In recent years, the genetic landscape of B-cell derived lymphoid malignancies, including chronic lymphocytic leukemia (CLL), has been rapidly unraveled, identifying recurrent genetic mutations with potential clinical impact. Interestingly, ~30% of all CLL patients can be assigned to more homogeneous subsets based on the expression of a similar or “stereotyped” B-cell receptor (BcR). Considering that biased distribution of genetic mutations was recently indicated in specific stereotyped subsets, in paper I, we screened 565 subset cases, preferentially assigned to clinically aggressive subsets, and confirm the SF3B1 mutational bias in subset #2 (45%), but also report on similarly marked enrichment in subset #3 (46%). In contrast, NOTCH1 mutations were predominantly detected in subsets #1, #8, #59 and #99 (22-34%). This data further highlights a subset-biased acquisition of genetic mutations in the pathogenesis of at least certain subsets. Aberrant NF-κB signaling due to a deletion within the NFKBIE gene previously reported in CLL warranted extended investigation in other lymphoid malignancies. Therefore, in paper II, we screened 1460 patients with various lymphoid malignancies for NFKBIE deletions and reported enrichment in classical Hodgkin lymphoma (27%) and primary mediastinal B-cell lymphoma (PMBL) (23%). NFKBIE-deleted PMBL cases had higher rates of chemorefractoriness and inferior overall survival (OS). NFKBIE-deletion status remained an independent prognostic marker in multivariate analysis. EGR2 mutations were recently reported in advanced stage CLL patients; thus, in paper III we screened 2403 CLL patients for mutations in EGR2. An overall mutational frequency of 3.8% was reported and EGR2 mutations were associated with younger age, advanced stage and del(11q). EGR2 mutational status remained an independent marker of poor outcome in multivariate analysis, both in the screening and validation cohorts. Whole-genome sequencing (WGS) of 70 CLL cases, assigned to poor-prognostic subsets #1 and #2 and indolent subset #4, were investigated in Paper IV and revealed a similar skewing of SF3B1 mutations in subset #2 and NOTCH1 mutations in subset #1 to that reported in Paper I. Additionally, an increased frequency of the recently proposed CLL driver gene RPS15 was observed in subset #1. Finally, novel non-coding mutational biases were detected in both subset #1 and #2 that warrant further investigation.

The Martin Aircraft Company Limited has been developing the Martin Jetpack for over 25 years. The recent worldwide launch of the Jetpack has enabled the company to step up its research and development programme. The goal of this project was to determine the feasibility of an electrically powered version of the Martin Jetpack. The feasibility of the Electric Jetpack was determined by researching energy storage technologies, researching power cable technologies, simulations of flight times, surveys of electric motors, and the development of a simulation program which was used to optimise some preliminary custom motor designs. The overall conclusion of this project was that the Electric Jetpack was feasible only when it was powered through a tethered power cable, and on-board energy storage was not used. An investigation into current energy storage technologies showed that the Electric Jetpack is not considered feasible when using on-board energy storage, however it is possible to obtain flight for a very short time. The energy storage technologies studied were batteries, fuel cells, and ultra-capacitors. It was found that the best performing technology was the lithium iron nano-phosphate battery. A simulation of flight time showed that this battery type would be able to provide flight for approximately 3.6 minutes. Future trends indicated that the Electric Jetpack with on-board energy storage may eventually be feasible when using a lithium-ion based battery due to improvements being made in energy density and power density. By using a tethered power cable, the weight of the on-board energy storage could be eliminated. This was shown to be a feasible method for powering the Electric Jetpack for applications where the Jetpack needs to only be operated in a small area. The best cable type to use was a multi-stranded flexible cable operating at a high DC bus voltage. The weight of a 5 meter power cable using a 1000 V bus voltage was shown to be 4.9 kg. Potential applications for this kind of Jetpack could include thrill rides and rescue operations from multi-storied buildings. A cable made from carbon nanotubes was shown to be a future technology that could offer a lighter cable. A survey of currently available electric motors showed that none met both the power density and speed required by the Electric Jetpack, even when using a tethered power cable to eliminate the energy storage weight. Because of this, a custom motor design was needed. Research into motor technologies showed that the permanent magnet brushless DC (PMBLDC) motor was the most suited type for the Electric Jetpack. The permanent magnet brushless AC (PMBLAC) motor was also suitable. A PMBLDC motor simulation program was developed using MATLAB which could be used to optimise preliminary custom designs. A characterisation of allowable motor time constants for the PMBLDC motor type was made in order to speed up the simulation time. The optimisation results showed that a power density of 5.41 kW/kg was achievable for the motor when it was located inside the ducted fan tubes, and a power density of 6.56 kW/kg was achievable when the motor was located outside the ducted fans and operated at a higher speed. The motor designs were shown to be within the expected torque per unit rotor volume (TRV) range for aerospace machines. The best power density figures would leave between 37 kg and 42 kg of weight for the motor driver/controller, cable weight, and miscellaneous motor parts. This was considered to be feasible. An FEM simulation was made on one of the optimised motor designs. The FEM results agreed with the parametric results within reasonable accuracy. The parametric back-EMF waveform over-estimated the effects of slotting.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. It is a molecular and prognostic heterogeneous disease. Three main genetic subtypes are called germinal center-like DLBCL (GC-like DLBCL), non-germinal center-like DLBCL (nonGC-like DLBCL) and primary mediastinal B-cell lymphoma (PMBL). These subtypes can be reliably distinguished only with usage of gene expression profiling (GEP). The GEP method can be applied only when fresh frozen tissue is available. The method is technically difficult and expensive. Thus, it is not used routinely. Since the DLBCL subtypes differ in prognosis, it is extremely important to be able to distinguish them. The presented thesis is focused on distinguishing of PMBL diagnosis in the group of DLBCL. Easily stored formalin-fixed, paraffin-embedded tissue (FFPE) and gene expression analysis using real-time quantitative polymerase chain reaction (RTqPCR) are used. In the first step, PMBL and DLBCL cases were distinguished with an internationally accepted clinical-pathological method. The agreement between clinical-pathological diagnosis and GEP is only 76%. In the presented text a genetic algorithm for PMBL/DLBCL distinguishing is suggested. It uses three carefully chosen genes and their expression is measured with RTqPCR. Both, the...

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. It is a molecular and prognostic heterogeneous disease. Three main genetic subtypes are called germinal center-like DLBCL (GC-like DLBCL), non-germinal center-like DLBCL (nonGC-like DLBCL) and primary mediastinal B-cell lymphoma (PMBL). These subtypes can be reliably distinguished only with usage of gene expression profiling (GEP). The GEP method can be applied only when fresh frozen tissue is available. The method is technically difficult and expensive. Thus, it is not used routinely. Since the DLBCL subtypes differ in prognosis, it is extremely important to be able to distinguish them. The presented thesis is focused on distinguishing of PMBL diagnosis in the group of DLBCL. Easily stored formalin-fixed, paraffin-embedded tissue (FFPE) and gene expression analysis using real-time quantitative polymerase chain reaction (RTqPCR) are used. In the first step, PMBL and DLBCL cases were distinguished with an internationally accepted clinical-pathological method. The agreement between clinical-pathological diagnosis and GEP is only 76%. In the presented text a genetic algorithm for PMBL/DLBCL distinguishing is suggested. It uses three carefully chosen genes and their expression is measured with RTqPCR. Both, the...