Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world, and continues to have very low cure rates. The bulk of the tumour cells are non-cycling peripheral cells that accumulate from a minority of dividing cells within proliferation centres (PCs), located the lymph nodes (LN) and spleen. The PCs are rich in activated T helper (TH) cells that express CD40L and secrete IL-4. Like normal B cells, CLL cells interact with TH via their expression of CD40 and receive signals from IL4. This stimulation provides the signal for B cells to divide, as well as protecting them from apoptotic stimuli. Consequently, many current therapies are unable to sufficiently target the cells in the PC, resulting in therapy resistance, residual disease (RD) and relapse. In addition, most therapies have associated toxicities, restricting their use to younger, fitter patients. Thus, there is an urgent need for new therapies with low toxicity, especially for older patients. New drug discovery is time consuming and expensive. Redeployment of existing drugs is one way to potentially combat this issue. The lipid lowering drug Bezafibrate (BEZ) and the sex steroid, medroxyprogesterone acetate (MPA) have been shown to have anti-leukaemic properties in other settings. In this study the in vitro efficacy of BEZ and MPA on resting CLL cells (representing resting cells in the periphery) and when stimulated to proliferate by CD40L (representing cells in the PCs) have been investigated. Both BEZ and MPA exerted pro-apoptotic actions against resting CLL cells and reduced CD40L stimulated proliferation. These actions were increased when both agents were combined and demonstrated selectivity against CLL cells compared to normal peripheral blood mononuclear cells. Combined BEZ+MPA, was as effective as the commonly used chemotherapeutic chlorambucil, with the combination of all 3 agents exerting the greatest effects. However none of the combinations induced apoptosis of CLL cells protected by CD40L. Investigations into the possible mechanisms of drug action revealed that MPA was unlikely to be working either by steroid receptors or by inhibition of the enzyme AKR1C3 and the mechanism remains unknown. BEZ alone and in the presence of MPA induced the production of prostaglandin D2 (PGD2) and exogenously applied PGD2 was found to exert apoptosis in a similar manner to BEZ. Both BEZ and MPA generated reactive oxygen species (ROS) in both culture settings and the combination was more effective than either drug alone. In the absence of CD40L, mitochondrial superoxide (MSO) was also produced but not in CD40L stimulated cells. This finding suggested that CD40L is able to prevent or protect against MSO production and, consequently, apoptosis. Attempts at overcoming this effect revealed that the plant derived compound lycorine exerted minimal effects alone but, when combined with BEZ+MPA, reinstated the induction of MSO and recapitulated BEZ+MPA induced apoptosis despite the continual presence of CD40L. In contrast, the reported ability of dasatinib to overcome CD40L mediated fluadarabine resistance was discovered to be to be unfounded.

Táto diplomová práca sa venuje problematike využitia strojového učenia na detekciu anomálií na základe analýzy systémových logov. Navrhnuté modely sú založené na algoritmoch strojového učenia s učiteľom, bez učiteľa a na hlbokom učení. Funkčnosť a správanie týchto algoritmov sú objasnené ako teoreticky, tak aj prakticky. Okrem toho boli využité metódy a postupy na predspracovanie dát predtým, než boli vložené do modelov strojového učenia. Navrhnuté modely sú na konci porovnané s využitím viacerých metrík a otestované na syslogoch, ktoré modely predtým nevideli. Najpresnejší výkon podali modely Klasifikátor rozhodovacích stromov, Jednotriedny podporný vektorový stroj a model Hierarchické zoskupovanie, ktoré správne označili 93,95%, 85,66% a 85,3% anomálií v uvedenom poradí.

This dissertation describes research into “Antennas with Frequency Domain Control for Future Communication Systems” and several novel antennas are shown, each of which addresses a specific issue for current and future communication systems, in terms of wideband coverage, channel capacity, antenna isolation and band-rejection. These antenna designs may be candidates for implementation in future multiband radios, and software defined radio (SDR) and cognitive radio (CR) systems, which are two new concepts in wireless communications in the foreseeable future, although it is evident that there are as yet no clear specifications for those future systems. A novel two-port reconfigurable antenna which can operate within a narrowband or wideband mode is presented. Three different structures of wideband reconfigurable balanced antennas, with a wide tuning range, have been proposed. When the balanced antenna is combined with the two-port chassis antenna, it becomes a reconfigurable MIMO antenna for small terminals and at least 15 dB of isolation is achieved. Several designs of conical monopole antennas, incorporating different types of slots to achieve good band-rejection behaviour, have been introduced. These are the 2 Cshaped, 4 C-shaped slots, 4 U-shaped slots, 4 tilted-U-shaped slots and 4 U-C-shaped slots. The study of wideband antennas with notched-band behaviour using a simple equivalent circuit model has been proposed. It has been noted that increasing the number of resonators and the coupling factor will increase the band-rejection. However, it will also widen the bandwidth of the frequency notched band. A novel pyramidal monopole antenna, with four loop shaped slots, offering wide tunable band-notch, is also presented.

This dissertation is a detailed analysis of the Epistle to the Colossians. The author uses rhetorical critical methods and recognizes that the New Testament epistles are greatly influenced by oratory. Also, the author demonstrates how rhetorical techniques assist Paul to express his thought that the central idea of Christianity - the divine nature and saving work of Christ - has unavoidable ethical implications. In the first chapter of his letter Paul cites Christological hymn; he uses Christological theme during the whole epistle; the apostle concludes his admonition with the Household code, in which social roles of the member of oikos are interpreted in relation to Christ. According to Paul's teaching in Colossians, the power of Christ has universal scope and, consequently, all aspects of human life, including everyday, societal relationships, must be brought into submission to Christ. / M.Th. (New Testament)

This dissertation is a detailed analysis of the Epistle to the Colossians. The author uses rhetorical critical methods and recognizes that the New Testament epistles are greatly influenced by oratory. Also, the author demonstrates how rhetorical techniques assist Paul to express his thought that the central idea of Christianity - the divine nature and saving work of Christ - has unavoidable ethical implications. In the first chapter of his letter Paul cites Christological hymn; he uses Christological theme during the whole epistle; the apostle concludes his admonition with the Household code, in which social roles of the member of oikos are interpreted in relation to Christ. According to Paul's teaching in Colossians, the power of Christ has universal scope and, consequently, all aspects of human life, including everyday, societal relationships, must be brought into submission to Christ. / M.Th. (New Testament)