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Pathogenic mechanisms and therapeutic target discovery in chronic immune-mediated inflammatory diseases:Insights into the role of the lymphatic system and drug repurposing strategies
No full textThe aim of this thesis was to unravel pathogenetic mechanisms and identify novel therapeutic strategies in immune-mediated inflammatory diseases (IMIDs), with a focus on the lymphatic system in inflammatory bowel disease (IBD) and on transcriptomics-driven drug repurposing across IMIDs.In the first part of this thesis, we investigated the role of lymphoid structures in IBD pathogenesis, treatment response, and immunogenicity to biologics. We showed that mesenteric lymph nodes and lymphatic vessels actively shape immune priming, antigen presentation, and lymphocyte trafficking. Using cytometry-based profiling, we found that anti-drug antibody formation against anti-TNF therapies was associated with elevated B-cell and dendritic cell frequencies within lymph nodes. Furthermore, we demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators, such as etrasimod, profoundly alter T-cell migration, highlighting lymphocyte trafficking as a tractable therapeutic axis in IBD.In the second part, we applied transcriptome-guided drug repurposing pipelines to identify novel therapeutic candidates. In systemic lupus erythematosus, we uncovered compounds, which could potentially restore monocyte-derived pathologic gene signatures, including heat shock protein-90 and inflammasome inhibitors. In individuals at risk for rheumatoid arthritis, we identified agents targeting the PI3K kinase and matrix metalloproteinase-9 pathways that could reverse preclinical synovial signatures, thus offering preventive potential. In Crohn’s disease–associated intestinal fibrosis, we discovered that dual blockade of PI3K and histone deacetylases synergistically attenuated fibroblast activation, proposing a new anti-fibrotic strategy.We conclude that the lymphatic system function is a central determinant of IBD pathogenesis and treatment outcomes, while omics-based drug repurposing provides promising, cost-efficient avenues for precision therapy across IMIDs. These insights pave the way for mechanism-driven interventions to improve outcomes in autoimmunity
Metaphor use in aphasia
No full textIn the conceptual metaphor theory (CMT), one tenant is that metaphors are ubiquitous in our everyday language. This dissertation tried to make a thorough investigation into how linguistic metaphors are used by people with aphasia (PWA). Aphasia is an acquired language disorder that affects people’s language production and understanding; it can be divided into two types: non-fluent and fluent, according to the fluency of sufferers’ speech. Some former studies have revealed deficiencies of certain word classes produced by these two groups of PWA. Apart from linguistic metaphors, the metaphor use in aphasia can be also discussed under the scope of CMT: in people’s speech about aphasia, aphasia treatment, and rehabilitation, we can find conceptual metaphors and analyse them to see how aphasia is conceptualized in discourse. The overall research goal of this dissertation is to examine how metaphors are used in aphasia from two perspectives: linguistic and conceptual.Results have shown features of PWA’s production of linguistic metaphors in some word classes; in some word classes, metaphor distribution is not balanced in different types of aphasia. By analysing the interaction between metaphor, word class, and participant group in English and Mandarin data, we can have a deeper understanding of metaphor use by PWA. As for the analysis of metaphorical framings about aphasia and aphasia recovery, it can be helpful for practitioners and family caregivers to communicate with PWA in the rehabilitation process. Moreover, metaphorical framings on aphasia can shape how we think about aphasia and PWA
Health outcome after preterm birth:A microbiota perspective
No full textIn this dissertation, we seek to understand health after preterm birth from a gut microbiota perspective. Neonatal antibiotic exposure and fecal metabolic and microbial changes were examined as potential risk factors for acute and chronic conditions after preterm birth. In addition, techniques for fecal odor analysis and spatial orientation of gut bacteria were explored in preterm infants. Our results might contribute to strategies to predict, prevent, recognize and treat necrotising enterocolitis, neonatal sepsis and meningitis, and long-term non-communicable diseases
EU coordinating competences:Hardening norms in European socio-economic governance
No full textThis dissertation aims to contribute to the theoretical discussion in EU legal scholarship on the relationship between law and other approaches to governance which coexist and interact with law in the EU legal order. More specifically, it analyzes the exercise of EU coordinating competences as one key instance of governance which differs from law in important ways. What is meant by EU coordinating competences is economic, employment and social policy coordination in the EU as laid down in Article 5 TFEU. The argument advanced in this dissertation is that we can observe a hardening of policy coordination over time in all three policy areas. In other words, the norms adopted through policy coordination processes can no longer be characterized as non-binding (or voluntary) even if they are formally laid down in non-binding legal instruments. More importantly, law has played a crucial role in the hardening of economic, employment and social policy coordination in the EU since the onset of the euro crisis. This finding supports the broader argument advanced in this dissertation that law and other approaches to governance in the EU are characterized by a relationship of mutual transformation
Artificial intelligence for intelligent care:How machine learning algorithms can enhance the personalised treatment of patients with haemophilia A
No full textThis thesis explores the integration of machine learning with pharmacometrics to enhance the treatment of haemophilia A, a rare X-linked bleeding disorder characterized by an increased risk of spontaneous bleeding. The introduction provides an overview of the disorder, the history of prophylactic treatment, and the role of pharmacokinetics (PK) in personalized care, concluding with a discussion of future therapies such as non-factor replacement. The potential of machine learning is introduced, emphasizing algorithms like random forests, neural networks, and Gaussian Processes, alongside challenges specific to pharmacometrics such as data sparsity and interpretability. Recent ML applications in pharmacometrics are reviewed, discussing usage as part of data preparation, hypothesis generation, and predictive modelling. The thesis then presents deep compartment models (DCMs), a hybrid framework combining neural networks with differential equations, which simplifies PK modelling, handles sparse data effectively, and outperforms traditional methods in speed and accuracy. Variational inference (VI) is proposed as an alternative to conventional mixed-effects estimation, yielding stable and precise results. Applications of machine learning algorithms for improving haemophilia A treatment are detailed, including models for predicting factor VIII (FVIII) pharmacokinetics in prophylactic and perioperative settings and for optimizing dosing based on bleeding risk using repeated time-to-event (RTTE) models. The OPTI-CLOT web-portal is introduced as a platform for personalized dosing recommendations. The thesis concludes by advocating for hybrid machine learning approaches to address challenges in personalized treatment, offering insights for broader adoption in rare disease management
Disentangling the metabolic and psychological wiring in obesity:A look beyond the scale
No full textThis thesis investigates the biological mechanisms underlying obesity and obesity-related diseases, such as type 2 diabetes and MASLD-MASH, through a systems biology perspective. It emphasizes the multifactorial nature of obesity and its complexities. At its core is the BARIA study, a large longitudinal cohort examining metabolic and psychological changes following bariatric surgery.A key focus is bile acid metabolism, leveraging a unique dataset of portal bile acids to gain deeper insights into the enterohepatic circulation in individuals with severe obesity. The interaction between portal bile acids and the gut microbiota emerges as critical. Alterations in bile acid profiles after surgery revealing pathways potentially linked to diabetes remission.The thesis also addresses complications of bariatric surgery, such as post-bariatric hypoglycemia. Using high-throughput sequencing, acylcholines were identified as a novel pathway that may influence glucose metabolism, providing new insights into the condition’s underlying mechanisms.Psychological dimensions of obesity are explored, including the identification of distinct psychological phenotypes that may impact post-surgery outcomes. Additionally, the role of self-compassion is highlighted as a potential factor in enhancing patients' overall well-being.Finally, the gut microbiota's role is underscored by the discovery of microbiota-generated ethanol in the portal vein, correlating with MASLD-MASH markers and suggesting a significant role in disease pathogenesis.In summary, this research integrates microbiome, metabolic, and psychological factors, advancing understanding of the complexity of obesity and metabolic diseases while paving the way for innovative, personalized treatments
Deserving refugees?:The evolution of a concept in the Dutch Republic (1570-1730s)
No full textThe Dutch word for ‘refugee’ (vluchteling) is relatively new according to the Woordenboek der Nederlandsche Taal and traces its origin to the early seventeenth century. It only became common in general language at the end of that century, specifically as a description for Protestants fleeing religious persecution and oppression in France. This linguistic development, however, must be seen in the light of a long-term and broader socio-cultural change in the attitude against foreigners. This study examines this development. It questions when, how and why the concept of ‘the refugee’ evolved into a specific category of migrant. To examine the emergence and evolution of the concept of ‘refugee’ during a period when this term was not part of a formal legal vocabulary, I distinguished between the development of the concept as a type of migrant and the terminology that was actually used. The concept was shaped by the distinction between ‘desirable’ and ‘undesirable’, and between those deemed ‘deserving’ and ‘undeserving’ of aid. The evolution of the ‘deserving refugee’ was driven by administrative needs, religious and geopolitical dynamics, economic interests of local elites, and the advocacy efforts of displaced communities. These factors collectively shaped the understanding of the ‘refugee’
De laatste heer van Amerongen, een Europees edelman in een Nederlandse dorpsgemeenschap:Godard John George Charles Godard graaf van Aldenburg Bentinck 1857-1940, edelman laverend tussen dynastieke, lokale en internationale belangen
No full textAristocraten kunnen zich in verschillende Europese landen verheugen in de belangstelling van historici. Ook in Nederland speelden aristocraten een belangrijke rol in het publieke leven. Nederland is in de geschiedenis geregeld neergezet als de burgerlijke natie bij uitstek. Vaak wordt daarbij verwezen naar het werk van de historicus Johan Huizinga. Daardoor werd minder aandacht geschonken aan de adellijke en patricische families en hun invloed op de zich ontwikkelende Nederlandse Staat. Deze studie naar het leven van de (Europese) edelman Godard Bentinck geeft een aanzet tot inzicht in adellijke families vanuit het perspectief van een individuele edelman binnen zijn omgeving. Het is een bijzonder onderzoek vanwege de biografische component zowel als de bredere betekenis voor de moderne Nederlandse geschiedenis in de Europese context. Kastelen en buitenplaatsen kunnen op een brede publieke belangstelling rekenen, er verschijnen diverse publicaties over huizen en tuinen, maar deze hebben over het algemeen een toeristische, of tuin- en architectuurhistorische insteek. Maar weinig studies belichten de historische relatie tussen dergelijke huizen en hun eigenaren, en vrijwel nooit wordt daarbij uitgezoomd naar de (inter)nationale, en ingezoomd op de lokaal-regionale context waartoe deze zich verhielden. De voormalige woning van deze edelman, kasteel Amerongen, is inmiddels een museum. De Nederlandse samenleving investeerde vele miljoenen in de metamorfose van dit Huis. Onderzoek naar de betekenis ervan dient een publieke zaak: inzicht en duiding geven aan de geschiedenis van de Nederlandse adel
Stronger together:Stabilizing the interactions between HCV E1 and E2 for vaccines
No full textHepatitis C virus (HCV) infection places a major burden on global health, affects 50 million people and causes 250,000 yearly deaths. Yet, there is no HCV vaccine available. The only target for neutralizing antibodies against HCV is the E1E2 glycoprotein on the virion surface. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. Furthermore, standardized tools to study immune responses and vaccine effectiveness are needed to help in vaccine development. This thesis explores both the design of vaccines against HCV and the tools needed to evaluate the immune responses. The first section focuses on refining in vitro methodologies to study antibody responses against HCV and on the study of a family of broadly neutralizing antibody (bNAbs) that targets an antigenic region that overlaps with the receptor binding site of HCV and that has been the focus of many vaccine strategies. The second part of the thesis is then focused on antigen design, where different design strategies are explored and protein engineering strategies culminate in the design of a stabilized soluble E1E2 that does not require dimerization domains to resemble the native E1E2. The set of stabilizing mutations is applied to different strains of HCV and even to a synthetic sequence generated from the consensus sequences of 10 major subtypes of HCV, which results in an antigenically superior immunogen. The results of this thesis are a milestone for HCV vaccine design and provide the foundations for the next generation of vaccines against HCV
Vaccination in patients with a hematologic condition:Challenging the dogmas in vaccination of the immunocompromised
No full textPatients with hematologic conditions are often immunocompromised due to the disease or the therapy they receive. This makes them prone to severe infections and infection-related mortality. Some infections can be prevented through vaccination. However, a key question remains: how effective are these vaccines in this immunocompromised population? In this thesis, I will explore vaccine immunogenicity in patients with hematologic conditions and seek to understand how their immunodeficiencies influence vaccine-induced immune responses. In part I of this thesis, humoral immune responses obtained after pneumococcal polysaccharide and conjugated vaccination are discussed in patients after allogeneic hematopoietic stem cell transplantation and patients with chronic lymphocytic leukemia. In part II, this thesis focused on the humoral and cellular immune response after SARS-CoV-2 mRNA vaccination in seventeen cohorts of patients with different hematologic conditions and treatments. We demonstrated that vaccination of these immunocompromised individuals is more effective than initially expected, inducing potent cellular and humoral immunity in the majority of patients, provided that multi-dose vaccination schedules are followed. This was observed both for mRNA vaccines and for conjugated vaccines. In case of high disease prevalence, for example in flu season or during a pandemic, inactivated vaccines should not be postponed in these patients, irrespective of treatment status, because it is more important to develop as much protection as possible, instead of achieving a protection rate comparable to that of healthy individuals. Future research should focus on both humoral and cellular immune responses after vaccination and always investigate the effect of booster vaccination(s) in this population