|
|
Epigenetic Dysregulation through Histone Modifications in Lymphoma
Hostaš, Ondřej ; Havránek, Ondřej (advisor) ; Malík, Radek (referee)
Lymphomas are a diverse group of malignant tumors that arise from lymphocytes, commonly affecting lymph nodes or the spleen. They are one of the most common types of tumors worldwide. Unfortunately, many subtypes have a poor prognosis, or are not currently fully curable with standard therapeutic approaches. Mutations in enzymes responsible for posttranslational modifications of histones are very common in certain subtypes of lymphoma, as well as in many other cancer types. These enzymes directly affect gene expression by changing the condensation state, and thus the accessibility, of chromatin. Some of these enzymes have been found to play an important role in the formation of germinal centers in lymphoid follicles. Therefore, their mutations can lead to uncontrolled proliferation and cancer development. Since many conventional therapeutic strategies are incapable of curing a large portion of lymphomas, novel and more targeted approaches are needed. Inhibition and/or modulation of the function of the aforementioned enzymes may be a basis for such approaches. Key words: lymphomas, epigenetic regulation, histone modifications, KMT2D, EZH2, CREBBP, EP300
|
|
|
Tumor Specific Signaling in T-Cell Lymphoma
Kulinich, Viktoriia ; Havránek, Ondřej (advisor) ; Kužílková, Daniela (referee)
T lymphomas are malignant tumors arising from T cells; they represent a rare variant of non-Hodgkin's lymphomas. As in other cancers, tumor T cells need to modify their signaling to support their growth and survival. T-lymphoma tumor cells are capable to adapt various signaling cascades important also in normal healthy T cells to their benefit. The aim of this work is to summarize tumor-specific signaling typical for different types of T-cell lymphomas; both, identical to the signaling of normal T lymphocytes and altered by tumor specific somatic mutations. Detailed focus is on T lymphoma most frequent and important alterations and signaling pathways. These are specifically alterations of signaling pathways associated with T-cell receptor, JAK/STAT cytokine signaling, and Notch signaling. These pathways are particularly important for the differentiation and growth of T lymphocytes in general, therefore, it is not surprising that these pathways are also often pathologically activated or deactivated in tumor cells. Keywords: lymphocytes, non-Hodgkin lymphomas, T-cell receptor, leukemia, JAK/STAT signaling, Notch signaling, oncogenic signaling pathways
|
|
|
Construction and characterization of chimeric antigen receptors
Ptáčková, Pavlína ; Otáhal, Pavel (advisor) ; Kuželová, Kateřina (referee) ; Havránek, Ondřej (referee)
Background: The CD19 chimeric antigen receptor (CAR) adoptive T-cell therapy for B-cell leukemia is a promising treatment for relapsed or refractory malignities. The overall response rate of CD19 CAR-T cells in clinical trials was greater than 80% for patients with B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin's lymphoma (NHL). However, CAR-T cell therapy of leukemias and solid tumors has been limited by a lot of factors such as antigen loss of tumor escape variants, reduced proliferation, persistence and tumor-infiltration of CAR-T cells in vivo, immunosuppressive tumor environment, absence of ideal antigens and on-target, off-tumor toxicities. Therefore, new strategies improving the safety and efficacy of CAR-T cells, including further T-cell modification to overcome the immune suppression, are tested. Aims: (i) Bispecific CARs designed to express two antigen-binding domains prevent of antigen escape. (ii) T-cells were genetically modified to express CAR along with an inducible IL-21 gene cassette driven by NFAT-responsive promoter. IL-21 directly enhances CAR-T cell activity and anti-tumor effects. (iii) Applying suicide epitope modification in CAR enables significantly increasing the therapeutic safety of CAR-T cells. Methods: CARs were constructed by using molecular biology...
|
|
|
Genetic factors in lymphoproliferative malignancies Focus on CHEK2 gene in lymphomas with comparison to distinct solid tumors
Havránek, Ondřej ; Trněný, Marek (advisor) ; Papajik, Tomáš (referee) ; Veselý, Pavel (referee)
Genetic factors in lymphoproliferative malignancies. Focus on CHEK2 gene in lymphomas with comparison to distinct solid tumors. MUDr. Ondřej Havránek Summary of PhD thesis: Background: The checkpoint kinase 2 gene (CHEK2) codes for an important mediator of DNA damage response pathway that among others interacts with the p53 protein. Mutations in the CHEK2 gene increase the risk of several cancer types, however, their role in non- Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is not clear. The most frequent TP53 gene R72P polymorphism was analyzed in several studies in NHL but not in HL. Methods: We have performed mutation analysis of the whole CHEK2 gene coding sequence in 340 NHL patients and the segment coding for CHEK2 forkhead-associated (FHA) domain in 298 HL patients and compared the results with our analyses of CHEK2 in breast, colorectal and pancreatic cancers. The TP53 R75P genotype was assessed in the same lymphoma populations. Both genes were analyzed using denaturing high-performance liquid chromatography. Results: The overall frequency of CHEK2 alterations within FHA-coding region was significantly higher in NHL and HL patients (19/340 - 5.6%; 17/298 - 5.7%, respectively) compared to non-cancer controls (19/683 - 2.8%; p = 0.03 and 0.04, respectively). These alterations were associated with...
|
|
|
The Role of B-cell Receptor Signaling in Lymphoid Malignancies
Kochmannová, Kateřina ; Havránek, Ondřej (advisor) ; Štěpánek, Ondřej (referee)
The aim of this thesis is to review current knowledge about tumor-specific B cell receptor (BCR) signaling and related novel therapy options in B-cell malignancies with the main focus on non-Hodgkin lymphomas (NHL). To a certain degree, the pathogenic BCR signaling mirrors normal forms of BCR signaling, antigen-induced and tonic. Differences between antigen- dependent and antigen-independent forms of BCR signaling are well characterized in two major subtypes of diffuse large B-cell lymphoma, the most common type of NHL. In addition to the conventional chemotherapy, several BCR inhibitors targeting BTK and PI3K have been approved for the treatment of lymphoid malignancies. However, improvements in the tumor specificity, toxicity profiles and patients selection are needed. A better understanding of BCR signaling deregulation and overall tumor pathogenesis is believed to further improve NHL treatment outcomes. Keywords: B-cell malignancies, non-Hodgkin lymphoma, B-cell receptor, tumor signaling, targeted therapy, inhibitors
|
|
|
Role of DISP3 in malignancy of medulloblastoma cell line
Jarošová, Šárka ; Zíková, Martina (advisor) ; Havránek, Ondřej (referee)
In the search for new genes that are regulated by thyroid hormone, DISP3, a new member of the SSD (sterol-sensing domain) protein family, has been identified. Expression analysis showed that DISP3 is expressed in cells of neural origin, and our previous results indicate that overexpression of this gene affects cell proliferation and differentiation. Oncomine database analysis also showed that DISP3 expression is increased in medulloblastomas, the most common malignancies of the central nervous system in children. The subject of this diploma thesis is studying the effect of increased DISP3 levels on cell apoptosis and cell ability to form a colony. Cell lines derived from medulloblastomas were used in the work. We compared the expression levels of the DISP3 gene in different medulloblastoma lines by quantitative PCR and selected a line with low expression of this gene for further experiments. Some medulloblastoma cell lines can form neurospheres when cultured in serum-free medium. Using quantitative PCR, we compared the expression levels of neural markers in cells cultured both as neurospheres and as adherent cells. By transfecting cells with a plasmid overexpressing DISP3, we prepared cells with increased levels of this gene. We induced apoptosis by radiation at different doses. Apoptosis was...
|
|
|
Genetic factors in lymphoproliferative malignancies Focus on CHEK2 gene in lymphomas with comparison to distinct solid tumors
Havránek, Ondřej ; Trněný, Marek (advisor) ; Papajik, Tomáš (referee) ; Veselý, Pavel (referee)
Genetic factors in lymphoproliferative malignancies. Focus on CHEK2 gene in lymphomas with comparison to distinct solid tumors. MUDr. Ondřej Havránek Summary of PhD thesis: Background: The checkpoint kinase 2 gene (CHEK2) codes for an important mediator of DNA damage response pathway that among others interacts with the p53 protein. Mutations in the CHEK2 gene increase the risk of several cancer types, however, their role in non- Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) is not clear. The most frequent TP53 gene R72P polymorphism was analyzed in several studies in NHL but not in HL. Methods: We have performed mutation analysis of the whole CHEK2 gene coding sequence in 340 NHL patients and the segment coding for CHEK2 forkhead-associated (FHA) domain in 298 HL patients and compared the results with our analyses of CHEK2 in breast, colorectal and pancreatic cancers. The TP53 R75P genotype was assessed in the same lymphoma populations. Both genes were analyzed using denaturing high-performance liquid chromatography. Results: The overall frequency of CHEK2 alterations within FHA-coding region was significantly higher in NHL and HL patients (19/340 - 5.6%; 17/298 - 5.7%, respectively) compared to non-cancer controls (19/683 - 2.8%; p = 0.03 and 0.04, respectively). These alterations were associated with...
|
|
|
Tourism in Bosnia and Herzegovina
Havránek, Ondřej ; Petrů, Zdenka (advisor) ; Indrová, Jarmila (referee)
This bachelor's thesis focuses on the tourism of the federation of Bosnia and Herzegovina. The thesis has two important aims to achieve. The first one is to characterise the development of the incoming tourism in the post-war period and the second aim is to evaluate the touristic development strategies, both in Federation of Bosnia and Herzegovina and in Republika Srpska. My determined hypothesis assumes a huge difference between these two strategies. The determined hypothesis expects a difference in more than a half of the minor points and achievements of both strategies. On the basis of similiarity of both strategies is the plan of the thesis to find out the possible cooperation between both federations. The huge difference between the strategies of both federations can be considered as a different approach of both federations to the tourism deveplopment within one state. In the theoretical part is defined the tourism term, namely the typology and also the form of supply and demand for tourist destination. The practical part focuses on the conditions. Namely the localization, cultural-historical, or technical, where is the focus on the accomodation and catering facility and finally transportation, where the thesis analyse the transport possibilities of going to Bosnia and Herzegovina. In the end the thesis focus on the outgoing tourism, on the aim of the thesis, and try to expertly predict the future development of the tourism, based on the professional preconditions and the previous progress.
|
guest ::
