag. After being selectively grown on ampicillin media, the bacteria were induced by IPTG and digested using lysozyme. The soluble rOPH suspended in the supernatant was separated from the pellet by centrifugation and further purified using Ni-NTA resin chromatography columns specific for the His7 tag sequence. The UM-UC-3 bladder cancer cell line, commonly used in published research to screen efficiency of chemotherapeutics, were cultured in accordance to ATCC. These cells were then compared against none tumorigenic bladder cancer cells and rOPH in a series of tests. Sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis (SDS-PAGE) were transferred for western blot analysis using antibodies specific for human OPH to investigate the expression levels present in cells. Native-PAGE electrophoresis showed OPH esterase activity across these cells using S-ANAA substrate as a specific esterase colorimetric stain. With these results, possible treatment options can be investigated with use of novel prodrug chemotherapy specifically targeting OPH in BCa cells, ultimately leading to apoptosis in effected cells. These events may also lead to possible biomarkers used for easier and earlier diagnosis of BCa across various spectrums.
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Sharp, Angela. "Assessment of putative markers for non-invasive detection of bladder cancer /." Assessment of putative markers for non-invasive detection of bladder cancerRead the abstract of the thesis, 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16763.pdf.
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Mathur, Pallavi. "Role of lysosome positioning in bladder cancer progression." Electronic Thesis or Diss., Université Paris sciences et lettres, 2022. http://www.theses.fr/2022UPSLS028.
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Les lysosomes sont un centre de régulation intracellulaire pour le métabolisme et la signalisation. De nombreuses fonctions des lysosomes sont impliquées dans le cancer et ils restent donc une cible intéressante pour les thérapies anticancéreuses. Nous avons précédemment étudié le paysage intracellulaire de cet organite dans une collection de lignées cellulaires de cancer de la vessie et de cellules urothéliales humaines normales et nous avons constaté que les lysosomes sont plus dispersés vers la périphérie des cellules dans les cellules agressives de cancer de la vessie. Nous constatons ici une régulation différentielle de la kinase mTORC1 (cible mammalienne du complexe 1 de rapamycine), qui émet des signaux à partir des lysosomes, entre des lignées cellulaires de cancer de la vessie non agressives et agressives, et nous constatons une translocation nucléaire constitutive du facteur de transcription EB (TFEB) dans les cellules de cancer de la vessie agressives. Le silençage de TFEB dans les cellules cancéreuses agressives inverse le phénotype de dispersion des lysosomes, ce qui suggère un rôle de TFEB dans la régulation de la dispersion lysosomale dans ces cellules. De manière cohérente, nous constatons que l'induction de la translocation nucléaire de TFEB après l'inhibition de mTORC1 induit un mouvement périphérique des lysosomes dans les cellules non agressives. Les phosphoinositols étant des régulateurs importants de la fonction et du mouvement des lysosomes, en particulier le phosphatidylinositol-3-phosphate (PI3P) qui est impliqué dans le positionnement des lysosomes, nous avons testé si TFEB régule les niveaux de PI3P dans les cellules cancéreuses agressives de la vessie et donc la dispersion des lysosomes. Nous constatons que la GFP-FYVE qui se lie à PI3P est fortement diminuée après un traitement avec un siTFEB dans les cellules agressives.L'ensemble de nos résultats indique que le positionnement des lysosomes est sous le contrôle de TFEB et que l'hyperactivation de TFEB conduit au phénotype cellulaire caractéristique de dispersion des lysosomes dans les cellules cancéreuses de la vessie agressives. De plus, nos résultats montrent que l'activation de TFEB entraîne une augmentation globale de PI3P au niveau des lysosomes et un fort recrutement des protéines contenant le domaine FYVE. Ainsi, nos résultats révèlent un nouveau rôle de TFEB dans la régulation des niveaux de PI3P. Cela clarifie conceptuellement le double rôle de TFEB en tant que régulateur de la maturation endosomale et de l'autophagie, deux processus cellulaires fondamentaux mais distincts qui dépendent et sont régulés par les niveaux de PI3P. Nous proposons que les changements de positionnement des lysosomes soient un biomarqueur crucial des altérations de la voie PI3P dans le modèle de cancer de la vessieLysosomes are an intracellular regulatory hub for metabolism and signaling. Many functions of lysosomes are implicated in cancer and thus they remain an interesting target for cancer therapies. We had previously investigate the intracellular landscape of this organelle in a collection of bladder cancer cell lines and normal human urothelium cells and found that lysosomes become increasingly scattered towards the cell periphery in aggressive bladder cancer cells. Here we find differential regulation of mTORC1 (mammalian target of rapamycin complex 1) kinase, which signals from lysosomes, between non- aggressive and aggressive bladder cancer cell lines and we find constitutive nuclear translocation of the transcription factor EB (TFEB) in aggressive bladder cancer cells . Silencing of TFEB in aggressive cancer cells reverses the scattered lysosome phenotype, suggesting a role of TFEB in regulation of lysosomal dispersion in these cells. Consistently, we find that inducing nuclear translocation of TFEB after inhibition of mTORC1 induces peripheral movement of lysosomes in non-aggressive cells. Since phosphoinositols are important regulators of lysosomal function and movement, especially phosphatidylinositol-3-phosphate (PI3P) which is involved in lysosomal positioning, we tested whether TFEB regulates levels of PI3P in aggressive bladder cancer cells and thus lysosomal dispersion. We find that GFP-FYVE that binds to PI3P is strongly decreased after siTFEB in aggressive cells.Together our results indicate that lysosome positioning is under the control of TFEB and that hyperactivation of TFEB leads to the characteristic cellular phenotype of lysosome dispersion in aggressive bladder cancer cells. Moreover, our results show that activation of TFEB leads to a global increase of PI3P at lysosomes and strong recruitment of FYVE-domain-containing proteins. Thus, our findings uncover a novel role of TFEB in regulating PI3Ps levels. This conceptually clarifies the double role of TFEB as regulator of endosomal maturation and autophagy, two fundamental but distinct cellular processes that rely and are regulated by PI3P levels. We propose that lysosome positioning changes are a crucial biomarker of alterations in the PI3P pathway in the bladder cancer model
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Streeter, Edward. "Stage progression in bladder cancer : mechanisms and therapies." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410571.
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Rajjayabun, Paul H. "The erbB oncogene family in human bladder cancer." Thesis, University of Newcastle upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405076.
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Sak, Sei Chung. "Molecular epidemiology of DNA repair and bladder cancer." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446441.
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Koo, V. S. W. "Bioimaging and quantitative analysis of bladder cancer invasion." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484961.
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TGF-beta1 is known to induce changes tumour morphology and motility which are associated with invasion and metastasis via the phenomenon of epithelial-mesenchymal transition (EMD. Although morphology and motility can be determined in vitro, tumour invasion and metastasis are best investigated in an animal model that can be monitored. The aim of this study was to quantify the effects ofTGF-bT;ta1 on AY-27 bladder tumour and to establish DsRed2 fluorescence monitoring in the AY-27/F344 Fisher rat bladder tumour model using IVIS®200 imaging system. Using cbnventional microscopic assessment, scratch wound and Matrigel assays, we showed that TGF-beta1 induces spindle-shape morphology and significantly increased the motility and invasion in AY-27 cells. Preliminary data showed decreased expression of cytokeratin 18 and polarised distribution of vimentin of TGF-beta1 treated cells, indicating the occurrence of EMT. We also developed the Spindle Index assay that objectively quantified morphology change; and invented a novel chemo-attractant based Koo Assay of Migration which quantified tumour motility. These novel assays concurred with the above reference assays and can serve as an adjunctive investigative tool. DsRed2 was transfected into AY-27 using Lipofectamine2000 and the fluorescent intensity and stability were quantified using IVIS®200 and phase-contrasUfluorescent microscopy. However. the DsRed2 fluorescence intensity was not bright or stable. In addition. the DsRed2 transfection has altered the. morphology and growth characteristics of the cell. Instead, we used tdTomato, a variant of DsRed, and found it superior to DsRed2 in the fluorescent intensity and stability and it did not alter the characteristics of AY-27 cells. We showed that fluorescence detection of SUbcutaneously injected AY-27/tdTomato in F344 rat was successful using IVIS®200. However. intravesical fluorescence detection was hampered due to the thick rat tissue overlying the bladder. We suggest that f1uorescently tagged bladder or other deep intra-abdominal tumour model in rats may not be suitable for monitoring using IVIS®200.
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Louhelainen, Jari. "Molecular progression and clonality or urinary bladder cancer /." Stockholm, 2000.
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Risch, Angela. "Polymorphism in arylamine N-acetyltransferase in bladder cancer." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297022.
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Hassanin, Wael Farouk Sedik. "Role of molecular genetic lesions in bladder cancer." Thesis, Glasgow Caledonian University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.547613.
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Abdel-Fattah, Rana. "TP53 and MDM2 alterations in human bladder cancer." Thesis, University of Newcastle Upon Tyne, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242350.
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Clifford, Steven Curtis. "Determinants of chemosensitivity in human primary bladder cancer." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239771.
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Abedin, Syed Asad. "Nuclear receptor co-repressor actions in bladder cancer." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/645/.
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Nuclear receptors (NR) are ligand dependent transcription factors. In the current study, expression of VDR and Farnesoid-X-receptor (FXR) protein is demonstrated along with relative mRNA expression of a range NRs and co-repressors in four bladder cancer cell lines. Nuclear co-repressor 1 (NCoR1) is over-expressed in RT-112 (1.6 fold) and EJ-28 cells (2.6 fold). This correlates with reduced sensitivity to NR ligands in EJ-28 cells. Stable over-expression of NCoR1 in sensitive RT-4 cells (lowest relative NCoR1 expression) led to reduced sensitivity to NR ligands; treatment with lithocholic acid (LCA - FXR and VDR ligand) led to expression of a cohort of genes consistent with a xenobiotic protective response (ABC transporter proteins, metabolizing enzymes and cell cycle arrest proteins) as assessed by microfluidic quantitative real-time reverse transcription polymerase chain reaction. NCoR1 over-expression was targeted with co-treatment with NR ligand and the histone deacetylase inhibitor Suberoylanilide hydroxamic acid (SAHA), resulting in strongly additive anti-proliferative responses to FXR, VDR and PPAR-γ ligands in NCoR1 over-expressing cells; confirmed as a G1/S phase cell cycle arrest in EJ-28. Microarray profiling revealed unique regulation of genes involved in cell proliferation. This study suggests NCoR1 acts as a selective regulator of NR function.
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Greensmith, R. M. D. "Novel approaches in the management of bladder cancer." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3007973/.
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Background: In recent decades, despite survival improvements in the majority of high incidence cancers, survival rates for patients with bladder cancers have remained static. Key challenges in the treatment of bladder cancer are the acquisition of chemotherapy resistance, and progression to lethal muscle- invasive bladder cancer. Aims: This thesis aims to explore methods of pharmacological inhibition of chemotherapy resistance, mechanisms of bladder tumour invasion, and gene expression in bladder cancer. Rationale: Nuclear factor (erythroid-derived 2)-like 2 (NRF2) overexpression has been associated with chemotherapy resistance in a number of cancers including bladder. Therefore, the utility of the purported specific inhibitor of NRF2, brusatol in the attenuation of cisplatin chemotherapy resistance was investigated. In bladder cancer, cluster of differentiation-40 (CD40)-ligation with membrane bound CD40-Ligand (CD40L) has been shown to induce marked cell death. However, little is known about the role of CD40-ligation in tumour cell invasion. With CD40 currently under investigation as a putative target for anti-cancer therapy, it was a timely goal of this thesis to understand more about its role in tumour cell invasion. Until recently, knowledge of gene expression profiles in bladder cancer has been limited. Understanding of gene expression patterns in cancer may allow for enhanced prognostication, identification of potential drug targets and move the management of bladder cancer towards the ideal of personalised medicine. Methods: In vitro cytotoxicity assays were employed to determine the effect of brusatol on cisplatin sensitivity. Western blotting was employed to determine the effects of brusatol on proteins downstream of NRF2. An organotypic model of bladder cancer was used to investigate the effect of CD40-ligation on bladder tumour cell invasion. Non-cleavable membrane bound CD40-ligand delivered by adenoviral vector was used in CD40 expressing cell lines of invasive and non-invasive origin. The effect of CD40-ligation was investigated downstream by western analysis and RNA microarray. Whole-transcript based microarray analysis was performed on bladder biopsies obtained from 19 patients, and 10 controls. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Hypergeometric analysis was used to identify canonical pathways and curated networks with statistically significant enrichment of differentially expressed genes. Samples from a further 6 patients (muscle invasive bladder cancer (MIBC) n = 3, normal tissue n = 3) were tested for osteopontin expression by immunohistochemistry. Results: Brusatol increased the sensitivity of bladder cancer cell lines to cisplatin in a dosage and cell line dependent manner. Furthermore, brusatol exhibited marked toxicity as a standalone treatment. However, evidence suggests that brusatol does not act as a specific inhibitor of NRF2. CD40-ligation with non-cleavable membrane-bound CD40-ligand led to marked cell death in CD40-positive non-muscle invasive cell lines. However, in muscle- invasive CD40-positive cell lines marked inhibition of tumour invasion was also observed. Expression analysis of family with sequence similarity member 83 d (FAM83D), fibronectin (FN1), matrix metalloproteinase 1 (MMP1) and anillin (ANLN) revealed downregulation of FN1, FAM83D, and ANLN, and upregulation of MMP1, with a concurrent upregulation of MMP1 and a paradoxical increase of FN1 in EJ cells, with no change in FN1 and MMP1 expression in RT112 cells. xiii Pathways associated with cell cycle and proliferation were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was significantly overexpressed in invasive cancer compared to healthy tissue. Conclusions: It is unlikely that brusatol is a specific inhibitor of NRF2 however its marked cytotoxicity as a stand-alone agent and potentiating effects in combination with cisplatin are rationale for further investigation. CD40-ligation attenuates the invasion of MIBC cells in an organotypic model of bladder cancer. However, it is unclear whether the attenuation of invasion is due to the inhibition of invasive pathways, or direct induction of apoptosis. Nevertheless, with the usage of CD40-agnoistic antibodies currently in clinical trials, attenuation of tumour invasion is a promising effect. Gene expression analysis identifies divergent pathways that may be useful in the stratification of bladder cancers, and the identification of drug targets. Furthermore, this study supports a key role for osteopontin in bladder cancer, which warrants further investigation as a marker prognostic of muscle invasive disease.
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Jackson, Andrew Mark. "Cytokines, cell adhesion molecules and bladder cancer immunotherapy." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/19867.
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The intravesical administration of Bacillus Calmette Guerin for the treatment of transitional cell carcinoma of the bladder is the most effective immunotherapy for any solid human malignancy. Despite this awesome accolade relatively little is understood of its mechanism of action. This study details the in vitro interaction between IL-2 activated lymphocytes and tumour cells, the effect of cytokines produced as a result of immunotherapy on tumour cells and the relationship of these findings to the situation in vivo. Bladder cancer cells were not found to be susceptible to NK cell activity but were found to be differentially susceptible to IL-2 activated lymphocytes. No correlation was evident between the histopathological grade of the tumour. The interaction between these cells was observed to involve intimate contact and the tumour cells were found to constitutively express either ICAM-1 or ICAM-2. The expression of these cell adhesion molecules correlated significantly with the sensitivity of the tumour cells to LAK mediated cytolysis. Following BCG therapy a variety of cytokines including IFNγ and TNFα are detected in the urine. When bladder cancer cells were cultured in the presence of recombinant IFNγ and TNFα an increase in the levels of ICAM-1 expression was observed. The optimal stimulation was found after 24 hours culture with 100Uml-1 IFNγ, whilst TNFα stimulated to a lesser extent. Culture in the presence of both cytokines was observed to synergistically induce or augment ICAM-1 expression. Following culture with IFNγ, the tumour cells displayed increased susceptibility to LAK activity, this was significantly correlated with increased ICAM-1 expression. The levels of tumour cell response to IFNγ could not be correlated with either the abundance or affinity of specific receptors as determined by Scatchard analysis. Thus investigations were initiated into the events down-stream of the ligand-receptor interaction. Monoclonal antibodies to ICAM-1, decreased the sensitivity of tumour cells to LAK activity. However, monoclonal antibodies to LFA-1 (the ligand for ICAM-1) further blocked the action of LAK cells.
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Månsson, As̊a. "The patient with bladder cancer from symptoms, through treatment, with special reference to psychosocial conqequences of radical cystectomy /." Lund : Dept. of Urology, Lund University Hospital, 1997. http://books.google.com/books?id=k-prAAAAMAAJ.
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Silina, Linda. "Targeting TYRO3 : A Novel Strategy to Radiosensitise Bladder Cancer Cells Review of Preclinical Studies to Improve Radiotherapy Response in Muscle-Invasive Bladder Cancer: Lessons and Perspectives TYRO3 Targeting as a Radiosensitizing Strategy in Bladder Cancer TYRO3 as a Molecular Target for Growth Inhibition and Apoptosis Induction in Bladder Cancer." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL024.
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Le cancer de la vessie est un problème majeur de santé publique. Il est le quatrième cancer le plus fréquent chez l’homme en termes d’incidence. 25% des cancers diagnostiqués sont des tumeurs envahissant le muscle (TVIM) présentant un mauvais pronostic. La cystectomie est le traitement standard de référence pour les TVIM, même si elle présente des inconvénients importants. La radiothérapie, associée à une chimiothérapie et à une résection transurétrale de la tumeur, émerge comme traitement conservateur alternatif. La chimiothérapie n’épargne pas les tissus sains et présentent de nombreux effets secondaires indésirables. Il est donc d’importance de découvrir de nouvelles stratégies de radiosensibilisation pour les tumeurs de la vessie. TYRO3 est un récepteur à activité tyrosine kinase de la famille TAM (qui comprend TYRO3, AXL et MERTK). TYRO3 est surexprimé dans de nombreux types de cancers et favorise la prolifération, la survie et la résistance des cellules tumorales à la chimiothérapie. De plus, la surexpression de TYRO3 a été associée à une diminution de la survie globale des patients. Cependant, le rôle de TYRO3 dans le cancer de la vessie n'a pas encore été étudié. Dans cette thèse, je me suis intéressée : (1) Au rôle de TYRO3 dans le cancer de la vessie; (2) A l'effet radiosensibilisant de la perte d’expression ou de l’inhibition de TYRO3 dans les cellules cancéreuses de la vessie; (3) A l'effet de l'inhibition ou de la perte d’expression de TYRO3 sur l’urothélium humain sain.Nous avons démontré que TYRO3 est surexprimé dans 50% des TVIM. De plus, nous avons mis en évidence que les cellules tumorales de vessie surexprimant TYRO3 développaient une dépendance à ce récepteur pour leur survie et leur croissance. Les résultats des données transcriptomiques suggèrent que la perte d’expression de TYRO3 induit des modifications importantes dans le contrôle du cycle cellulaire et de l’apoptose, ce qui laisse supposer que TYRO3 pourrait augmenter la sensibilité de ces tumeurs à la radiothérapie. La perte d’expression ou l’inhibition de TYRO3 dans les cellules dérivées de tumeur de vessie induit une radiosensibilisation significative des cellules traitées. A l’inverse, la surexpression de TYRO3 par transfection plasmidique sur des cellules exprimant peu TYRO3 induit une radiorésistance. En association avec le rayonnement, la perte d’expression de TYRO3 conduit à un arrêt du cycle cellulaire et à une persistance à 24h des foyers de réparation (détectés par immunofluorescence). Enfin, les travaux sur les cellules dérivées de l’urothélium sain ont montré que la perte d’expression de TYRO3 n'affectait pas leur viabilité suggérant que le ciblage de TYRO3 pourrait améliorer l'efficacité de la radiothérapie tout en épargnant les tissus normaux environnantsBladder cancer (BCa) is a major global health problem. It is the fourth most common cancer in men in industrialized countries. 25% of all diagnosed BCa are Muscle-invasive bladder cancers (MIBC) which have poor prognosis. Cystectomy is the standard treatment for MIBC, but for patients with comorbidities it presents significant drawbacks including increased risk of infection and impacted quality of life. Radiotherapy coupled with chemotherapy and tumor transurethral resection has emerged as a promising bladder sparing. Chemotherapy does not spare normal tissue and results in side effects. Therefore, it is of great interest to discover novel radiosensitisation strategies for bladder tumors.TYRO3 is a receptor tyrosine kinase of the TAM family (comprising TYRO3, AXL and MERTK) and is known to regulate diverse biological. TYRO3 is overexpressed in many types of cancer and promotes tumor cell proliferation, survival and resistance to chemotherapy. In addition, higher levels of TYRO3 expression have been associated with decreased overall survival in patients of diverse cancers. However, the role of TYRO3 in BCa has so far not been studied. In this thesis, I investigated:(1)The role of TYRO3 in BCa; (2) The radiosensitising effect of TYRO3 downregulation and inhibition in BCa cells; (3) The effect of TYRO3 downregulation and inhibition on normal human urothelial tissue.We first demonstrated that TYRO3 is overexpressed in 50% of MIBCs. TYRO3 overexpression conferred a TYRO3-dependance to bladder tumor cells for cell growth and viability. Transcriptomic analysis of TYRO3-downregulated cells suggested that TYRO3 signaling controlled cell cycle and protected from apoptosis, which indicated a potential to improve radiation response. TYRO3 downregulation lead to a significantly increased radiosensitivity of BCa cells and conversely, TYRO3-overexpression induced radioresistance. In combination with radiotherapy, TYRO3 dowregulation lead to a cell cycle arrest and a long term persistence of Ionizing Radiation-Induced Foci (IRIF). Finally, I demonstrated that TYRO3 downregulation and inhibition did not impact viability of normal human bladder cells suggesting that inhibiting TYRO3 could improve radiotherapy efficiency while sparing normal surrounding tissues
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Woolcott, Christy Gwen. "Bladder cancer and air pollution, a case-control study." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq20715.pdf.
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Smeets, Antonius Wilhelmus Godefridus Beatrix. "Chromosome and flow cytometric studies of urinary bladder cancer." Maastricht : Maastricht : Rijksuniversiteit Limburg ; University Library, Maastricht University [Host], 1987. http://arno.unimaas.nl/show.cgi?fid=5371.
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Sherif, Amir. "Experimental Diagnostics and Therapeutics of Invasive Urinary Bladder Cancer." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3504.
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Horvath, Andras. "Viral gene therapy for non-muscle invasive bladder cancer." Thesis, University of Surrey, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540942.
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Bhardwa, Jeetesh Maganlal. "Clinical and molecular prognostic factors in superficial bladder cancer." Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497943.
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Aim: To identify molecular clinical and molecular prognostic indicators markers for superficial bladder cancer. Univariate statistical analysis of the clinical database revealed grade (p<0.001, Log rank test) and positive urine cytology at presentation (p= 0.002 Log rank test) are highly significant for recurrence and progression.
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Liao, Hanqing. "Textural features for bladder cancer definition on CT images." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/7655.
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Genitourinary cancer refers to the presence of tumours in the genital or urinary organs such as bladder, kidney and prostate. In 2008 the worldwide incidence of bladder cancer was 382,600 with a mortality of 150,282. Radiotherapy is one of the main treatment choices for genitourinary cancer where accurate delineation of the gross tumour volume (GTV) on computed tomography (CT) images is crucial for the success of this treatment. Limited CT resolution and contrast in soft tissue organs make this difficult and has led to significant inter- and intra- clinical variability in defining the extent of the GTV, especially at the junctions of different organs. In addition the introduction of new imaging techniques and modalities has significantly increased the number of the medical images that require contouring. More advanced image processing is required to help reduce contouring variability and assist in handling the increased volume of data. In this thesis image analysis methodologies were used to extract low-level features such as entropy, moment and correlation from radiotherapy planning CT images. These distinctive features were identified and used for defining the GTV and to implement a fully-automatic contouring system. The first key contribution is to demonstrate that second-order statistics from co-occurrence matrices (GTSDM) give higher accuracy in classifying soft tissue regions of interest (ROIs) into GTV and non-GTV. Loadings of the principal components (PCs) of the GTSDM features were found to be consistent over different patients. Exhaustive feature selection suggested that entropies and correlations produced consistently larger areas under receiver operating characteristic (AUROC) curves than first-order features. The second significant contribution is to demonstrate that in the bladder-prostate junction, where the largest inter-clinical variability is observed, the second-order principal entropy from stationery wavelet denoised CT images (DPE) increased the saliency of the bladder prostate junction. As a result thresholding of the DPE produced good agreement between gold standard clinical contours and those produced by this approach with Dice coefficients. The third contribution is to implement a fully automatic and reproducible system for bladder cancer GTV auto-contouring based on classifying second-order statistics. The Dice similarity coefficients (DSCs) were employed to evaluate the automatic contours. It was found that in the mid-range of the bladder the automatic contours are accurate, but in the inferior and superior ends of bladder automatic contours were more likely to have small DSCs with clinical contours, which reconcile with the fact of clinical variability in defining GTVs. A novel male bladder probability atlas was constructed based on the clinical contours and volume estimation from the classification results. Registration of the classification results with this probabilistic atlas consistently increases the DSCs of the inferior slices.
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Nekeman, Duncan. "Quality of life in newly diagnosed bladder cancer patients." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6481/.
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It has been postulated that bladder cancer impacts health-related quality of life (HRQoL), but research is limited. This research is particularly important as survival for non-muscle invasive bladder cancer (NMIBC) is high, and these patients will need to live with acceptable HRQoL for many years. I investigated HRQoL in 1258 muscle invasive bladder cancer (MIBC) and NMIBC patients participating in the Bladder Cancer Prognosis Programme. Although I found no major difference in HRQoL around time of diagnosis between NMIBC and MIBC patients, I did find that different parts of HRQoL seemed to influence survival of NMIBC and MIBC. Also, patients prefer an invasive but accurate cystoscopy over a hypothetical non- invasive but less accurate urinary biomarker. Additionally, the European Organization of Research and Treatment of Cancer (EORTC) developed a quality of life questionnaire specifically for NMIBC (EORTC NMIBC-24). In this thesis, I have strengthened the structure of this questionnaire that was previously published by another UK research group. Finally, I found only a small difference in physical health between patients with incontinent and continent urinary diversion in a meta-analysis. These findings were discussed in each of the results chapters, and put into wider context in the general discussion chapter.
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Rehman, Haroon, Sukesh Manthri, Sonia Oad, and Kanishka Chakraborty. "Not Your Regular Run-of-the-Mill Bladder Cancer." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/77.
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Bladder cancer is the one of the most common malignancies of the genitourinary system and the overwhelming majority of those cases, approximately 90% in the United States(1), are of the urothelial/transitional cell histologic type. Small cell histologic type of bladder cancer is extremely rare with a mean frequency of 0.7% (1), and due to its rarity, there have not been any large phase III clinical trials in order to establish a definitive treatment regimen. We report here one such case of this rare type of bladder cancer and our approach towards treatment.
A 69-year-old man had an incidental finding of microscopic hematuria during routine annual testing performed by his primary care physician. He was referred to a urologist for further evaluation, and in the interim, he began to experience symptoms of nocturia, dysuria and gross hematuria. Cystoscopy revealed a 5 cm sessile mass within the bladder and transurethral resection of the tumor was performed. Histopathological analysis of the tumor revealed muscle invasive poorly differentiated urothelial carcinoma with neuroendocrine features suggestive of small cell carcinoma. Follow-up systemic imaging only revealed multiple lesions in the liver, with the largest solitary liver lesion measuring 4.4 x 3.4 cm and no discrete lung lesions. Patient was started on palliative systemic chemotherapy with carboplatin and etoposide and follow-up imaging demonstrated excellent response after four cycles of treatment; however, follow-up imaging after the completion of 6 cycles of treatment demonstrated disease progression. Patient was referred for consideration of enrollment into any clinical trials; however, unfortunately no trials were found to be available. Patient was subsequently offered systemic treatment with single-agent immunotherapy with pembrolizumab. Due to development of left sided hydronephrosis, nephrostomy tube placement was performed and patient was also started on palliative radiation.
Primary small cell carcinoma (SCC) of the bladder is an exceedingly rare malignancy and therefore, data is not readily available in order to guide treatment decisions. The most commonly administered regimen consists of etoposide with a platinum agent, and this regimen is extrapolated from the treatment of SCC of the lung. However, as for patients like ours, who had progression of disease in a short interval and are deemed primary treatment (platinum) refractory, the prognosis certainly becomes far more grim and the treatment choices even more limited. In sharing our treatment approach, we hope to be able to provide insight towards potential future treatment choices for this most-challenging diagnosis, primary small cell carcinoma of the bladder.
(1) Blomjous CE, et. al. Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases. Cancer. 1989 Sep 15; 64(6):1347-57.
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Bernardo, Carina Susana Diogo. "Establishment of direct bladder cancer xenografts in nude mice." Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/7249.
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Mestrado em Biomedicina MolecularA cistectomia radical e o tratamento standard do carcinoma urotelial invasivo da bexiga, contudo, cerca de metade dos paciente apresentam recidivas ap os a cirurgia e necessidade de quimioterapia sist emica. Pacientes com tumores invasivos da bexiga com caracter sticas id^enticas apresentam varia c~oes signi cativas na evolu c~ao natural da doen ca e resposta ao tratamento, re ectindo a composi c~ao heterog enea do tumor e a necessidade de uma tratamento personalizado. A avalia c~ao pr evia da sensibilidade do tumor a quimioterapia e especialmente importante e justi c avel em pacientes com elevado risco de apresentar resist^encia ao tratamento. Neste projecto, este risco e avaliado atrav es da an alise da express~ao de marcadores moleculares tais como o CD147, previamente associado a mau progn ostico e resist^encia a cisplatina. O principal objectivo deste projecto era estabelecer um modelo directo de carcinoma urotelial invasivo da bexiga humano atrav es de xenotransplante em ratinhos imunode cientes, caracterizar o modelo e avaliar a sua viabilidade como plataforma para o estudo da sensibilidade e resist^ encia dos tumores a quimioterapia. Um dos 9 fragmentos transplantados cresceu como implante prim ario nos ratinhos, tendo sido transferido com sucesso para novos animais, onde desenvolveu tumor em 2 dos 3 animais transplantados. A an alise histol ogica e immuno-histoqu mica (CD147, p53, p63, ki-67 e CK20) do xenotransplante, mostrou haver preserva c~ao da morfologia e fen otipo do tumor prim ario, pelo menos durante o estabelecimento do xenotransplante. Estes resultados preliminares suportam o valor deste modelo para ensaios com f armacos, por em, s~ao necess arios estudos adicionais para validar o modelo e determinar o per l dos pacientes que podem bene- ciar desta abordagem.
Radical cystectomy is a standard treatment for invasive bladder cancer, however, approximately half of the patients have disease recurrence after surgery and require systemic chemotherapy. Signi cant variations in the natural history and responses to treatment of patients with invasive bladder cancer are seen between tumors with identical features, re ecting the heterogeneity of the constituent tumor cells and the necessity of a personalized management approach. The assessment of tumor sensitivity to chemotherapeutic drugs is especially important and justi able for patients with higher risk of showing drug resistance. In this project this risk was evaluated through the expression of molecular markers, such as CD147, that have been associated with poor outcome and cisplatin resistance. With this project we aimed to establish an urothelial cancer xenograft model in nude mice from a sample of invasive urothelial carcinoma, characterize it, and assess the feasibility of this model for chemotherapy sensitivity and resistance testing. 1 of 9 specimens has grown as primary implant in nude mice and the xenograft generated was successfully transfered to other mice with a take rate of 2 in 3. Histologic and immunohistochemical (CD147,p53, p63, ki-67 and CK20) analysis showed that xenografts retain the morphology and phenotype of the original tumor, at least during xenograft establishment. These preliminary results supports the value of this model for drug testing, however future studies are required to validate the model and determine the pro le of the patients that may bene t for this approach.
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Cotton, Sofia Ribeiro. "Glycoproteomic characterization of advanced bladder cancer towards novel therapies." Master's thesis, Universidade de Aveiro, 2016. http://hdl.handle.net/10773/17366.
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Mestrado em Biologia Molecular e CelularA heterogenidade da natureza molecular dos tumores de bexiga tem dificultado o estabelecimento de abordagens no campo da medicina de precisão, revelando-se a necessidade de terapias mais eficientes e novas ferramentas de detecção não-invasivas. Contudo, têm-se denotado um desenvolvimento no estudo da carcinogénese de bexiga e na progressão do tumor, acompanhado de profundas alterações na glicosilação de proteínas que, dada a sua superfície celular e a natureza secretada, apresenta um potencial elevado na melhoria da gestão da doença. Segundo esta abordagem foi efectuado um estudo sobre tumores de bexiga de diferentes naturezas clinicopatológicas para O-glicanos de cadeia curta, regularmente encontrados na maioria dos tumores sólidos, recorrendo-se à imunohistoquímica. O estudo incluiu os antígenos Tn e T e os seus homólogos sialilados sialil-Tn (STn) e sialil-T (ST), geralmente associados com um mau prognóstico. Explorou-se ainda a sialilação da natureza dos antigénios T, especificamente as sialoformas sialil-3-T (S3T) e sialil-6-T (S6T), com base em combinações de tratamentos enzimáticos. Observou-se uma predominância de sialoglicanos, em comparação com as glicoformas neutras (antígenos Tn e T) em tumores de bexiga. Em particular, o antigénio STn foi associado ao estado avançado da doença e invasão muscular. Os antígenos S3T e S6T foram detectados pela primeira vez em tumores de bexiga, estando ausentes no urotélio normal, permitindo destacar a natureza específica em tumores. Verificou-se também a sobreexpressão dos glicanos em lesões avançadas, especialmente nos casos com invasão muscular.As análises glicoproteómicas dos tumores avançados de bexiga permitiram identificar diversas glicoproteínas-chave associadas ao cancro (MUC16, CD44, integrinas), denotando uma glicosilação alterada.As glicoformas da MUC16 STN positivas, características do cancro de ovário, encontram-se num subconjunto de tumores de bexiga em estado avançado, com um pior prognóstico. Em suma, os tumores de bexiga apresentam severas alterações no O-glicoma e no Oglicoproteoma devendo ser abordados de forma abrangente com o objectivo de desenvolver ferramentas de diagnóstico não invasivas e terapias dirigidas. As glicoformas aberrantes de MUC16 apresentam potencial como biomarcadores de mau prognóstico. Este trabalho estabeleceu um guia para a descoberta de glicobiomarcadores no cancro de bexiga, que pode ser utilizado para a estratificação dos pacientes e, por fim, levar à descoberta de novos alvos terapêuticos.
The heterogeneous molecular nature of bladder tumours has hampered the establishment of precision medicine approaches, more efficient therapeutics and novel non-invasive detection tools. Still, it has been long described that bladder carcinogenesis and tumour progression is accompanied by profound alterations in protein glycosylation which, given its cell surface and secreted nature, holds tremendous potential for disease management improvement. Therefore, we have screened series of bladder tumours of different clinicopathological natures for short-chain O-glycans, found in most solid tumours, by immunohistochemistry. These included the Tn and T antigens and their sialylated counterparts sialyl-Tn (STn) and sialyl-T(ST), generally associated with poor prognosis. We have also explored the nature of T antigens sialylation, namely the sialyl-3-T(S3T) and sialyl-6-T(S6T) sialoforms, based on combinations of enzymatic treatments. We observed a predominance of sialoglycans over neutral glycoforms (Tn and T antigens) in bladder tumours. In particular, the STn antigen was associated with high-grade disease and muscle invasion, in accordance with our previous observations.The S3T and S6T antigens were detected for the first time in bladder tumours, but not in healthy urothelia, highlighting their cancer-specific nature. These glycans were also overexpressed in advanced lesions, especially in cases showing muscle invasion. Glycoproteomic analyses of advanced bladder tumours identified several key cancer-associated glycoproteins (MUC16, CD44, integrins) carrying altered glycosylation. Particular interest was devoted to MUC16 STn+-glycoforms, characteristic of ovarian cancers, which were found in a subset of advanced stage bladder tumours facing worst prognosis. In summary, bladder tumours present severe O-glycome and O-glycoproteome alterations that should be comprehensively addressed envisaging novel non-invasive diagnostic tools and targeted therapeutics. Furthermore, abnormal MUC16 glycoforms holds potential as surrogate biomarkers of poor prognosis. Finally, this work established a roadmap for glycobiomarker discovery in bladder cancer, which may be used for patient stratification and ultimately lead to novel therapeutic targets.