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The expression of TP53 gene at the mRNA level in patients with myelodysplastic syndrome
Šeborová, Karolína ; Beličková, Monika (advisor) ; Španielová, Hana (referee)
Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases characterized by ineffective hematopoiesis which is caused by damage of differentiation of pluripotent haematopoietic stem cells. TP53 gene mutations are identified approximately in 10% of MDS and represent a negative prognostic factor. Altered TP53 gene expression may have similar effect as the mutation. Mutations or deregulated expression of this gene have an impact on many cellular processes including apoptosis, DNA repair, cell growth and angiogenesis. In this work, the expression mRNA levels of genes involved in p53 signalling pathway were studied in CD34+ pluripotent haematopoietic cells from bone marrow of patients with low- risk MDS. MDS patients showed increased expression of genes involved in apoptosis induction, regulation of cell cycle and DNA repair (BAX, BBC3, CCNE1, CDC25A, CDKN1A, FAS, GADD45A) as compared to healthy subjects. The patients with TP53 mutation had decreased expression of apoptotic genes (BAX, PIDD, TRAF2) and increased gene expression of apoptotic inhibitor (BCL2A1), indicating a reduced activity of apoptotic pathways and that way the pathological cell clone may gain a growth advantage. Deregulation of 21 genes (BAX, BBC3, EGR1, KAT2B, MDM2 etc.) was observed in patients with del (5q) compared to...
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A study of the HCV IRES variability: An experimental approach coupled with design of a large-scale mutation database
Khawaja, Anas Ahmad ; Pospíšek, Martin (advisor) ; Hirsch, Ivan (referee) ; Valášek, Leoš (referee)
Translation initiation in the hepatitis C virus (HCV) occurs through a cap- independent mechanism that involves an internal ribosome entry site (IRES) capable of interaction with and utilization of the eukaryotic translational machinery. We focused on the structural configuration of the different HCV-IRES domains and the impact of IRES primary sequence variations on secondary structure conservation and function. For this purpose we introduced into our laboratory, methods such as denaturing gradient and temperature gradient gel electrophoresis for screening the degree of heterogeneity and total amount of HCV-IRES variability accumulated in HCV infected patients over a period of time. The selected samples showed variable migration pattern of the HCV-IRES (from all the patients) visualized in DGGE and TGGE, were sequenced and evaluated for translation efficiency using flow cytometry. In some cases, we discovered that multiple mutations, even those scattered across different domains of HCV-IRES, led to restoration of the HCV-IRES translational activity, although the individual occurrences of these mutations were found to be deleterious. We propose that such observation may be attributed to probable long- range inter- and/or intra-domain functional interactions. We established a large-scale HCV-IRES...
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Genetic causes of medullary thyroid carcinoma and Hirschsprung's disease
Václavíková, Eliška ; Bendlová, Běla (advisor) ; Dvořáková, Lenka (referee) ; Stárka, Luboslav (referee)
Genetic causes of medullary thyroid carcinoma and Hirschsprung's disease Abstract Medullary thyroid carcinoma (MTC) and Hirschsprung's disease (HSCR) are classified as simple neurocristopathies, i.e. diseases linked to neural crest-derived cells. MTC is derived from parafollicular cells of the thyroid and HSCR is characterized by absence of enteric ganglia in the gastrointestinal tract. The RET proto-oncogene is only expressed in neural crest-derived cells, including parafollicular cells and enteric neurons. The RET encodes a transmembrane tyrosinekinase receptor that plays an important role during proliferation, differentiation and cell survival, and activates many signaling pathways. If the strictly regulated activation fails, e.g. due to mutations in the specific gene locations, the RET becomes a highly effective oncogene. Activating germline mutations in the RET proto- oncogene lead to hereditary forms of MTC, whereas sporadic forms of MTC are caused by somatic mutations in the tumor tissue. On the contrary, inactivating mutations induce migration failure of ganglion cell precursors during the development of enteric nervous system and result in the development of HSCR. In rare cases, the coexistence of both diseases is caused by mutations with a dual gain-of-function and loss-of-function character....
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Genetic causes of medullary thyroid carcinoma and Hirschsprung's disease
Václavíková, Eliška
Genetic causes of medullary thyroid carcinoma and Hirschsprung's disease Abstract Medullary thyroid carcinoma (MTC) and Hirschsprung's disease (HSCR) are classified as simple neurocristopathies, i.e. diseases linked to neural crest-derived cells. MTC is derived from parafollicular cells of the thyroid and HSCR is characterized by absence of enteric ganglia in the gastrointestinal tract. The RET proto-oncogene is only expressed in neural crest-derived cells, including parafollicular cells and enteric neurons. The RET encodes a transmembrane tyrosinekinase receptor that plays an important role during proliferation, differentiation and cell survival, and activates many signaling pathways. If the strictly regulated activation fails, e.g. due to mutations in the specific gene locations, the RET becomes a highly effective oncogene. Activating germline mutations in the RET proto- oncogene lead to hereditary forms of MTC, whereas sporadic forms of MTC are caused by somatic mutations in the tumor tissue. On the contrary, inactivating mutations induce migration failure of ganglion cell precursors during the development of enteric nervous system and result in the development of HSCR. In rare cases, the coexistence of both diseases is caused by mutations with a dual gain-of-function and loss-of-function character....
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Spectrum of FGFR3 gene mutations in hypochondroplasia
Janoušková, Simona ; Křepelová, Anna (advisor) ; Baxová, Alice (referee)
Hypochondroplasia (MIM 146000) is a skeletal dysplasia characterized by disproportional dwarfism with rhizomelic or mesomelic shortening of the upper and lower extremities, with variable severity. Patients often have macrocephaly with normal facial features. Hypochondroplasia is a disease with autosomal dominant inheritance. In some patients it is caused by germline mutations in the FGFR3 gene, in others the cause of the disease remains unknown . The FGFR3 gene encodes a tyrosine kinase receptor. This receptor negatively regulates the conversion of cartilage to bone. FGFR3 gene mutations that cause hypochondroplasia lead to constitutive activation of the receptor and inhibit the growth of long bones. In this study, we analysed selected regions (exons) of the FGFR3 gene in 98 patients with disproportional dwarfism and clinical diagnosis of hypochondroplasia. Eighteen patients from 12 families had familial and 80 patients had sporadic form of the disease. All patients were previously tested negative for frequent germline mutations in exon 13 (codon 540) and exon 15 (codon 650). Genomic DNA was isolated from patient's peripheral blood leukocytes. The examination was conducted with the informed consent of the patient or his legal representative. We performed mutational analysis by direct sequencing of...
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Replicator dynamics with mutations
Hrnčíř, Jakub ; Pražák, Dalibor (advisor) ; Kaplický, Petr (referee)
This thesis deals with the subject of implementing simplified principle of mutations into the replicator dynamics. In this thesis, I have shown the derivation of the basic replicator dynamics and on this basis I have derived generalized replicator dynamics with a deterministic model of mutations. Thesis also contains an analysis of general properties of these two models. Consequences of implementing mutations are demonstrated by means of analysis of three typical examples from the evolutionary game theory. I used the models called Hawk-Dove, Rock-Scissors-Paper and a modification of the Repeated Prisoner's Dilemma, to which I have paid the closest attention. The analysis shows in what ways the number of stationary points and their stability changes. Powered by TCPDF (www.tcpdf.org)
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Thyroid tumors and their molecular genetic causes.
Šmídová, Barbora ; Dvořáková, Šárka (advisor) ; Soták, Matúš (referee)
The aim of this work is to summarize actual literature overview and to collect the up- to-date knowledge on genetic causes of the development of thyroid carcinomas. Thyroid carcinomas represent the most often endocrine malignancy and its incidence is still growing. This work describes all types of thyroid carcinomas derived from different cell types and are distinguished also according to the degree of differentiation. The main genetic changes in the tumor tissues of the medullary, papillary, follicular and anaplastic thyroid carcinoma are described. Thyroid carcinomas occur mostly in sporadic form, rarely as a familial disease. The causes of familial forms of thyroid carcinomas are also summarized and the main mutations in the germ-line DNA are identified. Key words: carcinoma, genetics, mutation, thyroid
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Thyroid tumors and their molecular genetic causes.
Šmídová, Barbora ; Dvořáková, Šárka (advisor) ; Koudelková, Lenka (referee)
The aim of this work is to summarize actual literature overview and to collect the up- to-date knowledge on genetic causes of the development of thyroid carcinomas. Thyroid carcinomas represent the most often endocrine malignancy and its incidence is still growing. This work describes all types of thyroid carcinomas derived from different cell types and are distinguished also according to the degree of differentiation. The main genetic changes in the tumor tissues of the medullary, papillary, follicular and anaplastic thyroid carcinoma are described. Thyroid carcinomas occur mostly in sporadic form, rarely as a familial disease. The causes of familial forms of thyroid carcinomas are also summarized and the main mutations in the germ-line DNA are identified. Key words: carcinoma, genetics, mutation, thyroid
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Specific functions of ARP2/3 complex subunits
Fišerová, Kamila ; Fischer, Lukáš (advisor) ; Oulehlová, Denisa (referee)
Actin is one of the most abundant proteins in living organisms. Regulation of the actin cytoskeleton is provided by many mechanisms, one of the regulators of actin dynamics in plants and animals is highly conserved - Arp2/3 complex. In organisms it consists of two large subunits (Arp2 and Arp3) and five small subunits (ArpC1 - ArpC5). Arp2/3 complex controls actin filament branching at an angle of 70o . This thesis describes the functions of individual subunits with a special emphasis on those which are specific for individual subunits. This summarize exceeds the boundaries of the plant kingdom, and it also discusses animals and yeast, in which the complex is actively studied, and it is a lot of information available about the mechanisms of its regulation. The paper summarizes the interactions between the subunits and their interactions with regulators of Arp2/3 complex and other proteins. Some of the subunits are in some organisms encoded by, more than one gene in such cases, these isoforms may have different functions as well. Arp2/3 complex is for animals necessary for living, but in plants mutations in the subunits of the complex have moderate symptoms. In plants the Arp2/3 complex is used primarily in fast and oriented growth, mutations of subunits showing typical distorted trichomes. Key...
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Domain and structural characterization of tyrosine phosphorylation sites in cancer cells
Vávra, Dan ; Novotný, Marian (advisor) ; Brábek, Jan (referee)
Phosphorylation is an important mechanism for regulation of protein function and aktivity. Tyrosine phosphorylation plays a critical role in signaling pathways. Aberrant tyrosine phosphorylation was observed in many cancer types. My work follows patological details of tyrosine phosphorylation sites of lung and colorectal cancers. Point of view includes aminoacid sequence, secondary structure, domain localization, expression, model organism ortholog occurrence. The project is based on analysis of literary informations and data from protein databases. There are no new phosphorylation sites in observed cancer types. Regular secondary structures, α-helices and β-sheets, are significantly phosphorylated in compare with loops. Annexin and Kinase domains are the most phosphorylated. Gene expression change of phosphorylated proteins occurs in observed cancer cells. Powered by TCPDF (www.tcpdf.org)
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