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
Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac... Show moreSerum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients. The Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the Cardio-Oncology Council of the ESC have evaluated the current evidence for the role of cardiovascular biomarkers in cancer patients before, during and after cardiotoxic cancer therapies. The characteristics of the main two biomarkers troponin and natriuretic peptides are discussed, the link to the mechanisms of cardiovascular toxicity, and the evidence for their clinical use in surveillance during and after anthracycline chemotherapy, trastuzumab and HER2-targeted therapies, vascular endothelial growth factor inhibitors, proteasome inhibitors, immune checkpoint inhibitors, cyclophosphamide and radiotherapy. Novel surveillance clinical pathways integrating cardiac biomarkers for cancer patients receiving anthracycline chemotherapy or trastuzumab biomarkers are presented and future direction in cardio-oncology biomarker research is discussed. Show less
Background: Serum biomarkers may inform and improve care in traumatic brain injury (TBI). We aimed to correlate serum biomarkers with clinical severity, care path and imaging abnormalities in TBI,... Show moreBackground: Serum biomarkers may inform and improve care in traumatic brain injury (TBI). We aimed to correlate serum biomarkers with clinical severity, care path and imaging abnormalities in TBI, and explore their incremental value over clinical characteristics in predicting computed tomographic (CT) abnormalities.Methods: We analyzed six serum biomarkers (S100B, NSE, GFAP, UCH-L1, NFL and t-tau) obtained <24 h post-injury from 2867 patients with any severity of TBI in the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) Core Study, a prospective, multicenter, cohort study. Univariable and multivariable logistic regression analyses were performed. Discrimination was assessed by the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals.Findings: All biomarkers scaled with clinical severity and care path (ER only, ward admission, or ICU), and with presence of CT abnormalities. GFAP achieved the highest discrimination for predicting CT abnormalities (AUC 0.89 [95%CI: 0.87-0.90]), with a 99% likelihood of better discriminating CT-positive patients than clinical characteristics used in contemporary decision rules. In patients with mild TBI, GFAP also showed incremental diagnostic value: discrimination increased from 0.84 [95%CI: 0.83-0.86] to 0.89 [95%CI: 0.87-0.90] when GFAP was included. Results were consistent across strata, and injury severity. Combinations of biomarkers did not improve discrimination compared to GFAP alone.Interpretation: Currently available biomarkers reflect injury severity, and serum GFAP, measured within 24 h after injury, outperforms clinical characteristics in predicting CT abnormalities. Our results support the further development of serum GFAP assays towards implementation in clinical practice, for which robust clinical assay platforms are required.(C) 2020 The Authors. Published by Elsevier B.V. Show less
There is a lack of reliable, repeatable, and non-invasive clinical endpoints when investigating treatments for intellectual disability (ID). The aim of this study is to explore a novel approach... Show moreThere is a lack of reliable, repeatable, and non-invasive clinical endpoints when investigating treatments for intellectual disability (ID). The aim of this study is to explore a novel approach towards developing new endpoints for neurodevelopmental disorders, in this case for ARID1B-related ID. In this study, twelve subjects with ARID1B-related ID and twelve age-matched controls were included in this observational case-control study. Subjects performed a battery of non-invasive neurobehavioral and neurophysiological assessments on two study days. Test domains included cognition, executive functioning, and eye tracking. Furthermore, several electrophysiological assessments were performed. Subjects wore a smartwatch (Withings (R) Steel HR) for 6 days. Tests were systematically assessed regarding tolerability, variability, repeatability, difference with control group, and correlation with traditional endpoints. Animal fluency, adaptive tracking, body sway, and smooth pursuit eye movements were assessed as fit-for-purpose regarding all criteria, while physical activity, heart rate, and sleep parameters show promise as well. The event-related potential waveform of the passive oddball and visual evoked potential tasks showed discriminatory ability, but EEG assessments were perceived as extremely burdensome. This approach successfully identified fit-for-purpose candidate endpoints for ARID1B-related ID and possibly for other neurodevelopmental disorders. Next, results could be replicated in different ID populations or the assessments could be included as exploratory endpoint in interventional trials in ARID1B-related ID. Show less
Introduction. Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity... Show moreIntroduction. Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with an increasing incidence, especially in young women. Surgical treatment of VSCC is associated with significant morbidity and high recurrence rates, which is related to the limited ability to distinguish (pre)malignant from healthy tissue. There is a need for new tools for specific real-time detection of occult tumor lesions and localization of cancer margins in patients with VSCC. Several tumor-specific imaging techniques are developed to recognize malignant tissue by targeting tumor markers. We present a systematic review to identify, evaluate, and summarize potential markers for tumor-specific imaging of VSCC.Methods. Relevant papers were identified by a systematic cross-database literature search developed with assistance of an experienced librarian. Data were extracted from eligible papers and reported based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. VSCC-specific tumor markers were valued based on a weighted scoring system, in which each biomarker was granted points based on ranked eligibility criteria: I) percentage expression, II) sample size, and Ill) in vivo application.Results. In total 627 papers were included of which 22 articles met the eligibility criteria. Twelve VSCC-specific tumor markers were identified and of these 7 biomarkers were considered most promising: EGFR, CD44v6, GLUT1, MRP1, MUC1, CXCR-4 and VEGF-A.Discussion. This overview identified 7 potential biomarkers that can be used in the development of VSCCspecific tracers for real-time and precise localization of tumor tissue before, during, and after treatment. These biomarkers were identified in a small number of samples, without discriminating for VSCC-specific hallmarks such as HPV-status. Before clinical development, experimental studies should first aim at validation of these biomarkers using immunohistochemistry and cell line-based examination, discriminating for HPV-status and the expression rate in lymph nodes and precursor lesions. (C) 2019 Published by Elsevier Inc. Show less
BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was... Show moreBACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons.METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein Al were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms.CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity. Show less
Harmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based... Show moreHarmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based on a consensus report with the aim to move towards standardized protocols that facilitate clinical translation and comparison of data across sites. We used a recently published systematic review paper, which included a detailed summary of renal BOLD MRI technical parameters and areas of investigation in its supplementary material, as the starting point in developing the survey questionnaires for seeking consensus. Survey data were collected via the Delphi consensus process from 24 researchers on renal BOLD MRI exam preparation, data acquisition, data analysis, and interpretation. Consensus was defined as >= 75% unanimity in response. Among 31 survey questions, 14 achieved consensus resolution, 12 showed clear respondent preference (65-74% agreement), and 5 showed equal (50/50%) split in opinion among respondents. Recommendations for subject preparation, data acquisition, processing and reporting are given based on the survey results and review of the literature. These technical recommendations are aimed towards increased inter-site harmonization, a first step towards standardization of renal BOLD MRI protocols across sites. We expect this to be an iterative process updated dynamically based on progress in the field. 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
