This thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved... Show moreThis thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved in migraine and cluster headache, thereby identifying new targets for treatment. Uncovering the biological mechanisms on how patients differ from those without disease leads to a better understanding of the pathophysiology of primary headache disorders. The biological systems in our body are related to each other, and are based on the genomic blueprint and lead via epigenetics, transcription and translation to proteins and biomolecules. The first part of the dissertation focuses on the examination of biomolecules in body fluids (blood and cerebrospinal fluid) in migraineurs. Several studies showed that biomolecule concentrations differed between people with and without migraine for lipids, amino acids and metabolites of glucose metabolism. These results indicate a general disruption of the metabolic profile in migraineurs. For other substances, no differences were found. The second part of the thesis looked at the genetic blueprint of various headache disorders. There a genetic difference between people with migraine and people without migraine was found. In addition, a genetic difference between people with and without cluster headache was found. Show less
In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the... Show moreIn the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity. Show less
The ultimate goal of translational colon and rectal cancer research is to turn these types of cancer into curable or manageable chronic diseases. The approach to achieve this is to enable... Show moreThe ultimate goal of translational colon and rectal cancer research is to turn these types of cancer into curable or manageable chronic diseases. The approach to achieve this is to enable clinicians to make (adjuvant) treatment decisions, based on the individual patient characteristics and individual characteristics of a patient__s tumor. Identification of new prognostic and predictive biomarkers, based on the biology of individual tumor characteristics, is therefore warranted to further refine the current TNM classification. This thesis describes the use of molecular techniques for the identification of prognostic biomarkers for clinical outcome in (sporadic) colon and rectal cancer. We here present compelling candidate biomarker combinations for validation in further studies. Retrospective and prospective validation of these prognostic biomarker combinations in international and independent patient series is therefore the crucial next step. Additionally, the presented studies stress the importance of -1- combining biomarkers based on tumor biology, -2- integrative analysis of cancer hallmark related processes at all different cellular regulatory levels (genetics, epigenetics and protein level), -3- assessment of tissue specificity between colon and rectal tumors, and -4- studying age-related effects in future colorectal cancer research. Show less
