Acute lymphoblastic leukaemia is the most common childhood cancer with cure rates of approximately 80%. This success can be attributed to the introduction of risk stratification for patients and employment of intensified treatment regimes for patients with high risk disease. However, the identification of prognostically important leukaemia subtypes, unfortunately, is an labour-intensive process. In addition, despite the success in treating childhood ALL, specific subgroups of patients nevertheless still have poor survival rates. This is particularly true for leukaemias characterised by chromosomal translocations involving the MLL oncogene on chromosome 11q23. By using a novel bioinformatics approach, GeneRave, a set of 12 classifier genes (PTPRK, FOS, ENG, Lgal-S1, TCFL5, LRMP, CTGF, IGJ, MX1, PENK, CD3D and HBG1) was selected from a publicly available U95 Affymetrix microarray dataset. Real time PCR carried out on a blinded cohort of 58 primary ALL samples yielded an accuracy of 86%. The absence of PENK gene expression in the majority of ALL samples tested appears to have decreased the overall accuracy. Nevertheless, the results indicate that this method of classification can be easily and quickly performed and therefore may be useful as an adjunct to routinely used methodology in the diagnostic classification of childhood ALL. Parellal screening of a 34,000 chemical small molecules library identified 30 ???hits??? that exhibited specificity toward leukaemia, and many of which shared structural similarity. The cytotoxic effect of these compounds was further investigated in a panel of 19 cell lines that included 3 MLL-translocated (MV411, THP-1 and PER-485), 7 non-MLL-translocated leukaemias (REH, Jurkat, K562, HL60, Hal-01, UOB-B, NB4), 2 immortalized normal blood cell lines, 4 non-leukaemic tumour cell lines (Calu6, MCF7, BE(2)-C, and HeLa) and 3 normal cell lines (HSF, MCF10a and MRC5). In particular, two compounds were identified, SM6 and SM7, that were highly effective at killing MLL-translocated cell lines in the low micromolar range while having little or no effect on the other cell lines. Treatment of PER-485 cells with SM6 and SM7 showed mark down-regulation of the MLL chimaeric fusion protein together with its down-stream targets. One other more broadly acting anti-leukaemia compounds were also identified.

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Acute lymphoblastic leukaemia is the most common childhood cancer with cure rates of approximately 80%. This success can be attributed to the introduction of risk stratification for patients and employment of intensified treatment regimes for patients with high risk disease. However, the identification of prognostically important leukaemia subtypes, unfortunately, is an labour-intensive process. In addition, despite the success in treating childhood ALL, specific subgroups of patients nevertheless still have poor survival rates. This is particularly true for leukaemias characterised by chromosomal translocations involving the MLL oncogene on chromosome 11q23. By using a novel bioinformatics approach, GeneRave, a set of 12 classifier genes (PTPRK, FOS, ENG, Lgal-S1, TCFL5, LRMP, CTGF, IGJ, MX1, PENK, CD3D and HBG1) was selected from a publicly available U95 Affymetrix microarray dataset. Real time PCR carried out on a blinded cohort of 58 primary ALL samples yielded an accuracy of 86%. The absence of PENK gene expression in the majority of ALL samples tested appears to have decreased the overall accuracy. Nevertheless, the results indicate that this method of classification can be easily and quickly performed and therefore may be useful as an adjunct to routinely used methodology in the diagnostic classification of childhood ALL. Parellal screening of a 34,000 chemical small molecules library identified 30 ???hits??? that exhibited specificity toward leukaemia, and many of which shared structural similarity. The cytotoxic effect of these compounds was further investigated in a panel of 19 cell lines that included 3 MLL-translocated (MV411, THP-1 and PER-485), 7 non-MLL-translocated leukaemias (REH, Jurkat, K562, HL60, Hal-01, UOB-B, NB4), 2 immortalized normal blood cell lines, 4 non-leukaemic tumour cell lines (Calu6, MCF7, BE(2)-C, and HeLa) and 3 normal cell lines (HSF, MCF10a and MRC5). In particular, two compounds were identified, SM6 and SM7, that were highly effective at killing MLL-translocated cell lines in the low micromolar range while having little or no effect on the other cell lines. Treatment of PER-485 cells with SM6 and SM7 showed mark down-regulation of the MLL chimaeric fusion protein together with its down-stream targets. One other more broadly acting anti-leukaemia compounds were also identified.

Dissertation (PhD)--University of Stellenbosch, 2008. / Bibliography. Also available via the Internet.

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

Thesis. 1977. Ph.D.--Massachusetts Institute of Technology. Dept. of Biology. / Microfiche copy available in Archives and Science. / Vita. / Bibliography : leaves 115-120. / Ph.D.

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The lipopolysaccharide (LPS) translocation process was studied by a pulse-chase experimental procedure designed to follow the fate of newly synthesized LPS through the cell wall fractions of the marine bacterium Alteromonas haloplanktis, strain 214, variant 3 (ATCC 19855). It was determined that newly synthesized LPS I (the prominent LPS species under the conditions employed) initially enters an LPS fraction which can be released from the cell wall along with periplasmic material. This is followed by rapid entry of the newly synthesized LPS into a loosely bound LPS fraction (released from the cell wall by washing with NaCl) before final insertion into the outer membrane. The inhibition of protein synthesis with chloramphenicol was observed to have little or no effect on the rate of translocation of newly synthesized LPS. In contrast, both the respiratory inhibitor NaCN (10 mM) and the proton ionophore 3,3',4',5-tetrachlorosalicylanilide (TCS, 30 (mu)M), if added during the chase period, resulted in an immediate and complete inhibition of further LPS translocation. The results suggest an independence of the LPS transloction process from continued protein synthesis, but a requirement for an energy source. It was observed that newly synthesized LPS sedimented to a lower density position than previously formed LPS on sucrose density gradients, and displayed a faster migration rate during electrophoresis on sodium dodecyl sulfate polyarylamide gels (SDS-PAGE). This indicated compositional differences between the two LPS populations. Extended electrophoresis on SDS-PAGE separated both newly synthesized and previously formed LPS I into a number of distinct radiolabelled peaks and shoulders, indicating compositional microheterogeneity within each species. The fate of added radiolabelled galactose was also investigated. A one minute pulse with {('14)C} galactose resulted in a preferential labelling of components associated with the cell wall such that 57.3% of the total w

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Vita. Includes bibliographical references. Available also from UMI Company.