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Surveying and Creation of 3D Model for Hydro Technical Project
Bárta, František ; Foral, Jakub (referee) ; Hanzl, Vlastimil (advisor)
The thesis deals with the issues of digital terrain model creation. It aims to explain the solution of an international contract, starting from gathering the data and finishing with the creation and visualization of the digital terrain model of the given location. The software AutoCAD Civil 3D 2013 is used for modeling. Main outcomes of the thesis are volume calculation of flood line, contoured map of the dam area, the digital model and its visualization.
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Driving of a syringe pump stepper
Bárta, František ; Rampl, Ivan (referee) ; Chmelař, Milan (advisor)
The thesis is focused on the topic of a stepper motor control of injection dosing. At the beginning of the work are discussed properties , types, characteristics and possibilities of control of stepper motors. The thesis deals with the infusion dosing, their properties and parameters. They are shown both domestic and foreign manufacturers and their products. At the conclusion of the work is described by the theoretical design control circuit for stepper motor according to the selected engine.
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Biocompatible polymer systems for medical application
Hrochová, Michaela ; Etrych, Tomáš (advisor) ; Bárta, František (referee)
Polymer carriers for drug delivery are still an extensively studied topic in many research laboratories around the world. Polymer systems have an important role in the case of oncological diseases, where they allow to increase the therapeutic effect and significantly reduce the side effects of treatment. The present thesis is primarily focused on the synthesis of novel water-soluble biodegradable polymer systems based on N-(2- hydroxypropyl)methacrylamide enabling the treatment of solid tumors. As part of the work, four bifunctional transfer agents have been developed, which enable the direct synthesis of symmetric diblock polymers with a size of 20,000-100,000 g∙mol-1 with RAFT polymerization. The transfer agents introduce hydrolytically labile ester bonds into the structure of diblock polymers, which allow the diblock to break down into smaller fragments that can be excreted by the kidneys. The different structures of the chain transfer agents make it possible to control the breakdown of diblocks over a wide time range from 2,5 hours to 21 days. The advantages of the prepared diblock carriers are primarily the one-step synthesis, adjustable degradation time, and the possibility of modifying the end groups of the polymer chain. In the presence of bifunctional transfer agents, copolymers of HPMA...
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Polymer-based therapeutics for immunooncotherapy
Kashmel, Pavel ; Etrych, Tomáš (advisor) ; Bárta, František (referee)
This master thesis describes the synthesis, physico-chemical characterization and preliminary biological testing of water-soluble polymer conjugates of the model drug ZM241385. This drug was first derivatized and then connected to a polymer carrier in order to prepare a system suitable for targeted drug transport to tumor tissues. Improved pharmacokinetic parameters of the prepared polymeric systems carrying ZM241385 should be the basis for increased therapeutic activity of the polymeric nanosystem in tumor immunotherapy. Polymeric precursors were synthesized by controlled RAFT polymerization in order to prepare highly defined carrier systems. In the framework of this master thesis, two derivatives of the selected drug were prepared, differing in the carboxylic acid used and the mode of their binding to the polymeric carrier. For derivatization, 4-(2-oxopropyl)benzoic acid was used, in which case the prepared derivative was bound to the carrier via a hydrazone bond. This bond is pH sensitive and shows high stability at pH 7.4 (corresponds to the pH of the blood stream), and at a slightly acidic pH 5.5 (corresponds to the microenvironment of the tumor, or endosomes of tumor cells), its rapid hydrolysis occurs. For the second derivative, 5-azidopentanoic acid was used. An uncatalysed click reaction...
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Nephropathy and tumour development caused by plant alkaloids aristolochic acid
Bárta, František ; Stiborová, Marie (advisor) ; Šácha, Pavel (referee)
Aristolochic acids (AA) are alkaloids contained in plant species of the family Aristolochiaceae. These plants are used since antiquity in traditional medicine to treatment of many varied diseases. There are known anti-inflammatory effects of these compounds, however these alkaloids exhibit mutagenic and carcinogenic properties. Despite of this fact, plant extracts AA are still used in traditional medicine, e.g. in China, India, Taiwan. Aristolochic acids are proven to be the cause of disease designated Aristolochic Acid Nephropathy (AAN, theretofore known as Chinese Herbs Nephropathy (CHN). This unusual nephropathy leads to a total renal failure. The late complication of this disease is the development of tumours in urothelial tissue of patients. AA can form persistent stable covalent DNA adducts. Formation of these DNA adducts lead to AT→TA transversion, the unique mutation in tumour suppressor gene p53 responsible for tumour formation. Balkan Endemic Nephropathy (BEN) is associated with AA, too. In this instance is supported also influence of another factors, e.g. mycotoxins (ochratoxin A). However, in all probability AA contribute to a development of this disease particularly. This hypothesis is supported by finding of AA-DNA adducts in tissues of patients suffering from AAN and BEN and that of...
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Function of Biotransformation Enzymes in Development of Nephropathies Caused by Aristolochic Acid
Bárta, František ; Stiborová, Marie (advisor) ; Koblihová, Jitka (referee) ; Eckschlager, Tomáš (referee)
- 6 - ABSTRACT Plant alkaloid aristolochic acid (AA) is a proven human carcinogen which causes two serious diseases: Aristolochic Acid Nephropathy (AAN) and Balkan Endemic Nephropathy (BEN). One of the characteristic features of both AAN and BEN is their close association with the development of upper urothelial carcinoma (UUC) in the renal tissue of patients. Although both nephropathies are mediated by the same compound (i.e. AA), their development differs slightly. The differences might be explained by a different exposure schedule of patients or interindividual differences in expression levels and activities of the enzymes metabolising AA in organisms. Detailed knowledge of these enzymes can contribute to the elucidation of the interindividual susceptibility to AA. In this thesis, enzymes participating in both oxidative detoxification of AAI, a major component of natural mixture of AA, and its reductive activation leading to the formation of AA-DNA adducts were studied. In a rat experimental model (Rattus norvegicus), NAD(P)H:quinone oxidoreductase 1 (NQO1) and its role in reductive bio-activation of AAI in vivo were examined utilising a specific inhibitor of this enzyme, dicoumarol. Oxidative detoxification of AAI resulting in formation of a demethylated derivative AAIa (8-hydroxyaristolochic...
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Inhibitors of tyrosine kinases as anticancer drugs of a new generation
Hromek, Vlastimil ; Stiborová, Marie (advisor) ; Bárta, František (referee)
At the present time many types of treatment are used for curing of different cancer diseases. Among the most common types of such treatment belong a surgery, radiotherapy, chemotherapy, and immunotherapy. In the case of chemotherapy, there is used a wide (broad) spectrum of chemotherapeutics such as alkylating agents, platinum compounds, antimetabolites, anthracyclines and, at the present time, also inhibitors of tyrosine kinases. The bachelor thesis describes different types of tyrosine kinase inhibitors and their use in treatment of several cancers. They become popular because of their high specifity and minimal side efects. The first successful use of a tyrosine kinase inhibitor was treatment of the patients suffering from chronic myelogenous leukemia (CML) with imatinib. Vandetanib is another inhibitor of tyrosine kinases that is now used for treatment of another cancer, the medullary thyroid cancer. During treatment, vandetanib is biotransformed with cytochromes P450, which are the terminal oxidases of a mixed function oxidase (MFO) system, into the less efficient metabolites. In the practical part of the bachelor thesis we isolated enzymes, which metabolize xenobiotics, including vandetanib. Rat liver tissue was used for isolation of NADPH:cytochrome P450 reductase, which was isolated as a...
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Mechanism of carcinogenicity and nephrotoxicity of aristolochic acids
Bárta, František
Aristolochic acids (AA) are human carcinogens which have also very strong nephrotoxic properties. A mixture of AA is present in Aristolochiacae plant species. These plants were and still are used in traditional medicine in some countries, particularly in Asia. Aristolochic acids participate in development of two types of nephropathies. The first disease is designated as Aristolochic Acid Nephropathy (AAN), the second one is Balkan Endemic Nephropathy (BEN). Both nephropathies are associated with urothelial malignancies, which are caused by AA. One of the common features of ANN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumour development. One cause for these different responses may be individual differences in the activities and expression levels of the enzymes catalyzing the biotransformation of AAI, the major toxic component of AA contained in Aristolochia species. Detailed knowledge of enzymes which participate in metabolism of AAI may contribute to elucidation of inter-individual susceptibility to AAN, BEN and later urothelial malignancies. Aristolochic acid I is either oxidative detoxicated or reductive activated by biotransformation enzymes. Reductive bioactiovation of AAI leads to formation of covalent AA-DNA adducts in organism which result in producing of...
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The role of FANCI phosphorylation in the Fanconi anemia DNA repair pathway
Krejčová, Kateřina ; Šilhán, Jan (advisor) ; Bárta, František (referee)
Fanconi anemia is an autosomal recessive disorder caused by mutation in one of Fanconi genes and it is manifested by developmental abnormalities, bone marrow failure, predisposition to cancer, cellular sensitivity to cross-linking agents and many other symptoms. Proteins encoded by Fanconi genes and some other proteins are part of Fanconi anemia pathway (FA pathway), which is responsible for DNA repair of an interstrand cross-link (ICL). The repair by this pathway requires monoubiquitination of FANCD2, which is induced and regulated by ATR dependent FANCI phosphorylation. The FANCI phosphorylation initiates the FA pathway but the molecular mechanism of this initialization is not known. Furthermore the proper function of entire pathway requires both: sequence of phosphorylation events of FANCI and monoubiquitination of FANCI:FANCD2 complex . The principle of this work was to study molecular mechanism of initiation and regulation of FA pathway by FANCI phosphorylation. Therefore phosphomimetic mutants of FANCI have been created to investigate their role in processes leading to FANCD2 monoubiquitination. The main aim was to reveal how the phosphorylation of FANCI affects DNA binding and also DNA binding of FANCI:FANCD2 complex. Since both DNA and FANCI phosphorylation are required for proper FANCD2...
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