Heart failure is a major health care problem with high mortality. Although advances have been made in treatment of patients suffering from heart failure with reduced ejection fraction, this is not... Show moreHeart failure is a major health care problem with high mortality. Although advances have been made in treatment of patients suffering from heart failure with reduced ejection fraction, this is not true for patients suffering from heart failure with preserved ejection fraction. The mechanism underlying heart failure with preserved ejection fraction is still unclear. Recent evidence suggests that factors circulating in blood might have an effect on the microvessels, including those in the heart. To diagnose and treat microvascular diseases, we aim to explore the association of circulating plasma factors with microvascular integrity. As current human 2D models with cultured endothelial cells lack sufficient complexity to assess the function of microvascular endothelial-pericyte interactions, research on microvascular loss largely depends on animal models. To mimic the microarchitecture and functions of the human blood vessel in a more efficient way for drug discovery, we developed the microvessel-on-a-chip. This system allowed us to screen microvascular destabilization factors in blood and study the efficacy of potential drugs for microvascular diseases. In conclusion, our platform may serve as a unique tool for microvascular destabilization studies as well as for the development of novel therapeutic strategies to combat microvascular complications. Show less
In this thesis, we focus on recipients of donation after circulatory death (DCD) kidneys in the first months after transplantation. DCD kidney transplant recipients have an increased risk of early... Show moreIn this thesis, we focus on recipients of donation after circulatory death (DCD) kidneys in the first months after transplantation. DCD kidney transplant recipients have an increased risk of early complications post transplantation such as acute rejection and delayed graft function (DGF). A sensitive and specific biomarker to monitor the occurrence of an acute rejection episode or (the resolution of) DGF is unfortunately not available to date. For a definite diagnosis, a kidney allograft biopsy remains the so-called ‘golden standard’. A percutaneous kidney biopsy is, however, an invasive procedure with a risk of bleeding complications. Guidance in daily clinical practice by a simple but reliable marker is needed, and can help to monitor regular resolution of DGF and/or identify intercurrent problems such as acute rejection episodes. In the current thesis we investigated risk factors of acute rejection and DGF. In addition, the most promising biomarkers of kidney injury according to current literature (i.e. KIM-1, NGAL, TIMP-2, IGFBP7) were investigated in the prediction of DGF and acute rejection. Furthermore, we used an alternative approach in the search for biomarkers by analyzing smaller molecules with Nuclear Magnetic Resonance (NMR) spectroscopy.We still have not found the ‘perfect’ biomarker to monitor acute rejection DGF after kidney transplantation, however of all biomarkers investigated TIMP-2 showed the greatest potential. Using the approach of metabolomics, we were able to identify new biomarkers. Further studies are needed to confirm and validate these results and evaluate their usefulness in daily clinical practice. Show less
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most prevalent hereditary small vessel disease. CADASIL patients typically develop... Show moreCADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most prevalent hereditary small vessel disease. CADASIL patients typically develop recurrent strokes from mid-adult age onwards, leading to cognitive impairment and ultimately vascular dementia. As there is currently no therapy that can delay or prevent CADASIL, the CADASIL research group of the Leiden University Medical Center is developing a therapeutic approach for CADASIL, called “NOTCH3 cysteine correction”.The aim of this PhD-project was to advance CADASIL therapy development.The work in this thesis provides the first in human evidence that the therapeutic approach of NOTCH3 cysteine correction leads to reduced protein aggregation, by describing a family with naturally occurring NOTCH3 cysteine correction. Furthermore, this thesis includes the results of the longest follow-up study to date of individuals with CADASIL, as well as and the identification of Neurofilament Light-chain (NfL) as blood biomarker in CADASIL. In a pre-clinical CADASIL disease model, potential pre-clinical biomarkers were explored and this resulted in the development of a GOM deposit classification system. Show less
Patients with Parkinson's Disease may be eligible for Deep Brain Stimulation (DBS) in case of severe motor complications. This thesis provides indications for improving patient selection for DBS,... Show morePatients with Parkinson's Disease may be eligible for Deep Brain Stimulation (DBS) in case of severe motor complications. This thesis provides indications for improving patient selection for DBS, as well as describing new biomarkers based on Electroencephalography (EEG) to aid during the DBS selection process. Show less
Potential relevant biomarkers can be found at different levels in tumour developmentand disease progression. This thesis is divided into three overarching parts. Colorectalcancer was studied from... Show morePotential relevant biomarkers can be found at different levels in tumour developmentand disease progression. This thesis is divided into three overarching parts. Colorectalcancer was studied from a population-based perspective (part I) to a molecular level,detailed as protein expression (part II) and (epi)genetics (part III), as indicated in Figure 2.In part I the use of adjuvant chemotherapy in patients with locally advanced rectalcancer, who underwent resection after preoperative (chemo)radiotherapy, wasevaluated in a meta-analysis based on individual patient data. Since four randomizedcontrolled trials individually did not end the ongoing debate about the role of adjuvantchemotherapy 14,68-70. In part II the ability by tumour cells to evade the immunerecognition was studied, especially the role of the non-classical HLA class I moleculeHLA-G was studied in detail. In part III, an epigenetic biomarker, LINE-1 methylationlevel, was studied in a dedicated stage II colon cohort. In addition, an establishedgenetic biomarker for colon cancer, MSI, was studied in a large rectal cancer cohort. Show less
