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
In de loop van de eerste vier decennia van de twintigste eeuw dringt de poëzie vanaf 1880 door in bloemlezingen voor de hoogste klassen van gymnasium en h.b.s. In deze studie worden de overwegingen... Show moreIn de loop van de eerste vier decennia van de twintigste eeuw dringt de poëzie vanaf 1880 door in bloemlezingen voor de hoogste klassen van gymnasium en h.b.s. In deze studie worden de overwegingen om poëzie te bloemlezen en de keuzes die daaruit voortkomen van een vijftal bloemlezers (allen leraren) beschreven. Elk van hen propageert een methodiek om poëzie in de literatuurles te verwerken, van een open, globale kennismaking tot een intensieve analyse van een gedicht. Soms wordt een gedicht van een context voorzien maar doorgaans wordt een gedicht als zelfstandige tekst aangeboden. Naast deze bloemlezers brengt voordrachtskunstenaar Paul Huf ter ondersteuning van het onderwijs op een veertiental grammofoonplaten zijn gesproken bloemlezing. Zijn voordracht kan als voorbeeld dienen. Verder inventariseert deze studie de inhoud van 85 schoolbloemlezingen uit de periode 1898–1941 met in totaal 6758 gedichten van 254 dichters. Uit deze inventarisatie blijkt naast de voorkeur voor dichters uit de eerste jaren vanaf 1880 de vrij snelle popularisatie van anderen in de loop van de jaren 1920, 1930. Bloemlezers volgen op literair-historische gronden keuzes van voorgangers, daarnaast tonen zij een brede persoonlijke keuze. Schoolbloemlezingen representeren de voortgang van de contemporaine poëzieproductie en representeren het belang dat docenten voor de literatuurles hechten aan poëzie. Show less
Hydrocarbonylation of alkenes with carboxylic acids in synthesis of carboxylic acid anhydrides is relatively less explored. We herein present a study and optimization of a palladium-catalyzed... Show moreHydrocarbonylation of alkenes with carboxylic acids in synthesis of carboxylic acid anhydrides is relatively less explored. We herein present a study and optimization of a palladium-catalyzed hydrocarbonylation reaction of alkenes using carboxylic acids as the nucleophile, by which acid anhydrides can be obtained in moderate to excellent yields under mild conditions. Further, we have developed a method to synthesize symmetric acid anhydrides by in situ generation of carboxylic acids from the alkene itself, thereby eliminating the need of the corresponding pre synthesized Cn+1 carboxylic acid. The obtained anhydrides from the catalysis can be converted to (primary) amides, thioesters, esters or ketones via simple one-pot derivatization reactions. Following the establishment of the concept, we applied it in the synthesis of cyclic anhydrides from biobased sources such as pentenoic acid. A study on the regioselectivity demonstrated the different catalytic conditions that assisted in the formation of five-, six- or seven- membered cyclic anhydrides from pentenoic acid; with a major interest towards the formation of the seven-membered ring - a potential intermediate in the synthesis of caprolactam for nylon-6 production. Show less
Fungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health.... Show moreFungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health. Maximizing the effectiveness of existing antifungal drugs is imperative. Among these, fluconazole and posaconazole are commonly prescribed to treat severe and life-threatening fungal infections. In this thesis, among others, we aimed to understand better how well different posaconazole formulations are absorbed. Through computational modeling and simulation, we learned that posaconazole is best taken with food to reduce the risk of inadequate drug absorption and subsequent therapeutic failure. This applies not only to the suspension but also to the tablet, which results in higher and more predictable absorption even though it does not achieve concentrations similar to those upon intravenous administration. Fluconazole was studied in individuals with obesity. Our findings indicate that heavier adult males may require a higher dose to achieve the desired exposure. Consequently, we proposed dosing recommendations for treating obese patients. In summary, this research, a result of the long-term collaboration between Leiden University and Radboudumc, enhanced our knowledge of factors that reduce exposure to antifungal drugs, allowing us to guide how to individualize and optimize antifungal treatment in individual patients. Show less
Vestibular schwannomas (VS), also named acoustic neurinoma, are benign tumors that originate from the Schwann cells of one of the four vestibular nerves (two at each side). These nerves are part of... Show moreVestibular schwannomas (VS), also named acoustic neurinoma, are benign tumors that originate from the Schwann cells of one of the four vestibular nerves (two at each side). These nerves are part of the eighth cranial nerve, the vestibulocochlear nerve, also known as the statoacoustic nerve. The vestibular nerves are located in the cerebellopontine angle, the space between brainstem, cerebellum and temporal bone. VS are the most common neoplasm located in the cerebellopontine angle and account for 8% of all intracranial tumors (1). The majority (95%) of VS are sporadic and occur unilateral. VS may exhibit a remarkable variable growth pattern: some tumors show a clear progression while others remain dormant and on occasion undergo shrinkage (2). The clinical symptoms most frequently seen are progressive (unilateral) hearing loss, vertigo, and tinnitus. Options for Treatment are observation (wait and scan), radiotherapy, or microsurgery. The choice of treatment depends on tumor size, severity and progression of the clinical symptoms, age of the patient, and patient preference.This thesis describes some of the clinical aspects of VS which are relevant for treatment. These concern the epidemiology, diagnostic challenges, clinical predictors affecting selection, and surgical technique and outcome. Show less
Cancers accounts for approximately one-in-six deaths worldwide. Despite the advances in treatment options over the past couple decades surgery remains the cornerstone for almost all solid tumors.... Show moreCancers accounts for approximately one-in-six deaths worldwide. Despite the advances in treatment options over the past couple decades surgery remains the cornerstone for almost all solid tumors. Radical excision is crucial for curative treatment, however, intraoperative tumor identification is hampered by (1) fibrosis, inflammation and necrosis due to neoadjuvant therapy, and (2) an altered surgical field due to the adoption of laparoscopic and robotic procedures. In response, fluorescence guided surgery (FGS) has been introduced to the operating theater. FGS utilizes near-infrared light to visualize, an often intravenously administered, tumor-targeting tracer in real-time. In this thesis, uPAR was studied as target for FGS and uPAR-targeting FGS tracers were developed and compared in various cancer models. Show less
Central serous chorioretinopathy (CSC) is a multifactorial disease of the retina and the choroid in the human eye. The disease is characterized by a serous detachment of the neurosensory retina in... Show moreCentral serous chorioretinopathy (CSC) is a multifactorial disease of the retina and the choroid in the human eye. The disease is characterized by a serous detachment of the neurosensory retina in the central macula, which causes visual complaints including blurred vision, a central relative scotoma, metamorphopsia, and alterations in color and contrast vision. Multimodal imaging techniques have revealed that abnormally thickened, leaking choroidal blood vessels cause an excessive fluid outflow into the interstitial space, which presumably causes the characteristic thickened choroid. This thesis addresses the clinical spectrum of CSC including the acute CSC, the chronic CSC and the severe chronic CSC. Here we suggest a strict but practical classification of CSC phenotypes based on findings on multimodal imaging techniques. We also report on the outcome of treatment, especially photodynamic therapy (PDT), in all phenotypes of CSC and provide recommendation regarding disease management and therapy. Furthermore, in this thesis we assess the roll of genetic variations among different phenotypes of CSC for a better understanding of the pathogenesis of the disease. Despite the genetic associations found in CSC phenotypes, we conclude that the so far known genetic variations do not explain the different clinical disease presentation of CSC phenotypes. Show less
Uveal melanoma (UM) is a rare ocular tumor. Up to 50% of the patients develop distant metastases predominantly targeting the liver. The median survival after diagnosis of patients with hepatic... Show moreUveal melanoma (UM) is a rare ocular tumor. Up to 50% of the patients develop distant metastases predominantly targeting the liver. The median survival after diagnosis of patients with hepatic metastases is approximately 4-6 months and hardly increased in the past decades due to lack of novel effective therapeutic options. Within the scope of this thesis we investigated the signaling landscape of metastatic UM and searched for novel avenues of therapy. In Chapter 2 we demonstrate that combinations of the multitarget drug Trabectedin with either the CK2/Clk double-inhibitor Silmitasertib or with the c-MET/TAM receptor inhibitors show synergistic growth inhibitory effects and induce apoptosis of UM cells in vitro. Chapter 3 describes the application of a CRISPR-Cas9 synthetic lethality screen for identification of molecular targets whose inhibition synergistically enhances the effect of the mTOR inhibitor everolimus in UM cells. In Chapter 4 we show that the combination of genetic depletion YAP1/TAZ together with Mcl-1 inhibition resulted in a synergistic inhibitory effect on the viability of UM cell lines. In Chapter 5 we analyzed the phospho-proteome of two UM metastatic cell lines and a primary tumor cell line from the same individual, and studied the role of MARK3 in YAP1/TAZ signaling. Show less
Pancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently... Show morePancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently onlypatients with localized pancreatic tumors can undergo surgery, which is the cornerstone in thetreatment of pancreatic cancer, whether or not preceded by neoadjuvant (chemo/radio)therapy. To establish the diagnosis, imaging techniques are used, tumor tissue must be obtained, and certain tumor markers can be determined in the blood. During surgery, the tumor must be removed in its entirety to prevent early recurrence. This thesis describes the potential role of tumor markers, which can be determined in the blood, and several experimental optical imaging techniques applied to pancreatic cancer. Show less
This book contains two main messages. First, an attempt is made to explain the diverse beneficial findings on cognition and mental health in the literature of meditation practices by the factor of... Show moreThis book contains two main messages. First, an attempt is made to explain the diverse beneficial findings on cognition and mental health in the literature of meditation practices by the factor of breathing. In the respiratory vagal nerve stimulation model of contemplative practices (rVNS) specific respiratory patterns lead to changes in autonomic nervous system functioning that in turn produce changes in the central nervous system, which can be observed in a healthier cognitive and emotional balance. Second, there are two empirical chapters that show null-results on cognition with meditative movement (Tai Chi Chuan) and breathing interventions. The possible reasons for these lack of results are extensively discussed in this dissertation and put into a wider perspective within the scientific field. Show less
For each living organism health is ensured by correct functioning of its cells. Cells therefore have elaborate methods for regulation of their proteins. In this thesis we examine a set of highly... Show moreFor each living organism health is ensured by correct functioning of its cells. Cells therefore have elaborate methods for regulation of their proteins. In this thesis we examine a set of highly conserved proteins: microtubules (MTs), which are either in a growing or a shrinking phase, together with the MTs' end-binding proteins mal3, tea2 and tip1. Using total internal reflection fluorescence microscopy we grow these proteins in custom-made, patterned flow chambers. We also examine the influence of force on MTs by letting them grow against obstacles, using the same microscopy technique or optical tweezers.Focusing on the switch from a growing to a shrinking state, a so-called catastrophe, we investigate the trigger of a catastrophe. For this we create distributions of the length of MT growth phases and fit them with several functions. All of the functions describe reactions involving several steps. We find that MTs need two steps until a catastrophe, a process which is sped up by the end-binding proteins as well as by force. Besides, we also present another model for MT catastrophe in which noisy growth together with a specific state of the microtubule tip are capable to explain a lot of the published MT data. Show less
This dissertation is about intra-EU workers and labour law related (bogus) constructions under which they work in the Netherlands and other EU member states.Through the following two main research... Show moreThis dissertation is about intra-EU workers and labour law related (bogus) constructions under which they work in the Netherlands and other EU member states.Through the following two main research questions this situation is outlined and analysed.1. To what extent do intra-EU workers in the Netherlands work under labour law related (bogus) constructions that (financially) disadvantage them?2. What are the perceptions of intra-EU workers regarding the use of labour law related (bogus) constructions and their working conditions and circumstances under which they work in the Netherlands and other EU member states?In each chapter of this thesis, these questions are elaborated into more specific research questions.In this research both legal and empirical research that fits within the Empirical Legal Studies (ELS) framework is conducted. Through this combination of research methods it was viable to link the collected empirical (interview) data to the legal data based on literature and case law research. Hence, the theory (law in books) was tested against facts and observations (law in action). Moreover, by establishing this link the present research adds a new and valuable dimension to current academic legal and social scientific research. Show less
While immune checkpoint blockade (ICB) (CTLA4/ PD1) therapy has resulted in durable responses in patients with advanced stage cutaneous melanoma, some patients do not benefit from this, due to... Show moreWhile immune checkpoint blockade (ICB) (CTLA4/ PD1) therapy has resulted in durable responses in patients with advanced stage cutaneous melanoma, some patients do not benefit from this, due to resistance mechanisms. This thesis aims to improve response of a subset of melanoma patients to immunotherapy. Firstly, mouse melanoma tumor models are developed that closely resemble some of the resistance mechanisms occurring in patient tumors, which are useful for research. Thereafter, a prognostic biomarker is used to identify the subset of melanoma patients that are unlikely to benefit from ICB therapy. It is then evaluated whether this subset of patients would benefit from combining histone deacetylase inhibitor with ICB. Despite encouraging pre-clinical results showing enhanced anti-tumor immune responses using this combination, this did not result in improved responses in the clinic. Furthermore, this thesis focuses on an immune cell subset, namely regulatory T cells (Tregs), which are known to suppress anti-tumor immune responses. Thus, their presence in the tumor microenvironment (TME) is detrimental to tumor cell killing. This thesis provides an increased understanding of the metabolic adaptation of Tregs to conditions in the TME and propose that targeting these adaptations might overcome the suppression by Tregs and enhance responses to immunotherapy. Show less
Scholars have contended that the challenge for translators of poems lies in achieving equal fidelity between form and content. Most of the time, a decision must be made to prioritize either form or... Show moreScholars have contended that the challenge for translators of poems lies in achieving equal fidelity between form and content. Most of the time, a decision must be made to prioritize either form or content in the translation process. This research delves into the impact on readers when poems are translated, focusing exclusively on either form or content. It explores how the humor in children's poems, translated from English into Filipino, is preserved. Furthermore, it examines the influence of culture and gender on the appreciation of humor. Despite extensive studies on children's humor development, little is known about the interplay of culture and gender in children's responses to humor in translated literature. The poetry reading sessions conducted with children uncover interesting findings about preferred language for reading and humor perception, as well mode of input and perceived humor in the text. The sessions also provide insights into children's perspectives on children's literature and the role of discussion and comprehensibility on humor response. Other aspects that the study explores are the definition of children's literature and its link to the concept of childhood, current trends in translated literature in the Philippines, theories of humor, and humor within the realm of children's literature. Show less
The different kinds of cultural perspectives on health and disease of the participants are related to their knowledge, beliefs, values and practices manifested in various forms of lifestyle in... Show moreThe different kinds of cultural perspectives on health and disease of the participants are related to their knowledge, beliefs, values and practices manifested in various forms of lifestyle in Indonesia. The cultural diversity of the population is also related to differences in health behaviour. Nursing as a profession has to be able to encourage clients and patients, particularly with Cardiovascular Diseases (CVD) to obtain holistic nursing in an effort to meet all client needs, regardless of their ethno-cultural background and their diverse beliefs and values about health and healing. Every effort to improve cultural competency among nursing practitioners who fully work with diverse patients from the numerous ethno-cultural groups in Indonesia is a challenge. One important step which can be taken is to learn and understand the Sundanese people as the dominant cultural group in West Java. The situation certainly requires a deepening of understanding of social behaviour and public health in terms of how to use traditional institutions such as kearifan kesehatan lokal, as well as indigenous knowledge of jamu and ubar kampung in dealing with health care of the elderly with CVD. Show less
CrO2, a half-metal ferromagnet, has shown great promise for superconducting spintronics applications for nearly two decades. Josephson junctions consisting of superconducting (S) contacts on... Show moreCrO2, a half-metal ferromagnet, has shown great promise for superconducting spintronics applications for nearly two decades. Josephson junctions consisting of superconducting (S) contacts on ferromagnetic (F) structures of CrO2, have been shown to sustain remarkably high supercurrents over hundreds of nanometers. However, advancements in this area have been hindered by the metastable nature of CrO2 at ambient conditions. This results in a poorly controlled S-F interface transparency, which is critical for generation of spin triplets. This thesis explores the potential, challenges and possible solutions to overcome the issues with CrO2 devices. Show less
In a typical glycosylation reaction, a donor is activated to form a (variety of) electrophilic species which can react with a nucleophilic acceptor, following a reaction mechanism having both SN1... Show moreIn a typical glycosylation reaction, a donor is activated to form a (variety of) electrophilic species which can react with a nucleophilic acceptor, following a reaction mechanism having both SN1 and SN2 character. On the SN1-side of the spectrum oxocarbenium ions partake in the mechanism while covalent intermediates act as the product forming intermediates on the SN2-side. The result of a glycosylation reaction is influenced by the properties of both donor and acceptor and can be affected by external factors as well. Because the challenges in carbohydrate synthesis are typically solved for a specific synthetic problem, a general understanding of what effect changing a single variable has on the mechanistic pathway, and thus the (stereochemical) outcome is not available. This in turn means that synthesis of glycosidic bonds typically requires a considerable amount of optimisation at the expense of a significant amount of time and resources. The goal of this thesis is to systematically investigate how changes in stereochemistry and protecting group patterns on the donor and acceptor affect the mechanism and outcome of glycosylation reactions, to enable a more rational design of synthesis routes. Show less
This thesis is divided into three parts. The first part of this thesis describes the epidemiology of infections with Clostridioides difficile, meticillin-resistant Staphylococcus aureus and... Show moreThis thesis is divided into three parts. The first part of this thesis describes the epidemiology of infections with Clostridioides difficile, meticillin-resistant Staphylococcus aureus and colistin-resistant Enterobacterales. An important treatment strategy for recurrent C. difficile infections is restoring the disturbed gut microbiota by faecal microbiota transplantation (FMT). The second part discusses the risk of transmission of pathogenic and/or multidrug-resistant bacteria via FMT and procedures to prevent this. Apart from recurrent C. difficile infections, several new potential indications of FMT are being explored. In the third part of this thesis, FMT is explored as a potential new treatment strategy for several neurological disorders, with a main focus on Parkinson’s disease. Show less
What we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The... Show moreWhat we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The stress response is for an important part dependent on glucocorticoid hormones. By and large, the acute response to glucocorticoids is beneficial, but chronic exposure often becomes maladaptive. To improve prevention and treatment of disorders we can develop due to stress, it is important to better understand the effects and working mechanisms of glucocorticoids. While we already possess extensive knowledge regarding glucocorticoids and glucocorticoid receptor signaling, we introduced and studied five “aspects of context”, which we felt address important current misconceptions or gaps of knowledge. Corticosterone was at the center of all the studies we performed, yet the eventual outcome of glucocorticoid receptor activation differed extensively in all experiments. Thus, the context in which corticosterone exerts its effects matters, and it is to researcher to be aware of this when designing new studies and interpreting available data. Whilst our research merely addressed some specific processes, the lessons learned from these experiments can be applied much broader to the biology of glucocorticoid signaling and other nuclear family members. Show less
