Thesis (Ph. D.)--University of Canterbury, 2008. / Typescript (photocopy). Includes bibliographical references (leaves 323-367). Also available via the World Wide Web.

Thesis (M.S.)--Michigan State University. Dept. of Epidemiology, 2006. / Title from PDF t.p. (viewed on Nov. 20, 2008) Includes bibliographical references (p. 60-65). Also issued in print.

Thesis (M.S.)--Ball State University, 2008. / Title from PDF t.p. (viewed on Sept. 09, 2009). Includes bibliographical references (p. [93]-101).

Thesis (Ph. D.)--University of Chicago, Division of the Biological Sciences and the Pritzker School of Medicine, June 1999. / Includes bibliographical references. Also available on the Internet.

No description available.

[Truncated abstract] The treatment of childhood acute lymphoblastic leukaemia (ALL) is one of the great success stories of paediatric oncology, transforming a universally fatal disease into one where 75 to 90% of children are now cured. Although in the past survival for children with T-cell ALL (T-ALL) lagged behind that of children with pre-B ALL, the use of contemporary intensified treatment strategies has significantly diminished this difference, with many investigators reporting similar cure rates for both groups of patients. Despite these marked improvements, numerous challenges still face physicians treating children with T-ALL. Firstly, there have been no additional major improvements in outcome over the last decade, despite additional treatment intensification. Secondly, effective regimens remain elusive for treating children with relapsed T-ALL or patients with resistant disease. Finally, there is a need to identify patients currently potentially overtreated and thus unnecessarily subjected to acute and long term toxicities without benefit. A major challenge therefore, is the identification of novel reliable prognostic markers, in order to identify patients at high risk of relapse and conversely those least likely to relapse, to guide therapy appropriately. Children predicted with a high risk of relapse would be candidates for intensification of therapy and/or novel experimental agents. Conversely, patients predicted to be at low risk of relapse could be offered clinical trials using reduced intensity therapy, thereby minimising toxicity. '...' Crucially, the 3-gene predictor was validated in a completely independent cohort of T-ALL patients, also treated on CCG style therapy. Our 3-gene predictor appears to identify a high risk group of patients which require alternative therapeutic strategies in order to attain a cure. This study has also identified a potential novel agent for the treatment of T-ALL, which may be used as an anthracycline potentiator or anthracycline-sparing agent. We hypothesised that genes associated with a relapse signature provide promising targets for novel therapies. We tested the hypothesis that CFLAR, an inhibitor of the extrinsic apoptotic pathway and a member of the 3-gene predictor may be involved in the development of resistance to chemotherapy. To test our hypothesis we used a novel agent, 2-cyano-3, 12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO), previously shown to inhibit CFLAR protein, in two cell lines established in our laboratory from paediatric patients diagnosed with T-ALL. We found that CDDO displayed single agent activity at sub-micromolar concentrations in both cell lines tested. Importantly, minimally lethal doses of CDDO resulted in significant enhancement of doxorubicin mediated cytotoxicity in one of the cell lines assessed. The findings presented as part of this thesis have revealed the value of gene expression analysis of childhood T-ALL for identifying novel prognostic markers. This study has shown that expression profiles may provide better prognostic information than currently available clinical variables. Additionally, genes that constitute a relapse signature may provide rational targets for novel therapies, as demonstrated in this study, which assessed a potential novel agent for the treatment of T-ALL.

Literature on psychological aspects of childhood cancer has treated adolescents as a homogeneous group, while revealing little about their individuality. This study's purpose was to systematically explore similarities and differences in adolescent boys with leukemia and to explore nurses' perceptions of the boys. Participants were recruited from a pediatric oncology clinic; the boys were 13, 14, and 18 years old and were selected based on age, active treatment for leukemia, and rapport with the investigator. To elicit constructs used by each boy to interpret feelings, the study employed a variant of psychologist George Kelly's technique for eliciting unique organizing principles (personal constructs) by which Kelly theorized people interpret experience (1955). The boys rated themselves on their personal constructs; their nurses also rated them on the constructs. Results reveal distinctive differences and certain similarities in the boys' personal constructs. Nurses' ratings of each patient differ in varying degrees from his own.

Tal-1 is a transcription factor that is frequently ectopically expressed in the majority of cases of T-cell acute lymphoblastic leukemia (T-ALL). The ectopic expression of Tal-1 in patients with ALL has been found to decrease susceptibility to chemotherapeutic drugs and apoptosis. Thus, this study focuses on the effects of endogenously expressed Tal-1 in the Jurkat cell line on three Bcl-2 family members (Bcl-2, Bcl-xL, and Bid) and the inhibition of apoptosis and cell viability when exposed to apoptosis inducing drugs such as etoposide. The data obtained indicate that when treated with etoposide for 12 h Jurkat cells endogenously expressing Tal-1 have an 81% higher level of anti-apoptotic Bcl-2 expression, an 18% lower level of anti-apoptotic Bcl-xL, expression, and a 31% lower level of pro-apoptotic Bid expression compared to Jurkat cells lacking Tal-1 expression. The data also demonstrates that Jurkat cells endogenously expressing Tal-1 have a 15.94% lower amount of cell death after treatment with etoposide for 12 h and a 20.34% lower amount of cell death after treatment with etoposide for 24 h when compared to Jurkat cells that lack Tal-1 expression. Thus, the endogenous expression of Tal-1 increases the amount of the anti-apoptotic Bcl-2 expression and decreases the amount of the pro-apoptotic Bid creating an overall anti-apoptotic signal within the cell. / Department of Biology

Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Several proto-oncogenes that encode nuclear proteins are activated by various chromosomal translocations in ALL including TALI, TAL2, and LMO1 and LMO2. Ectopic TALI expression is observed in about 50 % of T-ALL and is the most common genetic anomaly associated with this pathology. Of interest to the present work is the characterization of various multiprotein complexes and protein protein interactions that drive T-ALL progression (as it relates to TALI and LMO1) and over expression of TALI and LMO1 has been shown to have inhibitory effects on apoptosis. Recent data suggests possible interactions between these two oncoproteins and the protein product of the lipoprotein lipase (LPL) gene. Lipoprotein lipase has a complex pattern of regulation and can be regulated in different ways including down-regulation upon induction of TNF-a in 3T3-L1 cells. Thus, this study was undertaken to determine if LPL is expressed in cells over expressing TAL1 and LMO1. Results from this study demonstrated an increase in LPL expression at both transcriptional and translational level in cells engineered to express TAL1 alone and TAL1 and LMO1 together. This finding is a step forward to understanding mechanisms that result in apoptosis prevention in T-ALL. Therefore, the apoptosis preventive role seen in cells that over express TAL and LMO1 and the presence of LPL in the same cell line, theorizes an apoptosis preventive role for lipoprotein lipase as well. / Department of Physiology and Health Science

Thesis (M.S.)--University of British Columbia, 2005. / Includes bibliographical references (leaves 33-41). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.