Leiden University Scholary Publications
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Generate what you can make: achieving in-house synthesizability with readily available resources in de novo drug design
Get PDFComputer-Aided Synthesis Planning (CASP) and CASP-based approximated synthesizability scores have rarely been used as generation objectives in Computer-Aided Drug Design despite facilitating the in-silico generation of synthesizable molecules. However, these synthesizability approaches are disconnected from the reality of small laboratory drug design, where building block resources are limited, thus making the notion of in-house synthesizability with already available resources highly desirable. In this work, we show a successful in-house de novo drug design workflow generating active and in-house synthesizable ligands of monoglyceride lipase (MGLL). First, we demonstrate the successful transfer of CASP from 17.4 million commercial building blocks to a small laboratory setting of roughly 6000 building blocks with only a decrease of -12% in CASP success when accepting two reaction-steps longer synthesis routes on average. Next, we present a rapidly retrainable in-house synthesizability score, successfully capturing our in-house synthesizability without relying on external building block resources. We show that including our in-house synthesizability score in a multi-objective de novo drug design workflow, alongside a simple QSAR model, provides thousands of potentially active and easily in-house synthesizable molecules. Finally, we experimentally evaluate the synthesis and biochemical activity of three de novo candidates using their CASP-suggested synthesis routes employing only in-house building blocks. We find one candidate with evident activity, suggesting potential new ligand ideas for MGLL inhibitors while showcasing the usefulness of our in-house synthesizability score for de novo drug design.Our core scientific contribution is the introduction of in-house de novo drug design, which enables the practical application of generative methods in small laboratories by utilizing a limited stock of available building blocks. Our fast-to-adapt workflow for in-house synthesizability scoring requires minimal computational retraining costs while supporting a high diversity of generated structures. We highlight the practicality of our approach through a comprehensive in-vitro case study that relies entirely on in-house resources, including in-silico generation, synthesis planning, and activity evaluation.Computer Systems, Imagery and MediaMolecular Physiolog
Clinical and patient reported outcomes in chronic kidney disease: Optimizing kidney care in an aging population
Get PDFPart 1 investigates urinary kidney injury markers using kidney transplantation as ischemia-induced acute kidney injury (AKI) model. In living donor-recipient pairs, urinary TIMP-2 and IGFBP7 excretion patterns seem indicative of glomerular filtration, while B2M and NGAL may reflect proximal tubular reabsorption. Among recipients of kidney donation after circulatory death, urinary NGAL may offer an alternative for 99mTcMAG3 renography to follow delayed graft function resolution. These results encourage research into the full potential of urinary biomarkers to pinpoint AKI. Part 2 examines serum potassium in advanced chronic kidney disease (CKD) and hemodialysis patients. A U-shaped relation was found between serum potassium and mortality, with a nadir in the upper normal potassium levels. These findings suggest cautious use of strict potassium-lowering treatment in advanced CKD. Part 3 assess health-related quality of life (HRQOL) and symptom burden in the year before and after dialysis initiation among older (≥65 years) patients. Both HRQOL and symptom burden worsened in the year before dialysis initiation, and stabilized but not fully recovered in the year thereafter. “Fatigue”, “decreased interest in sex” and “difficulty becoming sexually aroused” were most burdensome. This research helps set expectations for older patients starting dialysis and emphasizes the importance of monitoring patient-reported outcomes. LUMC / Geneeskund
Carving out success: identifying factors associated with metabolic and bariatric surgery outcomes
Get PDFThe global prevalence of overweight and obesity has reached epidemic proportions. Consequently, effective interventions such as metabolic and bariatric surgery (MBS) are essential for achieving substantial weight loss and reducing the elevated health risk associated with obesity. Nonetheless, it is important to acknowledge the significant variability in weight loss outcomes among individuals after these surgical procedures. This thesis explores factors associated with weight loss after MBS, highlighting the difficulty of predicting outcomes based on preoperative factors.Dutch Society for Metabolic and Bariatric Surgery, Celebrate Vitamins, WLS Products, Nederlandse Obesitas Kliniek, Dutch Obesity Academy, Elan Products|WLSvital, ABN AMRO and ChipSoftLUMC / Geneeskund
Artificial human ovary: advancing 3D ovarian culture for in vitro folliculogenesis, disease modelling and tissue regeneration
Get PDFInfertility affects over 186 million individuals worldwide, with female factors, particularly ovarian conditions, contributing to more than half of cases. Medically Assisted Reproduction (MAR) has transformed reproductive healthcare, yet significant challenges remain in understanding ovarian function and developing effective treatments for female infertility.This PhD thesis investigates innovative ex vivo culture strategies for ovarian cortical tissue, aiming to support the in vitro maturation of early follicles. Using cryopreserved-thawed ovarian tissue donated by transmasculine individuals, the research explores the potential of artificial ovary models for fertility preservation. Key findings include the identification of tissue fibrosis as a challenge in ovarian tissue culture and promising results regarding the use of Metformin to manage fibrotic ovarian tissue associated with aging and metabolic dysfunctions. Additionally, the thesis introduces a novel protocol for generating ovarian surface epithelium (OSE) organoids that retain donor-specific characteristics, highlighting their potential for personalized medicine.These findings represent a significant step forward in understanding ovarian physiology and developing innovative fertility preservation strategies. Beyond their scientific impact, they hold important social and medical relevance by underscoring the challenges that remain in developing in vitro folliculogenesis protocols and emphasizing the importance of considering the donor's metabolic and endocrine state, as well as the tissue source. Finally, by promoting more personalized and effective reproductive options while minimizing the use of animal models, this work contributes to advancing reproductive healthcare in an inclusive, ethical, and patient-centered manner.LUMC / Geneeskund
Metro van Thessaloniki: tussen blinkende façade en gemiste kansen
Get PDFZaterdag 30 november jongstleden was een gedenkwaardige dag voor Thessaloniki. Eindelijk, na vele jaren plannen en bouwen reed de metro onder de stad. Een modern wonder waarvan veel bewoners niet gedachthadden hem ooit in bedrijf te zien. Mensenmassa’s dromden samen om zich te vergapen aan de nieuwe stations en om een eerste rit te maken. Toch klonk er van meet af aan veel kritiek: op de haperende operatie,storingen en de gebrekkige infrastructuur op en rond de stations. Hoe vergaat het de metro twee maanden later? Lychnari ging ter plaatse.UBL - Publicaties niet-programma gebonde
Automated segmentation of the sacro-iliac joints, posterior spinal joints and discovertebral units on low-dose computed tomography for Na[18F]F PET lesion detection in spondyloarthritis patients
Get PDFPurpose: Spondyloarthritis (SpA) is a chronic inflammatory rheumatic disease which involves the axial skeleton. Quantitative sodium fluoride-18 (Na[F-18]F) PET/CT is a new imaging approach promising for accurate diagnosis and treatment monitoring by assessment of molecular bone pathology in SpA. Detection of Na[F-18]F PET positive lesions is time-consuming and subjective, and can be replaced by automatic methods. This study aims to develop and validate an algorithm for automated segmentation of the posterior spinal joints, sacro-iliac joints (SIJs) and discovertebral units (DVUs) on low-dose computed tomography (LDCT), and to employ these segmentations for threshold-based lesion detection. Methods: Two segmentation methods were developed using Na[F-18]F PET/LDCT images from SpA patients. The first method employed morphological operations to delineate the joints and DVUs, while the second used a multi-atlas-based approach. The performance and reproducibility of these methods were assessed on ten manually segmented LDCTs using average Hausdorff distance (HD) and dice similarity coefficient (DSC) for DVUs and SIJs, and mean error distance for the posterior joints. Various quantitative PET metrics and background corrections were compared to determine optimal lesion detection performance relative to visual assessment. Results: The morphological method achieved significantly better DSC (0.82 (0.73-0.88) vs. 0.74 (0.68-0.79); p < 0.001) for all DVUs combined compared to the atlas-based method. The atlas-based method outperformed the morphological method for the posterior joints with a median error distance of 4.00 mm (4.00-5.66) vs. 5.66 mm (4.00-8.00) (p < 0.001). For lesion detection, the atlas-based segmentations were more successful than the morphological method, with the most accurate metric being the maximum standardized uptake value (SUVmax) of the lesional Na[F-18]F uptake, corrected for the median SUV (SUVmedian) of the spine, with an area under the curve of 0.90. Conclusion: We present the first methods for detailed automatic segmentation of the posterior spinal joints, DVUs and SIJs on LDCT. The atlas-based method is the most appropriate, reaching high segmentation performance and lesion detection accuracy. More research on the PET-based lesion segmentation is required, to develop a pipeline for fully automated lesional Na[F-18]F uptake quantification
The evolutionary tale of gaseous exoplanets: a brief history of time - exoplanet edition
Get PDFThis thesis investigates the evolution and fate of gaseous exoplanets, which are continuously shaped by stellar activity across both short and long timescales. Short-term events, such as stellar flares, produce intense bursts of high-energy radiation that break apart molecules in the upper atmosphere of the exoplanet, driving significant chemical changes. Over longer periods, prolonged exposure to strong stellar irradiation gradually heats the planet, leading to atmospheric escape and potential transformation in its structure and composition. To better understand these processes, we employ chemical disequilibrium modelling, radiative transfer simulations, and planetary evolution codes to analyse the interiors and atmospheres of gaseous exoplanets. By doing so, we aim to determine how these external influences shape their composition, structure, and observable characteristics, shedding light on their long-term atmospheric evolution.High Energy Astrophysic
Review of Payne, L.A.; Zulver, J.; Escoffier, S. (2023) The right against rights in Latin America
Get PDFHistory and International Studies 1900-presen
Modelling the size distribution and bioaccumulation of gold nanoparticles under mixture exposure
Get PDFTo assess the bioaccumulation and toxicity of nanoparticles (NPs), analyzing and modelling the relationship between the size distribution of NPs in organisms and the exposure particle size distribution represents an important challenge. Previous studies mostly focused on the NPs with single size. However, the size distribution of NPs is wide and variable in the natural environment. There is a lack of research on the NPs with mixed sizes. This study investigated the size distribution of three gold (Au) NPs with different sizes and their mixtures within a ciliate Tetrahymena thermophila under the same number concentration of particles. Results revealed that smaller particles tended to aggregate and bioaccumulate more in cells. Using expectation–maximization algorithm, a particle size distribution model of NPs in cells was established. This model effectively simulated the size distribution of NPs with mixed sizes in cells, demonstrating high accuracy with a mean absolute error of Environmental Biolog
Healthcare utilisation patterns and drivers amongst inflammatory bowel disease patients in the outpatient clinic
Get PDFObjective Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, impose an escalating burden on healthcare systems globally, with a rising prevalence contributing to increased costs. This study explored healthcare utilisation patterns and its drivers amongst IBD patients in an outpatient clinic.Methods A longitudinal cohort study was conducted at a Dutch academic teaching hospital. IBD patients (n = 180) were followed for 1 year and were categorised based on disease activity and consultation frequency. Healthcare utilisation was assessed through consultations and laboratory tests. Patient-reported outcomes and biochemical disease activity were measured, and subsequently the reasons for consultations were analysed.Results The frequency of outpatient healthcare utilisation exceeded the recommended IBD care guidelines by two-fold. Comorbidities were the leading reason for consultations (40.4%), followed by remission induction, medication changes and pending test results. Moreover, clinical disease activity, reported problems with self-care, daily activities and pain were predictive of an increase in annual consultations.Conclusion This study identified factors influencing healthcare utilisation in IBD outpatients. Personalised care pathways using eHealth technologies have the potential to reduce unnecessary consultations and optimise resource allocation.Cellular mechanisms in basic and clinical gastroenterology and hepatolog