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Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and the current prognosis for patients is poor. New therapies are required that target the invasive cells that are characteristic of GBM. GBM is infiltrated by immune cells but, as with other cancers, immune evasion pathways minimise productive anti-tumour immunity. Natural killer (NK) cells are able to recognise and kill tumour cells and are being developed for the immunotherapy of other cancers. The aim of this work was to analyse the interaction between human NK cells and GBM cells in vivo and in vitro, as a prerequisite to future NK cell based immunotherapy of GBM. Analysis of the cell surface phenotype for GBM infiltrating NK and T cells revealed that the tumour microenvironment exerts localised immune evasion mechanisms which downregulate activation receptors and upregulate inhibitory receptors. The interaction of NK cells with patient-derived GBM stem cells, which are thought to be responsible for recurrent disease, was investigated in vitro. A high-throughput, multiplex flow cytometry-based screen of tumour cells revealed the expression of a number of cell surface molecules that regulate NK cell activation. Furthermore, GBM cells were more susceptible to NK cell lysis in vitro compared to a non-cancerous neural progenitor cell line, revealing specificity in the NK cell response. Furthermore, this screen identified potential mechanisms by which GBM might evade immune surveillance in vivo. Targeting these pathways and restoring functional immune surveillance provides a potential route for future immunotherapy of this disease. However, GBM patients often experience cerebral oedema and are treated with immunosuppressive corticosteroids, such as dexamethasone; this induces a similar immunosuppressed phenotype to that observed with the GBM infiltrating NK cells, and inhibits their lytic function. Gene expression profiling identified the transcription factor c-Myc as a key regulator of NK cell activation and as a hub for the immunosuppressive action of steroids and the immunosuppressive cytokine TGF-β. The demonstration that therapeutic steroids target the same pathway as TGF-β and induce immunosuppression has important implications for the use of steroids in patients undergoing immunotherapy.

The aim of this qualitative study was to explore the lived experience of chronic illness during and beyond diagnosis within the context of relationships between patients, family carers and service providers. Findings focus on the ways in which people with chronic illness and their family carers became aware of the prognostic limits of medical information, and the psycho-social processes involved in managing the uncertainty inherent in the illness trajectory within a context of creating and maintaining relationships with favourite members of staff. This has implications for the current policy imperative for self-care and challenges the assumption that biographical support and self-care are mutually exclusive concepts. Findings suggest that it is necessary to combine the promotion of independence with recognition of the importance of continuity of carer across the illness trajectory. This has implications for the introduction of case managers for people with complex chronic illness. Humanism was adopted as an organisational framework that called for primacy to be given to the voices of patients, children and family carers. Symbolic interactionism informed the interpretive premise that this study is only one representation of multiple realities, and grounded theory was used to guide the iterative process of data collection and analysis. Data were collected in two phases; phase one in a general hospital setting with stroke patients, phase two in a special school for physically disabled children with a variety of chronic illnesses. In phase one, observation and interviews were held with stroke patients (n = 9) and their family carers (n = 10) during the hospital stay and following discharge from hospital. Emerging themes influenced the design of a qualitative questionnaire used with service providers (n = 31) to explore contributions to care and interpretations of progress. In phase two the study was extended to explore perceptions held by physically disabled children (n = 12) in a special school setting and their informal carers (n = 16) about the lived experience of chronic illness. Observation and interviews were used with children, based on photographs they had taken. Data from service providers (n = 42) working within special education were collected using questionnaires. Data taken from different diagnostic and age groups were compared to explore commonalities and differences in representations of chronic illness. Common themes emerged that cut across diagnostic groups and service responses to those groups. The themes are presented in this thesis as three interdependent psycho-social processes intended to manage the uncertainty inherent within the illness trajectory. The processes of understanding, accepting and adapting to uncertainty emerged as central categories. Chronic uncertainty was managed via processes of information management, making comparisons with others, making biographical comparisons with one's self, and maintaining continuity of carer. Findings contribute to increased understanding of the processes of care available to people coping with chronic illness within a multiprofessional context. The innovative nature of this study informs knowledge on several aspects of research into the chronic illness experience, namely, methods of data collection with vulnerable people, practitioner-research, managing multiple pathology, the `expert patient', chronicity, and specialist care outcomes.

This research examines recent developments in the cognitive model of auditory hallucinations ("voices") in people with psychoses. Following the research of Chadwick and Birchwood (1994), data are presented on the behavioural, cognitive and affective responses to persistent voices of thirty participants with psychoses. After testing the reliability of their interview, data is then compared to that of the Chadwick and Birchwood (1994) sample. In addition, the research aimed to develop the cognitive model of the emotional impact of voices by examining further possible associations with participants' self-evaluations, hypothesising that these evaluations are associated with the affective response. The cognitive assessment of voices shows reasonable inter-rater and test re-test reliability. Compared to the Chadwick and Birchwood (1994) sample, the present sample had a greater proportion of negative affective responses to voices. regardless of their beliefs about the voices' benevolence or malevolence. Participants in this sample were less likely to endorse the voices' omnipotence or omniscience. Similarities were shown in behavioural responses and factors reported as proof of the voices' potential power. Although it was not possible to explore the associations between the content of voices, affective responses, self-evaluations and distress due to a preponderance of negative affective responses in this sample, nevertheless, it was possible to describe these responses. Participants in this sample had a predominantly negative content to their voices. Those who were able to access a personal meaning were found to have, predominantly, negative personal meanings, low self esteem and moderate distress as measured by standardised instruments.