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New kinase inhibitors
Hakrová, Kateřina ; Nencka, Radim (advisor) ; Tichý, Michal (referee)
Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by the occurrence of common myeloid progenitors, which then accumulate in the bone marrow and peripheral blood. This subsequently leads to a failure of hematopoiesis. Approximately one third of patients have a mutation in FMS-like tyrosine kinase (FLT3), which is associated with a higher risk of relapse and an overall worse prognosis. In recent years, several FLT3 inhibitors have been developed to facilitate the treatment of AML but patients develop resistance to most of them over time, leading to subsequent relapse of the disease. This bachelor's thesis discusses the synthesis of new potential inhibitors and the effect of imidazo[1,2-b]pyridazine core substitution on the inhibitory activity of these substances against the internal tandem duplication (ITD) type mutation in FLT3 kinase. Key words: AML, FLT3, imidazo[1,2-b]pyridazine, kinase inhibitors
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CHARACTERIZATION OF GILTERITINIB-RESISTANT LEUKEMIC CELL LINE
Zlesáková, Lucie ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Zlesáková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá, Ph.D. Title of diploma thesis: Characterization of gilteritinib-resistant leukemic cell line Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis for which therapy failure is often responsible. Development of drug resistance is among the most common causes of treatment failure. The exact mechanisms leading to the resistance are not known, especially for drugs recently introduced into the clinical practice such as gilteritinib. Therefore, the gilteritinib-resistant leukemic cell line (referred to as HL-60 g75) has been established in our lab and further characterized. The aim of this study was to evaluate the sensitivity of HL-60 g75 cells to gilteritinib and to clarify the stability of acquired resistance. We revealed that the resistance of HL-60 g75 cells is transient, since only after 4 weeks of gilteritinib-free cell culture, sensitivity of these cells was restored. While gilteritinib induced apoptosis similarly in both gilteritinib-sensitive (HL-60 wt) and -resistant cells, cell cycle analysis revealed lower responsiveness of HL-60 g75 to gilteritinib than HL-60 wt....
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What are substitutes for domestic money and what is their legal regime
Karpják, Jiří ; Kotáb, Petr (advisor) ; Vybíral, Roman (referee)
Domestic money substitutes and their legal regime Abstract Abstract Domestic money substitutes and their legal regime Abstract The thesis deals with the elementary legal aspects of the phenomenon of cash substitutes in the Czech legal system, especially in relation to the general prohibition of their issuance contained in Section 239 of the Criminal Code. In the introduction the thesis sets out to define the category of items falling under the concept of money substitutes and then to assess the extent to which the provisions constituting the legal regime of lawful money apply to these money substitutes. The thesis first defines the concepts of money, currency and the legal regime of lawful money, providing evidence in particular on the specifics impacting on the potential legal regime of money substitutes. After defining the basic concepts, the thesis analyses the current criminal law regulation of money substitutes. In this part, the author addresses selected problems described in the literature on the subject and discusses in detail the history of the current criminal law prohibition of money substitute, concluding that it is de lege lata an obsolete legal regulation which, without further action by the legislator, cannot be constitutionally applied within the framework of criminal law constrained by the...
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Virtual assets and money laundering
Špás, Martin ; Marková, Hana (advisor) ; Vybíral, Roman (referee)
and keywords Virtual assets and money laundering The thesis takes as its task the analysis of the connection of two phenomena. One is money laundering, which is characterized by a high social danger, and the other is virtual assets, which represent an advanced technology but are increasingly misused for money laundering. The aim of this thesis is to explain the issue of the use of virtual assets for money laundering and to evaluate the international fight against this illegal activity, in particular to assess the functionality and effectiveness of the current legislation at international, European and some national levels. The first part deals with the general characteristics of virtual assets. In particular, it focuses on the technical nature of virtual assets. The second part of the thesis focuses on money laundering in relation to virtual assets. The chapters deal with the concept of money laundering, the different stages of this activity, the current situation and some examples of the misuse of virtual assets for money laundering purposes. The third part of the thesis focuses on the fight against money laundering in the field of virtual assets. This part of the thesis will focus on measures against money laundering from the perspective of financial law. The first chapter deals with soft law, in...
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Non-face-to face customer identification
Farny, Adam ; Sejkora, Tomáš (advisor) ; Kotáb, Petr (referee)
Non-face-to-face customer identification The subject matter of this thesis is the analysis of the Czech legal regulation of customer identification as a core obligation arising from the regulation of the fight against money laundering. Customer identification is the first obligation that a customer encounters when using the services of obliged entities, and thus the way in which the legislation approaches customer identification directly influences the course of the customer's first interaction with the obliged entity. The topic is widely discussed because smooth onboarding processes are crucial for many obliged entities, and FinTech startups in particular. Sub-optimal regulation imposes an unnecessary burden on obliged entities and indirectly puts them at a disadvantage against foreign competitors who may be subject to more favorable regulation. However, the interest of obligated entities may collide with the regulator's interest in ensuring the most trustworthy identification output. Finding an appropriate way for balancing interests of both sides therefore poses a considerable challenge for the legislator. Getting the legislation right depends on ensuring that the legislation is able to keep pace with technological advances in this area and that it allows the use of the best available ways of performing...
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Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells
Králová, Adéla ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Králová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá Title of Diploma thesis: Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells Fms-like tyrosine kinase 3 (FLT3) inhibitors represent a new generation of drugs in the treatment of acute myeloid leukemia (AML). Standard therapeutic regimen of AML is initiated with induction therapy consisting of cytarabine and anthracyclines. The disadvantage of this combination is emerging resistance often caused by the ABCB1-mediated efflux. Therefore, simultaneous inhibition of FLT3 and ABCB1, which is inhibited by FLT3 inhibitors used in clinical practice, appears to be a beneficial approach to therapy. However, their effectiveness is declining hence the effort to develop new FLT3-inhibiting molecules. The aim of our work was to evaluate whether our two promising new FLT3-inhibiting compounds would inhibit ABCB1 as well. Promyelocyte cells overexpressing ABCB1 (HL60-ABCB1) and parent HL60-par were used in this study alongside AML-derived cell lines (MOLM-13, THP-1, Kasumi-1). Employing accumulation studies on HL60-ABCB1, strong inhibitory effect towards ABCB1 was demonstrated...
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The role of mTOR complexes in immunophenotype of leukemia cells
Kořánová, Tereza ; Kuželová, Kateřina (advisor) ; Krulová, Magdaléna (referee)
Acute myeloid leukemia (AML) is a cancerous disease of hematopoiesis characterised by accumulation of immature cells (blasts) of the myeloid lineage. AML blasts utilise a range of mechanisms to escape the immune system including alteration of their metabolism or expression of inhibitory molecules. Activation of these mechanisms is not yet fully understood. One of the pathways used to regulate a great number of cellular processes is the mammalian target of rapamycin (mTOR) pathway. mTOR kinase forms two complexes, mTORC1 and mTORC2, each regulating different substrates and cellular functions. The aim of this thesis was to analyze the influence of inhibition of each of the mTOR complexes on the metabolism (oxidative phosphorylation and glycolysis) and expression of immune escape markers (HLA-I, HLA-DR, CLIP, PD-L1, TIM-3) was analysed. The inhibitor JR-AB2-011 (an mTORC2 inhibitor) reduced the mitochondrial respiration rate in the majority of the cell lines, but its impact on the cell immunophenotype was only weak. Importantly, we found that the effect on the cell metabolism did not stem from the inhibition of mTORC2. Rapamycin (an mTORC1 inhibitor) decreased both metabolic rates, as well as glucose uptake. At the same time, CLIP, PD-L1, and TIM-3 expression was reduced in all the studied cell lines,...
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Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells
Králová, Adéla ; Čečková, Martina (advisor) ; Jirkovský, Eduard (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Adéla Králová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá Title of Diploma thesis: Impact of new FLT3 inhibitors on daunorubicin accumulation in ABCB1-expressing leukemic cells Fms-like tyrosine kinase 3 (FLT3) inhibitors represent a new generation of drugs in the treatment of acute myeloid leukemia (AML). Standard therapeutic regimen of AML is initiated with induction therapy consisting of cytarabine and anthracyclines. The disadvantage of this combination is emerging resistance often caused by the ABCB1-mediated efflux. Therefore, simultaneous inhibition of FLT3 and ABCB1, which is inhibited by FLT3 inhibitors used in clinical practice, appears to be a beneficial approach to therapy. However, their effectiveness is declining hence the effort to develop new FLT3-inhibiting molecules. The aim of our work was to evaluate whether our two promising new FLT3-inhibiting compounds would inhibit ABCB1 as well. Promyelocyte cells overexpressing ABCB1 (HL60-ABCB1) and parent HL60-par were used in this study alongside AML-derived cell lines (MOLM-13, THP-1, Kasumi-1). Employing accumulation studies on HL60-ABCB1, strong inhibitory effect towards ABCB1 was demonstrated...
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Legal and institutional security of the financial system against money laundering
Kubík, Tomáš ; Kohajda, Michael (advisor) ; Boháč, Radim (referee)
The main objective of this work 'Legal and institutional security of the financial system against money laundering' is to highlight the growing phenomenon of money laundering. It is a phenomenon causing collision of the global economic and financial system, which should not remain unnoticed. This phenomenon must be tackled by all, by legal means. To combat this effect was greatest, then it is necessary that there was a globally recognized legislation that would have embraced most states that there were institutions with qualified personnel with sufficient powers, primarily banking institutions, but not limited to those utmost efforts in the fight against money laundering. If the above conditions are not met, then it will hardly be able to face this phenomenon.
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Atomic swap: a risk for AML regulation?
Dolanský, Michal ; Sejkora, Tomáš (advisor) ; Kohajda, Michael (referee)
1 Atomic swap: a risk for AML regulation? Abstract This thesis deals with atomic swaps. Particularly it deals with their characteristics and relation to AML regulation. The aim of this thesis is to assess the risks that atomic swaps pose to AML regulation and the ways in which these risks can be addressed. The first part of this thesis briefly describes the concepts and technologies needed to understand atomic swaps. Among other things this part describes distributed databases, cryptographic keys, wallets, and virtual currency exchanges. This is followed by a description of the evolution of atomic swaps, how atomic swaps work and what are their advantages and disadvantages. The second part analyses the current regulation against money laundering and terrorist financing from the perspective of FATF, the European Union and the Czech Republic in relation to virtual currencies and atomic swaps. Particularly it focuses on the definition of virtual currencies and obliged entities. After the explanation how atomic swaps work and the analysis of AML regulation in relation to atomic swaps, it is possible to assess whether atomic swaps pose a risk to AML regulation. This is the focus of the third part of this thesis. It first introduces the issue of money laundering and the use of virtual currencies for illicit...
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