The Myc transcription factor activates expression of genes that promote cellular functions such as proliferation and cell growth. The deregulated Myc expression, characteristic for the tumor cell, also activates apoptosis, which selects for additional genetic changes deactivating the induced cell death. However, the continuous overexpression of Myc can also be a liability for a tumor, which can be taken advantage of in cancer treatment.  In Paper I, we describe a new way of using the DNA methyltransferase inhibitor Decitabine, in treating Myc overexpressing tumors. We show that Decitabine treatment activates cell death by reactivating silenced tumor suppressors such as Puma, but also by inducing DNA damage. Decitabine treatment of Myc driven lymphomas is also shown to prolong disease free survival in mouse models. Myc driven transformation requires a collaborative deregulation of genes. The family of Pim kinases has been shown to collaborate with Myc in tumorigenesis. In Paper II, we show that the Pim-3 kinase protein is highly expressed in many Myc overexpressing lymphomas from Myc transgenic mice as well as human Burkitt Lymphoma samples. The Pim-3 locus is shown to interact with the Myc protein and be a direct target for Myc activated transcription. Additionally, we demonstrate that the Pim kinase inhibitor, Pimi, targeting the Pim kinase family (Pim-1, Pim-2 and Pim-3), induce a cell death that is mediated by, but not dependent on caspase activity. The Pimi induced cell death was potentiated when combined with RNAi knockdown of the casein kinase II (CK2) protein.  In paper III, we describe the development of a somatic mouse model for lymphomagenesis, utilizing the RCAS-tva technology. We show that primary B cells from these mice are transducible and transformed when infected with a combination of RCAS- HA tagged Myc, KRasV12D and human Bcl-XL virus. In conclusion, we show that the labile milieu created by the deregulated expression of Myc facilitates new approaches in treatment of Myc overexpressing tumors. Also, our new tva mouse model show promise in modeling lymphomagenesis.

The impetus for this study grew from observations in clinical practice that many individuals survived all sorts of hardships with minimal distress, or with the ability to tolerate their distress, and move on with their lives in a positive manner. A review of the literature led to the conclusions that the research investigating resilience was making minimal inroads into understanding what made these people different, and that the richness of who they were was being lost in the scientific process. This dissatisfaction led to the decision to explore the construct from a phenomenological framework, and to try and discover the essential elements of resilience through analysis of the subjective experience of resilience. A qualitative study involving thirteen participants identified by their peers as resilient was undertaken and the underlying themes of their stories were analysed. This led to the development of a model of resilience that attempted to balance the need for parsimony with that of explanatory breadth, and which had the potential to tolerate the complexity and instability of the construct itself. The model developed identified three core elements that embraced the construct of resilience. These included the physiological capacity to be resilient, and from this basis the ability to be adaptive and the ability to maintain well-being emerge. Factors identified with these elements include individual reactivity to and recovery from adverse events, the ability to be effective and efficient in the management of adverse events, and the beliefs about the world and the self that promote well-being when exposed to adverse events. The model has a basis within neurobiology and is framed within the context of Dynamic Systems Theory. The theory itself is a culmination of clinical observations with what is known from within the current literature and the results of this study.

Thesis (M.A.) in Mathematics--University of Maine, 2004. / Includes vita. Includes bibliographical references (leaves 40-42).

Thesis (M.S.)--University of Nevada, Reno, 2006. / "December 2006." Includes bibliographical references (leaves 42-44). Online version available on the World Wide Web.

Thesis (Ph.D.)--McMaster University, 2005. / Supervisor: Suzanna Becker. Includes bibliographical references.

Thesis (Ph.D.)--University of Melbourne, Howard Florey Institute of Experimental Physiology and Medicine and Dept. of Anatomy and Cell Biology, 2003. / Typescript (photocopy). Includes bibliographical references (leaves 108-130).

Thesis (B.A.)--Haverford College, Dept. of Psychology, 2007. / Includes bibliographical references.

Thesis (Honors)--College of William and Mary, 2008. / Includes bibliographical references (leaves 78-83). Also available via the World Wide Web.

Thesis (Ph. D. in Neuroscience)--Vanderbilt University, Aug. 2008. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)--University of California, San Diego, 1998. / Vita. Includes bibliographical references (leaves 92-96).