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
Rheumatoid arthritis is a chronic auto-immune disorder, of which persistent synovitis, bone erosions and auto-antibody formation are characteristic features. Although the etiology of the disease... Show moreRheumatoid arthritis is a chronic auto-immune disorder, of which persistent synovitis, bone erosions and auto-antibody formation are characteristic features. Although the etiology of the disease remains largely unknown, it is established that genetic risk factors play a pivotal role in disease pathology. Both family and twin studies have shown that the genetic contribution to the disease can be estimated around 50%. In the current thesis the genetic contribution of non-HLA genes to RA susceptibility was further investigated and the functional relevance of these loci was explored. The studies described were able to establish several previously identified risk factors in a statistical robust manner. Also novel genetic risk factors that are associated with RA susceptibility could be identified, as well as risk factors that are conferred to specific subgroups of the disease. Show less
Juvenile idiopathic arthritis (JIA) is a non-common disease in children that can persist into adulthood. JIA is considered to be an auto-immune disease. Genetic factors play a role in the... Show moreJuvenile idiopathic arthritis (JIA) is a non-common disease in children that can persist into adulthood. JIA is considered to be an auto-immune disease. Genetic factors play a role in the pathogenesis. In a new cohort of JIA patients from North-West European descent genetic candidate gene association studies have been performed. In this cohort we have discovered new associations with the susceptibility of JIA and the genes/loci TRAF1/C5, 4q27, CD226 and CD28. These genes have already been associated with other auto-immune diseases and might be part of a shared common auto-immune susceptibility. Also genetic association with the course of disease has been studied, revealing an association of VTCN1 and the severity of JIA defined by the percentage of active disease in the first two years. VTCN1 encodes B7-H4 that is involved in the co-stimulation of T-cells and inhibits the immune-response. Until the precise role of VTCN1 will be clarified, the genetic association might be of use in predicting the course of disease and might be a lead point for new treatment. Show less
Primary vascular tumors of bone are a heterogeneous group. Numerous terms have been introduced as well as different classification systems. However, so far none of them have been generally accepted... Show morePrimary vascular tumors of bone are a heterogeneous group. Numerous terms have been introduced as well as different classification systems. However, so far none of them have been generally accepted.Therefor, there is a need for more specific morphological, immunohistochemical and molecular tools to support the classification of different vascular tumors of bone. In this thesis, we attempt to delineate the high-grade malignant vascular tumors of bone based on histomorphological criteria, protein expression profile based on a large panel of oncogenes, tumor-suppressor genes and signaling molecules, and molecular data. Moreover, we compared our dataset with a small groups of angiosarcoma of soft tissue in order to see whether these are truly different tumors or whether they should be regarded as one entity with a different localization. Finally, we question whether the rare vascular tumor previously designated as "haemangiopericytoma of bone" is a true entity or should rather be regarded as a growth pattern. Show less
Although much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs)... Show moreAlthough much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs) in which an initially promising compound appears to lack efficacy after all. Several experimental medicine models have been proposed as preclinical tools in order to predict drug efficacy before the stage large RCTs. Among the various experimental medicine models, the cognitive neuropsychological model has been proposed as a tool to predict the efficacy of antidepressant drug even before the stage of large scale and expensive RCTs. We applied the cognitive neuropsychological model of drug action to test antidepressant effects of a novel compound (ARA290) and a well-known compound (L-tryptophan). We further investigated the model by tapping into HPA-axis reactivity and social decision making as additional outcomes, and investigated their interaction with a genetic marker. Show less
Aim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the... Show moreAim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the Genomic investigation of Statin Therapy (GIST) consortium are presented. We identified and validated two new GWAS loci to be associated with LDL-cholesterol response after statin treatment. In addition, we confirmed two previous identified loci. In chapter 5 we showed that we were not able to identify any loci associated with differential event reduction after statin therapy within the PROSPER study. The results presented in chapter 8 show that even at old age a genetic predisposition to high LDL-cholesterol is a risk factor for mortality. The results of this thesis show that currently the possibilities to personalize statin treatment based on genetic variants is limited. New research methods will hopefully give new opportunities to improve cardiovascular disease treatment and give more insight into the biological mechanisms of statin treatment. Show less
