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High grade serous ovarian carcinoma: molecular background and platinum-based chemotherapy challenges
Ivančinová, Jana ; Heneberg, Petr (advisor) ; Brábek, Jan (referee)
Ovarian carcinoma (O.C.) represent a group of various disease entities derived from ovaries. The most common malignant gynaecological cancer is high-grade serous ovarian carcinoma (HGSOC). HGSOC is associated with a high mortality rate due to its aggressive behaviour and insufficient early-stage detection. The survival rate has not been significantly improved since 1970s. The most effective treatment of HGSOC patients is by cytoreductive surgery (for early stages I/II) and followed by platinum-based chemotherapy (HGSOC presented in advanced stage III/IV) combined with taxane or potentially with PARP inhibitors (for BRCA1/2 mutation carriers). Multiple factors affect the patient's outcome and prognosis. Chemoresistance, molecular mutational patterns, stage at presentation of HGSOC are one of the clinical challenges contributing to common relapses even though patients often initially respond well to the HGSOC chemotherapy. This thesis overviews the fundamental biology of HGSOC, the major obstacles in clinical management and its improvements by implementing of multitherapy approaches. Key words: CA-125; platinum−based chemotherapy treatment; homologous recombination deficiency; ovarian carcinoma; resistance; Tp53; mortality; survival rate
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New aspects of the cell submembrane signaling
Heneberg, Petr ; Dráber, Petr (advisor) ; Bilej, Martin (referee) ; Folk, Petr (referee)
This dissertation contributes to elucidation of some mechanisms of the mammalian cell submembrane signaling. Major part of the research was conducted on mast cells and basophils activated via the high affinity IgE receptor, FcεRI, or via the cell surface glycoprotein Thy-1. New roles of actin cytoskeleton in mast cell signaling via FcεRI and Thy-1 are described. Discovery of new transmembrane adaptor protein non-T cell activation linker, NTAL, short time before the initiation of work on the thesis led to the increased attention paid to this protein. Dramatic changes of signaling in mast cells deficient in NTAL, or with up- or down-regulated expression of this protein are described. NTAL was also found to be one of proteins phosphorylated following the Thy-1 aggregation. Spatiotemporal distribution of surface glycoprotein Thy-1 at different levels of resolution and some biochemical properties of cells activated via Thy-1 are depicted. Screen for nonreceptor hitherto unknown protein tyrosine phosphatases in mast cells and basophils was conducted and initial analysis of spatiotemporal distribution and function of phosphatase PTP20 in mast cell signaling was performed. Next, the role of reactive oxygen and nitrogen species in the regulation of mast cell protein tyrosine phosphatases was summarized. New...
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The role of ORMDL proteins in mast cell signaling
Paulenda, Tomáš ; Dráber, Petr (advisor) ; Heneberg, Petr (referee) ; Malý, Petr (referee)
1. Abstract (EN) This thesis is collection of work focused mainly on the understanding of mast cell activation and its regulation by Orm1-like (ORMDL) proteins. ORMDL family is a group of endoplasmic reticulum (ER) membrane resident proteins that are highly conserved amongst mammalian species. ORMDL proteins can be found in diverse range of organisms from plants through fungi to animals. ORMDL proteins were first discovered in yeasts and the interest in these proteins skyrocketed after the discovery that ORMDL3 is associated with childhood onset asthma in genome wide association studies. Following research connected ORMDL3 also with allergic inflammation and inflammatory bowel disease. Since mast cells are mainly known for their role in allergy and allergen induced inflammation, we decided to investigate the role of ORMDL proteins in regulation of mast cell activation and signaling. In our first study we focused on the role of ORMDL3 in mast cell activation via the high affinity IgE receptor 1 (FcεRI). We prepared bone marrow-derived mast cells with decreased (ORMDL3-KD) or increased (ORMDL3-OE) ORMDL3 expression. We showed that ORMDL3 is a negative regulator of mast cell activation events like degranulation, cytokine release and migration, without any effect on calcium mobilization. ORMDL3 was previously...
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The role of ORMDL proteins in mast cell signaling
Paulenda, Tomáš ; Dráber, Petr (advisor) ; Heneberg, Petr (referee) ; Malý, Petr (referee)
1. Abstract (EN) This thesis is collection of work focused mainly on the understanding of mast cell activation and its regulation by Orm1-like (ORMDL) proteins. ORMDL family is a group of endoplasmic reticulum (ER) membrane resident proteins that are highly conserved amongst mammalian species. ORMDL proteins can be found in diverse range of organisms from plants through fungi to animals. ORMDL proteins were first discovered in yeasts and the interest in these proteins skyrocketed after the discovery that ORMDL3 is associated with childhood onset asthma in genome wide association studies. Following research connected ORMDL3 also with allergic inflammation and inflammatory bowel disease. Since mast cells are mainly known for their role in allergy and allergen induced inflammation, we decided to investigate the role of ORMDL proteins in regulation of mast cell activation and signaling. In our first study we focused on the role of ORMDL3 in mast cell activation via the high affinity IgE receptor 1 (FcεRI). We prepared bone marrow-derived mast cells with decreased (ORMDL3-KD) or increased (ORMDL3-OE) ORMDL3 expression. We showed that ORMDL3 is a negative regulator of mast cell activation events like degranulation, cytokine release and migration, without any effect on calcium mobilization. ORMDL3 was previously...
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The role of glycolytic enzymes in the development of cancer and metabolic disorders
Šimčíková, Daniela ; Heneberg, Petr (advisor) ; Šimíček, Michal (referee) ; Vaňhara, Petr (referee)
In this Ph.D. thesis, we aimed to focus on molecular mechanisms that underlie the roles of hexokinases in health and disease. First, we focused on the molecular basis of GCK-MODY and possibilities how to predict effects of variations in genes causing Mendelian disorders in general. We performed in vitro experiments on GCK and its variants carrying activating, neutral or inactivating variations. Subsequently, we compared these experimental results with outcomes from the state-of-the-art prediction algorithms with distinct backgrounds. As a result of analyses, we realized that the prediction algorithms commonly suffered from low specificity. Therefore, we suggested a method how to tailor numerical outcomes of these prediction algorithms in order to increase specificity. Furthermore, we determined pH optimum of human GCK and HK2 and investigated the influence of ATP concentrations on buffering capacity of commonly used buffers in hexokinase assays. In the part concerning the role of HKs in tumorigenesis, we studied in vitro somatic cancer-associated variations in GCK, which did not give meaningful evidence for a role of GCK in tumorigenesis, although a subset of somatic cancer-associated variations were activating, thus potentially advantageous for tumors. Therefore, we rather moved to the study of...
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The role of the immune system in the immunopathogenesis of autoimmune diseases and the therapeutic modulation of autoimmune reaction by tolerogenic dendritic cells
Dáňová, Klára ; Palová Jelínková, Lenka (advisor) ; Prokešová, Ludmila (referee) ; Heneberg, Petr (referee)
Immunotherapy based on dendritic cells (DCs) was first tested in clinical trials for the treatment of cancer in the 1990s. Currently, the ability of DCs to modulate immune responses is also being tested in several clinical studies focusing on autoimmune disease treatment with the aim of suppressing the overactivated immune system and restoring immune tolerance. For this purpose, so-called tolerogenic DCs with considerable suppressive potential are used. Tolerogenic DCs can be generated ex vivo from monocytes using pharmacological agents, which in DCs induce a regulatory phenotype with low expression of activation markers, high expression of inhibitory markers and secretion of suppressive cytokines. In the first part of this study, we show that cultivation of human blood monocytes in the presence of glucocorticoid dexamethasone and 19- nor-1,25-dihydroxyvitamin D2 (paricalcitol) enables ex vivo generation of tolerogenic DCs with a highly stable suppressive phenotype characterized by upregulated IL-10 production, inhibitory IL- T3 and PD-L1 molecule expression, the low stimulatory capacity and the ability to induce regulatory T cell development. Moreover, we show that metabolic changes and signaling through NF-κB, p38 MAPK, ERK1/2 molecules and the mTOR/STAT3 pathway play an important role in the...
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New aspects of the cell submembrane signaling
Heneberg, Petr ; Dráber, Petr (advisor) ; Bilej, Martin (referee) ; Folk, Petr (referee)
This dissertation contributes to elucidation of some mechanisms of the mammalian cell submembrane signaling. Major part of the research was conducted on mast cells and basophils activated via the high affinity IgE receptor, FcεRI, or via the cell surface glycoprotein Thy-1. New roles of actin cytoskeleton in mast cell signaling via FcεRI and Thy-1 are described. Discovery of new transmembrane adaptor protein non-T cell activation linker, NTAL, short time before the initiation of work on the thesis led to the increased attention paid to this protein. Dramatic changes of signaling in mast cells deficient in NTAL, or with up- or down-regulated expression of this protein are described. NTAL was also found to be one of proteins phosphorylated following the Thy-1 aggregation. Spatiotemporal distribution of surface glycoprotein Thy-1 at different levels of resolution and some biochemical properties of cells activated via Thy-1 are depicted. Screen for nonreceptor hitherto unknown protein tyrosine phosphatases in mast cells and basophils was conducted and initial analysis of spatiotemporal distribution and function of phosphatase PTP20 in mast cell signaling was performed. Next, the role of reactive oxygen and nitrogen species in the regulation of mast cell protein tyrosine phosphatases was summarized. New...
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