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Individualized prognostic counseling in head and neck oncology
No full textHet besluitvormingsproces in de spreekkamer is vaak complex, zeker bij levensbedreigende ziekten zoals hoofd-halskanker. Het voorlichten van patiënten vraagt om een gepersonaliseerde aanpak, afgestemd op de wensen en behoeften van de patiënt. Ons doel was om de besluitvorming te verbeteren en patiënten met hoofd-halskanker te empoweren.Artsen blijken de levensverwachting in de palliatieve fase vaak te overschatten. Daarnaast komt de prognose zelden expliciet aan bod in de spreekkamer: meestal wordt er kwalitatieve informatie gedeeld zoals “goede vooruitzichten’’. Ongeveer de helft van de patiënten ervaart na voorlichting over de mogelijke behandeling(en) beslissingsonzekerheid. Uit gesprekken met patiënten blijkt dat algemene prognostische informatie, zoals “te genezen”, vaak voldoende geruststelling biedt. Bij een slechte prognose is er wel meer behoefte aan specifieke informatie zoals overlevingskansen. Dit leidde tot de doorontwikkeling van OncologIQ, een prognostisch model dat de persoonlijke overlevingskansen berekent van patiënten met behandelbare hoofdhalskanker o.b.v. persoonlijke kenmerken zoals leeftijd en geslacht. Het model werd extern gevalideerd en er werden nieuwe predictoren toegevoegd zoals roken en BMI. Patiënten gaven de voorkeur aan een cirkeldiagram om hun overlevingskansen te weergeven. Ook werd er een separaat model voor patiënten in de palliatieve fase ontwikkeld. De implementatie van OncologIQ in de spreekkamer leidde tot een significante afname van beslissingsonzekerheid en beslissingsspijt bij patiënten. Tevens namen patiënten vaker een actieve rol in het besluitvormingsproces. Voor zorgverleners bood het model waardevolle ondersteuning bij het bespreken van complexe casuïstiek tijdens multidisciplinaire overleggen.Kortom: dit proefschrift toont hoe gepersonaliseerde prognostische informatie patiënten kan empoweren, artsen kan ondersteunen en het gezamenlijke besluitvormingsproces aanzienlijk kan verbeteren.<br/
Libyan civic contributions to development during conflict:Dynamics of actors, ambitions, and approaches
Full text linkMacrophage-augmented organoids:Unraveling host-virus interactions for advancing therapeutic strategies
No full textCardiometabolic risk:Novel molecular and pharmacological insights
No full textVacuolar H+-ATPase (V-ATPase) is a multi-subunit protein, which predominantly acts as proton pump to maintain the acid environment in intracellular vesicles that are required for protein secretion, transport and degradation. Recent data support that it also determines receptor-mediated signaling. As such it may contribute to both physiological and pathophysiological processes, including diabetes. For instance, it influences insulin secretion, sensitivity and resistance. In relationship to hypertension/renal disease, it affects the cellular trafficking of various key members of the renin-angiotensin system (RAS) and is a determinant of sodium reabsorption [8-10]. Finally, the prorenin receptor [(P)RR], an accessory protein of V-ATPase, is a regulator of the low density lipoprotein (LDL) receptor and LDL cholesterol (LDL-c) metabolism. It is also required for the formation of high density lipoprotein, which facilitates cholesterol efflux. Thus, V-ATPase may also contribute to atherosclerosis.The RAS is a major player in the regulation of blood pressure. The membrane receptor megalin is capable of endocytosing multiple RAS members, including angiotensinogen, renin, and prorenin. It also contributes to protein reabsorption in the kidney. Previous studies in BN16 cells have suggested that the (P)RR is involved in megalin-mediated prorenin uptake, most likely because the (P)RR is an essential component of V-ATPase. Hence, we screened which other elements of V-ATPase affect prorenin uptake in BN16 cells, making use of siRNA. It turned out that the subunits Atp6v0a1 and Atp6ap1 played prominent roles, with silencing Atp6v0a1 downregulating prorenin uptake, and silencing Atp6ap1 upregulating this uptake. Mechanistically, inhibiting Atp6v0a1 reduced the cell surface megalin content, without altering the megalin mRNA and protein levels or endoplasmic reticulum stress (ERS). In contrast, inhibiting Atp6ap1 upregulated ERS and the mRNA and protein levels of megalin, yet without modifying the cell surface megalin levels. There was no effect on either lysosomal function or autophagy. Results for albumin resembled those for prorenin.Elevated levels of LDL-c associate with atherosclerosis. LDL-c clearance depends on its endocytosis by the hepatic LDL receptor. The transcriptional factor sterol regulatory element-binding protein 2 (SREBP2) upregulates the LDL receptor, while proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDL receptor (IDOL) exert the opposite. MicroRNAs (miRs), non-coding small RNAs, are critical regulators of the expression and function of genes. In HepG2 and Huh 7 cells, miR-148a was found to reduce the amount of LDL receptor protein, thereby reducing LDL uptake. The underlying mechanism turned out to involve targeting the 3'-UTR region of the (P)RR, resulting in (P)RR downregulation. In support of this concept, overexpression of the (P)RR attenuated the reduction in LDL receptor protein and LDL uptake after miR-148 exposure. A link between the (P)RR and the LDL receptor has already been established, and likely involves sortilin-1. Since the (P)RR points to V-ATPase as the main player, we next evaluated the roles of other V-ATPase subunits as determinants of cell surface LDL receptor expression, again by using siRNA. This yielded the subunit ATP6V1B2 as the most prominent contributor. Silencing ATP6V1B2 upregulated cell surface LDL receptor expression and LDL uptake both by approximately 50%. The upregulation involved SREBP2, given that ATP6V1B2 silencing increased the mRNA levels of SREBP2-targeted genes (SQLE, HMGCR, HMGCS1 and NPC1). There was no role for PCSK9 or IDOL. Applying an adeno-associated virus expressing shAtp6v1b2 to mice, in order to generate liver-specific Atp6v1b2 knockdown, resulted in increased hepatic LDL receptor mRNA and protein levels, and decreased plasma total cholesterol levels, while plasma total triglyceride levels were unaltered. Thus, we were able to fully replicate our in vitro data in an in vivo model. Both statins and PCSK9 inhibitors lower LDL-c in patients with familial hypercholesteremia. Chemerin is a recently discovered SREBP2-induced adipokine that regulates adipogenesis and lipid metabolism. Unexpectedly, only statins, and not PCSK9 inhibitors lowered chemerin in the aforementioned patients. To address the underlying mechanism, we made use of HepG2 cells and activated macrophages. It turned out that statins inhibit chemerin secretion from HepG2 cells by upregulating the LDL receptor. The latter involved SREBP2, which then was no longer available to increase chemerin. Chemerin bound to the high-density lipoprotein component Apolipoprotein A-I, thus diminishing cholesterol efflux in macrophages. These data are among the first demonstrating that the protective effects of statins are not fully identical to those of PCSK9 inhibitors.<br/
Moral self-regulation across contexts:From pandemic responses to behaviors in the workplace
Full text linkThis dissertation investigates moral self-regulation across real-world contexts, examining how people navigate complex situations where moral standards guide their actions. Its goal is to offer theoretical and practical insights into people's efforts to align themselves with moral standards in a range of real-world situations, with the aim of bridging the gap between theoretical models and real-world implications. To this end, the three empirical chapters in this dissertation examine distinct yet related issues. Chapter 2 focused on moral self-regulation during the COVID-19 pandemic, investigating how individuals' moral standards changed in response to the threat of the pandemic and how individuals adjusted their behaviors accordingly. Chapter 3 investigated moral self-regulation in the workplace, examining how two aspects of moral identity, internalization and symbolization, relate to behaviors that are unethical yet may help the organization. Chapter 4 centered on organizational justice and employee wellbeing, investigating the role of job autonomy in situations where employees perceive violations of moral standards with regard to outcomes (distributive justice) and procedures (procedural justice)
Cognitive and behavioral characteristics of neurofibromatosis type 1:From etiology to therapeutic strategies
No full textNeurofibromatosis type 1 (NF1) is a relatively common monogenetic disorder, primarily diagnosed based on somatic features affecting the skin and nervous system. Beyond these physical characteristics, most individuals with NF1 show distinct characteristics in cognitive, behavioral, and motor domains, which profoundly impact their daily lives and educational outcomes. The cognitive and behavioral characteristics associated with NF1 are linked to disrupted molecular mechanisms that lead to increased GABAergic inhibition and subsequent synaptic plasticity. This thesis aims to improve our understanding of the cognitive and behavioral characteristics associated with NF1 and aims contribute to the development of effective treatments and support for these characteristics in children and adolescents with NF1.<br/
Functional genetics on congenital intestinal motility disorders
Full text linkThis thesis explores primary pediatric intestinal pseudo-obstruction (PIPO), focusing on the genetic causes and cellular mechanisms behind the neuropathic (ENS defects) and myopathic (smooth muscle dysfunction) forms of the disorder. Chapter 2 identifies the TFAP2B gene as a new candidate for neuropathic PIPO, showing that a deletion in this gene causes abnormal exon splicing and impaired gastrointestinal function in zebrafish models. Chapter 3 investigates Filamin A (FLNA) mutations in myopathic PIPO, demonstrating that the loss of the long FLNA isoform disrupts smooth muscle contraction and intestinal development, leading to congenital short bowel syndrome and delayed motility.Chapter 4 examines the role of DNA methylation in Hirschsprung disease (HSCR), a common form of neuropathic PIPO, finding hypermethylation in key genes like MAB21L2, which may contribute to the disease by disrupting enteric nervous system (ENS) development. The study suggests that both RET and MAB21L2 interact in the same molecular pathway, offering insights into potential epigenetic influences on HSCR pathogenesis. Finally, Chapter 5 uses patient-derived induced pluripotent stem cells (iPSCs) to model HSCR, highlighting defective migration and proliferation of enteric neural crest cells (ENCCs) caused by genetic variants, and suggesting that genetic correction may be necessary for cell therapy approaches.Taken together, the thesis contributes new genetic insights into PIPO and HSCR, advancing the understanding of their pathogenesis and offering potential strategies for future therapies, including genetic correction and cell replacement therapies for patients with these disorders.<br/
By invisible hands:Work, exploitation, and the migrant division of labour
Full text linkAcross Europe, tens of millions of migrants work in key sectors of the economy, from agriculture to construction, logistics, and domestic care. Today, they play an essential role in filling growing shortages at the bottom of the labour market, where they do mostly standardised, low-skilled work, under wages and conditions increasingly refused by native workers. Yet, despite the essential economic role they play, many migrant workers are subject to exploitative and harmful labour practices, as well as broader conditions of economic insecurity, inequality, and social exclusion. This book provides a criminological investigation of the conditions of migrant workers and the nature of contemporary labour exploitation. Focusing on the Netherlands as a case study, the research involved twelve months of fieldwork in various low-wage jobs, including construction, agrifood, and logistics warehousing. Drawing on direct observations on the work floor itself, combined with labour market data and interviews with experts and practitioners, it sheds light not only on the working conditions of low-wage migrants, but also how exploitation and harmful labour practices emerge. Moreover, it explains how these conditions are rooted in broader political economic transformations in the sphere of work, including increasing labour mobility, flexibilisation, and inequality.<br/
Human-centric digital transformation:Exploring human information behavior through three field studies in digital policy, artificial intelligence, and emerging technologies
Full text linkIn today's rapidly evolving digital landscape, organizations often struggle to implement human-centric digital transformation effectively. Despite significant investments in advanced technologies, many digital initiatives fail to resonate with users because they overlook how humans seek, process, and utilize information. This disconnect arises from a gap in aligning technological advancements with the complex informational behaviors and preferences of individuals. Addressing this gap, this thesis investigates human-centric digital transformation through three distinct studies: the implementation of digital policies like General Data Protection Regulation (GDPR) and their reliance on understanding customers’ informational proactiveness; the application of machine learning algorithms such as life-event targeting to address customer uncertainties during decision-making; and the integration of emerging technologies like Artificial Intelligence (AI)-infused Augmented Reality (AR) in industrial settings, focusing on aligning their use with workers’ information processing capabilities. These studies explain how organizations can tailor digital transformation efforts to individuals' informational characteristics, offering insights into achieving human-centric digital strategies.Through three comprehensive studies corresponding to the stages of Digitization, Digitalization, and Digital Innovation, the research examines how aligning technological initiatives with human informational attributes enhances the success of digital transformation efforts. The first study explores how tailoring consent acquisition strategies to customers' information proactiveness under regulations like GDPR enhances compliance and trust, emphasizing the importance of human-centric approaches in the initial digitization stage. The second study investigates how addressing customers' information-seeking needs during uncertain decision-making periods improves the effectiveness of machine learning applications like life-event targeting, highlighting the value of personalized engagement in the digitalization stage. The third study examines how adapting advanced technologies like AI-infused augmented reality to match workers' information processing capabilities enhances productivity in industrial settings, underscoring the necessity of considering human factors in the digital innovation stage.Collectively, these studies affirm that prioritizing human-centric strategies aligned with end-users' informational behaviors will improve specific outcomes within each stage of digital transformation. While effectiveness was measured through stage-specific metrics—such as compliance rates in GDPR implementation, engagement rates in life-event targeting, and productivity enhancements with AR—these findings collectively demonstrate how aligning technology with informational behaviors fosters more impactful digital transformation efforts. By understanding and integrating how individuals seek, process, and utilize information, organizations can design and implement digital solutions that resonate deeply with users, leading to higher engagement, better adoption rates, and meaningful impacts. This thesis concludes that technological advancements alone are insufficient; success in digital transformation depends on the harmonious integration of technology with human informational characteristics. Future work could explore additional informational characteristics and contexts to further refine human-centric strategies, ensuring that digital transformation efforts remain aligned with the evolving ways humans interact with information. By adopting these approaches, organizations can navigate the complexities of the digital landscape more effectively, fostering a more inclusive, efficient, and responsive digital ecosystem.<br/
