FLT3-driven redox signalling in acute myeloid leukaemia

Acute myeloid leukaemia refers to cancer of the blood and bone marrow characterised by the rapid expansion of immature blasts of the myeloid lineage. The aberrant proliferation of these blasts interferes with normal haematopoiesis, resulting in symptoms such as anaemia, poor coagulation and infections. The molecular mechanisms underpinning acute myeloid leukaemia are multi-faceted and complex, with a range of diverse genetic and cytogenetic abnormalities giving rise to the acute myeloid leukaemia phenotype. Amongst the most common causative factors are mutations of the FLT3 gene, which codes for a growth factor receptor tyrosine kinase required by developing haematopoietic cells. Disruptions to this gene can result in constitutively active FLT3, driving the de-regulated proliferation of undifferentiated precursor blasts. FLT3-targeted drugs provide the opportunity to inhibit this oncogenic receptor, but over time can give rise to resistance within the blast population. The identification of targetable components of the FLT3 signalling pathway may allow for combination therapies to be used to impede the emergence of resistance. However, the intracellular signal transduction pathway of FLT3 is relatively obscure. The objective of this study is to further elucidate this pathway, with particular focus on the redox signalling element which is thought to be involved. Signalling via reactive oxygen species is becoming increasingly recognised as a crucial aspect of physiological and pathological processes within the cell. The first part of this study examined the effects of NADPH oxidase-derived reactive oxygen species on the tyrosine phosphorylation levels of acute myeloid leukaemia cell lines. Using two-dimensional phosphotyrosine immunoblotting, a range of proteins were identified as undergoing tyrosine phosphorylation in response to NADPH oxidase activity. Ezrin, a cytoskeletal regulatory protein and substrate of Src kinase, was selected for further study. The next part of this study established that NADPH oxidase is subject to regulation by FLT3. Both wild type and oncogenic FLT3 signalling were shown to affect the expression of a key NADPH oxidase subunit, p22phox, and FLT3 was also demonstrated to drive intracellular reactive oxygen species production. The NADPH oxidase target protein, Ezrin, undergoes phosphorylation on two tyrosine residues downstream of FLT3 signalling, an effect which was shown to be p22phox-dependent and which was attributed to the redox regulation of Src. The cytoskeletal associations of Ezrin and its established role in metastasis prompted the investigation of the effects of FLT3 and NADPH oxidase activity on the migration of acute myeloid leukaemia cell lines. It was found that inhibition of either FLT3 or NADPH oxidase negatively impacted on the motility of acute myeloid leukaemia cells. The final part of this study focused on the relationship between FLT3 signalling and phosphatase activity. It was determined, using phosphatase expression profiling and real-time PCR, that several phosphatases are subject to regulation at the levels of transcription and post-translational modification downstream of oncogenic FLT3 activity. In summary, this study demonstrates that FLT3 signal transduction utilises a NADPH oxidase-dependent redox element, which affects Src kinase, and modulates leukaemic cell migration through Ezrin. Furthermore, the expression and activity of several phosphatases is tightly linked to FLT3 signalling. This work reveals novel components of the FLT3 signalling cascade and indicates a range of potential therapeutic targets.

Monasticism and its limits: rematerialising monastic space in early medieval Ireland

This thesis creates a multi-faceted archaeological context for early Irish monasticism, so as to ‘rematerialise’ a phenomenon that has been neglected by recent archaeological scholarship. Following revision of earlier models of the early Irish Church, archaeologists are now faced with redefining monasticism and distinguishing it from other diverse forms of Christian lifestyle. This research addresses this challenge, exploring the ways in which material limits can be set on the monastic phenomenon. The evidence for early Irish monasticism does not always conform to modern expectations of its character, and monastic space must be examined as culturally unique in its own right - though this thesis demonstrates that early Irish monasticism was by no means as unorthodox in its contemporary European setting as has previously been suggested. The research is informed by theories of the body, habitus and space, drawing on a wide body of archaeological, religious, sociological and anthropological thought. The data-set comprises evidences gathered through field-survey, reassessment of archaeological scholarship, historical research and cartographic research, enabling consideration of the ways in which early Irish monastics engaged with their environments. A sample of thirty-one early Irish ecclesiastical sites plus Iona forms the basis for discussion of the location and layout of monastic space, the ways in which monastics used buildings and space in their daily lives, the relationship of monasticism and material culture, the setting of mental and physical limits on monastic space and monastic bodies, and the variety of monastic lifestyles that pertained in early medieval Ireland. The study then examines the Christian landscapes of two case-studies in mid-Western Ireland in order to illustrate how monasticism functioned on the ground in these areas. As this research shows, the material complexities of early Irish monastic life are capable of archaeological definition in terms of both communal and personal lived experience.

Aesthetic campaigns and counter-campaigns. Jorge Luis Borges and a century of the Argentine detective story (1877-1977)

This cultural history of Argentine crime fiction involves a comprehensive analysis of the literary and critical traditions within the genre, paying particular attention to the series of ‘aesthetic campaigns’ waged by Jorge Luis Borges and others during the period between 1933 and 1977. The methodological approach described in the introductory chapter builds upon the critical insight that in Argentina, generic discourse has consistently been the domain, not only of literary critics in the traditional mould, but also of prominent writers of fiction and specialists from other disciplines, effectively transcending the traditional tripartite ‘division of labour’ between writers, critics and readers. Chapter One charts the early development of crime fiction, and contextualises the evolution of the classical and hardboiled variants that were to provide a durable conceptual framework for discourse in the Argentine context. Chapter Two examines a number of pioneering early works by Argentine authors, before analysing Borges’ multi-faceted aesthetic campaign on behalf of the ‘classical’ detective story. Chapter Three examines a transitional period for the Argentine crime genre, book-ended by the three Vea y Lea magazine-sponsored detective story competitions that acted as a vital stimulus to innovation among Argentine writers. It includes a substantial treatment of the work of Rodolfo Walsh, documenting his transition from crime writer and anthologist to pioneer of the non-fiction novel and investigative journalism traditions. Chapter Four examines the period in which the novela negra came to achieve dominance in Argentina, in particular the aesthetic counter-campaigns conducted by Ricardo Piglia and others on behalf of the hard-boiled variant. The study concludes with a detailed analysis of Pablo Leonardo’s La mala guita (1976), which is considered as a paradigmatic example of crime fiction in Argentina in this period. The final chapter presents conclusions and a summary of the dissertation, and recommendations for further research.

Learning to 'understand backwards' in time: children's temporal cognition and the primary history curriculum

This study examines children’s temporal ways of knowing and it highlights the centrality of temporal cognition in the development of children’s historical understanding. It explores how young children conceptualise time and it examines the provision for temporal cognition at the levels of the intended, enacted and received history curriculum in the Irish primary school context. Positioning temporality as a prerequisite second-order concept, the study recognises the essential role of both first-order and additional second-order concepts in historical understanding. While the former can be defined as the basic, substantive content to be taught, the latter refers to a number of additional key concepts that are deemed fundamental to children's capacity to make meaningful sense of history. The study argues for due recognition to be given to temporality, in the belief that both sets of knowledge, the content and skills, are required to develop historical thinking (Lévesque, 2011). The study addresses a number of key research questions, using a mixed methods research design, comprising an analysis of history textbooks, a survey among final year student teachers about their teaching of history, and school-based interviews with primary school children: What opportunities are available for children to develop temporal ways of knowing? How do student teachers experience being apprenticed into the available culture for teaching history and understanding temporality at primary level? What insights do the cognitive-developmental and sociocultural perspectives on learning provide for understanding the dynamics of children’s temporal ways of knowing? The study argues that the skill of developing a deeper understanding of time is a key prerequisite in connecting with, and constructing, understandings and frameworks of the past. The study advances a view of temporality as complex, multi-faceted and developmental. The findings have a potential contribution to make in influencing policy and pedagogy in establishing an elaborated and well-defined curriculum framework for developing temporal cognition at both national and international levels.

Alcohol consumption and related harm among university students in Ireland

Aim: Alcohol consumption is a leading cause of global suffering. The harms caused by alcohol to the individual, their peers and the society in which they live provokes public health concern. Elevated levels of consumption and consequences have been noted in those aged 18-29 years. University students represent a unique subsection of society within this age group. University authorities have attempted to tackle this issue throughout the past decade. However, the issue persists. Thus, the aim of this study is to contribute to the evidence base for policy and practice in relation to alcohol harm reduction among third-level students in Ireland. Methods: A mixed methods approach was employed. A systematic review of the prevalence of hazardous alcohol consumption among university students in Ireland and the United Kingdom from 2002 to 2014 was conducted. In addition, a narrative synthesis of studies of drinking types evidenced among youths in western societies was undertaken. A cross-sectional study focused on university students’ health and lifestyle behaviours with particular reference to alcohol consumption was undertaken using previously validated instruments. Undergraduate students registered to one university in Ireland were recruited using two separate modes; classroom and online. Studies investigated the impact of mode of data collection, the prevalence of hazardous alcohol consumption and resultant adverse consequences for mental health and wellbeing. In addition a study using a Q-methodology approach was undertaken to gain a deeper understanding of the cultural factors influencing current patterns of alcohol consumption. Data were analysed using IBM SPPS statistics 20, Stata 12, MPLUS and PQ Method. Results: The literature review focusing on students’ alcohol consumption found that there has been both an increase in hazardous alcohol consumption among university students and a convergence of male and female drinking patterns throughout the past decade. Updating this research, the thesis found that two-thirds of university students consume alcohol at a hazardous level, detailing the range of adverse consequences reported by university students in Ireland. Finally, the heterogeneous nature of this drinking was described in a narrative synthesis exposing six types of consumption. The succeeding chapters develop this review further by describing three typologies of consumption, two quantitative and one quali-quantilogical. The quantitative typology describes three types of drinking for men (realistic hedonist, responsible conformer and guarded drinker) and four types for women (realistic hedonist, peer-influenced, responsible conformer and guarded drinker). The quali-quantilogical approach describes four types of consumption. These are defined as the ‘guarded drinker’, the ‘calculated hedonist’, the ‘peer-influenced drinker’ and the ‘inevitable binger’. Discussion: The findings of this thesis highlight the scale of the issue and provide up-to-date estimates of alcohol consumption among university students in Ireland. Hazardous alcohol consumption is associated with a range of harms to self and harms to others in proximity to the alcohol consumer. The classification of drinkers into types signal the necessity for university management, health promotion practitioners and public health policy makers to tackle this issue using a multi-faceted approach.

Social paranoia and absurdist fiction in Cold War America and Soviet Russia: a comparative study

This thesis explores the theme of social paranoia as depicted in the Absurdist fiction of Cold War America and Soviet Russia. The central hypothesis informing this research maintains that, despite the ideology of moral and cultural “Otherness” constructed and reinforced by both nations throughout much of twentieth century, the US and the Soviet Union more often than not functioned as mirror images of paranoia and suspicion. Much of the fiction produced in Russia from the Revolution onwards and in the US during the Cold War period highlights how these two ostensibly irreconcilable nations were consumed by similar fears and gripped by an equally pervasive paranoia. These parallel conditions of anxiety and mistrust led to a surprising congruity of literary responses, which transcended the ideological divide between capitalism and communism and, as such, underscored the homogeny of fear which lay beneath the façade of constructed difference. I contend that, because Soviet Russia and the America of the Cold War period were nations consumed by fear and suspicion, authors living in both countries became preoccupied by the mechanics of such deeply paranoid societies. Consequently, much of the fiction of the US and the Soviet Union during this period was preoccupied with the themes of paranoia, conspiracy, intensive bureaucracy and the politicisation of science, which resulted in the terror of the Nuclear Age. This thesis explores how these central themes unite apparently diverse literary texts and illustrate the uniformity of terror which transcended both the physical and ideological boundaries separating the United States and the Soviet Union. In doing so, this research focuses primarily on the multi-faceted manifestations of paranoia in selected works by Soviet authors Mikhail Bulgakov, Daniil Kharms and Yuli Daniel, and American authors Joseph Heller, Thomas Pynchon and Kurt Vonnegut. Focusing on key works by each author, this research considers these texts as products of two culturally diverse, yet equally paranoid societies and explores their preoccupation with issues of spying, infiltration and conspiracy. This thesis thus emphasises how these authors counter simplistic notions of Cold War Otherness by revealing two nations possessed by a similar sense of vulnerability and insecurity. Furthermore, this thesis examines how this social anxiety is reinforced by the way in which these authors position issues such as the mechanics of the bureaucratic system and clandestine scientific experimentation as the focal point of the paranoid imagination. Ultimately, by examining the concordance of paranoiac representation in America and the Soviet Union during this period, I demonstrate that these ostensibly divergent nations harboured similar fears and insecurities.

The knowledge, attitudes and beliefs of patients and their healthcare professionals around oral dosage form modification: a systematic review of the qualitative literature

Objectives: The objective of this systematic review was to synthesize the available qualitative evidence on the knowledge, attitudes and beliefs of adult patients, healthcare professionals and carers about oral dosage form modification. Design: A systematic review and synthesis of qualitative studies was undertaken, utilising the thematic synthesis approach. Data sources: The following databases were searched from inception to September 2015: PubMed, Medline (EBSCO), EMBASE, CINAHL, PsycINFO, Web of Science, ProQuest Databases, Scopus, Turning Research Into Practice (TRIP), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR). Citation tracking and searching the references lists of included studies was also undertaken. Grey literature was searched using the OpenGrey database, internet searching and personal knowledge. An updated search was undertaken in June 2016. Review methods: Studies meeting the following criteria were eligible for inclusion; (i) used qualitative data collection and analysis methods; (ii) full-text was available in English; (iii) included adult patients who require oral dosage forms to be modified to meet their needs or; (iv) carers or healthcare professionals of patients who require oral dosage forms to be modified. Two reviewers independently appraised the quality of the included studies using the Critical Appraisal Skills Programme Checklist. A thematic synthesis was conducted and analytical themes were generated. Results: Of 5455 records screened, seven studies were eligible for inclusion; three involved healthcare professionals and the remaining four studies involved patients. Four analytical themes emerged from the thematic synthesis: (i) patient-centred individuality and variability; (ii) communication; (iii) knowledge and uncertainty and; (iv) complexity. The variability of individual patient’s requirements, poor communication practices and lack of knowledge about oral dosage form modification, when combined with the complex and multi-faceted healthcare environment complicate decision making regarding oral dosage form modification and administration. Conclusions: This systematic review has highlighted the key factors influencing the knowledge, attitudes and beliefs of patients and healthcare professionals about oral dosage form modifications. The findings suggest that in order to optimise oral medicine modification practices the needs of individual patients should be routinely and systematically assessed and decision-making should be supported by evidence based recommendations with multidisciplinary input. Further research is needed to optimise oral dosage form modification practices and the factors identified in this review should be considered in the development of future interventions.