With the introduction of population-based screening, early-stage colorectal cancers (T1CRCs) are increasingly detected. The treatment of patients with T1CRC is complex, as these tumors have... Show moreWith the introduction of population-based screening, early-stage colorectal cancers (T1CRCs) are increasingly detected. The treatment of patients with T1CRC is complex, as these tumors have metastatic potential despite their early stage. As a result, local organ-sparing endoscopic tumor resection is not always sufficient, thereby giving rise to various challenges throughout the entire treatment process.The overarching goal of this thesis is to improve clinical care for T1CRC patients. Part 1 is centered around the biology and translational potential of the tumor microenvironment, and in particular cancer-associated fibroblasts (CAFs), in T1CRC. The studies in this part show that CAFs in T1CRCs exhibit T1 stage-specific phenotypic traits and can promote cancer cell invasion in T1CRC through diverse mechanisms. These findings provide promising leads for developing better predictors of metastasis, which can be used to determine which T1CRC patients will (not) benefit from major bowel surgery.Part 2 focuses on the clinical aspects of T1CRC treatment. The studies in this part show that local endoscopic tumor resection has become a mature alternative to surgery, from both the patient’s and oncological perspective. However, further optimizations of local resection techniques and surveillance thereafter are needed to increase the use of organ-sparing treatment for T1CRC patients. Show less
Aim Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes... Show moreAim Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank. Methods The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged >= 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers. Conclusion To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies. Show less
Purpose There is an annual incidence of 50,000 glioma cases in Europe. The optimal treatment strategy is highly personalised, depending on tumour type, grade, spatial localization, and the degree... Show morePurpose There is an annual incidence of 50,000 glioma cases in Europe. The optimal treatment strategy is highly personalised, depending on tumour type, grade, spatial localization, and the degree of tissue infiltration. In research settings, advanced magnetic resonance imaging (MRI) has shown great promise as a tool to inform personalised treatment decisions. However, the use of advanced MRI in clinical practice remains scarce due to the downstream effects of siloed glioma imaging research with limited representation of MRI specialists in established consortia; and the associated lack of available tools and expertise in clinical settings. These shortcomings delay the translation of scientific breakthroughs into novel treatment strategy. As a response we have developed the network "Glioma MR Imaging 2.0" (GliMR) which we present in this article. Methods GliMR aims to build a pan-European and multidisciplinary network of experts and accelerate the use of advanced MRI in glioma beyond the current "state-of-the-art" in glioma imaging. The Action Glioma MR Imaging 2.0 (GliMR) was granted funding by the European Cooperation in Science and Technology (COST) in June 2019. Results GliMR's first grant period ran from September 2019 to April 2020, during which several meetings were held and projects were initiated, such as reviewing the current knowledge on advanced MRI; developing a General Data Protection Regulation (GDPR) compliant consent form; and setting up the website. Conclusion The Action overcomes the pre-existing limitations of glioma research and is funded until September 2023. New members will be accepted during its entire duration. Show less
Kemp, V.; Lamfers, M.L.M.; Pluijm, G. van der; Hoogen, B.G. van den; Hoeben, R.C. 2020
The use of oncolytic viruses forms an appealing approach for cancer treatment. On the one hand the viruses replicate in, and kill, tumor cells, leading to their intra-tumoral amplification. On the... Show moreThe use of oncolytic viruses forms an appealing approach for cancer treatment. On the one hand the viruses replicate in, and kill, tumor cells, leading to their intra-tumoral amplification. On the other hand the viral infection will activate virus-directed immune responses, and may trigger immune responses directed against tumor cells and tumor antigens. To date, a wide variety of oncolytic viruses is being developed for use in cancer treatment. While the development of oncolytic viruses has often been initiated by researchers in academia and other public institutions, a large majority of the final product development and the testing of these products in clinical trials is industry led. As a consequence relatively few pre-clinical and clinical studies evaluated different oncolytic viruses in competitive side-by-side preclinical or clinical studies. In this review we will summarize the steps and considerations essential in the development and characterization of oncolytic viruses, and describe our multidisciplinary academic consortium, which involves a dozen departments in three different Dutch universities, collaborating in the development of oncolytic viruses. This consortium has the ambition to develop a small series of oncolytic viruses and to evaluate these in various cancers. Show less
Putten, M. van; Hmeljak, J.; Aartsma-Rus, A.; Dowling, J.J. 2020
Neuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment... Show moreNeuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment exists for any of the NMDs. For multiple disorders, however, therapeutic strategies are currently being tested in clinical settings, and the first successful treatments have now entered clinical practice (e.g. spinraza for spinal muscular atrophy). Successful clinical translation depends on the quality and translatability of preclinical findings and on the predictive value of the experimental models used in their initial development. This Special Issue of Disease Models & Mechanisms has a particular focus on translational research for NMDs. The collection includes original research focusing on advances in the development of novel in vitro and in vivo models, broader understanding of disease pathology and progression, and approaches to modify the disease course in these models. We also present a series of special articles and reviews that highlight our understanding of cellular mechanisms, biomarkers to tract disease pathology, the diversity of mouse models for NMDs, the importance of high-quality preclinical studies and data validation, and the pitfalls of successfully moving a potential therapeutic strategy to the clinic. In this Editorial, we summarize the highlights of these articles and place their findings in the broader context of the NMD research field. Show less
Doef, T.F. van der; Domingo, S.Z.; Jacobs, G.E.; Drevets, W.C.; Marston, H.M.; Nathan, P.J.; ... ; Kas, M.J.H. 2018
Clinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of... Show moreClinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of efficacy during clinical development. To improve the prediction of CNS drug effects, knowledge of the drug concentration at the CNS target-site is indispensable. Unfortunately, measuring drug concentrations in the human CNS has major practical and ethical constraints. Therefore, alternative approaches to predict the drug pharmacokinetics (PK) at the target-site(s) in the human CNS should be searched for.In this research, a comprehensive CNS physiologically based PK (PBPK) model for prediction of drug concentration-time profiles in multiple CNS compartments was developed for both rats and humans. The CNS PBPK model only requires knowledge of physicochemical properties of the drugs, with the influence of the net active transporters on the drug exchange across the BBB and the BCSFB that can be obtained from in silico predictions, literature information and in vitro studies (if needed). Because of this, the developed CNS PBPK model is a powerful tool to predict drug PK in the CNS in the early stage of the drug development. Show less
Buikhuisen, W.A.; Scharpfenecker, M.; Griffioen, A.W.; Korse, C.M.; Tinteren, H. van; Baas, P. 2016
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
