Thesis (M.S.)--University of Wisconsin--Stevens Point, 2007 / Includes bibliographical references.

No description available.

Thesis--Agra University. / Includes bibliographical references (p. 361-368).

Philadelphia positive (Ph+) Acute Lymphoblastic Leukaemia (ALL) is characterised by the presence of the BCR-ABL fusion gene, which encodes a protein tyrosine kinase with aberrant activity. Imatinib, a chemical Bcr-Abl inhibitor, is rarely effective in Ph+ ALL patients as a single agent. In this study, insight into molecular and signalling changes occurring in Ph+ ALL during Imatinib therapy were investigated using cDNA microarrays. An optimal microarray assay was established to examine the gene expression changes in leukaemic cells from Ph+ ALL patients treated with Imatinib. Over 500 genes with ≥1.5-fold up- or down-regulation were identified. Based on gene ontology and novelty to Bcr-Abl signalling, six genes were selected and expression changes in five of these genes (PKCε, PINK1, SPRY2, ATF4 and PECAM1) confirmed by real time RT-PCR in Imatinib treated primary Ph+ ALL cells or the SUP-B15 cell line. The functional role of Protein Kinase C epsilon (PKCε) in response to Imatinib was further investigated using the Ph+ lymphoid and myeloid cell lines, SUP-B15 and K562. Detection of Imatinib-induced apoptosis by annexin V and PI staining demonstrated that SUP-B15 cells were less sensitive to Imatinib compared to K562 cells. PKCε mRNA was 50-fold higher in Ph+ ALL cells than Ph+ myeloid cells. In SUP-B15 cells, Imatinib upregulated PKCε mRNA but the protein was reduced by proteolytic cleavage. Inhibition of caspases showed that this cleaved product was not required for Imatinib induced-apoptosis. The treatment of SUP-B15 and primary Ph+ ALL cells with TAT-εV1-2 peptide, a specific inhibitor of PKCε, increased Imatinib-induced apoptosis. While the forced overexpression of PKCε in K562 cells reduced Imatinib-induced apoptosis. This increased expression of PKCε was associated with the increase of survival and anti-apoptotic proteins, Akt and Bcl-2. In summary, Gene expression profiling of Ph+ ALL cells during Imatinib therapy identified PKCε as an Imatinib responsive gene. A novel role of PKCε in Ph+ ALL response to imatinib is proposed. Experimental data presented in this thesis indicate that PKCε mediates pro-survival/anti-apoptosis signals in Ph+ ALL thereby reducing Imatinib-induced death. Thus, targeting PKCε during Imatinib therapy may be beneficial for the future treatment of Ph+ ALL.

Thesis (M.Ag.Sc.)--University of Adelaide, Dept. of Plant Science, 1997. / Bibliography: leaves 82-89.

Thesis--Agra University. / Includes bibliographical references (p. 361-368).

New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.

The aim of the present project was to quantify and compare differences in impact performance and damping effectiveness among various off-road bicycle suspension systems. Two experiments were conducted to compare suspensions. Fork impact performance was tested by measuring peak antero-posterior braking forces and impulses during impact with bumps of 6- and 10-cm height for five mountain bike suspension systems. These results were compared to a rigid fork condition. Comparisons among suspension systems showed small but significant differences in performance. While only marginal differences in peak force were found for the suspension conditions, more substantial differences in braking impulse were observed. Air-Oil design forks had the lowest braking impulse for the range of speeds and impact characteristics of this experiment. In another setting, an analysis of acceleration signals over a range of frequencies on two surface conditions (gravel and trail) was conducted to assess the damping effectiveness of the five suspension systems. The mountain bike was equipped with accelerometers mounted at the axle and frame. A spectral analysis of the signal was performed for each signal to provide a measure of fork effectiveness. Results showed that accelerations ranged from -33 to +40 g at the axle and from -13 to +13 g at the frame, while spectral analyses of the acceleration signals revealed two distinct frequency regions from 0 to 100 Hz and from 300 to 400 Hz. The various suspension systems were all effective in attenuating vibration over the first region. Vibration amplitudes at the frame were considerably less than at the axle for the suspension conditions while similar axle-frame vibrations were observed with the rigid fork. Lower frequency vibration amplitudes were typically greater on the trail than on gravel. In the frequency region between 300-400 Hz, the signal was attenuated at the frame for all conditions including the rigid fork. The quantification and comparison process of the various suspension forks using impulse provided an objective marker for performance, and allowed differentiation between various suspension conditions. Moreover, the effectiveness analysis through the use of accelerometers provided insight into the range of frequencies dampened by a suspension. The lower frequency range dampening suggested that effectiveness of a suspension fork can be quantified even though the experiment did not conclusively differentiate between the forks. / Graduation date: 2001

Modern processors rely on cache memories to reduce the latency of data accesses. Extensive cache misses would thus compromise the usefulness of the scheme. Cache-aware algorithms make use of the knowledge about the cache, such as the cache line size, L, and cache size, Z, to be cache efficient. However, careful tuning of these parameters for these algorithms is needed for different hardware platforms. Cache-oblivious (CO) algorithms were first introduced by Leiserson to work without the knowledge of the cache parameters mentioned earlier, but still achieve optimal work complexity and optimal cache complexity. Here we present CO algorithms for all-to-all operations (analogous to the cross-product operation). Its applications include Convolution, Polynomial Arithmetic, Multiple Sequence Alignment, N-Body Simulation, etc. Given two lists each with n elements, a naive implementation of all-to-all operation incurs O(n²/L) cache misses. Our CO version incurs only O(n²/L²√Z) cache misses. Preliminary experiments on Opteron 1.4GHz and MIPS 250MHz show that the CO implementation achieves two times faster. The profiling tool further confirms that the amount of cache misses is significantly lower. We also consider various situations where (a) the elements have non-uniform sizes, (b) an element cannot fit into the cache, (c) the lengths of the lists vary, and (d) an element is linked list. In addition, we study the extension to K-lists All-to-All Operation and its application. Finally, we will present the empirical results and compare with cache-aware algorithms. / Singapore-MIT Alliance (SMA)

This thesis describes the development and evaluation of a manual black-box testing method inspired by Zweben's test adequacy criteria, which apply white-box analogues of all-DU-pairs and all-nodes to a flow graph generated from the black-box specification. The approach described herein generates tests from a matrix representation of a class interface based on the flow graph concept. In this process, separate matrices for all-DU-pairs and all-nodes guide the generation of the required tests. The primary goal of the research is not to optimize the number of tests generated but to describe the process in a user-friendly manner so that practitioners can utilize it directly, quickly, and efficiently for real-world testing purposes. The approach has been evaluated to assess its effectiveness at detecting bugs. Both strategies - all-DU-pairs and all-nodes - were compared against three other testing methods: the commercial white-box testing tool Jtest, Orthogonal Array Testing Strategy (OATS), and test cases generated at random. The five approaches were applied across a sample of eleven java classes selected from java.util.*. Experimental results indicate that the two versions resulting from this research performed on par with or better than their respective equivalent approaches. The all-DU-pairs method performed better than all other approaches except for the random approach, with which it compared equally. Experimental evaluation results thus indicate that an automated approach based on the manual method is worth exploring. / Master of Science