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The serotonin transporter gene - polymorphism incidence study.
Bílá, Nikola ; Macek, Milan (advisor) ; Goetz, Petr (referee)
Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter in the central and peripheral nervous systems. Serotonin transporter 5-HTT plays an important role in serotogenic transmisssion and the serotonin transporter gene is under investigation in connection with multiple psychiatric disorders. Three polymorphisms, an insertion/deletion and SNP in the promoter region and a variable nucleotide tandem repeat (VNTR) in intron 2, influence expression of the 5-HTT gene. We examined these polymorphisms at the serotonin transporter protein locus (SLC6A4) in three specific and representative cohorts drawn from the Czech population. These cohorts were stratified according to their age: a) randomly selected elderly individuals (over 75 years of age), b) young adults (age ranging between 19- 45 years) and c) newborns, all with balanced gender representation. The two regions were amplified and resolved on a 2% agarose gel and/or analyzed using the capillary electrophoresis in order to discriminate lenght polymorphisms. SNP in intron 2 was examined by RFLP after using MspI restriction. This analysis revealed that elderly individuals were statistically more likely than controls to carry two copies of the L allele of the lenth polymorphism. This may be due to the protective character of L allele, which is associated with...
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Function of SWI/SNF chromatin-remodeling complex in tumor initiation and progression of melanoma cells
Ondrušová, Ľubica ; Vachtenheim, Jiří (advisor) ; Goetz, Petr (referee) ; Hejnar, Jiří (referee)
There is an increasing evidence that alterations in chromatin remodeling play an important role in tumorigenesis. The SWI/SNF chromatin remodeling complexes contribute to the regulation of gene expression by altering the local chromatin structure. Depending on the context, they can act as either transcriptional activators or repressors. All SWI/SNF subcomplexes contain one of two ATPase subunits, Brm (Brahma) or Brg1 (Brahma related gene 1), which provide the energy for remodeling. Malignant melanoma is an aggressive cancer and is known for its notorious resistance to conventional anticancer therapies. MITF (microphthalmia-associated transcription factor) plays an essential role in melanoma biology and is placed on the central crossroad in the regulation of melanocyte development, differentation, maintenance of lineage identity, and survival of both normal and malignant melanocytes. Our results show that the active SWI/SNF complex is strictly required for the expression of MITF. This complex is also required for expression of some transcriptional MITF targets. The survival of melanoma cells is absolutely dependent on functional SWI/SNF complex and all subunits of this complex are expressed at high levels in melanoma cell lines. Primarily, Brg1-containing subcomplexes are more important for MITF...
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Analysis of structural chromosomal rearrangements in hematological neoplasias; Study of structural chromosomal rearrangements of cells of chronic lymphocytic leukemia after DSP30/IL2 stimulated cultivation
Hrubá, Martina ; Michalová, Kyra (advisor) ; Goetz, Petr (referee) ; Březinová, Jana (referee)
Cytogenetic analysis of cells of chronic lymphocytic leukemia (CLL) is difficult because of their low proliferative activity. To obtain sufficient number of mitoses for performing chromosomal analysis a suitable stimulation of cell division is needed. Using DSP30/IL2 stimulated cultivation 391 CLL samples were investigated in 5 years' period. The cultivation was showed to have high success rate (96%; 375/391) with also high rate of detection of pathological clones by both karyotype and metaphase FISH analyses (in 84% of samples; 329/391). Almost in half of samples (44%; 171/391) other aberrations than recurrent FISH (i.e. 13q14 deletion, trisomy 12, TP53, ATM genes deletions) were found. Also high frequency of translocations (37%; 144/391), complex karyotypes (28%; 111/391) and clonal evolution, which was detected in one third of all samples (34% of samples with presence of more than two clones; 133/391) and like a new event in disease duration even more frequently (in 39% of samples repeatedly investigated after stimulated cultivation; 21/54), was revealed. The presence of translocations, complex karyotypes and clonal evolution was associated with progressive form of disease (P 0,000003, resp. P 0,0002 and P 0,05/P 0,04). In cases of the recurrent deletions the detailed analysis of metaphase...
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The role of molecular genetic and cytogenetic analyses in the diagnosis and prediction of treatment response in patients with non-Hodgkin lymphomas
Berková, Adéla ; Zemanová, Zuzana (advisor) ; Goetz, Petr (referee) ; Smolej, Lukáš (referee)
Malignant lymphoproliferative disorders include highly heterogeneous entities, i.e. lymphomas (Non-Hodgkin - NHL, as well Hodgkin's lymphoma), lymphoid leukemias, multiple myeloma and others. As currently many chromosomal aberrations with diagnostic and prognostic significance are known, molecular cytogenetic analyses of tumor cell genome has become a substantial examination also in lymphoproliferative disorders. This thesis focuses primarily on chronic lymphocytic leukemia (CLL), which is one of the mature B-cell neoplasms and represents the most common type of leukemia. We analyzed four most frequently found aberrations (13q14 deletion, ATM and TP53 gene deletion, and trisomy 12) by fluorescence in situ hybridization (FISH) and also IgH gene aberrations in some patients. We compared the findings with other factors and clinical characteristics. This work shows that the conventional G-banding is analysis relatively little relevant. FISH was more effective in detecting aberrations in CLL. Although none of the four aforementioned changes is specific to CLL, the prognostic impact is significant, particularly that of TP53 deletion. Next, detection of some IgH gene translocations is essential in differential diagnosis of CLL and other NHL (follicular, mantle cell, diffuse large B cell, Burkitt's...
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Study of polymorphisms in candidate genes in the population of ADHD children
Kopečková, Marta ; Goetz, Petr (advisor) ; Šantavý, Jiří (referee) ; Kemlink, David (referee) ; Zvolský, Petr (referee)
The research of tbc way of participatioo of each Iransmitte ystem in pathology of ADHD cao be of belp. in tbe future, in tbe seleetion of the approprisle drug ss substances witb different mechanisms of functioniog are used to Ireat UlC byperklnctic syndrome. For our resear h the genes of dopominergic (DR02, DRD3 a DATl ). noradrenergic (OBH) and serotoninergic (5-HTT) systems were selected. ln these geoes I1 polymorphisms were analysed by molecular-genetic metbods based on sssociation slrategy "case-conlrol". Tbe presence of risk allcles was compared betweeo tbe sarople of 100 ADHD childreo BOd a coolrol group of 100 subjects, in whom tbc ADHD symptoms were excluded by Coooers' test. Tbc results of our research suggest tbc an association of thc gcnes witb ADI·ID. Specifically, after multiple testlng correction, sex correction, and power analysis, it could be coocJuded: I) tbe risk of ADHD is sigolficantJy lncreased in tbc presence oť one risk allele in genes DRD2 (7,5-fold), 5-HTT (2,7-fold) and DATl (l ,6-fold) 2) tbe risk of ADHD is significaotJy increased at homozygotes for risk alleles in genes DRD2 (54-fold), 5-HTT (6,7-fold) BOd DATl (6,6-fold) For polymorphisms G444A and Cl603T in DBH, which were detected by univariant analysis, baplotype artaIysis was performed and resultedln conclusion...
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The role of molecular genetic and cytogenetic analyses in the diagnosis and prediction of treatment response in patients with non-Hodgkin lymphomas
Berková, Adéla ; Zemanová, Zuzana (advisor) ; Goetz, Petr (referee) ; Smolej, Lukáš (referee)
Malignant lymphoproliferative disorders include highly heterogeneous entities, i.e. lymphomas (Non-Hodgkin - NHL, as well Hodgkin's lymphoma), lymphoid leukemias, multiple myeloma and others. As currently many chromosomal aberrations with diagnostic and prognostic significance are known, molecular cytogenetic analyses of tumor cell genome has become a substantial examination also in lymphoproliferative disorders. This thesis focuses primarily on chronic lymphocytic leukemia (CLL), which is one of the mature B-cell neoplasms and represents the most common type of leukemia. We analyzed four most frequently found aberrations (13q14 deletion, ATM and TP53 gene deletion, and trisomy 12) by fluorescence in situ hybridization (FISH) and also IgH gene aberrations in some patients. We compared the findings with other factors and clinical characteristics. This work shows that the conventional G-banding is analysis relatively little relevant. FISH was more effective in detecting aberrations in CLL. Although none of the four aforementioned changes is specific to CLL, the prognostic impact is significant, particularly that of TP53 deletion. Next, detection of some IgH gene translocations is essential in differential diagnosis of CLL and other NHL (follicular, mantle cell, diffuse large B cell, Burkitt's...
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Molecular-cytogenetic analysis of chromosome 11 aberrations in hematological malignancies
Šárová, Iveta ; Březinová, Jana (advisor) ; Goetz, Petr (referee) ; Jarošová, Marie (referee)
Chromosome 11 abnormalities are found in many hematological malignancies. In acute myeloid leukemia (AML), a proto-oncogene MLL (11q23.3) is frequently altered. However, rearrangements to other regions of chromosome 11 have been reported. Therefore, we have identified and characterized the chromosome 11 breakpoints and common deleted and amplified areas in the bone marrow or peripheral blood cells of newly diagnosed patients with AML. Many recurrent and random chromosome 11 breakpoints were identified (recurrent in bands 11p15.4 (in NUP98 gene), 11q23.3 (in the MLL gene), 11p13, 11p12 and 11q13.2) and deleted or duplicated/amplified regions were determined. We notified new possibly significant genes in the development of AML. Contrary to the MLL rearrangements, patients with other chromosome 11 changes were older, with complex karyotype, unbalanced aberrations and short survival. FISH screening was proved very helpful in case of deviding cells lack and cryptic MLL gene rearrangement. In conclusion, molecular analyses of chromosomal breakpoints and amplified or deleted areas are very important not only for the patient stratification into specific prognostic and clinical subgroups but also for the identification of genes involved in tumour pathogenesis. Further investigation of the affected genes and...
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Function of SWI/SNF chromatin-remodeling complex in tumor initiation and progression of melanoma cells
Ondrušová, Ľubica ; Vachtenheim, Jiří (advisor) ; Goetz, Petr (referee) ; Hejnar, Jiří (referee)
There is an increasing evidence that alterations in chromatin remodeling play an important role in tumorigenesis. The SWI/SNF chromatin remodeling complexes contribute to the regulation of gene expression by altering the local chromatin structure. Depending on the context, they can act as either transcriptional activators or repressors. All SWI/SNF subcomplexes contain one of two ATPase subunits, Brm (Brahma) or Brg1 (Brahma related gene 1), which provide the energy for remodeling. Malignant melanoma is an aggressive cancer and is known for its notorious resistance to conventional anticancer therapies. MITF (microphthalmia-associated transcription factor) plays an essential role in melanoma biology and is placed on the central crossroad in the regulation of melanocyte development, differentation, maintenance of lineage identity, and survival of both normal and malignant melanocytes. Our results show that the active SWI/SNF complex is strictly required for the expression of MITF. This complex is also required for expression of some transcriptional MITF targets. The survival of melanoma cells is absolutely dependent on functional SWI/SNF complex and all subunits of this complex are expressed at high levels in melanoma cell lines. Primarily, Brg1-containing subcomplexes are more important for MITF...
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