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
Betrokken burgers vormden de ruggengraat van de Republiek. Het dagelijks leven draaide voor een groot deel op buurtorganisaties, gilden en schutterijen – en dat waren juist de stedelijke... Show moreBetrokken burgers vormden de ruggengraat van de Republiek. Het dagelijks leven draaide voor een groot deel op buurtorganisaties, gilden en schutterijen – en dat waren juist de stedelijke instituties waar zij deel van uitmaakten. In 1796 kondigden de Bataafse revolutionairen het einde van sommige van deze instellingen af en introduceerden zij het staatsburgerschap. Maar was daarmee de rol van de stedelijke burger ook uitgespeeld?Dat komen we te weten als we luisteren naar de stadsbewoners zelf. Aan de hand van de levens van Haarlemmers en Groningers tussen 1747 en 1848 illustreert dit boek het voortbestaan van lokaal burgerschap. Zij komen aan het woord via verzoekschriften, kronieken, gelegenheidsgedichten, vergadernotulen en mondelinge klachten op de burgemeesterskamer. Hoe zag de ideale stedelijke gemeenschap er volgens hen uit? Welke rechten en plichten had een burger in hun ogen? En wat waren de dure plichten van een stadsbestuurder? Voor dit burgerschap putten stadsbewoners met souplesse uit traditionele én revolutionaire idealen en praktijken. 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
Interest groups play an important role within a democratic society. Less is known about their role within the legal system. Meanwhile, interest groups are the driving force behind many high-profile... Show moreInterest groups play an important role within a democratic society. Less is known about their role within the legal system. Meanwhile, interest groups are the driving force behind many high-profile lawsuits against the Dutch government, such as the lawsuits concerning climate change, the quality of asylum facilities, and the Dutch nitrogen policy. This research focuses on the access of interest groups to the courts. How extensive is their access? Does it threaten or protect a democratic society under the rule of law? The access of interest groups to Dutch administrative and civil courts is evaluated in terms of legitimacy and effectiveness. Since interest group litigation is at the intersection of politics and law, the research adopts an interdisciplinary approach. Beyond the boundaries of Dutch legal scholarship, it seeks insights from social sciences regarding the role of interest groups within the political decision-making process. Additionally, it examines, from a legal sociological perspective, the role that interest groups play in public interest litigation in the United States. As a result, the research explores approaches, concepts, and arguments that have largely remained outside of the Dutch legal legal discourse. Ultimately, this leads to a reassessment of both the legitimacy and effectiveness of interest groups' access to the courts. 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
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
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
Contrary to common belief, sign languages are distinct across different communities and cultures, evolving organically through interactions among deaf people, rather than being based on spoken... Show moreContrary to common belief, sign languages are distinct across different communities and cultures, evolving organically through interactions among deaf people, rather than being based on spoken languages. Each sign language has its own grammar, vocabulary, and cultural nuances, with variations even within a single country, showcasing the diverse communication methods within the deaf community. Deaf individuals often face encouragement to use spoken language techniques like lipreading or text communication, highlighting a bias towards spoken languages. This is compounded by the lack of sign languages in linguistic technologies, emphasizing the need for more inclusive research and development. This dissertation aims to address this gap using machine and deep learning to improve sign language processing and recognition. It covers six chapters, introducing methods for video-based sign annotation, webcam-based sign language dictionary search, and ranking systems for sign suggestions. It also explores tools for visualizing and comparing sign language variation, contributing valuable resources to linguistic research. Show less
Palliative care is care improving the quality of life of patients and their families, who are facing a life-threatening condition or frailty, through prevention and relief of suffering by means of... Show morePalliative care is care improving the quality of life of patients and their families, who are facing a life-threatening condition or frailty, through prevention and relief of suffering by means of early identification and careful assessment, and treatment of problems of a physical, psychological, social, and spiritual nature. This thesis describes five studies that evaluated the support of clinicians not specialized in palliative care, or generalists in palliative care. The results show that generalists need education on basic palliative care principles and need support with the initiation of a palliative care approach on time, especially when they care for patients with life-limiting illness other than cancer. To have mor attention for alle problems in the physical, psychological, social and spiritual dimension of care, they can be supported with a more structured approach to the total burden of symptoms and problems. This could be achieved by supporting them with a clinical decision support system for symptom management in palliative care. Such a system can be used for every individual patient, includes a symptom predictor, and provides recommendations on treatment and referral possibilities. Show less
The work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related... Show moreThe work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related risk factors described in young and middle-aged populations and the risk of venous thrombosis (VT) in the elderly; second, we aimed to provide insight into several long-term consequences (i.e., health-related quality of life (HRQoL) and long-term risk of mortality) after a first VT at old age. Show less
The early history and development of the historiographical method and theory of “conceptual history” resp. “Historical Semantics”—the latter being the overarching term that includes the... Show moreThe early history and development of the historiographical method and theory of “conceptual history” resp. “Historical Semantics”—the latter being the overarching term that includes the specifically German version of conceptual history (= Begriffsgeschichte)—is still widely unknown. One of the first central protagonists of the beginnings of this now widely appraised historiographical approach was the German-Jewish historian Richard Koebner (1885-1958). As a transnational actor, Koebner was not only part of the specifically German beginnings of Begriffsgeschichte during the Weimar Republic, but he was also—after his forced emigration to Jerusalem and during his retirement-years in London—influential for the development of Historical Semantics in Israel and England. Show less
Acute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is... Show moreAcute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is atherosclerosis, which is caused by the accumulation of lipids and inflammatory cells in the vessel wall, in so-called atherosclerotic plaques. Current therapies mainly target the disturbed lipid homeostasis, but recent clinical trials have shown a clear benefit in treating patients with anti-inflammatory drugs. However, more specific targeting is required to avoid unwanted side effects. In this thesis, we have generated a detailed atlas of all the cells present in human atherosclerotic plaques using a novel state-of-the-art technique called single-cell RNA sequencing. This data set can be applied as a powerful tool to select potential drug targets with a functional relevance for atherosclerosis. We showed that the majority of the immune cells in the human atherosclerotic plaque consisted of T cells. Subsequently, we identified a pro-inflammatory population of T cells that likely responds to a plaque-derived antigen, suggesting that atherosclerosis has an autoimmune-like component. Finally, we have applied our single-cell atlas to define and validate targets to intervene with the recruitment and activation of mast cells and other immune cells in atherosclerosis. Show less
Synthetic methodlogy is described, aiding in the synthetic preparation of putative inhibitors of retaining and inverting glycosidases and glycosyl transferases. All constructs are cyclophellitol... Show moreSynthetic methodlogy is described, aiding in the synthetic preparation of putative inhibitors of retaining and inverting glycosidases and glycosyl transferases. All constructs are cyclophellitol-based cyclitols. Show less
This dissertation addresses the dynamic process of the Arab Muslim conquests in Bactria and their socio-political impacts in the region. It covers almost a century from 31–128/651–746. It discusses... Show moreThis dissertation addresses the dynamic process of the Arab Muslim conquests in Bactria and their socio-political impacts in the region. It covers almost a century from 31–128/651–746. It discusses the conquests within the context of the geographical and political complexity of the region. It highlights the local political situation before the Arab Muslims’ arrival and the active role of Bactrian rulers whose cooperation and resistance shaped and reshaped the conquests. In doing so, it combines a broad spectrum of sources. It brings Bactrian, Arabic (and relevant Middle Persian and Sogdian) documents with the literary sources, specifically Arabic narratives related to the conquests and Persian and Chinese reports. It also consults numismatic data, seals and sealings, inscriptions, and archaeological reports. Based on a systematic analysis of these sources, this dissertation shows that the Arab Muslim conquests of Bactria were not simply the results of a series of ‘pre-planned’ military operations initiated and led by the Arab Muslims, as it is often assumed to have been the case. In contrast, the conquests were highly complicated as they were deeply affected by the local and regional political situation that were not considered. The local and regional political competitions in late Sasanian Khurasan pulled the Arab Muslims into the region, where they helped the local rulers to implement their political agendas. However, being in Sasanian Khurasan allowed the Arab Muslims to learn about local political competition, become part of it, create their niche of power, and eventually establish their political domination over the region. The conquests of Sasanian Khurasan, Bactria, Sogdiana and Khwarazm (that formed Umayyad Khurasan) became possible only with the help of some local rulers who viewed the Arab Muslims as powerful allies to overcome their internal or neighbouring rivals. The local rivalries benefited the Arab Muslims the most as they provided space for the expansion and consolidation of Arab Muslim authority in the region in the long term. At the same time, the Arab Muslim settlements in the region marked the beginning of a centuries-long process of Islamicisation in Bactria, out of which the Islamic Balkh has emerged. Show less
Climate change is one of the largest challenges faced by humanity. To combat this research into alternatives to fossil fuels is ongoing. Dihydrogen is considered a good alternative fuel, since its... Show moreClimate change is one of the largest challenges faced by humanity. To combat this research into alternatives to fossil fuels is ongoing. Dihydrogen is considered a good alternative fuel, since its burning only forms water. A promising means of acquiring dihydrogen is photocatalysis, which can be driven by sunlight. This involves water oxidation and proton reduction, both half-reactions require a catalyst and photosensitizer, generally metal complexes. The limited aqueous solubility and stability of these complexes poses a challenge in their application. In this thesis we investigated the use artificial metalloenzymes (ArMs) for the catalysis and photosensitization of both half-reactions. ArMs can improve the aqueous solubility of these catalysts and provide a second coordination sphere that can be used to improve the stability and activity. The ArMs in this thesis were prepared using the axial coordination of a catalyst or photosensitizer to a protein via histidine. We set up an effective screening method for this coordination using semi-native PAGE. We then prepared and characterized one of the first ArMs with photocatalytic water oxidation activity. We prepared eight photosensitizing ArMs, of which two also able to catalyse hydrogen evolution. Two of these ArM systems were entirely earth-abundant metal-based and showed good activity. Show less
