Academic literature on the topic 'Granulocyte-macrophage colony-stimulating factor; imatinib; chronic myeloid leukemia gene therapy'
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Journal articles on the topic "Granulocyte-macrophage colony-stimulating factor; imatinib; chronic myeloid leukemia gene therapy"
1
Maifrede, Silvia, Dan Liebermann, and Barbara Hoffman. "Stress Response Transcription Factor Egr-1 As Tumor Suppressor Of CML." Blood 122, no. 21 (November 15, 2013): 4905. http://dx.doi.org/10.1182/blood.v122.21.4905.4905.
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The transcription factor early growth response 1 (Egr-1) gene was identified as a macrophage differentiation primary response gene, shown to be essential for and to restrict differentiation along the macrophage lineage. There’s evidence consistent with Egr-1 behaving as a tumor suppressor of leukemia, both in vivo and in vitro, including (1) loss of Egr-1 associated with treatment derived AMLs; (2) deregulated Egr-1 overriding blocks in myeloid differentiation, and (3) haplo-insufficiency of Egr-1 in mice leading to increased development of myeloid disorders following treatment with the potent DNA alkylating agent, N- ethyl-nitrosourea (ENU). BCR-ABL driven leukemia (Chronic Myelogenous Leukemia [CML]) was chosen as a model system to investigate the role of Egr-1 as a tumor suppressor for different leukemias. CML is a disease resulting from the neoplastic transformation of hematopoietic stem cells (HSC) with the BCR-ABL oncogene. The BCR-ABL protein is a constitutively active tyrosine kinase, which promotes cell survival and proliferation by means of diverse intracellular signaling pathways, thereby being the culprit for malignant transformation. Although the Tyrosine Kinase Inhibitor (TKI) imatinib mesylate (Gleevec, Novartis) is effectively used on CML patients, resistance to imatinib has been described. Thus there is a high priority to enhance our understanding of how BCR/ABL subverts normal hematopoiesis and to identify novel targets for therapy. It was observed that Egr-1 expression is reduced in bone marrow (BM) of CML patients, and its expression is further reduced in more advanced stages of CML. Consistent with this data, Egr-1 expression is reduced in BCR-ABL-expressing murine BM. The tumor suppressor role of Egr-1 in CML was validated using mouse models. Lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr-1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). Loss of Egr-1 accelerated the development of BCR-ABL driven leukemia in recipient mice. Furthermore, no statistically significant difference in the percentage of stem cells (Lin-Sca+c-Kit+, LSK) was observed between Egr-1 WT and Egr-1-/- BM. Thus, the BM stem cell compartment of the Egr-1-/- mice does not offer a quantitative advantage to justify the faster development of leukemia compared to Egr-1 WT mice. An increased population of lineage negative BM cells was observed in Egr-1-/- BCR-ABL recipients when compared to animals transplanted with WT BCR-ABL BM, consistent with more rapid development of disease. Preliminary results from serial BMT has shown that Egr-1-/- BCR-ABL BM has an increased leukemic burden when compared to the WT counterpart. Data from serial colony transfer and studies using spleens from diseased mice as well as BCR-ABL-expressing BM will be presented. These data could result in novel targets for diagnosis, prognosis, and targeted therapeutics, including strategies for activating Egr-1 expression, that can be used to treat CML, as well as other leukemic diseases. Disclosures: No relevant conflicts of interest to declare.
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Kim, Theo D., Michaela Schwarz, Karl-Anton Kreuzer, Jaspal Kaeda, Kamran Movassaghi, Peggy Grille, Peter Daniel, Bernd Dörken, and Philipp le Coutre. "Long-Term Follow-up of Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Patients After Stem Cell Mobilisation Under Imatinib." Blood 116, no. 21 (November 19, 2010): 3418. http://dx.doi.org/10.1182/blood.v116.21.3418.3418.
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Abstract Abstract 3418 Introduction: Mobilisation and collection of in vivo-purged CD34+ stem cells for chronic myeloid leukemia (CML) patients while in complete cytogenetic remission (CCyR) may offer a therapeutic option for those who develop resistance to the tyrosine kinase inhibitor imatinib mesylate (IM), the recommended first line therapy. Indeed, several groups have reported on retrospective studies showing autologous stem cell mobilisation to be safe and efficacious during IM therapy. However, assessing the clinical utility of managing patients using this approach is difficult as long-term follow-up is lacking. Here, we report the clinical outcome for 22 CML patients with a median of 99.5 months follow-up post G-CSF induced stem cell mobilisation. We assessed the efficacy and the the impact on BCR-ABL1 expression levels in these individuals. Material and Methods: Stem cell mobilisation was achieved by administering 10 mg/kg body weight (bw)/day filgrastim (granulocyte-colony stimulating factor, G-CSF) subcutaneously. Stem cell apheresis was performed if the absolute number of circulating CD34+ cells exceeded 5/ml. Target stem cell yield was 32×106 CD34+ cells/kg body weight. BCR-ABL1 transcripts were quantified by real time PCR (Q-PCR) of reverse transcribed total RNA using LightCycler® with β-actin as endogenous control gene. Results: For the twenty-two patients included in the present study, median age was 47 years (range, 24 – 71) and median disease duration was 20 months (range, 1 – 77). At the start of IM, 19 patients were in chronic phase (CP), and 3 in accelerated phase (AP). With a median duration on IM of 16 months (range, 2 – 29), time to first CCyR was 6 months (range, 0 – 25) and time from CCyR to apheresis was 8.5 months (range, 1 – 20). Mobilisation was performed once in 16 patients and twice in 6 patients, of whom eighteen patients (82 %) proceeded to apheresis. Overall, mobilisation was successful in 17 of 22 patients (78 %) with a median CD34+ cell number of 3.1×106/kg body weight (range, 0,7 - 6). BCR-ABL1 transcripts were undetectable in 12 of 22 peripheral blood samples (55 %) at the time of apheresis and 7 of 14 stem cell harvests (50 %) without discernible correlation with matched peripheral blood samples. Progression-free survival at 5 and 8 years was determined to be 63 %, and overall survival at 5 years and 8 years was 95 % and 90 %, respectively. Sixteen of 22 patients (73 %) continue to be treated with IM and twelve of 22 patients (55 %) are without detectable BCR-ABL1 transcripts, i.e. in complete molecular remission (CMR). Of the six patients that stopped IM (3 resistant and 3 intolerant), all received nilotinib as second-line TKI. Five of these six patients are still alive (1 in CHR; 1 in MCyR; 1 in MMR; and 2 in CMR), and one patient who subsequently received dasatinib died after progressing to blast crisis. Conclusion: These observations show G-CSF induced stem cell mobilisation and collection during IM therapy for autologous transplantation to be safe and efficient with a favourable long-term outcome. Disclosures: No relevant conflicts of interest to declare.
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Kassem, Neemat M., Alya M. Ayad, Noha M. El Husseiny, Doaa M. El-Demerdash, Hebatallah A. Kassem, and Mervat M. Mattar. "Role of Granulocyte-Macrophage Colony-Stimulating Factor in Acute Myeloid Leukemia/Myelodysplastic Syndromes." Journal of Global Oncology, no. 4 (December 2018): 1–6. http://dx.doi.org/10.1200/jgo.2017.009332.
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Purpose Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine stimulates growth, differentiation, and function of myeloid progenitors. We aimed to study the role of GM-CSF gene expression, its protein, and antibodies in patients with acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) and their correlation to disease behavior and treatment outcome. The study included 50 Egyptian patients with AML/MDS in addition to 20 healthy volunteers as control subjects. Patients and Methods Assessment of GM-CSF gene expression was performed by quantitative real-time polymerase chain reaction. GM-CSF proteins and antibodies were assessed by enzyme-linked immunosorbent assay. Results There was significant decrease in GM-CSF gene expression ( P = .008), increase in serum level of GM-CSF protein ( P = .0001), and increase in anti–GM-CSF antibodies ( P = .001) in patients with AML/MDS compared with healthy control subjects. In addition, there was a significant negative correlation between serum levels of GM-CSF protein and initial peripheral blood blasts, percentage as well as response to therapy. Conclusion Any alteration in GM-CSF gene expression could have implications in leukemogenesis. In addition, GM-CSF protein serum levels could be used to predict outcome of therapy. GM-CSF antibodies may also play a role in the pathogenesis of AML/MDS. The use of these GM-CSF parameters for disease monitoring and as markers of disease activity needs further research.
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Dewar, Andrea L., Antony C. Cambareri, Andrew C. W. Zannettino, Bernadette L. Miller, Kathleen V. Doherty, Timothy P. Hughes, and A. Bruce Lyons. "Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib." Blood 105, no. 8 (April 15, 2005): 3127–32. http://dx.doi.org/10.1182/blood-2004-10-3967.
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AbstractImatinib is a tyrosine kinase inhibitor that suppresses the growth of bcr-abl–expressing chronic myeloid leukemia (CML) progenitor cells by blockade of the adenosine triphosphate (ATP)–binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs). Although initially considered to have minimal effects of normal hematopoiesis, recent studies show that imatinib also inhibits the growth of some nonmalignant hematopoietic cells, including monocyte/macrophages. This inhibition could not be attributed to the known activity profile of imatinib. Here, we demonstrate for the first time that imatinib targets the macrophage colony-stimulating factor (M-CSF) receptor c-fms. Phosphorylation of c-fms was inhibited by therapeutic concentrations of imatinib, and this was not due to down-regulation in c-fms expression. Imatinib was also found to inhibit M-CSF–induced proliferation of a cytokine–dependent cell line, further supporting the hypothesis that imatinib affects the growth and development of monocyte and/or macrophages through inhibition of c-fms signaling. Importantly, these results identify an additional biologic target to those already defined for imatinib. Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions.
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Borrello, Ivan M., Hyam I. Levitsky, Wendy Stock, Dorie Sher, Lu Qin, Daniel J. DeAngelo, Edwin P. Alyea, et al. "Granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting cellular immunotherapy in combination with autologous stem cell transplantation (ASCT) as postremission therapy for acute myeloid leukemia (AML)." Blood 114, no. 9 (August 27, 2009): 1736–45. http://dx.doi.org/10.1182/blood-2009-02-205278.
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AbstractPreclinical models have demonstrated the efficacy of granulocyte-macrophage colony-stimulating factor-secreting cancer immunotherapies (GVAX platform) accompanied by immunotherapy-primed lymphocytes after autologous stem cell transplantation in hematologic malignancies. We conducted a phase 2 study of this combination in adult patients with acute myeloid leukemia. Immunotherapy consisted of autologous leukemia cells admixed with granulocyte-macrophage colony-stimulating factor-secreting K562 cells. “Primed” lymphocytes were collected after a single pretransplantation dose of immunotherapy and reinfused with the stem cell graft. Fifty-four subjects were enrolled; 46 (85%) achieved a complete remission, and 28 (52%) received the pretransplantation immunotherapy. For all patients who achieved complete remission, the 3-year relapse-free survival (RFS) rate was 47.4% and overall survival was 57.4%. For the 28 immunotherapy-treated patients, the RFS and overall survival rates were 61.8% and 73.4%, respectively. Posttreatment induction of delayed-type hypersensitivity reactions to autologous leukemia cells was associated with longer 3-year RFS rate (100% vs 48%). Minimal residual disease was monitored by quantitative analysis of Wilms tumor-1 (WT1), a leukemia-associated gene. A decrease in WT1 transcripts in blood was noted in 69% of patients after the first immunotherapy dose and was also associated with longer 3-year RFS (61% vs 0%). In conclusion, immunotherapy in combination with primed lymphocytes and autologous stem cell transplantation shows encouraging signals of potential activity in acute myeloid leukemia (ClinicalTrials.gov: NCT00116467).
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Schuster, Christine, Karin Forster, Henning Dierks, Annika Elsässer, Gerhard Behre, Nicola Simon, Susanne Danhauser-Riedl, Michael Hallek, and Markus Warmuth. "The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate." Blood 101, no. 2 (January 15, 2003): 655–63. http://dx.doi.org/10.1182/blood-2002-01-0043.
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The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine–kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)–induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule–1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein–α [C/EBPα], C/EBPε, and PU.1), and of the cyclin-dependent kinase inhibitor p27Kip1. In 32Dcl3 cells transfected with thebcr-abl gene (32DBcr-Abl), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPα, C/EBPε, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27Kip1 by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32DBcr-Ablwtcells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPα and C/EBPε expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPα and C/EBPε.
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Lewis, Ian D., Louise A. McDiarmid, Leanne M. Samels, L. Bik To, and Timothy P. Hughes. "Establishment of a Reproducible Model of Chronic-Phase Chronic Myeloid Leukemia in NOD/SCID Mice Using Blood-Derived Mononuclear or CD34+ Cells." Blood 91, no. 2 (January 15, 1998): 630–40. http://dx.doi.org/10.1182/blood.v91.2.630.
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Abstract An animal model of chronic myeloid leukemia (CML) will help characterize leukemic and normal stem cells and also help evaluate experimental therapies in this disease. We have established a model of CML in the NOD/SCID mouse. Infusion of ≥4 × 107chronic-phase CML peripheral blood cells results in engraftment levels of ≥1% in the bone marrow (BM) of 84% of mice. Engraftment of the spleen was seen in 60% of mice with BM engraftment. Intraperitoneal injection of recombinant stem cell factor produced a higher level of leukemic engraftment without increasing Philadelphia-negative engraftment. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor did not increase the level of leukemic or residual normal engraftment. Assessment of differential engraftment of normal and leukemic cells by fluorescence in situ hybridization analysis with bcr and abl probes showed that a median of 35% (range, 5% to 91%) of engrafted cells present in the murine BM were leukemic. BM engraftment was multilineage with myeloid, B-cell, and T-cell engraftment, whereas T cells were the predominant cell type in the spleen. BM morphology showed evidence of eosinophilia and increased megakaryocytes. We also assessed the ability of selected CD34+ CML blood cells to engraft NOD/SCID mice and showed engraftment with cell doses of 7 to 10 × 106 cells. CD34− cells failed to engraft at cell doses of 1.2 to 5 × 107. CD34+ cells produced myeloid and B-cell engraftment with high levels of CD34+ cells detected. Thus, normal and leukemic stem cells are present in CD34+ blood cells from CML patients at diagnosis and lead to development of the typical features of CML in murine BM. This model is suitable to evaluate therapy in CML.
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Lewis, Ian D., Louise A. McDiarmid, Leanne M. Samels, L. Bik To, and Timothy P. Hughes. "Establishment of a Reproducible Model of Chronic-Phase Chronic Myeloid Leukemia in NOD/SCID Mice Using Blood-Derived Mononuclear or CD34+ Cells." Blood 91, no. 2 (January 15, 1998): 630–40. http://dx.doi.org/10.1182/blood.v91.2.630.630_630_640.
Full textAbstract:
An animal model of chronic myeloid leukemia (CML) will help characterize leukemic and normal stem cells and also help evaluate experimental therapies in this disease. We have established a model of CML in the NOD/SCID mouse. Infusion of ≥4 × 107chronic-phase CML peripheral blood cells results in engraftment levels of ≥1% in the bone marrow (BM) of 84% of mice. Engraftment of the spleen was seen in 60% of mice with BM engraftment. Intraperitoneal injection of recombinant stem cell factor produced a higher level of leukemic engraftment without increasing Philadelphia-negative engraftment. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor did not increase the level of leukemic or residual normal engraftment. Assessment of differential engraftment of normal and leukemic cells by fluorescence in situ hybridization analysis with bcr and abl probes showed that a median of 35% (range, 5% to 91%) of engrafted cells present in the murine BM were leukemic. BM engraftment was multilineage with myeloid, B-cell, and T-cell engraftment, whereas T cells were the predominant cell type in the spleen. BM morphology showed evidence of eosinophilia and increased megakaryocytes. We also assessed the ability of selected CD34+ CML blood cells to engraft NOD/SCID mice and showed engraftment with cell doses of 7 to 10 × 106 cells. CD34− cells failed to engraft at cell doses of 1.2 to 5 × 107. CD34+ cells produced myeloid and B-cell engraftment with high levels of CD34+ cells detected. Thus, normal and leukemic stem cells are present in CD34+ blood cells from CML patients at diagnosis and lead to development of the typical features of CML in murine BM. This model is suitable to evaluate therapy in CML.
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Li, Shaoguang, Silke Gillessen, Michael H. Tomasson, Glenn Dranoff, D. Gary Gilliland, and Richard A. Van Etten. "Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL." Blood 97, no. 5 (March 1, 2001): 1442–50. http://dx.doi.org/10.1182/blood.v97.5.1442.
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Primitive hematopoietic progenitors from some patients with Philadelphia chromosome (Ph)–positive chronic myeloid leukemia (CML) express aberrant transcripts for interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF), and exhibit autonomous proliferation in serum-free cultures that is inhibited by anti–IL-3 and anti–IL-3 receptor antibodies. Expression of the product of the Ph chromosome, the BCR/ABL oncogene, in mice by retroviral bone marrow transduction and transplantation induces CML-like leukemia, and some leukemic mice have increased circulating IL-3, and perhaps granulocyte-macrophage colony-stimulating factor (GM-CSF). These observations raise the possibility of autocrine or paracrine cytokine production in the pathogenesis of human CML. Mice with homozygous inactivation of the Il-3 gene, the Gm-csf gene, or both, were used to test the requirement for these cytokines for induction of CML-like disease by BCR/ABL. Neither IL-3 nor GM-CSF was required in donor, recipient, or both for induction of CML-like leukemia by p210 BCR/ABL. Use of novel mice deficient in both IL-3 and GM-CSF demonstrated that the lack of effect on leukemogenesis was not due to redundancy between these hematopoietic growth factors. Analysis of cytokine levels in leukemic mice where either donor or recipient was Il-3−/−indicated that the increased IL-3 originated from the recipient, suggestive of a host reaction to the disease. These results demonstrate that IL-3 and GM-CSF are not required for BCR/ABL-induced CML-like leukemia in mice and suggest that autocrine production of IL-3 does not play a role in established chronic phase CML in humans.
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Shaknovich, Rita, Patricia L. Yeyati, Sarah Ivins, Ari Melnick, Cheryl Lempert, Samuel Waxman, Arthur Zelent, and Jonathan D. Licht. "The Promyelocytic Leukemia Zinc Finger Protein Affects Myeloid Cell Growth, Differentiation, and Apoptosis." Molecular and Cellular Biology 18, no. 9 (September 1, 1998): 5533–45. http://dx.doi.org/10.1128/mcb.18.9.5533.
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ABSTRACT The promyelocytic leukemia zinc finger (PLZF) gene, which is disrupted in therapy-resistant, t(11;17)(q23;q21)-associated acute promyelocytic leukemia (APL), is expressed in immature hematopoietic cells and is down-regulated during differentiation. To determine the role of PLZF in myeloid development, we engineered expression of PLZF in murine 32Dcl3 cells. Expression of PLZF had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle and an increased incidence of apoptosis. PLZF-expressing pools also secreted a growth-inhibitory factor, which could explain the severe growth suppression of PLZF-expressing pools that occurred despite the fact that only half of the cells expressed high levels of PLZF. PLZF overexpression inhibited myeloid differentiation of 32Dcl3 cells in response to granulocyte and granulocyte-macrophage colony-stimulating factors. Furthermore, cells that expressed PLZF appeared immature as demonstrated by morphology, increased expression of Sca-1, and decreased expression of Gr-1. These findings suggest that PLZF is an important regulator of cell growth, death, and differentiation. Disruption of PLZF function associated with t(11;17) may be a critical event leading to APL.
Dissertations / Theses on the topic "Granulocyte-macrophage colony-stimulating factor; imatinib; chronic myeloid leukemia gene therapy"
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Viboonjuntra, Pongtep. "GM-CSF protection of CML CD34+ cells from the inhibitory effect of imatinib." Thesis, 2006. http://hdl.handle.net/2440/63564.
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The aim of this study was to test whether GM-CSF could modulate the response of chronic myeloid leukemia progenitors to imatinib. In addition it was aimed to examine CML cell production of GM-CSF. Findings suggest that non-CD34+ cells may be a source of GM-CSF.Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2006