Leiden University Scholary Publications
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Multifractal formalism from large deviations
Full text linkProbability TheoryAnalysis and Dynamical System
Molecular profiling and immunotherapy in the real-life clinical setting in non-small cell lung cancer
Full text linkModern treatment of non-small cell lung cancer (NSCLC) has evolved to include targeted therapy and immunotherapy. Because these treatments require specific genetic targets or PD-L1 expression, precise molecular profiling is essential.The first two studies in this thesis investigated ways to optimize these diagnostics. One study showed that systematic, comprehensive profiling of tumor tissue can achieve success rates up to 91%. Both studies also evaluated circulating tumor DNA (ctDNA) from blood samples. This ‘liquid biopsy’ was successful in over 98% of cases. In metastatic NSCLC, ctDNA analysis reached over 75% sensitivity for identifying actionable targets, providing a vital alternative when tissue biopsies are unavailable.The second part of the research focuses on immunotherapy efficacy. Analysis of pembrolizumab and nivolumab (the latter studied in a real-world cohort of 248 patients) showed significant survival benefits. For nivolumab, the 3-year survival rate was 17.1%, rising to 55.3% for those who responded to treatment. Adverse events were generally mild and manageable.Ultimately, optimizing molecular diagnostics through both tissue and blood analysis is crucial for delivering personalized, effective treatment to more NSCLC patients.LUMC / Geneeskund
Conservation and management of lions in Kenya: an assessment of factors influencing Panthera leo melanochaita (Hamilton Smith, 1842) population dynamics
Full text linkDespite their ecological, cultural, and economic importance, lion (Panthera leo) populations in Kenya are declining rapidly due to retaliatory killings following livestock depredation, depletion of wild prey, habitat loss driven by human activities, climate change, and disease. To counter these declines, Kenya has adopted a range of conservation strategies aimed at promoting human–lion coexistence and protecting suitable habitats. However, these strategies are often applied uniformly, without fully accounting for the substantial ecological, anthropogenic, and genetic differences influencing lion populations.Kenya encompasses diverse climatic conditions and habitats, with lions managed across a fragmented network of state-protected national parks and reserves, community conservancies, group ranches, and private ranches or conservancies. These areas differ markedly in ecological characteristics, protection levels, and management objectives, ranging from strictly protected national parks to multi-use landscapes that integrate conservation with human land-use needs. Such variation is likely to have population-specific effects on lion ecology and dynamics.This thesis investigates key factors influencing lion population dynamics across multiple populations in Kenya, with a focus on: (i) the effects of management strategies on genetic diversity, (ii) the influence of ecological and anthropogenic factors on lion grouping patterns, and (iii) the effects of rainfall on lion home range and movement. In addition, the thesis evaluates the applicability of Spatially Explicit Capture–Recapture (SECR) methods as a robust tool for long-term lion monitoring and conservation.Genetic analyses of 171 lions from 12 core areas revealed clear population structure without evidence of inbreeding, with differentiation shaped by geographic barriers, human activities, climatic factors, fencing, and translocations. Analyses on lion grouping patterns showed that group size varied across management types and landscapes, with smaller groups occurring closer to human, suggesting that edge effects were impacting lions on a national scale. While larger groups were associated with proximity to water sources. Movement analyses demonstrated that increased rainfall was associated with greater travel distances and, in some cases, expanded home ranges, highlighting the influence of climate variability. SECR analyses revealed seasonal differences in density and movement.Collectively, these findings underscore the importance of community involvement, functional habitat connectivity, and adaptive, site-specific management strategies. The thesis supports the establishment of landscape-scale lion management units that foster collaboration among government agencies, local communities, private landholders, and group ranches to ensure the long-term conservation of lions in Kenya.Environmental Biolog
Philological analysis of ancient Egyptian recipes supported by modern chemical profiling approaches
Full text linkNaturali
How to self-organise?: Insights from workers at Albert Heijn (Ahold) and Unox (Unilever) in the Netherlands, 1960–2020
Full text linkCities, Migration and Global Interdependence 1350-200
Exploring the landscape of rheumatoid arthritis: piecing together risk factors and autoantibodies
Full text linkRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and progressive tissue damage. Autoantibodies are a hallmark of RA. However, little is known about the risk factors and clinical outcomes associated with different isotypes of anti-modified protein antibodies (AMPAs), such as ACPA-IgG, AMPA-IgA, and AMPA-IgM. AMPAs found in RA include anti-citrullinated protein antibodies (ACPA), anti-acetylated protein antibodies (AAPA), and anti-carbamylated protein antibodies (anti-CarP). This thesis focuses on clarifying these aspects.The main findings of this research reveal that ACPA-IgG is specifically associated with genetic risk factors, particularly the HLA-DRB1 shared epitope. This genetic predisposition is linked to the glycosylation of the variable domain of ACPA, which plays a significant role in disease development. In contrast, smoking is associated with the production of AMPA-IgA, supporting the mucosal origin hypothesis of RA.Clinically, ACPA was found to be a key biomarker for both radiological progression and the likelihood of achieving sustained drug-free remission. Anti-CarP, on the other hand, was associated with radiological progression in ACPA-negative patients, while AAPA showed no additional value in predicting clinical outcomes such as radiological progression or remission. These findings underscore the clinical relevance of autoantibodies in disease prognosis and treatment strategies for RA.LUMC / Geneeskund
Bioorthogonal tools to study fatty acid uptake in immune cells
Full text linkThe cellular metabolism of immune cells constitutes an important part of their proper function and activation. Using T cells as an example, this phenomenon is highlighted by the metabolic reprogramming that occurs in these cells upon activation. The metabolic reprogramming is supported by an increased uptake of exogenous nutrients, such as glucose, amino acids, and fatty acids (FAs). The ability to unravel this complex interface between the immune system and cellular metabolism relies on the development of appropriate chemical tools. The aim of this thesis was to develop sterculic acid (StA) as a bioorthogonal analogue of the immunomodulatory FA oleic acid (OA), and to use this as a tool to study the uptake of StA in different immune cells. Here, we report the first use of StA as a bioorthogonal analogue of OA. It was shown that StA was readily taken up in vitro by a plethora of immune cells and could react with tetrazine-modified reporter molecules (e.g. fluorophores) via an inverse electron-demand Diels-Alder reaction, presenting a non-toxic, live-cell compatible alternative to other commonly used bioorthogonal reactions. The versatility of this approach allowed for multiplexing with other bioorthogonal reactions, permitting the simultaneous study of multiple biomolecules (Chapter 2). The workflow could further be adapted and applied to study the lipidation of proteins as a PTM (Chapter 3), as well as to investigate phenotypic and multiomic differences between T cells with a differential StA-uptake (Chapter 4). The adaptability of the workflow emphasises its strength and applicability as a chemical tool to study FA uptake.Bio-organic Synthesi
Alternative approaches to enhance risk stratification and evaluation of treatment in valvular heart disease
Full text linkTransthoracic echocardiography is key for risk stratification in patients with valvular heart disease. This thesis shows the value of echocardiography to assess the optimal timing for AVR in patients with severe AS. Advanced echocardiographic measurements such as RV strain together with PFT could improve risk stratificationof patients undergoing AVR. Comprehensive echocardiographic assessment using the staging concept, and integrating this with advanced echocardiography,appears fundamental for risk stratification of patients undergoing intervention of the mitral or aortic valve, but also for follow-up after the procedure. LUMC / Geneeskund
