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Role of proteinase-activated receptor 2 in pathogeneiss of neurodegenerative diseases
Rohan, Zdeněk ; Matěj, Radoslav (advisor) ; Hermanová, Markéta (referee) ; Dundr, Pavel (referee)
This Thesis discusses the complex topic of the role of proteinase-activated receptors (PARs) in the physiology and pathophysiology of central nervous system diseases, and to some extent, the role of PARs in cancer pathobiology. Based on the results from this Thesis, we can conclude that PAR2 levels in the CSF do not track neuronal damage; therefore, PAR2 cannot be used as a marker of neuronal damage. Expression and activity of PAR2 in the brain appears to be mostly related to the activity of the disease process itself. To study the role of PAR2 in neurodegenerative diseases characterized by white matter and oligodendrocyte degeneration, a precise morphological descritption of individual diseases is essential. In the study aimed pathology of motor neuron disease we found reactive incre- ase in oligodendrocyte density in corticospinal tracts in reaction to white matter damage. In other study we confirmed the existence of a new variant of multiple system atrophy, atypical MSA (aMSA) charcterized by specific degenration of hippocampal neurons. Since the activity of kallikrein 6-PAR2 axis attenuates α-synuclein aggregation, its deficiency in hippocampus may be a prerequisite for its dominant degeneration leading to the develop- mant of α-synuclein neuronal inclusions and aMSA phenotype. Regarding the...
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Expression of miRNAs in pancreatic adenocarcinoma-relationship to morphological characteristics and disease prognosis.
Szabó, Arpád ; Mandys, Václav (advisor) ; Hermanová, Markéta (referee) ; Daum, Ondřej (referee)
Ductal adenocarcinoma (PDAC) is the most common primary pancreatic neoplasm. It's frequently diagnosed in late inoperable stage and has high resistance to chemotherapy; this situation contributes to its unfavourable prognosis. Therefore, there is a need for biomarkers enabling early detection of PDACs and by this way to improve patient prognosis. MicroRNAs (miRNA), short non-coding RNA molecules involved in post-transcriptional regulation of gene expression, belong to such markers. Contrary to other RNA molecules, miRNAs are stable in biological samples. Their expression is measured by several analytical methods, including real-time quantitative PCR (RT-qPCR). Normalization of methods determining miRNA levels requires adequate endogenous controls. However, variable expression of endogenous controls in tumors may cause bias in determining miRNA levels. The aim of the first study was to investigate the expression of six miRNAs isolated from formalin fixed paraffin embedded (FFPE) samples of PDACs. Four controls were chosen for RT-qPCR result normalization: artificial spike miR-39 from C. elegans, U6 snRNA, miR-16 and snoRNA U91. Expression values of all studied miRNAs in tumors were significantly different depending on selected endogenous controls. Additionally, stability of the controls varied...
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Serrated Lesions of Gastrointestinal Tract and Significance of Serrated Changes in Mucosa of Inflammatory Bowel Disease Patients
Kamarádová, Kateřina ; Laco, Jan (advisor) ; Hermanová, Markéta (referee) ; Ehrmann, Jiří (referee)
Patients with inflammatory bowel disease (IBD) have an elevated risk of developing colorectal carcinoma (CRC). IBD-dysplasia is regarded as a conventional precursor for IBD- associated carcinoma. (1-2) Other types of non-conventional mucosal changes with serrated and villous hypermucinous morphology have also been reported but their preneoplastic potential is still not well elucidated. (3-4) The aim of the study was to retrospectively review samples from IBD patients focusing on detection of mucosal lesions including non-conventional lesions and evaluate their relationship and immunohistochemical and molecular properties. Surgical specimens and/or endoscopical biopsy samples of IBD patients examined during a 10-year period were reviewed. Mucosal lesions were divided into three groups - group 1 of non-conventional lesions, group 2 of true serrated polyps, and group 3 of IBD-dysplasia and colorectal carcinoma. Detailed morphological evaluation, immunohistochemical analysis of mismatch repair proteins and/or MLH1, p53 and O6 -methylguanine DNA methyltransferase (MGMT) expression, and molecular analysis for KRAS, NRAS and BRAF gene mutation was performed in all lesions. Overall, samples from 309 IBD patients were reviewed. A total of 88 mucosal lesions were found in 51 patients. Most common were lesions...
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Role of proteinase-activated receptor 2 in pathogeneiss of neurodegenerative diseases
Rohan, Zdeněk ; Matěj, Radoslav (advisor) ; Hermanová, Markéta (referee) ; Dundr, Pavel (referee)
This Thesis discusses the complex topic of the role of proteinase-activated receptors (PARs) in the physiology and pathophysiology of central nervous system diseases, and to some extent, the role of PARs in cancer pathobiology. Based on the results from this Thesis, we can conclude that PAR2 levels in the CSF do not track neuronal damage; therefore, PAR2 cannot be used as a marker of neuronal damage. Expression and activity of PAR2 in the brain appears to be mostly related to the activity of the disease process itself. To study the role of PAR2 in neurodegenerative diseases characterized by white matter and oligodendrocyte degeneration, a precise morphological descritption of individual diseases is essential. In the study aimed pathology of motor neuron disease we found reactive incre- ase in oligodendrocyte density in corticospinal tracts in reaction to white matter damage. In other study we confirmed the existence of a new variant of multiple system atrophy, atypical MSA (aMSA) charcterized by specific degenration of hippocampal neurons. Since the activity of kallikrein 6-PAR2 axis attenuates α-synuclein aggregation, its deficiency in hippocampus may be a prerequisite for its dominant degeneration leading to the develop- mant of α-synuclein neuronal inclusions and aMSA phenotype. Regarding the...
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Pathologic prognostic factors in the experimental surgical therapy of malignant tumors of the lower female genital tract (uterine cervix, vulva)
Škapa, Petr ; Zámečník, Josef (advisor) ; Hermanová, Markéta (referee) ; Špaček, Jiří (referee)
The aim of the presented thesis is to introduce modern procedures of histopathological analysis including immunohistochemical and molecular methods for the diagnosis, prevention and innovative surgical approaches for the therapy of precancerous lesions and malignant tumors of the lower female genital tract (vulva, uterine cervix). In the first part of the thesis, we focused on the prevalence of human papillomavirus (HPV) types in non-precancerous, precancerous and neoplastic squamous cell lesions of the vulva. We aimed at estimating the efficacy of prophylactic HPV vaccination as well as at evaluating the usefulness of the modified classification scheme of vulvar intraepithelial neoplasia (VIN). We analyzed the spectrum of HPV types in particular histological categories of vulvar lesions and confirmed the justification of the concept of two independent pathways of vulvar carcinogenesis - HPV associated and HPV negative. We identified several heterogeneous groups of precancerous vulvar lesions with variable HPV profiles, for which the application of the new revised VIN classifications may be misleading for the estimation of their biological behavior. We also pointed out the fact that the efficacy of the prophylactic HPV vaccination will depend on the extent of cross-protection against the...
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