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Role of selected ABC transporters in breast cancer development
Perglerová, Karolína ; Souček, Pavel (advisor) ; Stiborová, Marie (referee)
Breast cancer is a leading cause of death among women in many countries. In the treatment of the breast cancer cytotoxic drugs (chemotherapy) are often used. Interindividual differences of drug response are an important cause of treatment failures. Bioavailability also depends on a major extent from the expression and activity of drug transport across biomembranes. In particular efflux transporters of the ATP-binding cassette family such as ABCB1, ABCC1 and ABCC2 have been identified as major determinants of chemoresistance in tumor cells. It was hypothesized that variance in the gene expression of membrane transporters and their genetic variance could explain at least in part interindividual differences of pharmacokinetics and clinical outcome of a variety of drugs. This thesis focuses on the functional significance of gene expression of ABCB1, ABCC1 and ABCC2 and single nucleotide polymorphisms in ABCC1 gene.
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Association of genetic polymorphism of oxidative stress with diabetes mellitus type 1 and 2
Kloboučková, Lucie ; Kotrbová - Kozak, Anna Katarzyna (advisor) ; Daňková, Pavlína (referee)
Diabetes mellitus is a chronic autoimmune disease in which the immune system attacks the insulin-secreting ß-cells in the pancreas. It leads to an absolute deficiency of insulin. Chronic hyperglycemia induces increased production of reactive oxygen species, which leads to a decrease of natural antioxidant level in blood, and it contributes to genesis of diabetes complications (e.g. vascular or pulmonic). Moreover, the oxidative stress results in onset of pancreas inflammations and the damage of its ß-cells. Aims: Our aim was to assess whether or not certain genotypes or their combinations occur with higher frequency among groups of patients of type 1 diabetes (T1D) and type 2 diabetes and in a control group of healthy individuals. Methods: The study included groups of 40 T1D patients, 40 T2D patients and 45 healthy individuals. The polymorphisms of genes involved in the oxidative stress response were analyzedby using RFLP, PCR with TaqMan probes and allele specific PCR. The target genes involved superoxide dismutase SOD1 and SOD3 genes; glutathione-S-transferase GSTM1, GSTT1, GSTP1 genes; glutathioneperoxidase gene GPX1 and catalase gene CAT. The levels of plasma malondialdehyde were measured by using liquid chromatography. Results: Statistically significant differences were found in the...
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The prevalence of chosen polymorphisms of luteinizing hormone receptor gene in Czech population and patients with ovarian hyperstimulation syndrome
Chrudimská, Jana ; Macek, Milan (advisor) ; Schierová, Michaela (referee)
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic potentially life-threatening complication of assisted reproduction techniques (ART). It is caused by an increased sensitivity of ovaries to gonadotropins administered during the controlled ovarian hyperstimulation (COH). Thus, the degree of ovarian response can be gently tuned by genetic polymorphisms of gonadotropins and their receptors. The aim of this study is to ascertain the prevalence of polymorphisms Asn291Ser (rs1470652), Ser312Asn (rs2293275) and insLQ (insertion of leucine and glutamine, rs58356637) in the luteinizing hormone chorionic gonadotropin receptor (LHCGR) gene in 102 Czech fertile men, 149 fertile women and 58 patients with serious grade of OHSS. Detection of the Asn291Ser and Ser312Asn polymorphisms was performed using TaqMan SNP Genotyping Assays. The insLQ variation was detected by the capillary electrophoresis with fluorescence-labeled primers. This study ascertained the prevalence of studied variants in Czech fertile population. Obtained results are in concordance with the majority of data from other European populations. There is no difference in prevalence between control-men and control-women. No relation to the development of OHSS was disclosed. The number of analyzed samples is too small for haplotype analysis. These...
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Relation of fruitfulness in reduction therapy of child obesity at samplet genetics polymophisms
Janoudová, Veronika ; Sedlak, Petr (advisor) ; Daňková, Pavlína (referee)
The aim of the thesis is to analyze the relationship of polymorphisms Ala54Thr FABP2 (protein binding long chain fatty acids in the enterocytes of the small intestine), Gln27Glu B2AR (lipolytic receptor in white adipose tissue) and A-3826G UCP1 (uncoupling protein in the inner membrane of mitochondria in brown adipose tissue) to pursued antropometric and biochemical markers and judge their impact on the success of reducing therapy on children. Association of observed polymorphisms with obesity has already been proven in other studies, the results are inconsistent and most studies have dealt with adults. The study includes of 335 individuals (216 girls and 119 boys) who completed a reduction stay in the Children's hospital of Dr. Filip in Poděbrady. The subjects were studied for anthropometric and biochemical markers at the beginning and at the end of reduction stay. Genetic analysis of polymorphisms were performed with use of PCR-RFLP. Girls Thr/Thr in polymorphism Ala54Thr FABP2 were showing greater thickness of skin fold on abdomen (p=0,009) and higher fat percentage in body composition (p=0,023). Significantly greater reductionof both these markers have been demonstrated (p=0.008, p=0.040). For boys the relationship was observed of homozygote Ala/Ala in a lower weight reduction (p=0,040). In...
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The disruption of the circadian system in bipolar disorder and its association with the polymorphism of L-type calcium channel
Filipovská, Eva ; Bendová, Zdeňka (advisor) ; Novosadová, Zuzana (referee)
Bipolar affective disorder is a serious psychiatric disease with prevalence of about 1% in general population. Typical symptoms are mood changes: manic periods are followed by depressions, with possible asymptomatic period of variable duration between them. It alters patient's everyday life and often leads to suicidal tendencies. Bipolar disorder is related to impaired circadian rhytms that are regulated from suprachiasmatic nuclei in hypothalamus. Impaired circadian rhytms in bipolar disorder are manifested by abnormalities of sleep and daily activity and by disrupted circadian secretion of several hormons. One of many factors that link bipolar disorder to circadian system at molecular level is the function of voltage-dependent calcium channels of L-type. Expression of these channels is regulated by the clock genes and their proper function is important for maintaining endogenous oscillations in the main oscillator located in suprachiasmatic nuclei. A common finding in patients with bipolar disorder is polymorphism of the gene for 1 subunit of the Cav1.2 channel. Abnormal function of calcium channels, consequent to the polymorphism, may be one of the causes that alter circadian rhytms in bipolar disorder. Key words: circadian system, suprachiasmatic nucleus, bipolar disorder, L-type calcium...
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Molecular aspects of calcium-phosphate metabolism in renal complications of diabetes mellitus.
Šimáková, Eva ; Černá, Marie (advisor) ; Zajíčková, Kateřina (referee)
Introduction: This thesis deals with the calcium-phosphate metabolism and its role in the development of chronic diabetic complications. It examines calcium sensitive receptor, which can be crucial in affecting calcium metabolism. Calcium-sensitive receptor may play a role in intracellular signaling and metabolic pathways that lead to cell proliferation and extracellular matrix early diabetic nephropathy. We investigated two polymorphisms of the gene for calcium-sensitive receptor (intron 4 and codon 990). Material and Methods: The study included 313 diabetic patients, 41 patients with type 1 diabetes, 106 patients with type 2 diabetes, 110 diabetic patients with type 2 diabetes who had diabetic nephropathy and 56 patients with renal failure non-diabetic (NDRD). It was also examined 72 non-diabetic patients with chronic renal failure (CKD) and 96 healthy blood donors (ZK). Classification of diagnoses is listed in the theory. DNA was isolated by QIAamp DNA Blood Mini Kit and salting method. The specific fragments of gene for the CaSR were amplified by PCR. For detection, restriction fragment length polymorphism and TaqMan probes were used. The expression levels of mRNA were determined by real-time PCR. Results: For the codon 990 polymorphism, we found statistical significance of the genotype frequencies (AA,...
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Genetic study of obesity in children
Říhová, Aneta ; Daňková, Pavlína (advisor) ; Novota, Peter (referee)
Obesity is multifactorial dissease. Genetics factors participate in its origin of 40-70% (Barsh et al., 2000). Incidence of obesity is associated with a number of complications, which affect quality of life and abbreviate its length. It is projected in constantly younger age and its prevalence in the world grows. Even though several hundred genetics markers associated with obesity have been described, we still do not know all causes, which complicates efficiancy of treatment. Subject of this study was research of selected genes and their polymorphisms: FABP2 (rs1799883) and PLIN (rs1052700 and rs894160). The aim was to establish association between genotypes and antropometric and biochemical parameters related to obesity in group of 299 children and adolescents aged 7-18 years. Next goal was to establish whether these polymorphisms affect success of reduction therapy. SNP associations with antropometric and/or biochemical parameters were evaluated for boys and girls separately. Observed genotype frequencies between sex did not differ and they were in accordance with those explored in other populations. In rs1799883 polymorphism neither association with measured anthropometric and biochemical parameters nor effect on weight loss during reduction therapy have been found. The TT homozygote subjects of...
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The mitochondrial genome in the ontogenesis
Töröková, Petra ; Brdička, Radim (advisor) ; Černý, Viktor (referee)
The main goal of this study is the comparison of sequences of the HVRII region of the mitochondrial genome in the cord blood sample and the saliva sample of the same individual, taken at average ten years from his/her birth. It is known that during ontogenesis the human genome changes. All the more the mitochondrial genome which shows a higher mutation rate, and moreover it is not taken care of it by repair mechanisms. In older individuals, there was found a distinctive amount of mitochondrial variations cumulated in different tissues in the process of the ontogenesis. This study is focused on the detection of these changes already in younger individuals. The tissue-specific variability which is created during ontogenesis might have an adverse influence on all sorts of the mtDNA based studies. The samples were taken in two regions (Teplice / Prachatice) that differ in the pollution of environment. With regard to that, the samples with discovered changes were compared from the standpoint of the region, which they had come from, with the aim to prove the influence of environment on the mutagenesis of the mitochondrial DNA. Samples were also compared from the point of view of sex. Furthermore the variability of the collection of Czech population was evaluated and the estimation of the genetic...
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Evolution and function of polymorphism in warningly coloured prey
Fárová, Monika ; Exnerová, Alice (advisor) ; Šulc, Michal (referee)
Polymorphism can be expected in warningly colored prey if the prey is protected from predation by nothing else but its coloration. On the contrary, in defended prey, polymorphism was only until recently considered a controversial phenomenon due to its longer and costly avoidance learning. Individual moprhs can vary in different components of warning coloration: color, pattern, melanization degree, and internal and external contrast of colour patterns. This makes it difficult for predators to learn and remember warning signals of defended prey and avoid it in the future. Predator selection pressures and mechanisms leading to polymorphism differ between defended and undefended prey. For undefended prey, it is a negative frequency-depended selection that supports rare morphs or the multiple models hypothesis for one mimetic species. For defended prey, the polymorphism can occur temporarily (i. e., be unstable) and it also can be allowed by spatial heterogeneity of morphs or, as for undefended prey, one species can mimic multiple models. Quasi-Batesian mimesis could also contribute to the existence of the polymorphism, due to mechanisms similar to those in unprotected prey. Apart from selection by predators, there are other factors, that contribute to the existence of polymorhism in prey warning...
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Pharmacogenetic prediction of tamoxifen efficiacy and adverse effects in hormonal dependent breast karcinoma patients.
Argalácsová, Soňa ; Slanař, Ondřej (advisor) ; Vrána, David (referee) ; Paluch, Zoltán (referee)
ABSTRACT/SUMMARY Background: The clinical efficacy of tamoxifen therapy may be modified by the drug-metabolizing enzymes and transporting molecules involved into the pharmacokinetics of tamoxifen. The aim of this study was to evaluate the association of CYP2D6, ABCB1 polymorhisms and comedication with efficacy and safety of tamoxifen treatment. Methods: Totally 258 women with hormonal positive breast carcinoma were retrospectively evaluated in relation to CYP2D6, ABCB1 polymorphisms and comedication. Results: CYP2D6 polymorphisms or co-medication affecting CYP2D6 activity demonstrated no statistically significant effect on the efficacy of tamoxifen therapy or adverse event incidence; there was only a trend towards shortening the time to event (TTE) in CYP2D6 poor metabolizers. ABCB1 polymorphism rs2032582 was not associated with clinical outcomes, while a trend towards an increase of TTE in variant allele carriers was noted. The ABCB1 polymorphism rs1045642 demonstrated statistical significance in premenopausal patients (p = 0.0012, HR 0.69 (95% CI 0.21 to 2.31), and its significant association was noted with gynaecological /vasomotor adverse events (p = 0.0221, HR = 1.0588), with no evidence of the influence on the incidence and onset of venous complications. Conclusions: Although this work did not show...
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