Melbourne Medical School Collected Works - Theses
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ItemExploring Contextual Influences on the Ethical Dimensions of Clinical Practice: Perspectives from Physiotherapists in Singapore( 2023-05)Ethics is embedded in all aspects of physiotherapy. The importance of ethics in physiotherapy professional practice is reflected in the growing interest in clinical-based ethical issues and the ethical decision-making strategies used by physiotherapists. With emerging evidence of both contextual and individual influences affecting the ethical dimensions of clinical practice, there is a realisation that one cannot address an ethical issue by simply applying a universal set of principles without consideration of context. Context and culture play prominent roles in how we view, comprehend, and construct our world yet the majority of the ethics norms in healthcare practice are grounded in Western theories of ethics, and most of the physiotherapy research on ethics has been done from the Western viewpoint. There is a paucity of the Asian perspective, specifically the East and Southeast Asian regions. This research sought to contribute to current physiotherapy ethics literature by exploring the contextual influences, specifically the organisational and more broadly societal influences on clinical ethical issues and decision-making, as interpreted by physiotherapists in Singapore. Utilising the interpretive description methodological approach, data regarding the types of ethical situations encountered and physiotherapists’ ethical decision-making were collected through in-depth interviews with 42 physiotherapists practising in four different healthcare settings (acute, community, specialised institutions, and private practice) in Singapore. Inductive content analysis was used to analyse the interview data. The empirical findings reflect current literature indicating that individual, organisational and societal context can influence ethical situations, and illustrate context’s critical influencing role in ethical decision-making, as experienced and perceived by physiotherapists in their unique geographical and clinical settings. This research also highlights variations in the way individual clinicians interpret and prioritise contextual influences in their workplaces and social communities, indicating that ethical decision-making cannot be separated from the values and beliefs held by the physiotherapist. In summary, the findings suggest that physiotherapists’ ethical decisions and actions are ultimately determined by the dynamic interaction between individual characteristics and contextual influences. Finally, physiotherapists practising in the Singaporean context prioritise the maintenance of harmonious relationships and pragmatic considerations as important contextual influences in their ethical practice. By focusing on the organisational and societal influences on the ethical dimensions of physiotherapy practice in the Singaporean context, this research contributes to the body of ethical literature from the Asian perspective. Identifying the contextual factors that influence physiotherapists’ moral agency will allow the local physiotherapy community to understand both the facilitators and barriers to ethical practice. This research provides the impetus to move beyond universal moral theories and code of conduct, and to consider the workplace context as an important inclusion in ethics education and support for clinicians. The empirical data from this research can also inform the development of ethics curricula to ensure that universal ethical principles are situated within the realities of clinical practice. Locally relevant and realistic ethical case studies will better enable students to recognise and address these situations.
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ItemGuiding educators in learner-centred feedback: designing, testing and refining the Feedback Quality Instrument( 2020)Feedback is important but problematic in the health workplace. The aim of this research is to promote quality feedback discussions that enhance learner outcomes. This thesis reports the process of developing, testing and refining an instrument to guide and systematically evaluate an educator’s role in quality face-to-face feedback in clinical practice. It is underpinned by social constructivism, and uses a multiphase mixed methods design to achieve the research objective. The research was conducted in three phases. Phase 1 comprised a systematic review and meta-analysis to summarise the empirical evidence available concerning the impact of face-to-face feedback on workplace task performance involving health professionals. Phase 2 focused on the development of a provisional feedback instrument. An extensive narrative literature review identified the distinct elements of an educator’s role with the potential to influence learner outcomes. These elements were then operationalised into corresponding observable educator behaviours and refined in collaboration with an expert panel using a Delphi process. This resulted in consensus on a set of twenty-five descriptions of educator behaviours that manifest quality feedback, which constituted a provisional instrument. Phase 3 involved refining the provisional instrument to create the Feedback Quality Instrument using quantitative and qualitative analyses. Thirty-six videos of authentic clinical feedback discussions were collected. Six raters independently administered the provisional instrument to evaluate educator behaviours seen in the videos, compared with recommended behaviours in the provisional instrument, using a Likert scale: 0 = not seen, 1 = done somewhat, 2 = done consistently. This enabled usability testing and generated 174 sets of ratings data. Quantitative analysis of these ratings data were used to describe a) how commonly each recommended behaviour was demonstrated by the group of educators and b) variation across educators’ practice, which was achieved by describing how many of the recommended behaviours each individual educator demonstrated. This afforded rare observational insights into contemporary feedback interactions, confirmed a gap between recommended and workplace practice, and indicated priorities for professional development initiatives. These ratings data were also used for psychometric analysis of the provisional instrument using multifaceted Rasch model analysis and exploratory factor analysis. In addition, using thematic analysis, qualitative analysis of the video data was performed to explore two key emergent phenomena 1) the potential for promoting learners’ own evaluative judgement and 2) ways in which educators could help to cultivate psychological safety with learners within feedback conversations. The qualitative analyses further clarified desirable educator approaches to feedback, enabling refinement of the instrument and addressing gaps identified during psychometric testing. Finally, the provisional instrument was refined, informed by the usability testing, psychometric testing, qualitative analysis, and foundational literature and theory. This resulted in the Feedback Quality Instrument (FQI), ready-for-use in clinical practice. The FQI includes 25 items, grouped into five domains: set the scene, analyse performance, plan improvements, foster learner agency, and foster psychological safety. These domains characterise five core concepts underpinning quality feedback identified by exploratory factor analysis. The items offer practical guidance for clinicians in fostering learner-centred feedback in collaboration with learners by describing behaviours that engage, motivate and enable a learner to improve. The instrument also provides a platform for future research investigating the impact of specific components of feedback on learner outcomes in the clinical workplace. This PhD program of research leading to the FQI includes four published articles, one article under submission and one published book chapter.
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ItemOverseas Qualified Nurses’ intercultural communication: An exploration of perspectives, experiences, and practices( 2020)Overseas qualified nurses (OQNs) from non-English speaking backgrounds comprise a significant proportion of Australia's health workforce. While numerous studies have identified that OQNs encounter intercultural communication challenges and dissonance, there has been little exploration into nurse educator perspectives and few observational studies of OQNs’ intercultural communication with healthcare teams and patients. The aim of this research was to examine OQNs’ perspectives, experiences, and intercultural communication practices. The overall study design was qualitative, using semi-structured interviews and participant observation with thematic and discourse analyses, respectively. The theoretical underpinnings and principles of this research are informed by frameworks of intercultural communication, Communities of Practice, and patient-centred communication. This research comprises three studies: an interview study with nurse educators; an interview study with OQNs; and an observational study with OQNs. The first study comprised interviews with 12 nurse educators of the pre-registration course, revealing the areas and causes of communication challenges encountered by OQNs, as well as engagement strategies to address these challenges. The second study involved interviews with 21 OQNs to explore their intercultural communication experiences. The OQNs’ transition process evoked uncertainty due to concerns about language and cultural and contextual issues, leaving OQNs feeling like uncertain novices, even for those working in Australia for several years. Findings of the two interview studies informed the design of the third study, which was observational and investigated inter-professional, intra-professional and nurse-patient communication. Participants were 13 OQNs who were shadowed for a 2.5 to 3 hr period during their clinical work at a public teaching hospital. Linguistic evidence of inter-professional and intra-professional communication from the observational study showed limited casual interactions, such as small talk between OQNs and other members of the team. This lack of informal interactions can contribute to a lack of team cohesion and negatively impact open team communication. Patient-centred communication was achieved to varying degrees. The findings provided evidence of positive rapport building strategies, including non-verbal communication that assisted and countered communication hindered by lack of fluency, vocabulary and accents. Brevity in information provision to a team member or missed opportunities in offering advice or reassurance to a patient or a family member are features that impeded desirable outcomes in team communication and patient-centred communication. Collectively, this research makes an original contribution to existing knowledge by revealing patterns of OQNs’ intercultural communication through interactional evidence from the observational study with patients and the healthcare team. In addition, the combined reflections and evidence from educators, the OQNs, and the observed interactions add to existing literature in terms of the interplay of language features on comprehension and effective communication, and also contextualise this interplay in the conduct of clinical work. These findings provide evidence that could enable OQNs to gain insight into their practices, and the local team members to reflect on their role in effective team communication. Another application of this research is its potential contribution to inform the national accreditation body for nursing, curriculum developers, and employers of the significance of developing intercultural communication competence for OQNs and healthcare teams.
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ItemAssessor grades and comments: private thoughts and public judgements( 2020)Assessment of medical trainees’ performance in the workplace aims to provide them with accurate and meaningful information and guidance on their learning and developing competence. However, in practice, such goals aren’t always achieved. Sometimes assessors find it difficult to deliver clear and consistent assessment messages to a trainee, especially when the information or judgement they have to give is negative. While this can occur for many reasons, including disagreement with or uncertainty about assessment processes, the MUM effect — the widespread human tendency to keep mum about undesirable messages — may also have relevance for the situation. With reference to this framework, this thesis explores how and why reluctance to deliver negative assessment messages manifests in a medical specialty training setting in Australia. Literature reviews on the MUM effect and trainee perspectives of assessment messages informed the design of a mixed methods study which explores the MUM effect in this context. The study involved four parts: - a questionnaire study of assessor self-reports of discomfort and MUM behaviours in assessment; - a questionnaire study of trainee perspectives of MUM behaviours by their assessors and their views of the clinical performance assessments; - a review of a sample of previously submitted assessment forms comparing the messages sent by numerical ratings with those by written comments; and - an interview study of assessors to further understandings of their experiences with and perspectives of these assessment formats. The findings show that reluctance to deliver negative assessment messages — which can result in failure to give feedback, failure to fail and grade inflation — are real and continuing issues in medical education. The MUM effect offers one explanation for their persistence, despite the many methods which have been employed to date to address them. The study shows how the MUM effect permits an expanded view of the problem and that assessor reluctance can lead to behaviours beyond the commonly reported failure to fail and grade inflation. These include behaviours such as delay, avoidance and distortion of assessment information. Further, the results show that reluctance can affect the comments part of an assessment in addition to the ratings, which have been the main focus to date. This study reveals the many pressures and dilemmas that assessors face in their role and in particular, that the amount of discomfort they experience can potentially affect their assessment behaviours and result in MUMing. This work also shows that trainees are aware that their assessors sometimes keep mum, meaning the judgement delivered may differ from the assessor’s private thoughts on their performance. Potential solutions are seen to be multifactorial and include addressing perceptions about “failure” in clinical performance assessments and the responsibility that assessors feel for the assessment decisions.
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ItemThe role of Dlk1 in haematopoiesis, leukaemia and angiogenesis( 2017)Delta-Like Homologue 1 (DLK1), also known as Preadipocyte Factor 1 (PREF-1), is a non-canonical EGF-like NOTCH ligand. It is maternally imprinted at the Dlk1-Dio3 imprinted locus, and has been shown to regulate embryonic growth, lipid metabolism and skeletal development. However, the precise role of Dlk1 in haematopoiesis, leukaemia and angiogenesis, processes in which it has been previously implicated, is unknown. We generated Dlk1 knockout and conditional knockout mice and used a constitutive overexpression system via retroviral transduction to specifically study Dlk1 in these contexts. Dlk1 knockout mice showed distinctive phenotype of increased perinatal mortality and growth retardation. In foetal livers, significant expression of Dlk1 was detected in the haematopoietic cells, with higher level of expression in the haematopoietic stem cells compared to lineage positive mature cells, with overall expression decreasing with embryonic age. Dlk1 knockout mice were not significantly different from wild type mice in the mature haematopoietic lineages, but serial competitive transplant assays demonstrated Dlk1 knockout bone marrow cells were inferior to controls in reconstituting lethally irradiated recipient mice in short term haematopoietic reconstitution assays, suggesting that Dlk1 knockout led to a defect in adult short term haematopoietic stem cells. Despite frequent overexpression of DLK1 found in many human acute myeloid leukaemias, constitutive overexpression of Dlk1 did not lead to increase in acute leukaemia or death in reconstituted mice. However, Dlk1-overexpressing haematopoietic cells demonstrated competitive repopulation advantage compared to MIG-transduced controls. Using a retinal model of angiogenesis, Dlk1 was found to be expressed by the pericytes rather than endothelium of newly developing blood vessels in postnatal murine pups, in contrast to the published data. Conditional knockout of Dlk1 in endothelial cells using the endothelial specific Tie2 Cre transgene did not lead to significant abnormality in postnatal retina, confirming that Dlk1 did not have a functional role in the retinal endothelium. These new findings add to our current knowledge of stem cell biology and leukaemia, and the role of Dlk1 in angiogenesis.
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ItemTargeting cyclin-dependent kinase 9 and myeloid cell leukaemia 1 in MYC-driven B-cell lymphoma( 2016)Aggressive B-cell lymphomas include diffuse large B-cell lymphoma, Burkitt lymphoma and intermediate forms. Despite high response rates to conventional immuno-chemotherapeutic approaches, an unmet need for novel therapeutic strategies is required in the setting of relapsed and refractory disease, typified by resistance to chemotherapy and radiotherapy. The proto-oncogene MYC is frequently dysregulated in the aggressive B-cell lymphomas, however, it has proven an elusive direct therapeutic target. A significant body of evidence is accumulating to suggest that MYC-dysregulated disease maintains a ‘transcriptionally-addicted’ state, whereby perturbation of RNA polymerase II activity may indirectly antagonise MYC activity. Furthermore, very recent studies implicate anti-apoptotic myeloid cell leukaemia 1 (MCL-1) as a critical survival determinant of MYC-driven lymphoma. This thesis utilises pharmacologic and genetic techniques in MYC-driven models of aggressive B-cell lymphoma to demonstrate that cyclin-dependent kinase 9 (CDK9) and MCL-1 are oncogenic dependencies of this subset of disease. The cyclin-dependent kinase inhibitor, dinaciclib, and more selective CDK9 inhibitors are used to demonstrate efficient apoptosis induction conferred at least in part by downregulation of MCL1 transcription. Furthermore, a genetic screen identifies other transcriptional cyclin-dependent kinases that are required for viability of MYC-driven lymphoid disease. Finally, having established MCL-1 as a critical oncogenic dependency of MYC-driven lymphoma, this thesis demonstrates the significant activity that is conferred by direct pharmacologic antagonism of MCL-1 using a small molecule BH3-mimetic inhibitor of MCL-1. These findings confirm a druggable pathway of oncogenic cMYC dependency involving CDK9 regulated RNA polymerase II-mediated transcription of MCL-1, and proposes pharmacologic inhibition of CDK9 and MCL-1 as novel anti-lymphoma strategies.
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ItemExploring the qualities of Electronic Health Record medical student documentation( 2016)Written communication within the health professions has been rapidly changing over the last decade. Implementation of Electronic Health Records (EHR) in health services is now widespread. Medical student teaching and learning of the skills specifically required for EHRs has lagged behind the implementation. Very few original studies have focused on EHR skills and there are no validated measures by which to assess any of the EHR skills students are expected to develop. Our study explored the attributes of quality EHR documentation recorded by medical students, with the purpose of the EHR documentation being the communication between health care professionals to share or transfer the clinical care of a patient. Recently there have been published validated instruments for measuring quality in physician EHR documentation, one being Physician Documentation Quality Instrument (PDQI-9). The purpose of this study was to explore the attributes of quality of EHR documentation written by first-year clinical medical students by building upon existing literature. The PDQI-9 was used as a basis for defining the attributes of quality in EHR documentation as a foundation for assessing and providing feedback on the performance of documentation to medical students. With the focus on assessment, and providing a content validated test domain for assessment in quality EHR documentation, we utilised Kane’s framework for validity to structure the study and a mixed method study design to achieve the depth of exploration required to examine the performance of quality documentation fully. The study was conducted in two stages. In the first stage of the study, an expert panel of assessors applied the PDQI-9 to existing EHR data recorded by first clinical year medical students in a graduate entry program. The assessors both scored the records and justified their grading. Descriptive statistics and thematic analysis were undertaken on the data collected, and the findings triangulated with the literature review. The second stage employed explanatory semi-structured interviews with the expert assessors to better understand the findings of the first stage and reach consensus on a test domain for assessing quality documentation recorded by medical students. Outcomes from our study indicated that the PDQI-9 in its current format was not valid in a medical student setting, however most of the attributes assessed by the PDQI-9 were deemed relevant and meaningful to assess if their interpretations were clarified. In addition, Professionalism of documentation was regarded as a quality attribute. Consensus was reached on modifications that have the potential to improve the validity of the assessment of quality documentation recorded by medical students. Further studies need to complete Kane’s framework of validity for an assessment instrument and collect evidence to broaden the validity of the scoring, the generalization of the assessment items, the extrapolation to the real world and the implications of this assessment for students and health services.
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ItemLinguistic change in an online support group( 2016)Online support groups (OSGs) are popular sources of both health information and social support. Though early research into OSGs highlighted a concern that non-expert members may give harmful advice, more recent studies have typically shown that engagement with OSGs can increase consumer satisfaction with the treatment process, enhance wellbeing, and ultimately improve health outcomes. OSGs are well-researched within applied linguistics. Qualitative studies have focussed on member roles within OSGs, as well as the ways in which group members discursively construct their identities, especially with respect to their illness. These approaches have generated rich insights into consumer healthcare discourse that can inform strategies for fostering consumer-centred care. Qualitative approaches, however, are resource-intensive, di cult to reproduce, and limited in terms of generalisability and representativeness. Quantitative and computational approaches are able to overcome these shortcomings, adding transparency, reproducibility, scalability, and reducing the potential for researcher bias. Current computational approaches to consumer healthcare discourse, however, tend to rely on simplified conceptualisations of language, prioritising lexis over grammar, and thus ignoring the central role played by grammar in the meaning-making process. To address current methodological shortcomings in OSG discourse research, this thesis presents an interdisciplinary, corpus-based investigation of lexicogrammatical and discourse-semantic choices made by members over the course of membership in an online bipolar disorder support community. 8.2 million words in over 66,000 posts from approximately 3,500 members were transformed into a metadata-rich, grammatically annotated corpus and investigated from a systemic-functional linguistic (SFL) perspective using purpose-built corpus/computational linguistic tools. An analysis of MOOD and MODALITY choices made over ten stages of membership highlights differences in the ways members negotiate role-relationships, with changes in Mood Type, Modality and Speech Function reflecting a longitudinal increase in the provision of advice and social support. An analysis of the TRANSITIVITY system shows longitudinal changes in the kinds of participants and processes construed by Forum members, as well as changes in how these participants and processes behave lexicogrammatically. The diagnosis Event, for example, is represented by newcomers as a process and modi ed temporally; at later stages of membership, it is more often reconstrued as a participant in discourse, framed in terms of veracity. Longitudinal shifts were also observed in the preferred ways of ascribing/attributing bipolar disorder to Forum members: new members use bing forms (I’m bipolar), while veteran members prefer having constructions (I have bipolar). The thesis has implications for corpus linguistics, systemic-functional linguistic theory, and healthcare communication research. For corpus linguistics and corpus-assisted discourse studies, the main contribution is corpkit, an open-source software tool designed to build and analyse parsed and metadata-rich corpora. it is suggested that the developed tools and methods can circumvent theoretically problematic current practices, and increase the accuracy and automatability of the analytical process. For healthcare communication research, the case study demonstrates the importance of expanding the conceptualisation and analysis of the consumer healthcare journey to include intra–consumer communication that occurs outside of hospitals and clinics. The thesis also advances an argument that the emerging eld of clinical natural language processing stands to benefit from increased engagement with functional linguistic theory and insights generated within the qualitative paradigm. I argue that combining the insights from functional linguistics and discourse analysis with automated computational workflows is a step toward an important future goal of improvement of consumer health outcomes through analysis of large, digital collections of spoken and written healthcare discourse.
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ItemThe malaria vaccine candidate Apical Membrane Antigen 1 – antigenic diversity and its potential as effective multi-allele vaccine( 2016)Understanding naturally acquired immunity to malaria and how human antibodies protect against clinical malaria is essential for vaccine development. Antibodies against Plasmodium falciparum apical membrane antigen 1 (AMA1), a leading vaccine candidate, can inhibit merozoite invasion of erythrocytes and protect from P. falciparum malaria. However, polymorphism in antigens like AMA1 is a common mechanism for immune evasion and presents major challenges in vaccine development. This study aims to understand antigenic diversity of AMA1, the correlation between sequence polymorphism and antigenic differences, the impact of polymorphism on potential vaccine escape, and the structural differences of the protein amongst various alleles, with the goal to ultimately ascertain which AMA1 alleles should be included in an effective multi-allele vaccine.
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ItemImproving epigenetic therapies for haematological malignancies( 2016)The work presented here is the product of several years of clinical trial and laboratory endeavour focused on the theme of understanding and improving currently available epigenetic therapies for blood cancers, and understanding fundamental aspects of clinical trial design. Several classes of epigenetically active drugs with proven clinical usefulness have received regulatory approval for the therapy of haematological malignancies in the last 5 years. At the same time, advances in high throughput sequencing technologies have provided landmark discoveries that reinforce the hypothesis that epigenetic mechanisms play a central role in the neoplastic process, as well as giving us new opportunities to develop targeted therapies. Some of the most exciting new targeted biological therapies arising from these discoveries such as inhibitors of histone methyl-transferases, the BET bromodomain inhibitors and the isocitrate dehydrogenase inhibitors are only now in the earliest phase of clinical development with initial signals that many of these agents will be both tolerable and active therapies for blood and solid tumours. In the context of the field at the start of 2010, only two classes of agent were available in clinical trials and for early investigator-initiated development. Even today, only these classes of epigenetic agents have marketing approval. As a consequence, histone deacetylase inhibitors and DNA methyl-transferase inhibitors are the focus of this thesis. The thesis presents investigator-initiated trials of agents in these two drug classes as well as the theory associated with the design of the trials. The literature review in Chapter 1 establishes the foundation for the clinical trial work. Here, the mechanism of action of the histone deacetylase inhibitors and the DNA-demethylating agents is reviewed. Activity of these agents in industry-sponsored clinical trials is presented as well as key toxicity data that informs the hypotheses and design of the clinical research presented in the thesis. The theories underlying the combination therapies that form the backbone of the thesis are discussed. Eltrombopag, a thrombopoietin agonist, is given particular prominence for its potential as a supportive care agent. The clinical trials that represent the majority of the thesis were designed to explore the critical questions of improving the tolerability of the DNA-demethylating agent azacitidine, and developing novel combination therapies for HDAC inhibitors. As experimental design is a critical question, a discussion on clinical trial design is presented in Chapter 2, which closes with a relevant case study. Several clinical trials were developed during the conduct of this higher degree from concept through to funding and clinical recruitment. Three, presented in Chapters 3, 4, and 7 have completed accrual and a further trial (Chapter 5) has been interrupted due to administrative challenges and is currently being reworked. The protocol for each study was in itself an extensive body of novel work contributing to the thesis. These are included in the appendices but summarised within the body of the thesis. Chapter 3 presents finalised and novel data analysed in depth of a trial of the combination of eltrombopag, a thrombopoietin-receptor agonist and azacitidine. The purpose of the study was to develop a supportive care therapy for patients with myelodysplastic syndromes, a disease that causes low platelets (thrombocytopenia), and has a risk of transforming to acute myeloid leukaemia, an almost invariably fatal event. Thrombopoietin mimetic agents have a somewhat complicated relationship with myeloid malignancies in the minds of researchers and while the receptor (mpl) and the role of the mpl receptor in haematopoietic stem cell survival and fate has been the subject of the research for at least 20 years, many questions about their theoretical safety remain open. There is considerable debate over the theoretical safety of mpl in agonists in patients with myeloproliferative diseases. Hence, attention is given to the rationale for the choice of eltrombopag for myelodysplastic syndrome in Chapter 1; also, the established body of preclinical data is presented to provide a context. This particular trial, “AzaE”, has been presented in international fora and the data has provided a foundation for a 170-centre, 43-country international randomised study that, if positive, may change clinical practice for patients with myelodysplastic syndrome and thrombocytopenia. Hence Chapter 3 is a central part of the novel data in this thesis. Based on the hypothesis that HDAC inhibition would up-regulate CD20 on the surface of malignant B-cells, a collaborating colleague, Mark Bishton, developed a phase 1 clinical trial of the combination of the radio labelled rituximab and the HDACi panobinostat. Dr Bishton and Prof Seymour wrote the trial protocol. As Principal Investigator of the study, I set up the study, moving it from protocol to execution. I oversaw the conduct of the study as the principal investigator and reviewed and approved the clinical data. The combination was toxic and the lessons learned are cogent and argue against further developing this sort of combination therapy. This study is presented in Chapter 4. In order to address the moderate activity of the HDACi inhibitor romidepsin and to broaden its clinical indications, a phase I/II study was designed in collaboration with academic partners from Yale University. The strategy behind the design of that study, the protocol itself, and initial data from six patients that have been recruited is presented in Chapter 5. That study has been halted due to regulatory challenges in the USA and Yale University that interrupted the research without warning. The trial strategy is discussed and preliminary results are presented. HDACi are highly active in cancers of the immune system, where the symptomatic and physical manifestations are to a considerable extent driven by cytokine changes which serve a both disease epiphenomena and drivers of the malignancy itself. In Chapter 6, I investigate the effect of the HDACi on human monocyte derived dendritic cells, identifying a mechanism by which these agents are likely shift the T-cell populations, altering patient symptoms and potentially inducing clinical responses. The findings support the contention that HDACi are immunosuppressive and do not make suitable partner drugs for treatments that benefit from an intact antigen presentation apparatus. Histone deacetylase inhibitors and DNA demethylating agents are often conceptually explained as driving a single cellular mechanism. However, the effects within the cell are pleiotropic and there are very few studies that provide data on predictors for response, especially so for the HDAC inhibitors. Therefore, a part of this work was to design a clinical trial that enables future scientific studies on predictors of response to HDAC inhibitors. Several academic questions were faced in developing the approach to this study. Chapter 7 presents the approach to the design of the clinical study, and presents the clinical features of the patients who have been recruited and key response data. An overview of planned experiments is presented. Having concerned itself with the design of investigator-initiated clinical trials of novel combinations and presented successes and failures of trial design and execution as well as original laboratory work that may inform combinations, the thesis concludes with a discussion on future directions for the projects arising from this work and epigenetic agents in general.