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The Role of Cellular Metabolism in Carcinogenesis. Molecular Pathophysiology of Bladder Cancer Chemoresistance
Kripnerová, Michaela ; Kuncová, Jitka (advisor) ; Nevoral, Jan (referee) ; Chovanec, Miroslav (referee)
Therapeutic resistance of tumours represents an important clinical issue. We can classify the therapeutic tumour resistance in two ways. According to the clinical course, tumours can behave either as primary resistant, i.e. from the very beginning not responsive, or they can display a secondary (also called acquired) resistance, whereby an initial clinical response is lost and the tumour develops into chemo-, radio- or immunoresistant disease. An alternative classification distinguishes cell autonomous resistance mechanisms from resistance that relies on complex interactions within the context of tumour microenvironment. From the research perspective, modelling therapeutic resistance frequently involves experimental treatment of sensitive cancer cells and selection of daughter resistant cell lines. The Ph.D. thesis includes derivation of two unique models of urothelial bladder carcinoma therapeutic resistance. The first model involves newly established urothelial carcinoma cell lines BC44 and BC44DoxoR, which resulted from a prolonged doxorubicin exposure of the mother cell line. The daughter chemoresistant cell line exhibits multidrug resistant phenotype, which extends beyond the selecting drug - doxorubicin - to four additional chemotherapeutic drugs (cisplatin, methotrexate, vinblastine, and...
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Perineural spread of pelvic tumors: mechanism and diagnosis
Čapek, Štěpán ; Sameš, Martin (advisor) ; Haninec, Pavel (referee) ; Hořínek, Daniel (referee)
Perineural spread of pelvic tumors mechanism and diagnosis Abstract Neoplastic lumbosacral plexopathies are infrequent affections of the lumbosacral plexus. Cases with minimal or non-specific finding on imaging can be particularly puzzling to diagnose. We describe a series of patients with perineural spread from the site of the primary tumor along the visceral autonomous nerves to the lumbosacral plexus and further proximally to the spinal nerves and even intradurally and also distally to the sciatic nerve. On series of 17 patients diagnosed with perineural spread of pelvic malignancy we describe characteristic clinical presentation and imaging finding. In many of these cases a tissue biopsy is necessary to finalize the diagnosis. We describe operative technique of targeted fascicular biopsy of the sciatic nerve and our experience with this procedure. On series of 117 patients, we report the outcome and complication: diagnostic yield was 84.8% and complication rate was 2.7 %. If a tissue sample is needed to conclude the diagnosis, targeted fascicular biopsy does increase the yield at an acceptable complication rate. Perineural spread of pelvic cancer is a new clinical-pathological entity with an unknown natural history or ideal treatment strategy. Based on the imaging finding in this group we present a...
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The Role of Cellular Metabolism in Carcinogenesis. Molecular Pathophysiology of Bladder Cancer Chemoresistance
Kripnerová, Michaela ; Kuncová, Jitka (advisor) ; Nevoral, Jan (referee) ; Chovanec, Miroslav (referee)
Therapeutic resistance of tumours represents an important clinical issue. We can classify the therapeutic tumour resistance in two ways. According to the clinical course, tumours can behave either as primary resistant, i.e. from the very beginning not responsive, or they can display a secondary (also called acquired) resistance, whereby an initial clinical response is lost and the tumour develops into chemo-, radio- or immunoresistant disease. An alternative classification distinguishes cell autonomous resistance mechanisms from resistance that relies on complex interactions within the context of tumour microenvironment. From the research perspective, modelling therapeutic resistance frequently involves experimental treatment of sensitive cancer cells and selection of daughter resistant cell lines. The Ph.D. thesis includes derivation of two unique models of urothelial bladder carcinoma therapeutic resistance. The first model involves newly established urothelial carcinoma cell lines BC44 and BC44DoxoR, which resulted from a prolonged doxorubicin exposure of the mother cell line. The daughter chemoresistant cell line exhibits multidrug resistant phenotype, which extends beyond the selecting drug - doxorubicin - to four additional chemotherapeutic drugs (cisplatin, methotrexate, vinblastine, and...
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Analysis of cell-free nucleic acids and its potential clinical application.
Pazourková, Eva ; Korabečná, Marie (advisor) ; Drábek, Jiří (referee) ; Vodička, Radek (referee)
This work presents the results ofour research of cell-free nucleic acids (cfNA). The first part shows changes in methylation patterns of immune response genes promoters that are detectable in plasma during the hemodialysis sessions and also differences in methylation between patients and healthy subjects. Alterations include genes that play their role in the regulation of hematopoiesis and these changes are in close relation with the need of anemia therapy. In the other plasma cfNA study we detected miRNA signatures in patients with acute myeloid leukemia at diagnosis (6 highly abundant miRNAs found) and in remission achieved after standard chemotherapy (trend to n01malization, lower levels ofthese miRNAs). Another part of work presents data from the study of potential non-invasive biomarker of bladder cancer. The amounts of cfDNA in urine are higher in patients than in healthy subjects and there were found 5 down-regulated miRNAs. Simultaneously it was established set of 30 miRNAs that are constantly present in urine supematants independently on sex, age and healthy status of subjects. The last part presents analysis ofcell-free fetal DNA. We analyzed differences between a new quantification method - droplet digital PCR and real-time PCR which is used routinely nowadays. Slightly more precise was...
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Somatic driver mutations during early differentiation of bladder carcinoma cell of origin
Brázdilová, Ludmila ; Drbal, Karel (advisor) ; Láníková, Lucie (referee)
A normal healthy cell traves through different routes to become a tumor cell, which according to the cell-of-origin theory initiates the whole tumor. Deregulation of cell processes by somatic mutations directs the cell into transformation. To this day, many mutations that cause a tumor phenotype, termed driver mutations, have been identified by genomic and targeted analyses. Not only for optimal therapy management but also for the prediction of disease progression the detection of driver mutations accumulating in the cell of origin of a specific tumor is very important. This thesis is focused on driver mutations of bladder carcinoma cell of origin, which is a tumor with a high mutation load. Bladder carcinomas compose a very heterogeneous group of tumors, having phenotype parallels in many other carcinomas, such as breast cancer. The driver mutations could be used as diagnostic and prognostic markers, but are not yet used in clinical practice. This thesis intends to summarize known findings about bladder carcinoma tumor initiation, based on understanding its cell of origin. Further characterisation of important driver mutations in bladder carcinoma and a comparison to other carcinomas is shown here, with respect to their molecular classification.
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