The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology. In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM. In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted. In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.

The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology. In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM. In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted. In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.

Doctor of Philosophy / ABSTRACT Integrative medicine (IM) is a dynamic and increasingly prevalent model of primary health care that combines complementary and alternative medicine with mainstream medicine. This research is about the practice of IM and its value to primary health care in Australia. It locates IM within Australian health care by revealing its processes and outcomes in terms of: practice styles, interactions between practitioners and clients and among practitioners, range of diagnostic and treatment options, and health benefits. In this research I examine the nature of integrative medicine (IM) in co-located primary health care practices and consider the influence that integrating mainstream medicine and CAM can have on the perceived quality of primary health care in Australia. My goal was to contribute the knowledge of the phenomenon of IM through a deeper understanding and interpretation of IM gained by investigating the perceptions of core stakeholders, in this case clients and practitioners of IM. This research was situated in the interpretive paradigm and used two research methodologies: hermeneutics (to interpret the value of IM as reported in the literature) and hermeneutic phenomenology (to understand meanings and significance that clients and practitioners attach to their experiences of IM). Data collection involved the collation of existing literature texts and by cumulative case studies (using semi-structured interviews and observation), focus groups, and key informant interviews. Using a blend of methodologies provided a rich and powerful means of understanding the processes and outcomes of IM through the interpretations of its core stakeholders’ lived experiences. In particular I sought perceptions of clients and practitioners of IM about their health and health care including assessment and treatment options, health outcomes, congruence with beliefs and values, collaborative practices and power sharing. Data analysis was conducted concurrently with and subsequent to data collection so that questioning, observation and textual interpretation were progressively guided by the data. A set of meta-themes emerged from the fusion of findings from all phases of the research. These meta-themes represented answers to key research questions. They are: • Power/authority • Mutual respect • Professionalism • Ontological perspectives • Duty of care. This thesis identifies IM practice styles according to different levels of client agency and degrees of power sharing that exist among CAM and mainstream medical practitioners. A theorised model based on the research findings which depicts quality of health care as a variable consequence of diverse practice styles of IM is produced in two parts: Part 1 acknowledges that IM is a variable phenomenon in practice with different levels of collaboration, power-sharing and quality of health care; Part 2 presents an optimum mode of IM practice. Authentically client-centred health care is at the core of all of these practice styles. This thesis has significant implications for the way IM is practised and for primary health care delivery more broadly. IM that is mutually respectful and genuinely collaborative is flexible, inclusive, and socially relevant and has a substantial and far-reaching contribution to make to the quality of primary health care.

Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request

Zugl.: Köln, Univ., Diss., 2008

Zugl.: Würzburg, Universiẗat, Diss., 2009.

Diplomarbeit Hochschule für Angewandte Psychologie Zürich, 2004.

No description available.

Includes bibliographical references and index.

Includes bibliographical references and index.