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Nodal and Extranodal Lymphomas: Clinicopathological, Immunohistochemical, Molecular-Biological Charactersistics
Veselá, Pavla ; Boudová, Ludmila (advisor) ; Křížková, Věra (referee) ; Křen, Leoš (referee)
3 Abstract The doctor thesis is composed of two major studies, both of them focused on the mantle cell lymphoma (MCL). The first part deals with the verification of the prognostic influence of Mantle Cell Lymphoma International Prognostic Index (MIPI) and of the proliferative activity in 235 patients with MCL diagnosed in 1996-2008 in the Czech Republic. This population study was performed in the collaboration with the Czech Lymphoma Study Group. The clinical data of patients were completed in April 2012. The diagnosis of MCL was confirmed by our central histopathologic examination of pretherapeutic histological samples. The median overall survival (OS) was 47 months, median progression free survival (PFS) was 22 months. We demonstrated the influence of proliferative activity, MIPI and of the therapy type (intensive/non-intensive) on OS and PFS in univariate and multivariate analysis. Using univariate analysis we showed the prognostic influence of aggressive/other cytomorphological variants of MCL, nodal/extranodal localization of primary sample and also of the variants of MIPI - s-MIPI, MIPIb and a completely new variant of MIPI - combined MIPI. The prognostic influence of growth pattern and of the results of immunohistochemical reaction with CD23, CD5 and cyclin D1 antibodies were not confirmed. The other...
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The functional in vitro analysis of the BRCA1alternative splicing variants
Ševčík, Jan ; Kleibl, Zdeněk (advisor) ; Stopka, Tomáš (referee) ; Macůrek, Libor (referee)
BACKGROUND: The inactivation of the tumor suppressor gene BRCA1 is a predisposing factor for a breast/ovarian cancer development. Formation of cancer-specific alternative splicing variants with aberrant biological properties can represent additional mechanism decreasing the overall BRCA1 activity in DNA double strand break (DDSB) repair. In this study, we analyzed BRCA1 alternative splicing variants BRCA114-15 and 17-19 ascertained previously during the screening of high-risk breast cancer individuals. METHODS: We established a stable MCF-7 cell line-based model system for an in vitro analysis of BRCA1 variants. Using this system, we analyzed the impact of BRCA114-15 and 17-19 variants on DNA repair kinetics using comet assay and confocal immunomicroscopy. The capacity of DNA repair was assessed directly by an in vitro NHEJ assay and indirectly by a mitomycin C sensitivity test. The proliferation activities were determined by a clonogenic assay and growth curves. RESULTS: Overexpression of BRCA114-15 and 17-19 increases the endogenous level of DNA damage, slows down the DDSB repair, and decelerates the initial phase of radiation-induced foci formation and prolongs their persistence. Moreover, BRCA114-15 and 17-19 differentially influence the activity of HR and NHEJ and sensitivity of MCF-7 cells to ionizing...
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Nodal and Extranodal Lymphomas: Clinicopathological, Immunohistochemical, Molecular-Biological Charactersistics
Veselá, Pavla ; Boudová, Ludmila (advisor) ; Křížková, Věra (referee) ; Křen, Leoš (referee)
3 Abstract The doctor thesis is composed of two major studies, both of them focused on the mantle cell lymphoma (MCL). The first part deals with the verification of the prognostic influence of Mantle Cell Lymphoma International Prognostic Index (MIPI) and of the proliferative activity in 235 patients with MCL diagnosed in 1996-2008 in the Czech Republic. This population study was performed in the collaboration with the Czech Lymphoma Study Group. The clinical data of patients were completed in April 2012. The diagnosis of MCL was confirmed by our central histopathologic examination of pretherapeutic histological samples. The median overall survival (OS) was 47 months, median progression free survival (PFS) was 22 months. We demonstrated the influence of proliferative activity, MIPI and of the therapy type (intensive/non-intensive) on OS and PFS in univariate and multivariate analysis. Using univariate analysis we showed the prognostic influence of aggressive/other cytomorphological variants of MCL, nodal/extranodal localization of primary sample and also of the variants of MIPI - s-MIPI, MIPIb and a completely new variant of MIPI - combined MIPI. The prognostic influence of growth pattern and of the results of immunohistochemical reaction with CD23, CD5 and cyclin D1 antibodies were not confirmed. The other...
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The functional in vitro analysis of the BRCA1alternative splicing variants
Ševčík, Jan ; Kleibl, Zdeněk (advisor) ; Stopka, Tomáš (referee) ; Macůrek, Libor (referee)
BACKGROUND: The inactivation of the tumor suppressor gene BRCA1 is a predisposing factor for a breast/ovarian cancer development. Formation of cancer-specific alternative splicing variants with aberrant biological properties can represent additional mechanism decreasing the overall BRCA1 activity in DNA double strand break (DDSB) repair. In this study, we analyzed BRCA1 alternative splicing variants BRCA114-15 and 17-19 ascertained previously during the screening of high-risk breast cancer individuals. METHODS: We established a stable MCF-7 cell line-based model system for an in vitro analysis of BRCA1 variants. Using this system, we analyzed the impact of BRCA114-15 and 17-19 variants on DNA repair kinetics using comet assay and confocal immunomicroscopy. The capacity of DNA repair was assessed directly by an in vitro NHEJ assay and indirectly by a mitomycin C sensitivity test. The proliferation activities were determined by a clonogenic assay and growth curves. RESULTS: Overexpression of BRCA114-15 and 17-19 increases the endogenous level of DNA damage, slows down the DDSB repair, and decelerates the initial phase of radiation-induced foci formation and prolongs their persistence. Moreover, BRCA114-15 and 17-19 differentially influence the activity of HR and NHEJ and sensitivity of MCF-7 cells to ionizing...
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