Thesis (M.D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 130-155).

Thesis (M. Med. Sc.)--University of Queensland, 2001. / Includes bibliographical references.

Thesis (M. Med. Sc.)--University of Queensland, 2002. / Includes bibliographical references.

published_or_final_version / Medicine / Master / Doctor of Medicine

Thesis (M.D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 130-155) Also available in print.

Thesis (Master Diploma(Medical Technology) -- Cape Technikon, Cape Town, 1990 / Eighty six patients with acute l.eukaemia were studied using morphol.ogical., cytochemical. and immunol.ogical. techniques. The acute l.eukaemias were subdivided using the French-American-British (FAB) cl.assification. The immunophenotyping studies were compared with the morphological classification to assess their contribution to the diagnosis. Acute non-lymphoblastic leukaemia (ANLL) was diagnosed on the basis of morphol.ogy and cytochemical. criteria. In addition this group of patients was studied with antibodies directed against myel.omonocytic antigens. However, no further cl.inical.l.y useful. information was obtained. Patients whose bl.asts did not stain with Sudan black or myel.operoxidase were considered to have acute lymphoblastic leukaemia (ALL). After assessment with monocl.onal. antibodies directed against epitopes expressed on cel.l.s from the l.ymphoid lineage, these patients were subgrouped into non-T-ALL, common-ALL, B-ALL, T-ALL and l.ymphoblastic lymphoma categories. This study confirmed the val.ue of monocl.onal. antibodies for accurately assigning l.ineage to the acute l.eukaemias and particularly in those situations where conventional morphol.ogical. criteria and cytochemical. markers are inconclusive.

Thesis (Ph.D.)--George Mason University, 2008. / Vita: p. 175. Thesis director: Ancha Baranova. Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biosciences. Title from PDF t.p. (viewed Jan. 8, 2009). Includes bibliographical references (p. 156-174). Also issued in print.

published_or_final_version / Pathology / Master / Master of Philosophy

A mathematical model of the interaction between chronic lymphocytic leukemia (CLL) and CD4+ (helper) T cells was developed to study the role of T cells in cancer survival. In particular, a system of four nonlinear advection diffusion reaction partial differential equations were used to simulate spatial effects such as chemical diffusion and chemotaxis on CLL survival and proliferation.

B cell chronic lymphocytic leukemia (B-CLL) is a hematologic neoplasm characterised by the proliferation and accumulation of sIgM+/D+ B cells that fail to progress to the final stages of B cell development. The malignant cells in B-CLL also express the pan-T cell antigen CD5, suggesting that CLL is a malignancy of the CD5+ subset of B cells. Additional characteristics of the malignant clone include a low proliferative index, enhanced in vivo survival and constitutive expression of the anti-apoptosis oncoprotein bcl-2. The behaviour of leukemic CD5 B cells in vitro contrasts their arrested in vivo state. That is, despite the majority of cells being arrested in the G0 phase of the cell cycle, the leukemic B cells are not irreversibly frozen as they can be induced to differentiate to Ig-secreting cells under appropriate in vitro conditions. Furthermore, leukemic CD5 B cells rapidly undergo death by apoptosis following in vitro culture. This thesis describes the requirements for in vitro activation of leukemic CD5+ B cells, the characterisation of the events involved in apoptosis of these cells as well as the identification of various growth factors capable of modulating these events. Stimulation of unfractionated peripheral blood lymphocytes (PBLs) from three patients with B-CLL with the phorbol ester PMA and the mitogens PHA and PWM resulted in significant increases in cell proliferation, RNA synthesis and 1gM secretion when compared to unstimulated cell populations. PMA was the most potent inducer of 1gM secretion and this occurred irrespective of the presence of residual T cells. PMA-induced proliferation and RNA synthesis were also independent of T cells. However, in the presence of T cells, these parameters of cellular activation were enhanced during in vitro culture. Thus, the inductive ability of PMA on leukemic CD5 B cells was independent of T cells. In contrast, activation and differentiation of the leukemic CD5 B cells into 1gM-secreting cells following culture with mitogens did not occur in the absence of T cells. Interestingly, co-stimulation of leukemic CD5+ B cells with PMA and anti-Ig induced cellular responses that exceeded those induced by either activator alone. Thus, leukemic CD5+ B cells from patients with B-CLL can be activated in vitro and differentiate in response to stimulation via both T cell-dependent and T cell-independent mechanisms. Apoptotic cell death was characterised in purified leukemic CD5 B cells obtained from six B-CLL patients. All leukemic CD5 B cell populations entered an apoptotic pathway in vitro as evidenced by a reduction in cell size, loss of cell viability and fragmentation of DNA into multimers of -180 base pairs. Following 24 hours of in vitro culture 24.0±16% of DNA was fragmented. After 8 days, the majority of DNA was fragmented, and fewer than 10% of cultured cells were viable. Examination of bcl-2 expression in the malignant B cells by flow cytometry revealed a unimodal pattern of expression in greater than 85% of cells from each B-CLL patient prior to culture. During in vitro culture, bcl-2 expression became bimodal such that the B cells displayed a bcl-2hjgh and bcl-2iow phenotype. The level of expression by the bCl2hjgh cells was similar to that observed prior to in vitro culture, indicating that bcl-2 is down-regulated in apoptosing cells. Interestingly, despite this downregulation, the overall number of cells positive for bcl-2 remained constant. This suggests that the enhanced survival of leukemic CD5+ B cells in vivo is mediated by the sustained expression of bcl-2 and that additional mechanisms exist capable of overriding the protective effect of bcl-2 when bcl-2 is present at reduced levels. Leukemic B cell apoptosis has previously been reported to be delayed or prevented by IL-4, IFN-y and IFN-a. These results were confirmed in this study where it was found that culture of leukemic CD5 B cells with IL-4 or IFN-y enhanced cell viability and delayed apoptosis in 6/6 and 5/6 populations of leukemic B cells, respectively. This function was also found to be shared by IL-2, IL-6, IL-13 and TNF-a as these cytokines enhanced cell viability and delayed apoptosis in some of the cell populations examined at a level similar to that observed for IL-4 and IFN-y. These cytokines may mediate their effect via the expression of bcl2 as culture in the presence of IL-2, IL-4, IL-6, IL-13, IFN-y or TNF-a resulted in a higher percentage of cells displaying the bcl-2high phenotype, compared to unstimulated cells. Taken together, these results suggest that autocrine and/or paracrine growth loops may play a role in the pathogenesis of B-CLL and that cytokines that prevent apoptosis in vitro may be targets for treatment of this B cell malignancy.