Long-term survival for univentricular heart patients with a Fontan circulation is nowadays excellent, with the majority of patients expecting to reach adulthood. Nevertheless, a general attrition... Show moreLong-term survival for univentricular heart patients with a Fontan circulation is nowadays excellent, with the majority of patients expecting to reach adulthood. Nevertheless, a general attrition rate remains present and the majority of Fontan patients will be faced with significant morbidity. However, no Fontan patient is the same and there is a need for better understanding which patients will do worse, ideally by (early) identification of adverse factors that can be optimized. In this thesis, the role of flow efficiency in the TCPC was thoroughly investigated leading to multiple new insights. A novel three-dimensional blood flow MR sequence (3D flow MRI) was developed and shown to be superior to conventional 2D and 4D flow MRI sequences which could potentially lead to a more widespread use. Adverse flow patterns associated with reduced flow efficiency were shown at multiple areas within the TCPC which were related to adverse energetics. Increased 4D flow MRI derived energetics in turn are associated with reduced exercise capacity and increased levels of liver fibrosis/venous congestion. A focus on conduit size adequacy demonstrated that the currently used 16-20mm extracardiac conduits become undersized for teenage and adolescent Fontan patients. Undersized conduits proved to be an important factor leading to reduced flow efficiency, especially during exercise conditions. Achievement of optimal blood flow in Fontan patients may ultimately lead to improved long-term outcome. Show less
After standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the... Show moreAfter standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the goal of finding out where differences in functional outcomes after surgery come from and how artificial intelligence can improve the diagnostic and prognostic process. The initial idea that differences in functional recovery were due to surgical technique was refuted by an RCT from this dissertation. The differences in functional recovery between three different surgical groups (removal of the intervertebral disc without artificial material, placement of intervertebral disc prosthesis, and fusion of vertebrae with a cage) were found to be minimal. It was striking that not surgical technique, but patients' mental health and preoperative, radiological imaging were found to be predictive of clinical recovery after surgery. Although the intervertebral disc prosthesis did not deliver on the promise of preserving mobility and thus could not prevent degeneration at adjacent levels, using Deep Learning based solely on the preoperative MRI of the neck, researchers were able to predict, among other things, which patients would require reoperation after surgery for that adjacent degeneration. The Deep Learning model did that significantly better than an experienced neuroradiologist and neurosurgeon. Such Deep Learning models eliminate the need for time-consuming questionnaires and are thus more cost-effective and less stressful for the patient, while they can be used to identify radiological features important for predicting the postoperative course. After validation with larger radiological datasets, these models can support clinical decision-making and help physicians develop personalized treatment strategies. Challenges within image analysis research for the spine lies in integrating different models into one automated process, preferably built into the electronic health record. Show less
Prenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two... Show morePrenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two outflow-tract anomalies, by adding an additional mandatory plane to the national screening program. The second part of this thesis, studies the development of the fetal brain in children affected by congenital heart defects. These children are known to have worse neurodevelopmental outcome than their healthy counterparts. There is some evidence describing a prenatal origin of the delay in neurodevelopment. In the studies that were described in part two of this thesis, we have used a deep-learning algorithm that can assess the maturation (or development) of the fetal brain. We have found small delays in brain maturation as compared to healthy control fetuses. The clinical significance of these outcomes however, remains unclear. A multifactorial cause of brain damage in children with CHD is much more likely. Whatever the exact cause of the long-term neurodevelopmental delay in children with congenital heart defects is, the correlation is undeniable. And thus, expecting parents must be informed of this matter. Show less
To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
In this thesis, we unraveled the immunostimulatory potential of oncolytic reovirus and investigated how these immunostimulatory characteristics could be exploited for effective anticancer... Show moreIn this thesis, we unraveled the immunostimulatory potential of oncolytic reovirus and investigated how these immunostimulatory characteristics could be exploited for effective anticancer immunotherapy. We demonstrated that administration of oncolytic reovirus does not lead to strong oncolytic effects in tumors, but instead unleashes a very potent immune response, including the priming of reovirus-specific CD8 T cells. We showed that these reovirus-specific CD8 T cells can be effectively employed for anticancer immunotherapy, by either bypassing their specificity (with CD3-bsAbs) or by exploiting their specificity (via installing a preinduced pool using SLP vaccination). Besides the induction of reovirus-specific CD8 T cells, reovirus administration also leads to very fast B-cell responses. We demonstrated that the presence of neutralizing antibodies (NAbs) restricts the use of reovirus as an oncolytic agent, but that the reovirus-induced influx of CD8 T cells is retained and the use of reovirus in combination with T-cell-based immunotherapy can still result in potent antitumor responses. Lastly, we showed that blockade of Transforming Growth Factor-β (TGF-β) does not impair reovirus infection and reovirus-induced ISG expression or the reovirus-induced attraction and activation of T cells, but that intrinsic differences between preclinical tumor models can determine if TGF-β blockade is a beneficial addition to combined reovirus and T-cell-based immunotherapy. Show less
There is a lack of knowledge regarding the definition, classification and appropriate treatment of malignant lateral lymph nodes in patients with (locally advanced) rectal cancer. This thesis aimed... Show moreThere is a lack of knowledge regarding the definition, classification and appropriate treatment of malignant lateral lymph nodes in patients with (locally advanced) rectal cancer. This thesis aimed to increase this knowledge and improve treatment practices for this population. Show less
Although urbanization has long been associated with human development and progress,recent research has revealed that urban environments can also result in significant inequalitiesin many areas... Show moreAlthough urbanization has long been associated with human development and progress,recent research has revealed that urban environments can also result in significant inequalitiesin many areas including health. In particular, urban areas in low and middle incomecountries (LMIC), often see a widening gap in economic growth which contributes to healthdisparities between wealthy and underprivileged children. Several studies have establishedthe association between socioeconomic status (SES) and child health, showing that childrenof low-income parents had poorer health status. The rise of non-communicable diseases,the persistence of communicable disease, and the challenge of re-emerging diseases arecurrently a burden in developing countries. Given the rapid increases of urbanization andurban poverty in several developing countries including Indonesia, it is important to elaborateto what extent SES affects child health. We have done so, in relation to outcome of BCGvaccination, atopic sensitization, and intestinal barrier function. We have also investigatedthe interaction between intestinal parasitic infections and bacterial gut microbiota in orderto be able to delineate the contribution of this interaction on the function of intestinal barrier. Show less
The aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into... Show moreThe aim of this thesis was to assess the efficacy (part 1) and tolerability (part 2) of antiseizure medications (ASMs) in glioma patients with epilepsy. In addition, we aimed to get insight into the ASM prescription behavior and treatment policy in brain tumor-related epilepsy (part 3).First-line levetiracetam seems to be the most efficacious ASM in glioma patients, with favourable tolerability. This is demonstrated in multicenter retrospective observational cohort studies, a systematic review, and is the opinion among the vast majority of European neuro-oncology professionals. Enzyme-inducing AMSs should be avoided in glioma patients due to the high risk of adverse effects. ASM use was not independently associated with neuropsychiatric symptoms in glioma patients, but alternative factors seem to pose a greater risk for developing neuropsychiatric symptoms. If patients experience uncontrolled seizures on ASM monotherapy, levetiracetam combined with valproic acid has better efficacy than other ASM combinations in glioma patients, while toxicity is similar. Subsequently, potential add-on ASMs in glioma patients experiencing uncontrolled seizures on ASM dual therapy include clobazam, lamotrigine, and lacosamide. Show less
This thesis presents the development of quantitative imaging tools to study parasite migration. Since migration is crucial for malaria parasites to continue their life cycle, factors influencing... Show moreThis thesis presents the development of quantitative imaging tools to study parasite migration. Since migration is crucial for malaria parasites to continue their life cycle, factors influencing their migration capability may also impact the efficacy of malaria vaccine candidates. Here, imaging of parasite migration was used to gain insights that can support the development of antiparasitic vaccines. SMOOT (Sporozoite Motility Orienting and Organizing Tool) was developed and established as a quantitative software analysis tool for tracking the migration of malaria sporozoites in vitro and in human skin explant. This tool provides a readout with high kinematic detail, enabling the quantitative characterization of novel factors influencing the migration capability of malaria sporozoites. Subsequently, the study of sporozoite migration was expanded beyond in vitro and ex vivo models. A hybrid tracer labeling approach for malaria sporozoites was developed and used to reveal the in vivo dissemination of malaria sporozoites in a murine model. This multimodal imaging approach was also applied to investigate human skin invasion by helminth larvae. This thesis concludes with a review of the broader potential for imaging technology to advance the development of new diagnostic methods, therapeutic interventions and vaccines for combating parasitic infections. Show less
In dit proefschrift is gekeken naar de afweercellen die een rol spelen bij het ontstaan van alvleesklierkanker of als reactie teweeg worden gebracht door de tumor. daarnaast hebben we oude... Show moreIn dit proefschrift is gekeken naar de afweercellen die een rol spelen bij het ontstaan van alvleesklierkanker of als reactie teweeg worden gebracht door de tumor. daarnaast hebben we oude chemotherapeutica onderzocht op alvleesklierkanker cellen in vitro. Show less
Rheumatoid arthritis (RA) is an autoimmune disease affecting joints which is hallmarked by the presence of autoantibodies against citrrulianted protein (ACPA). This thesis describes the phenotypic... Show moreRheumatoid arthritis (RA) is an autoimmune disease affecting joints which is hallmarked by the presence of autoantibodies against citrrulianted protein (ACPA). This thesis describes the phenotypic and functional characteristics of ACPA-expressing autoreactive B cells which suggest potential pathologic roles of these B cells in RA pathogenesis. The thesis also describes strategies to specifically deplete ACPA-expressing B cells to improve current RA therapeutic options. Show less
The Fontan procedure is currently the palliative solution for children born with a univentricular heart. Despite an improved survival rate, many patients still suffer from complications, such as... Show moreThe Fontan procedure is currently the palliative solution for children born with a univentricular heart. Despite an improved survival rate, many patients still suffer from complications, such as heart failure. For this reason, both patients with and without heart failure are often treated with angiotensin-converting enzyme (ACE) inhibitors, although the effectiveness is unclear. In this thesis, we investigated various aspects of the Fontan circulation to assess not only the efficacy and side effects of ACE inhibition, but also the limitations of exercise capacity and the response of the circulation of these patients to acute volume loading tests. We showed that short-term ACE inhibition had no positive effects on exercise capacity, haemodynamics and cardiac function. It also appeared to have no negative effect on the Fontan circulation, apart from side effects during the titration period. Furthermore, we found that even relatively healthy young Fontan patients have reduced exercise capacity associated with diastolic dysfunction and aortic stiffness. Nevertheless, we found that paediatric Fontan patients are able to respond adequately to acute volume changes and they seem to adapt well to the Fontan circulation. Show less
Clinician-scientists are the driving force behind advancements in the medical field by connecting clinical care with medical research. The pathway of clinician-scientist careers is often referred... Show moreClinician-scientists are the driving force behind advancements in the medical field by connecting clinical care with medical research. The pathway of clinician-scientist careers is often referred to as 'the leaky pipeline', as many (potential future) clinician-scientists during their career are leaking out of this pipeline, resulting in acurrent clinician-scientist shortage worldwide. This shortage of clinician-scientists has been attributed to a lack of supply and/or (too many) obstacles to stay actively engaged in research, considered as leaks. Research training interventions in medical education are often opted as part of the solution. In this thesis we investigated undergraduate and postgraduate research programmes including its challenges, outcomes and the role of motivation for research during these programmes; therebyaiming to contribute to a sustainable clinician-scientist workforce. Show less
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. Despite the strives into growing knowledge on ALS, fundamental... Show moreAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. Despite the strives into growing knowledge on ALS, fundamental obstacles remain into understanding disease causation and nominating drug targets for a cure. With this work, we widen our understanding of ALS through the analysis of single-nuclei RNA-sequencing dataset of patients’ and control motorcortices. We show intrinsically higher expression of ALS-related genes in Extratelencephalic Neurons accompanied by selective vulnerability of subsets of cortical motor neurons. These changes are found with alterations in oligodendrocytes and microglia that widen our knowledge of cell-to-cell interactions in ALS. We use hiPSC-derived in vitro systems to model the molecular changes identified. Secondly, we offer a wide view on models of human brain cells in a dish to encompass protocols useful for modelling complex cell-to-cell interactions in ALS. Moreover, we describe a human in vitro system for the study of motor neuron that is highly reproducible, scalable and high-throughput. This new method allows the assessment of multiple cell lines in the same dish and could provide insights into heterogeneity in human populations and mechanisms disrupted in disease. We then use these models to further dissect molecular mechanisms disrupted in ALS. We undertake a discussion onto the future of the field and hopefully the opening to a more holistic approach to the understanding of ALS, where multidisciplinary techniques and the use of different models might expand our perspectives on the disease. Show less
This thesis aims to advance anti-cancer therapy development through a comprehensive exploration.In Chapter 1, the focus is on understanding the immune system's role in breast cancer and... Show moreThis thesis aims to advance anti-cancer therapy development through a comprehensive exploration.In Chapter 1, the focus is on understanding the immune system's role in breast cancer and chemotherapy response. It examines the paradoxical roles of immune cells and macrophages, seeking novel biomarkers and immunomodulatory strategies.In Chapter 2, the impact of the adaptive immune system on HER2+ breast cancer is explored. Contrary to other breast cancer types, the adaptive immune system neither suppresses nor promotes spontaneous HER2-driven tumorigenesis or metastasis formation.Chapter 3 investigates the relationship between chemotherapy and the adaptive immune response using GEMMs. The study highlights that the endogenous adaptive immune system's role in chemotherapy response might not be as vital as previously believed when utilizing tumor cell line transplantation models. This finding leads to a reevaluation of the conventional understanding of the immune system's involvement in chemotherapy response.Chapter 4 focuses on macrophage-targeted cancer therapy. In non-immunogenic breast cancer, CSF-1R inhibition enhances chemotherapy, especially with platinum drugs. Intratumoral type I interferon activation drives their synergistic impact. Also, neutralizing immunosuppressive neutrophils is crucial for a strong anti-tumor immune response.In Chapter 5, the thesis discusses how its findings align with existing research and suggest clinical applications. Show less
This research uncovered the relevance of integrating experiential knowledge used by established mental health professionals. While its use is still sparse and organisations are struggling to... Show moreThis research uncovered the relevance of integrating experiential knowledge used by established mental health professionals. While its use is still sparse and organisations are struggling to meaningfully incorporate the lived experience perspective in practice, the available qualitative data indicate positive outcomes for those that succeed in this integration. Based on our research, the value of experiential knowledge is captured in relational ethics, practical and emotional insights, existential transformation, and emancipatory politics.In conclusion, the experiential knowledge of professionals has an empathising, normalising, humanising, demystifying, destigmatising and empowering impact on mental health services. Show less
The aim of this dissertation was to identify gaps in knowledge and room for improvements in certain aspects of the current system of prevention and care regarding RBC alloimmunization in pregnancy.... Show moreThe aim of this dissertation was to identify gaps in knowledge and room for improvements in certain aspects of the current system of prevention and care regarding RBC alloimmunization in pregnancy. The focus in this thesis was to evaluate the performance of new measures in the prevention program, the follow-up with laboratory monitoring in alloimmunized pregnancies and the counseling of pregnant women and their partners, in cases of RBC alloimmunization. Show less
De ziekte van Crohn (CD) en colitis ulcerosa (UC) zijn chronisch inflammatoire darmziekten (IBD). Ondanks dat er de laatste jaren significante stappen zijn gezet in de medicamenteuze behandeling... Show moreDe ziekte van Crohn (CD) en colitis ulcerosa (UC) zijn chronisch inflammatoire darmziekten (IBD). Ondanks dat er de laatste jaren significante stappen zijn gezet in de medicamenteuze behandeling van IBD, ervaart een groot deel van de IBD patiënten klachten van aanhoudende ontsteking en bijwerkingen van de behandeling, wat de noodzaak voor het zoeken naar nieuwe behandelingsopties onderstreept. Door ons te richten op zowel de ontsteking die de klachten van IBD veroorzaakt, als op de onderliggende pathogenese die deze ontsteking aanstuurt middels het introduceren van een gezond microbioom en een gebalanceerde leefstijl, hopen we een (kleine) stap voorwaarts gezet te hebben richting een toekomst met een betere kwaliteit van leven voor patiënten met IBD. Show less
