Cancer immunotherapies utilizing immune checkpoint blockade (ICB) therapy targeting CTLA-4 and PD-1/PD-L1 relieve tumor-induced immune suppression and induce durable tumor regression. The use of... Show moreCancer immunotherapies utilizing immune checkpoint blockade (ICB) therapy targeting CTLA-4 and PD-1/PD-L1 relieve tumor-induced immune suppression and induce durable tumor regression. The use of ICB therapy have demonstrated remarkable therapeutic efficacy in a proportion of patients with melanoma. However, still a substantial percentage of patients does not respond (durable) to ICB treatment and many questions remain. Therefore, in this thesis, the aim is to improve our understanding of ICB efficacy. We demonstrate the promise of neoadjuvant ICB therapy (approach in which ICB therapy is applied before surgery) and analyze different cohorts of melanoma patients. This results in the identification of several markers that are associated with prognosis, including IFN-y related gene signature score, Batf3 dendritic cell associated gene signature score, tumor mutational burden and systemic LRG1 expression. These markers can potentially be targeted and might facilitate rational combination therapies that can boost the efficacy of ICB therapy. For this purpose, we perform a repurposing compound screen that targets antigen cross-presentation. Togethers, this work increases our understanding of factors that determine ICB therapy efficacy and toxicity, with the goal to identify novel strategies to improve outcome of melanoma patients in a rationale and personal manner. Show less
In between 1968 and 1973, the Dutch Atlantic was home to four Black Power organizations: the Black Panthers of Curaçao (1968-1970), Antillean Black Power (1969-1970), the Dutch Black Panther... Show moreIn between 1968 and 1973, the Dutch Atlantic was home to four Black Power organizations: the Black Panthers of Curaçao (1968-1970), Antillean Black Power (1969-1970), the Dutch Black Panther Solidarity Committee (1969-1970), and Black Power Suriname / Afro-Sranan (1970-1973). This dissertation asks why and how these organizations aligned with the transnational movement. Based on archival research conducted in Curaçao, Suriname, the United States, and the Netherlands, it argues that they did so because Black Power offered them an alternative path to decolonization. Instead of striving for equal participation in the Kingdom of the Netherlands, as colonial reformists did, or promoting self-reliance, as nationalists did, Black Power activists believed the best way to free themselves from the legacies and realities of colonialism was to join the movement's global network of Black solidarity, cooperation, and unity. Show less
Online behavioral advertising (OBA) is a form of advertising that relies on data about users’ behavior (e.g., clicks, likes, voice commands) and uses artificial intelligence (AI) to place ads that... Show moreOnline behavioral advertising (OBA) is a form of advertising that relies on data about users’ behavior (e.g., clicks, likes, voice commands) and uses artificial intelligence (AI) to place ads that users may be interested in. Ads that AI chooses to display often leave users in awe and concern them about the potential of total surveillance. People using these services have (legitimate) expectations that tech companies or democratic institutions protect their interests. Indeed, the European Union (EU) heavily regulates OBA, requiring, for example, that companies have users’ consent before their surveillance. Yet, these ads monetize most “free” online services and turn companies like Alphabet and Meta into the world’s wealthiest. Therefore, the industry is incentivized to acquire consumers’ consent by any means necessary, often through manipulation. As almost everyone has encountered manipulative “cookie banners” online, many have started to doubt if EU law can effectively protect consumers from the growing power of the tech industry. This thesis builds a framework of manipulation, describes consumer manipulation via OBA, constructs a theory of the harms of this phenomenon, and analyses its boundaries in the EU legal framework. The thesis concludes that the EU framework can effectively safeguard consumers, anticipating that the enforcement of the Digital Services Act (DSA) and the Digital Markets Act (DMA) will put an end to consumer manipulation (and exploitation) via OBA. Show less
Security is something that people tend to care about. But is it also something that they should care about? To explore this question, this dissertation first develops a new conceptual framework of... Show moreSecurity is something that people tend to care about. But is it also something that they should care about? To explore this question, this dissertation first develops a new conceptual framework of security. Next, it analyses how security relates to some key values for liberal democratic societies. The first of these is well-being. It is argued that there are important ways in which security can contribute to somebody’s well-being – but there are also ways in which security may hamper a person’s flourishing. The second value is freedom. It is shown that in public decision-making freedom and security may come at each other’s cost – yet there are also ways in which the two can work to each other’s benefit. The third value is equality. It is demonstrated that in order for a society to meet the demands of equality it must provide its members with a particular set of securities – while at the same time the pursuit of equality puts another set of securities out of reach. Ultimately, this dissertation finds no reason for considering security to be good for its own sake, but it argues that security can be good for the sake of well-being, freedom, and equality. Show less
This thesis summarizes a PhD research project, in which we successfully developed and tested a smartphone-based version of the AAT. We used the mobile AAT to show that approach-avoidance tendencies... Show moreThis thesis summarizes a PhD research project, in which we successfully developed and tested a smartphone-based version of the AAT. We used the mobile AAT to show that approach-avoidance tendencies can undergo substantial state-like changes. We further demonstrate how these changes can be systematically related to other state-variables and how important health-related outcomes such as overweight and obesity, can be explained by disruptions of these dynamics. Our findings have broad implications for approach-avoidance research and task-based research in general, as they reveal how smartphones can be used to get insights into the dynamic nature of task outcomes and how (disruptions of) these dynamics can have important real-life consequences. Show less
Thyroid cancer is a rare cancer with an excellent prognosis with standard care (including surgery and radioactive iodine therapy). However, a minority may show progression to refractory status.... Show moreThyroid cancer is a rare cancer with an excellent prognosis with standard care (including surgery and radioactive iodine therapy). However, a minority may show progression to refractory status. These advanced radioactive iodine-refractory thyroid cancer patients often have an aggressive disease course and poor prognosis. Unfortunately, no good treatment options are available for these patients.The registered drugs for this purpose include molecularly targeted therapy with the tyrosine kinase inhibitors (TKIs) lenvatinib, sorafenib, and as second-line cabozantinib. These agents were shown to delay progressive disease in clinical trials, but not overall survival. Moreover, the setting of a clinical trial is often stricter than real-life, as reflected by less favorable outcomes in real-world data. Furthermore, these drugs frequently have (intolerable) adverse events. When the limited treatment options for refractory thyroid cancer have been exhausted, inclusion in clinical trials is often recommended by international guidelines.More recent ‘basket trials’ also study tumor type-agnostic prescription of drugs based on molecular tumor profiling; e.g. an ALK TKI in presence of an ALK gene fusion. The molecular characterization of neoplasms may also improve diagnosis and/or help direct the further management strategy; e.g. in indeterminate thyroid cytopathology, or in specific cases of Multi-UniFocality in contrast to multifocality. Show less
Accurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have... Show moreAccurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have supported the PK prediction of the CNS target sites and the translation of PK data between species and between populations, given their mechanistic, physiology-based structure. In this thesis, we have developed a CNS PBPK model which could predict adequately the brainECF, brainICF, and CSF unbound PK profiles and provide important insights into the brain unbound pharmacokinetics of patients with CNS diseases. Early prediction of the brain target site pharmacokinetics of the right patient population can prioritize drugs with the favored brain PK profiles, which might optimize and accelerate the CNS drug development process. Show less
This thesis aims at identifying the conducive conditions of coercive diplomacy in the context of nuclear proliferation. Drawing on the US experience with Iran, Libya, and South Africa, we examined... Show moreThis thesis aims at identifying the conducive conditions of coercive diplomacy in the context of nuclear proliferation. Drawing on the US experience with Iran, Libya, and South Africa, we examined the driving factors behind US coercive diplomacy’s divergent and paradoxical results or outcomes in these countries. We chose our case studies based on two factors: the different stages or levels of their nuclear programs when confronted by the US and the nature of the demands formulated by the coercer in relation to the bilateral relations of the parties involved. We hypothesized that two conditions could compel a target subjected to coercive diplomacy to abandon its nuclear (weapons) program: if the coercer’s strategy exploits the target’s vulnerabilities and if the coercer demonstrates the motivation to have a sustained campaign to compel its target to abandon its nuclear weapons program. The interactions between the US and each of the targets mentioned above provide insights into improving coercive diplomacy, both theoretically and practically. The interplay between domestic politics and international pressures theoretically inspires our approach. We emphasized the critical role of domestic actors in alleviating or increasing systemic pressure related to the targets’ nuclear programs. We used neoclassical realism and process tracing to describe these dynamics and unravel the causal relationships between the coercer’s demands and the targets’ responses. Using the structured-focused comparative methodology, we reinforced our findings’ relevance and triangulated our primary and secondary sources. Our findings support the hypothesis of the driving effect of domestic variables in relation to external pressures. Hence, we identified similar and diverse mechanisms in our three cases, which helped us verify the validity of our initial hypotheses and confirmed the relevance of our research strategy regarding the complexity of coercion dynamics in the non-proliferation domain. Show less
This book examines the issuance of mining licenses in Indonesia from an environmental perspective. It shows how mining licensing has directly contributed to environmental degradation and how... Show moreThis book examines the issuance of mining licenses in Indonesia from an environmental perspective. It shows how mining licensing has directly contributed to environmental degradation and how consecutive governments have failed to take effective action addressing this problem. The main cause is the low quality of the relevant laws and policies, which is mostly a result of the priority law- and policymakers accord to mining development and a lack of interest in and knowledge about solving environmental problems. This situation has been exacerbated by a lack of public participation and bureaucratic “siloism”: government agencies often develop their own policies and regulations without efforts at co-ordination with other relevant government agencies. Only in a few cases have there been better results, when government agencies developing a policy had a strong interest in its implementation, when their officials disposed of adequate expertise, and when there was a favourable national political situation. Unfortunately, these conditions have rarely been present in Indonesia. Show less
The application of nanomaterials in industrial processes and consumer products provides many societal benefits, but can also lead to the release of nanomaterials into the environment. The work in... Show moreThe application of nanomaterials in industrial processes and consumer products provides many societal benefits, but can also lead to the release of nanomaterials into the environment. The work in this dissertation aims to provide insights into the potential environmental impacts that may follow from this, with specific reference to populations and communities of freshwater invertebrates. Based on experimental studies conducted under conditions reflecting those in natural ecosystems, this dissertation shows that commonly applied methodological approaches can lead to an underestimation of the long-term impacts of nanomaterials on freshwater organisms, particularly at the level of populations and communities. In doing so, this dissertation provides perspective on the role of relevance and realism in ecotoxicological assessments, and shows that impact assessments at higher ecological levels can provide sensitive and reliable insights that can serve as a basis for regulation, and guide the development of safer and more sustainable chemicals, substances and materials. Show less
This research investigates tensions associated with positive organizational change (POC) that prioritizes strengths-based dialogue over talk about organizational problems or deficits (Fitzgerald et... Show moreThis research investigates tensions associated with positive organizational change (POC) that prioritizes strengths-based dialogue over talk about organizational problems or deficits (Fitzgerald et al., 2010) by bridging the concept of organizational shadow (Bowles, 1991; Fitzgerald et al., 2010; Jung, 1968) with dialectical tension theory (Baxter & Simon, 1993). A recent flurry of studies suggests toxic positivity results in the marginalizing of individuals for expressing their emotions that may not always be positive (Collins, 2022; Cross, 2022; Tufvesson, 2020). A key question this research addresses is what do with the "elephants in the room" that represent what people think is undiscussable in a POC context? Interviews with 41 organizational development practitioners, with more than 600 cumulative years of experience leading POC initiatives using the Appreciative Inquiry (AI) methodology, identified the contexts in which tensions are likely to arise, the theoretical implications of tensions, and practical strategies to navigate tensions in a POC context. This study’s findings advance scholarship on positive organizing by naming the voice, leadership, and temporal shadows. These shadows emerge as three dialectical tensions: free expression and limited expression of what is discussible in the change process, hierarchical and collaborative leadership, and short-term orientation versus long-term orientation. The results of this study demonstrate experienced POC practitioners navigate tensions underlying the voice, leadership, and temporal shadows by using nuanced strategies, such as creating space to hear divergent perspectives, coaching leaders to demonstrate agility in support of collaborative initiatives, and reframing tension such that one pole does not negate the other. Show less
AI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services... Show moreAI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services increasingly find their way into daily life. Are the EU's fundamental rights to privacy and data protection equipped to protect individuals effectively? In addressing this question, the dissertation concludes that no new legal framework is needed. Instead, adjustments are required. First, the extent of adjustments depends on the AI discipline. There is nothing like 'the AI'. AI covers various concepts, including the disciplines machine learning, natural language processing, computer vision, affective computing and automated reasoning. Second, the extent of adjustments depends on the type of legal problem: legal provisions are violated (type 1), cannot be enforced (type 2) or are not fit for purpose (type 3). Type 2 and 3 problems require either adjustments of current provisions or new judicial interpretations. Two instruments might be helpful for more effective legislation: rebuttable presumptions and reversal of proof. In some cases, the solution is technical, not legal. Research in AI should solve reasoning deficiencies in AI systems and their lack of common sense. Show less
This thesis adopts a data-driven, multimodal approach to explore the complexity of psychiatric disorders, emphasizing the integration of diverse datasets to achieve a deeper understanding of these... Show moreThis thesis adopts a data-driven, multimodal approach to explore the complexity of psychiatric disorders, emphasizing the integration of diverse datasets to achieve a deeper understanding of these conditions. It illustrates this methodology across several chapters, each focusing on different aspects and biomarkers relevant to stress-related psychiatric disorders. Chapter 2 reevaluates the effects of intranasal oxytocin through a multimodal lens. Chapter 3 connects cortisol's in-vivo effects with brain responses and molecular architectures. Chapter 4 introduces a multimodal machine learning model to predict remission in depressive disorder, aiming for both accuracy and explanatory power. Chapter 5 examines the concept of resilience as a discrepancy between expected and observed mental health post-stress, assessing its predictive value for mental health outcomes. Finally, Chapter 6 explores a novel genetic risk score for stress-related disorders, testing its utility and applicability in various contexts. Through a comprehensive and data-centric approach, the thesis aims to uncover new insights into the etiology and treatment of psychiatric disorders, highlighting the importance of considering their multimodal nature. Show less
In the Netherlands, the title of Minister of State is granted to a select set of senior politicians and administrators, generally towards the end of their career. They are appointed by the monarch,... Show moreIn the Netherlands, the title of Minister of State is granted to a select set of senior politicians and administrators, generally towards the end of their career. They are appointed by the monarch, acting on a proposal by the cabinet. In this capacity, they are then asked to perform certain activities or to carry out specific tasks. Both the content of the Minister of State role itself and the appointment process are quite vague. Nevertheless, this exclusive ministerial title has considerable social status. The aim of this research study is to provide insight into the title of Minister of State. The problem description is as follows: What development has taken place in the role of Minister of State; what has the legal and political significance of the Minister of State been; and what can be said about the present-day role of Minister of State, in the Netherlands and in various other countries? Chapter 2 investigates the development of the Minister of State from a historical perspective. In Chapter 3 the various appointments as Minister of State are studied for each monarch. Chapter 4 examines the present-day role of Minister of State. In Chapter 5 a comparative legal study is made of whether other countries also have a Minister of State and what parallels and differences can be seen in relation to this title in the Netherlands.Chapter 6 brings together the findings of the research study and presents the conclusions that were drawn. Show less
In this thesis I highlight the applications of Oxford Nanopore Technologies (ONT) sequencing. This technique is a relatively new approach in the sequencing field, where nanopores are embedded in a... Show moreIn this thesis I highlight the applications of Oxford Nanopore Technologies (ONT) sequencing. This technique is a relatively new approach in the sequencing field, where nanopores are embedded in a membrane, DNA molecules are pulled through nanopores and an electrical current serving as the sequencing signal. This technique yields reads-lengths of >10Kbp and has no theoretical upper limit towards read-length. The positive impact on data quality due to improved chemistry is underlined, improved chemistry leads to less sequencing errors and a more homogeneous coverage over complex genomic architectures. Benefits for increased read-lengths are assessed for resolving fragmented genome assemblies that were previously based solely on short-read sequencing data. Furthermore, the assembly of a large genome using ONT data is described, indicating ONT is a suitable candidate for resolving extremely large genomes using sophisticated assembly approaches. And finally, the potential for on-site sequencing is evaluated. Exploiting simplicity, mobility and accuracy provided by this new technique. The central hypothesis of this thesis is that Oxford Nanopore Technologies long-read sequencing can be valuable for established genomics applications, such as whole genome sequencing and metagenomic characterization of microbial communities. Show less
In the light of the fragility of current liberal democracies, this dissertation aims to contribute to rethinking political order by reconstructing Hegel’s account in the Philosophy of Right. His... Show moreIn the light of the fragility of current liberal democracies, this dissertation aims to contribute to rethinking political order by reconstructing Hegel’s account in the Philosophy of Right. His theory of political order has relevance as it explores how modern freedom, i.e. liberal rights and a market, can coexist with republican self-government. The reconstruction shows how a liberal order, i.e. based on the principle of individual autonomy and an instrumental account of government, must entail a loss of freedom and social and political pathologies: citizens for instance cannot acquire stable identities in the social whole and alienate themselves from the political realm. Moreover, it works out Hegel’s alternative account of political order in which freedom depends on the interplay of the opposed dynamics of the state and society: the state institutions pursuing the good of the community as a whole, while the members of civil society pursue their own good. Finally, the dissertation shows how Hegel offers a coherent and subtle account of republican citizenship and self-government, in which self-government does not depend primarily on the influence citizens exercise on political outcomes but on their ability to identify with the good of the community as a whole. Show less
This dissertation explores the United Nations' comprehensive approach to managing the Israel-Arab Conflict from 1967 to 1982, presenting a shift from examining peace operations as isolated efforts... Show moreThis dissertation explores the United Nations' comprehensive approach to managing the Israel-Arab Conflict from 1967 to 1982, presenting a shift from examining peace operations as isolated efforts to viewing them as interconnected elements of a broader peace architecture. It introduces a critical analysis of the roles played by the Office of Special Political Affairs and the Office of Chief Coordinator of Peacekeeping in the Middle East, arguing that these entities were pivotal in forming a cohesive strategy despite the static mandates of individual peace missions. The research spans six chapters, starting with a historical overview of the UN’s peacekeeping framework since 1948, setting the groundwork for understanding the conflict and the evolution of peacekeeping entities. It then delves into Inter-Operation Collaboration (IOC) and the Secretariat’s political maneuvering, highlighting the impact of significant events like the Camp David Accords and the 1982 Israeli invasion of Lebanon. These events marked a shift in focus from state-centric to Israeli-Palestinian issues, challenging the UN’s influence. The conclusion assesses the UN’s role in shaping the diplomatic and security landscape of the region, underlining the organization's contributions and limitations in fostering peace and stability amidst a complex geopolitical scenario. This research offers valuable insights into the dynamics of UN peacekeeping operations in regional conflicts. Show less
Drug candidates with a covalent binding mode have gained interest since the approval of multiple covalent anticancer drugs, but were long avoided due to concerns regarding promiscuous reactivity... Show moreDrug candidates with a covalent binding mode have gained interest since the approval of multiple covalent anticancer drugs, but were long avoided due to concerns regarding promiscuous reactivity with off-target proteins. In this dissertation, the scope and versatility of the newly discovered in situ thiol–alkyne reaction is evaluated: the nonactivated alkynes exhibit an unprecedented target reactivity with excellent thiol selectivity, thus potentially outperforming currently used cysteine-reactive warheads. Chapter 1 starts with the history of (ir)reversible covalent inhibition, the reactivity of (non)activated alkynes, and the serendipitous discovery of the thiol–alkyne reaction. Established technologies for direct detection of covalent protein–drug adducts are reviewed in Chapter 2, and in Chapter 3 a detailed guide for the evaluation of (ir)reversible covalent inhibitors to obtain relevant kinetic parameters is provided, accompanied by kinetic simulations and step-wise protocols for enzymatic activity assays. In Chapter 4, the nitrile warhead in reversible CatK inhibitor odanacatib (ODN) is replaced with alkyne warheads to investigate whether it an irreversible covalent adduct is formed with cysteine protease cathepsin K (CatK) despite having a small recognition element. In Chapter 5, we evaluate if nonactivated alkynes can target noncatalytic cysteine residues by replacing the irreversible covalent acrylamide warhead in EGFR/HER2 inhibitor neratinib by an alkyne warhead. In Chapter 6, the impact of substituents on the alkyne warhead is explored using a panel of ubiquitin-based ABPs bearing substituents on the propargylamide warhead. Finally, the most important findings are summarized in Chapter 7, and placed in the context of covalent drug discovery. Show less
Schistosomiasis is a parasitic infection caused by worms of the genus Schistosoma. It is a neglected tropical disease, affecting mainly populations living in poverty without adequate sanitation.... Show moreSchistosomiasis is a parasitic infection caused by worms of the genus Schistosoma. It is a neglected tropical disease, affecting mainly populations living in poverty without adequate sanitation. Treatment relies on one drug mainly, praziquantel, and its efficacy is dependent on the diagnostic tool used.Due to the parasite’s intravascular localisation, it is difficult to directly quantify them in infected humans. Thus, methods of detection like worm-derived circulating cathodic antigen (CCA) in urine or circulating anodic antigen (CAA) in urine and serum, have gained more attention. This thesis aims to explore and shed light on how to interpret schistosome-related circulating antigens CCA and CAA. We have addressed the interpretation of schistosome related assays in endemic and non-endemic regions, supported by data obtained from an animal study. Different diagnostic value can be attributed to different assays within different contexts. The results highlight the importance of a better understanding of antigen excretion patterns by different species to support optimalisation of antigen-based diagnostics of schistosomiasis. Show less