Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by limited treatment options and unfavorable clinical outcomes. Therefore, the research described in this thesis... Show moreTriple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by limited treatment options and unfavorable clinical outcomes. Therefore, the research described in this thesis focused on the exploration of novel targeted therapies for TNBC. Through high-throughput screening, we assessed the responsiveness of TNBC cells to kinase inhibitors, which indicated a notable sensitivity to cyclin-dependent kinase (CDK) inhibitors. Building upon these findings, this thesis systematically compares the efficacy of targeting various transcription-associated CDKs, with CDK9 and CDK12 emerging as highly potent targets for disrupting TNBC cell proliferation. Transcription-associated CDKs play multiple roles in regulating mRNA transcription. Yet, inhibitors of these CDK’s induced selective, rather than global, changes in gene expression. This provides insights into their mechanisms of action and suggesting potential opportunities for combination therapy. Furthermore, our research elucidated the mechanism underlying the synergistic effects of combining kinase inhibitors with transcriptional CDK inhibitors, by demonstrating that this is mediated through the inhibition of cellular drug efflux by ABCG2. In conclusion, this thesis highlights the potential of transcription-associated CDK inhibitors as a promising avenue for treating TNBC. The insights from this thesis will help to further steer the (pre)clinical development and strategy of using transcription-associated CDK inhibitors for the treatment of TNBC. 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
This dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded... Show moreThis dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded matter. Unblinding might partially mitigate the limitation, but current measurement methods have gaps that we should remain aware of. Detailed measurements of subintervals with characterization of ion channel profiles, concentration QTc modelling, or machine learning might help physicians in their decision making in the future. 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
In this thesis we push the boundaries of high-resolution imaging at radio frequencies between 100 and 200 MHz. Using the International LOFAR Telescope that spans across Europe we achieve sub... Show moreIn this thesis we push the boundaries of high-resolution imaging at radio frequencies between 100 and 200 MHz. Using the International LOFAR Telescope that spans across Europe we achieve sub-arcsecond angular resolution. We demonstrate mapping of the full field of view of the telescope at its native resolution and use the resulting images to study active galactic nuclei in the Lockman Hole field. Show less
This thesis describes a set of excitability measurements -transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG), nerve excitability threshold... Show moreThis thesis describes a set of excitability measurements -transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG), nerve excitability threshold tracking (NETT), and muscle velocity recovery cycles (MVRC)- and the applicability of these tools in early phase clinical drug development. We validated the biomarkers in healthy subjects with registered drugs and showed that the measurements are all repeatable and sensitive to pharmacological effects, even in a small number of subjects. Furthermore, we have evaluated effects of a novel AMPA-positive allosteric modulator with TMS-EMG/EEG, and a first-in-class skeletal muscle-specific chloride channel (ClC-1) inhibitor with MVRC, and the findings helped us to confirm proof-of-mechanism of these compounds in healthy subjects. In conclusion, these measurements proved to be valuable pharmacodynamic biomarkers in two drug development programs, encouraging their further use in clinical development of other future drug candidates targeting cortical-, neuronal-, and muscle cell excitability. The use of such clinical pharmacodynamic biomarkers could improve the quality and efficiency of the development process of drugs for e.g. amyotrophic lateral sclerosis, chronic pain, depression, treatment-resistant epilepsy, and neuromuscular diseases. Show less
This work explores the notion of independence as it relates to international civil servants and secretariats. It identifies the fundamental characteristics of the term and examines how the... Show moreThis work explores the notion of independence as it relates to international civil servants and secretariats. It identifies the fundamental characteristics of the term and examines how the independence of international civil service can erode. It describes the acts and omissions of three main actors responsible for preserving this independence: member states, international organizations, and international civil servants. The work concludes by providing concrete recommendations for strengthening the independence of the international civil service. Show less
The healthcare landscape is constantly evolving. eHealth (electronic health) presents opportunities to alleviate pressure in healthcare, for example by empowering patients to take more control over... Show moreThe healthcare landscape is constantly evolving. eHealth (electronic health) presents opportunities to alleviate pressure in healthcare, for example by empowering patients to take more control over their care. This thesis has examined various digital applications that have already been (partially) implemented. The research primarily focuses on the user-friendliness and effectiveness of these digital applications, aiming to promote self-management and accessibility of healthcare. The digital applications in this thesis relate to requesting diagnostic tests, both with and without involvement of healthcare professionals. Diagnostic tests enable the detection of conditions, such as sexually transmitted diseases for instance. Additionally, research has been conducted on the effectiveness of a self-management program for asthma and COPD. The results generally indicate that patients and citizens, particularly the younger generation, are receptive to online applications aimed at supporting their self-management of health and illness. Nevertheless, certain factors influence their acceptance, such as reliability and user-friendliness. Therefore, it is essential to promote collaboration among all stakeholders to enhance usability and ensure that online applications effectively meet their intended purpose and objectives. 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 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
Thromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it... Show moreThromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it at the same time increases risk of bleeding. With nationwide data from Statistics Netherlands, antithrombotic therapy and relevant clinical outcomes were comprehensively examined in the patient population of atrial fibrillation, overall or among those with comorbid cancer. The results suggest the patient population was increasingly receiving anticoagulants, driven by the newly introduced medication- direct oral anticoagulant and guided by the CHA2DS2-VASc score, and meanwhile the patient population experienced fewer ischemic stroke and major bleeding. In spite of these promising changes, suboptimal medication adherence and potential underuse of anticoagulants remain directions for further improvement. Antithrombotic agent use during pregnancy was also examined in the general Dutch pregnant population, which featured a surge in antiplatelet prescriptions, and risk of preeclampsia/eclampsia decreased and several newborn outcomes improved simultaneously. Together, the studies presented in this thesis provide an overview of antithrombotic therapy in the Netherlands in recent years, providing insights for further improving this treatment and relevant patient outcomes. Show less
This dissertation explores the ways in which affective responses to disabled bodies are represented and how this invites us to read these bodies aesthetically. I argue that this affective impact... Show moreThis dissertation explores the ways in which affective responses to disabled bodies are represented and how this invites us to read these bodies aesthetically. I argue that this affective impact can be understood as an affordance, a term I use to describe how the appearance of and interaction with disabled bodies produces affective responses such as fear, wonder, or disgust. I study the relationship between representation and affective reactions through literature and other art forms. Through close readings of literary texts and works of art, this dissertation offers an alternative to so-called model thinking—an approach that emphasizes categorization. Instead, I propose a reading that focuses on how bodily capacities are culturally and socially translated into (dis)abilities. Unlike taxonomic approaches that categorize and generalize, this method allows moving from the particular to the private. Works of art, although prone to generalization, emphasize their unicity and resist categorization. By analyzing how different art forms represent disabled bodies, the dissertation brings a new dimension to understanding our emotional responses and the aesthetic appreciation of bodily diversity. 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
In this PhD study, I aim to deepen our understanding of the influence of major mycorrhizal types, namely arbuscular mycorrhizae (AM) and ectomycorrhizae (EM), on the global soil carbon cycle and... Show moreIn this PhD study, I aim to deepen our understanding of the influence of major mycorrhizal types, namely arbuscular mycorrhizae (AM) and ectomycorrhizae (EM), on the global soil carbon cycle and their potential distribution changes under future environmental shifts. The investigation comprises two main perspectives: Firstly, Chapter 2 delves into their direct impact on fungal biomass input to the soil via lab experiments. Secondly, Chapters 3, 4, and 5 explore their role in mediating litter decomposition through modeling. This thesis sheds light on the significance of mycorrhizal fungi in the soil carbon cycle and underscores the necessity of accounting for their effects when analyzing global soil carbon dynamics. Additionally, the research underscores the importance of understanding mycorrhizal fungi responses to environmental changes, given their sensitivity to factors like temperature and precipitation. Show less
