Multiple Sclerosis is an immune mediated disease of the central nervous system associated with a wide range of mainly irreversible psychological and physical disabilities in young adults. Despite the invaluable knowledge gained from the research into the disease, its aetiology and mechanism of progression are poorly understood. The natural history of multiple sclerosis is complex and there are still many unanswered questions in respect to the risk factors associated with its development and the way that the disease evolves with age. Over the years numerous theories about the disease aetiology have been postulated, but the one that best describe the disease, on the basis of our current understanding, both in terms of susceptibility and progression is the gene-environment hypothesis. According to this hypothesis, multiple sclerosis occurs as the result of an exposure(s) to some unknown environmental factor(s) in genetically susceptible individuals. In multiple sclerosis, it has been hypothesised that tobacco smoking is associated with an increased risk of the disease occurrence and adverse effects on the progression of disabilities. Despite the relatively large amount of data on the adverse effect of smoking on multiple sclerosis risk and clinical course, data from a large population based cohort was lacking. The aim of the current work was to investigate the influence of tobacco smoking on the natural history of the disease from the risk of occurrence to mortality. In the first part of the investigation, our age- and sex-matched case-control study showed that tobacco smoking is associated with higher risk of disease occurrence. However, we did not observe any association between parental smoking during patients’ childhood and the risk of multiple sclerosis. When investigating the impact of tobacco smoking on the clinical course and prognosis of the disease, our cohort study failed to show any evidence of the influence of tobacco smoking on the risk of progressive onset multiple sclerosis. However, tobacco smoking was associated with more severe disease and significantly higher levels of psychological and physical disability in current smokers. Moreover, tobacco smoking in current smokers was associated with faster disability progression and shorter time to the progressive stage of the disease in patients with relapse onset multiple sclerosis. A significant impact of tobacco smoking on the risk of premature death and patients’ life expectancy was also evident in our data where tobacco smoking in our cohort was associated with more than 2.5-fold increase in the risk of premature death and almost 10 years reduction in the patients’ life expectancy. Our data also showed that tobacco smoking can account for some of the excess mortality seen in multiple sclerosis patients. A novel finding of our research was that smoking cessation significantly reduced patients’ risk of disease progression and premature death. Although the benefits of smoking cessation were greater for patients who stopped at earlier ages, cessation was found to be beneficial at all ages. To our knowledge, this is the first study that showed smoking cessation could potentially be beneficial in reducing the risk of disability progression and premature mortality in patients with multiple sclerosis. Overall, our findings point toward adverse health impact of tobacco smoking on the clinical course of multiple sclerosis from the occurrence to mortality.

CNS PNET and pineoblastomas are highly malignant embryonal brain tumours of poor prognosis. Current treatment strategies are based on the histologically similar medulloblastoma; however, patients with CNS PNET and pineoblastoma have significantly worse outcomes. Specific therapies based on the underlying biology and genetics of CNS PNET and pineoblastoma are needed. To provide evidence of the fundamental genetics driving tumour pathogenesis and to identify novel targets for therapy, 46 CNS PNETs and pineoblastomas were analysed using the Affymetrix 100K/500K mapping sets to identify genome-wide copy number alterations and loss of heterozygosity. Overall, frequent gains of 1q, 2p and 21q and frequent loss of 16q were identified. Unsupervised hierarchical clustering showed marked differences in the frequency of genetic imbalance in the CNS PNETs and pineoblastomas, with pineoblastomas containing fewer genomic changes clustering separately to the CNS PNETs. Novel gene copy number alterations were identified; gain of PCDHGA3 (5q31.3) and FAM129A (1q25) and losses of OR4C12 (11p11.12), CADPS (3p14.2), and SALL1 (16q12.1). Loss of CDKN2A and CDKN2B was also identified, in keeping with previous genetic studies of CNS PNET. Linking gene copy number data with patient clinical information, loss of CADPS was associated with poor prognosis in patients with primary CNS PNETs (p = 0.033 and p = 0.046, by SNP array and real time qPCR analyses, respectively). On comparison of 5 primary and recurrent CNS PNET pairs, gain of 2p21 was the most common alteration maintained in 80% of cases. Immunohistochemistry for p15INK4B (encoded by CDKN2B) was performed which demonstrated the loss in gene copy number had lowered the expression of the encoded protein. Finally an immunohistochemical and mutational screen for INI1 (commonly lost in the malignant embryonal brain tumour, ATRT) was performed in the CNS PNET/pineoblastoma cohort which showed the loss of INI1 protein expression in the tumour cohort was not due to mutations residing in the mutational hotspots of exons 5 and 9 of the INI1 gene. Patients with INI1 immunonegative CNS PNETs had a worse prognosis than those with INI1 immunopositive CNS PNETs (p < 0.0001). This project demonstrated the first application of SNP array technology in the analysis of the largest cohort of CNS PNETs and pineoblastomas to date, identified novel gene copy number alterations, linked genetic alterations with clinical factors and identified 2 potential markers of prognosis.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.