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Study of molecular markers correlating with prognosis and result of therapy colorectal carcinoma.
Protivová, Martina ; Souček, Pavel (advisor) ; Hromadníková, Ilona (referee)
Colorectal cancer is one of the most common cancer in this country and abroad. A major problem in the treatment of this disease is interindividual variability in response to treatment, since a large proportion of patients show resistance or adverse toxicity to the drug. The cause of this variability can be an individual's genetic makeup. From this perspective a need to find molecular markers for prognosis of the disease and markers through which we can predict response to therapy is growing. The main aim of this study was to find differences in gene expression between healthy and tumor tissue from patients well and poorly responding to treatment based on 5-fluorouracil and compare the results to clinical data. This study aimed to evaluate gene expression of 14 potential molecular markers involved in 5-FU pathways involving metabolism, transport, and objectives of the drug. Patients selection for the study was based on 5-FU regimens treatement. Expression was evaluated in two independent sets consisting of patients with indicated palliative or adjuvant chemotherapy. For each patient malignant and paired nonmalignant tumor tissue was available. Gene expression in these samples was measured using real-time RT-PCR with relative quantification using the preamplified cDNA. In the first phase the gene...
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User oriented web portals
Souček, Petr ; Souček, Martin (advisor) ; Šidlichovská, Zuzana (referee)
My dissertation is focused on customer-oriented websites. It explains the basic principles of creating customer-targeted websites. It also deals with common suggestions to web design, web navigations and contents. I conclude my dissertation with application of the theoretically acquired knowledge on the analysis of business web presentation, including the e-shop.
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Combination of ellipticine chemotherapy and a5b1 integrin-targeted therapy in human glioblastoma
Martínková, Eva ; Stiborová, Marie (advisor) ; Souček, Pavel (referee) ; Eckschlager, Tomáš (referee) ; Barberi-Heyob, Muriel (referee)
Charles University Prague Faculty of Science Department of Biochemistry SUMMARY OF THE THESIS COMBINATION OF ELLIPTICINE CHEMOTHERAPY AND α5β1 INTEGRIN-TARGETED THERAPY IN HUMAN GLIOBLASTOMA by MARTÍNKOVÁ Eva Supervisors: Prof. RNDr. Marie STIBOROVÁ, DrSc. Dr. Monique DONTENWILL 2 Table
of
Contents INTRODUCTION............................................................................................................................... 3
AIMS
OF
THE
STUDY ...................................................................................................................... 5
RESULTS............................................................................................................................................. 6
PART
A ................................................................................................................................................................6
PART
B.................................................................................................................................................................6
DISCUSSION....................................................................................................................................... 8
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The role of ATM in breast cancer
Soukupová, Jana ; Pohlreich, Petr (advisor) ; Souček, Pavel (referee) ; Foretová, Lenka (referee)
Incidence of breast cancer is continuously increasing in the Czech Republic. Tumor development is a result of gene alterations'accumulation, particulary associated with genes involved in regulation of cell growth and division. Hereditary carcinomas account for approximately 5-10% of all breast tumors and in 60-80% cases are caused by a germline mutation in the major predisposition genes BRCA1 and BRCA2. Nevertheless, other genes, mostly of lower penetrance, may play a role in breast pathogenesis such as the ATM tumor-suppressor gene. ATM is the apex of the repair pathway of DSB. This protein kinase activates through phosphorylation of its substrates cell cycle checkpoints, which leads either to the delay of the cell cycle progression until DSB are repaired or to the promotion of apoptosis. To sum up, the ATM gene seems to have a role in breast cancer development in a minority of the high-risk families in our population which is significantly lower compared to BRCA1/2 and it also seems to be involved in pathogenesis of sporadic breast cancer. Despite the ATM gene's length, we do not perform the preventive screening of this gene in breast cancer high-risk families. Nevertheless, we offer the molecular diagnostics of ATM to ataxia telangiectasia patients.
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The study of the role of biotransformational enzymes in chemical carciogenesis
Kondrová, Eliška ; Souček, Pavel (advisor) ; Skálová, Lenka (referee) ; Vobořilová, Jana (referee) ; Bořek Dohalská, Lucie (referee)
In vitro biotransformation studies are an integral part of both toxicological research and drug development. They allow for a significant reduction of tests on human volunteers and provide detailed information about the metabolism of a given compound. Due to limited availability of human liver tissue, it is necessary to make use of alternative model systems and model animal species in the study of the interactions between biotransformation enzymes and xenobiotics. Since the activities of the most important human biotransformation enzymes are absent in the most commonly used laboratory species, rat, information gained in experiments with minipigs is very valuable. Recombinant human biotransformation enzymes expressed in bacteria can be used in biotransformation studies in the form of isolated bacterial membranes. These model systems provide information about the metabolism of a given xenobiotic by a defined enzyme and thein advantages compared to purified enzymes include low cost and quicker and easier preparation with lower loss of enzymatic activity during isolation. The aims of this study were: 1) To prepare a model system with recombinant human biotransformation enzymes expressed in bacterial membranes and to compare the properties of this system with minipig liver microsomes. To assess the usefulness of...
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Role of selected ABC transporters in breast cancer development
Perglerová, Karolína ; Stiborová, Marie (referee) ; Souček, Pavel (advisor)
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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Study of alternatively spliced variants of estrogen receptor alpha in breast cancer cell lines
Lhota, Filip ; Kleibl, Zdeněk (advisor) ; Souček, Pavel (referee)
Filip Lhota: Study of alternatively spliced variants of estrogen receptor alpha in breast cancer cell lines Abstract: Estrogen receptor α (ER-α) is a transcription factor responsible for mediation of the activities of its natural ligand 17-β-estradiol (E2), the hormone that together with progesterone belongs to the key regulators of mammary epithelial as well as breast cancer cells proliferation. Except to the major gene product consisting of all eight coding exons of ER-α, numerous qualitatively and quantitatively different spliced variants originated from primary transcript by activity of alternative splicing is expressed. Despite that some of these spliced variants have been functionally characterized, their precise role on final ER-α cellular activity remains to be elucidated. The functional characterization of individual alternative forms of ER-α and description of its participation on the overall ER-α activity is important for our understanding of their biogenesis and is also critical for the delineation of molecular bases for ER-α regulation during anti cancer chemotherapy. This work aimed to study the influence of alternatively spliced ER-α variants on the growth characteristics of clones constructed from stable mammary tissue cell lines in regulation to cultivation conditions and cellular...
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The effect of histone deacetylase inhibitor vaplroate on activity and expression of cytochromes P450 and peroxidases oxidizing ellipticine
Göttlicherová, Markéta ; Souček, Pavel (referee) ; Stiborová, Marie (advisor)
Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and inhibition of topoisomerase II. Ellipticine was also found to form covalent DNA adducts mediated by its enzymatic activation with cytochromes P450 (CYP) and peroxidases. The next study demonstrated increasing formation of these ellipticine-DNA adducts by histone deacetylase inhibitor valproate (VPA) in neuroblastoma cells. This phenomenon correlates with increasing cytotoxicity of ellipticine induced by this histone deacetylase inhibitor. This observation can be explained by several mechanisms. One of them can be loosening the structure of chromatine, which leads to accessing DNA for modification. Another one is the effect of VPA on activities and expression of enzymes metabolizing ellipticine. This study was aimed to test the second hypothesis. Since VPA has been shown to be metabolized by similar enzymes as ellipticine is, we have studied the effect of VPA (i) on oxidation of ellipticine by cytochromes P450 and peroxidases, (ii) on activities of the CYP enzymes, which significantly participate in oxidation of ellipticine (CYP1A, CYP3A) and (iii) on expression of enzymes oxidizing ellipticine (CYP1A1, CYP3A4, lactoperoxidase). Oxidation of ellipticine in vitro by model...
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Age related macular degeneration - modern diagnostic and therapeutic preventive approach
Gogelová, Blanka ; Souček, Petr (advisor)
Age-related macular degeneration (AMD) is a disease associated with aging that gradually destroys sharp, central vision. Central vision is needed for seeing objects clearly and for common daily tasks such as reading and driving. AMD affects the macula, the part of the eye that alows seeing of fine details. AMD occurs in two form: dry and wet. In dry AMD, the light sensitive cells in the macula slowly break down. As fewer cells in the macula are able to function, people will see details less clearly in front of them, such as faces or words in book. Dry AMD often occurs in just one eye at first. Later the other eye can be affected. The most common early sign is blurred vision. The dry form is much more common. More than 85 % of all people have thy dry form. Once dry AMD reaches the advanced stage, no form of treatment can prevent vision loss. The National Eye Institute's Age-Related Eye Disease Study (AREDS) found that taking a specific high-dose formulation of antioxidants and zinc significantly reduces the risk of advanced AMD and it's associated vision loss. Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. Damage to the macula occurs rapidly. With wet AMD, loss of central vision can occur quickly. The classic early symptom is that straight lines appear crooked...
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