Introduction: Many patients with brain tumours experience dysfunction in several cognitive domains. Given the limited survival times of the majority of patients with brain tumours, maintenance or improvement of quality of life is as important as increasing survival time. Impaired cognition has a negative impact on quality of life and as such, cognitive function is becoming an increasingly important endpoint in clinical trials in neuro-oncology. However, measuring cognition in patients with brain tumours is problematic for a number of reasons. Most intracranial tumours are initially treated with surgery and studies of neurosurgical morbidity often evaluate physical as opposed to cognitive domains, yet the latter can have a greater negative impact on the patient’s quality of life. This thesis therefore details cognition in brain tumour patients at the time of presentation (pre-operatively) and examines the effects of surgical intervention on cognitive function. Of particular interest is the potential utility of inspection time, a computer-based measure of the brain’s information processing efficiency, as a measure of brain slowing as a result of the tumour and as an indicator of response to surgical intervention. Methods: The study is based on a cohort of 118 newly-presenting patients with a supratentorial brain tumour who were to have surgery (biopsy or resection). Each patient was administered a comprehensive battery of cognitive tests prior to surgery (baseline). The battery comprised inspection time testing, other standardised cognitive measures and assessment of mood, quality of life and functional status. Post-operatively, each patient repeated the inspection time test in addition to a selected number of the other tests administered at baseline. For comparison, a group of patients admitted for elective spinal surgery (n = 85) were also tested pre- and post-operatively. A group of healthy volunteers provided a second control group by being tested twice (n = 80). Results: The brain tumour cohort were significantly impaired by comparison with both control groups at baseline (pre-operatively) on the majority of the cognitive measures, including inspection time. Baseline inspection time scores were significantly related to some scores on the EORTC Quality of Life Questionnaire in the brain tumour group, but not in the spinal surgery group. There was no significant difference between the brain tumour and spinal surgery groups in term of the levels of pre-operative anxiety and depression. The brain tumour cohort showed significantly greater relative deterioration on inspection time following surgery by comparison with both control groups. The brain tumour cohort also deteriorated significantly on several other measures postoperatively by comparison with the healthy control group. Detailed analyses were carried out to determine the differential effects of tumour type, location, and type of surgery (biopsy or resection) on inspection time and other functions in the brain tumour group. Conclusions: Tumour-related cognitive impairment appears to be common in a heterogeneous group of brain tumour patients with a variety of different tumours located throughout the brain. Surgical intervention has a negative impact on function in brain tumour patients, although this deterioration may be transient. General slowing of visual information processing appears to be common to brain tumour patients and the inspection time task provides a feasible and useful method of assessment in brain tumour patients. The task is sensitive to tumour-related brain slowing and can provide a reliable assessment of response to surgery. Given the task’s advantages over more commonly-used cognitive measures, it could be usefully incorporated into cognitive tests batteries in neuro-oncology.

Cardiovascular and heart diseases are the leading causes of death worldwide. In mammals, when heart damage occurs this organ is unable to regenerate itself. Understanding how to induce a regenerative process has been the focus of a great deal of attention recently. The understanding of heart development and the initial formation of several heart lineages could be used in finding a regenerative approach to heart damage that can mimic developmental processes. The Wilms’ tumour 1 gene (Wt1) is essential in the epicardium, the outer layer of cells around the heart, which during development has a multipotent potential and is the source of progenitors for several heart cell lineages such as: cells of the coronary vasculature, fibroblasts and cardiomyocytes. In my thesis I have focused on using an in-vitro (immortalized epicardial cells where Wt1 can be deleted by adding tamoxifen), and an in-vivo approach (genome wide expression analyses of Wt1 control and Wt1 knock-out epicardial enriched cells), to identify novel targets of Wt1 in the epicardium during development. I found that the chemokines Cxcl10 and Ccl5 are up-regulated in tamoxifen induced immortalized Wt1 knock-out epicardial cells and ex-vivo in heart explants when Wt1 is down-regulated. Ccl5 was found to be able to inhibit cardiomyocyte proliferation and Cxcl10 also inhibited epicardial cell migration, which could further explain ventricular thinning in Wt1 mutant mouse hearts. Wt1 is able to bind directly to the promoter of a chemokine and interferon response regulator gene, Irf7, which is also up-regulated in our in-vivo model. This could provide a mechanism by which Wt1 can inhibit chemokine expression during development, and could link Wt1 with immunological responses, which recently have been shown to play a role in the physiology and development of cells outside immunity, as well as being involved in physiological roles during damage and repair in adult tissues. I have also identified two Wt1-GFP populations (Wt1GFP++ and Wt1GFP+) in the ventricles of Wt1-GFP knock-in mice. The Wt1GFP++ population is enriched for epicardial cells, and a genome wide transcriptome analysis of these cells from E11.5 to E16.5 demonstrates they have a very dynamic regulation of a wide variety of genes, and also it indicates the existence of an early, transient and late Wt1GFP++ gene expression programs. The transcriptome analysis of Wt1GFP++ control and Wt1GFP++ Wt1 knock-out cells, from Gata5-Cre Wt1loxP/gfp mice at E13.5, reveals that Wt1 could regulate a number of previously un-described Wt1 targets related to the early Wt1GFP++ program, and gene ontology analyses indicate that many targets are related to cell to cell signalling and interaction, cell to extracellular matrix interaction, tissue development and morphogenesis. The Wt1GFP+ cell population is positive for a number of cardiomyocyte specific markers and has a low or negative expression of endothelial, epithelial and mesenchymal markers according to my transcriptome analysis. The findings I have described here shed light on the variety of targets of Wt1 and further reveal the function of Wt1 during epicardial development, which could be used in finding a regenerative approach to heart disease.

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