Leiden University Scholary Publications
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Inflammatory and metabolic features of stromal cell subtypes in inflammatory bowel disease
Get PDFThe different studies present in this thesis have contributed to the complex puzzle of stromal subsets in IBD and their role in inflammation and metabolism. In Chapter 2, we reported the stromal cell subsets in the three most commonly used experimental colitis models: DSS-induced colitis, IL-10 KO colitis, and T cell transfer colitis for IBD. Additionally, the effects of commonly used IBD therapies (thiopurines/anti-TNF-α/anti-p40) were assessed on stromal subset abundance. In order to further investigate the role of stromal cells in IBD pathogenesis, in Chapter 3, we investigated the metabolic status of IBD derived stromal cells. The effect of glycolysis on the inflammation status was investigated in vivo and in vitro, possibly opening new avenues to explore this further in clinical strategies for treatment of IBD. The second part of this thesis focuses on a common complication in IBD, the perianal fistulas. In Chapter 4, the current literature on the diagnosis and characteristics of perianal fistulas was summarized and discussed, including the differences and similarities of CD-associated and cryptoglandular perianal fistulas. To increase our understanding of the role of the stromal cells in perianal fistulas, in Chapter 5, the role of fistula-derived fibroblast was further explored. LUMC / Geneeskund
Improving outcome of melanoma patients upon immunotherapy
Get PDFImmunotherapy with immune checkpoint inhibitors (ICB) has greatly improved survival for advanced melanoma patients. This thesis examines strategies to further optimize these therapies. We found that neoadjuvant ICB in stage III melanoma offers advantages over adjuvant therapy, including enhanced immune activation and the ability to assess treatment response. The OpACIN study revealed that standard dosing of ipilimumab and nivolumab was too toxic, but the OpACIN-neo study demonstrated that a lower dose of ipilimumab reduced side effects while maintaining high response rates. Patients with a pathological response had excellent outcomes with the IFN-γ gene signature and tumor mutational burden identified as key biomarkers for response and survival. For BRAFV600-mutated melanoma, both targeted therapies (BRAF/MEK inhibitors) and ICB are effective. The IMPembra study found that short-term addition of dabrafenib and trametinib to pembrolizumab was feasible, and seems to improve progression-free survival. Anti-PD-1 monotherapy remains attractive for patients with favorable characteristics, but optimal treatment duration is unknown. In a cohort of patients who stopped treatment without progression or toxicity, median treatment duration was only 12 months, and the majority remained free of progression. Early increases in LDH or S100B can identify patients who may need additional therapy. The findings in this thesis contribute to the significant advances in the treatment of advanced melanoma and have the potential to reshape the standard of care for stage III melanoma.NKI-AVLLUMC / Geneeskund
Civilizational Wilsonianism from Woodrow Wilson to Donald Trump
Get PDFHistory and International Studies 1900-presen
Petrarchism and Petrarch's reception in Haarlem and Leiden around 1600
Get PDFMedieval and Early Modern Studie
Activated CD27+PD-1+ CD8 T cells and CD4 T regulatory cells dominate the tumor microenvironment in refractory celiac Disease type II
Get PDFBACKGROUND AND AIMS: Refractory celiac disease type II (RCDII) is characterized by a clonally expanded aberrant cell population in the small intestine. The role of other tissueresident immune subsets in RCDII is unknown. Here, we characterized CD8 and CD4 T cells in RCDII duodenum at the single-cell level and in situ. METHODS: We applied mass cytometry on CD45þ duodenal cells derived from intestinal biopsies (n ¼ 23) and blood samples (n ¼ 20) from RCDII patients and controls. Additionally, we analyzed intestinal biopsies from celiac disease (n ¼ 11) and RCDI (n ¼ 2) patients. We performed single-cell RNA-sequencing on CD45þ duodenal cells derived from a RCDII patient, immunofluorescence staining for in situ analysis and flow cytometry for phenotyping of RCDII aberrant and CD8 T cells. RESULTS: Compared to healthy controls, we observed that CD27þPD1þ memory CD8ab cells and CD4 T regulatories (Tregs) were more abundant in RCDII duodenum (CD8 **0.0029; CD4 ***0.0001). The CD27þPD-1þ memory CD8ab cells expressed the tissue-resident marker CD69, immunoregulatory markers (TIGIT, HAVCR2, TNFRSF9), NKG2A, were enriched for activated pathways and displayed cytotoxic gene signatures (NKG7, PRF1, GZMA). The absence of CD103 accords with their localization in the lamina propria as determined by in situ analysis. The CD25þFoxP3þCD27þCD127dim/- CD4 Tregs expressed IL1R2 and IL32 and costimulatory molecules (TNFSRS4, ICOS and TNFRSF18) and resided in the lamina propria as well. Flow cytometry confirmed the presence of the inhibitory receptor NKG2A on expanded duodenal CD8 T cells and HLA-E, the ligand for NKG2A, on expanded aberrant cells. CONCLUSION: RCDII is characterized by the simultaneous presence of an activated CD27þPD-1þ memory CD8ab T cell subset and CD4 Tregs, suggesting that checkpoint blockade with anti-NKG2A/PD-1 and/or anticytotoxic T lymphocyte antigen 4 may be an attractive treatment option.Transplantation and autoimmunit
eDNA-based approaches advance ecotoxicology: insights and best practices from eDNA metabarcoding studies in evaluating stress-induced aquatic (macro-) invertebrate community composition
Get PDFEnvironmental Biolog
Design and characterization of porphyrin-based photosensitizing metalloproteins integrated with artificial metalloenzymes for photocatalytic hydrogen production
Get PDFMetals in Catalysis, Biomimetics & Inorganic Material
A multicomponent similarity approach to identify potential substances of very high concern
Get PDFThe number of chemicals being placed on the market is increasing. As such, there is an increased need for screening and evaluation of chemical hazards and risks. Particularly, chemicals with intrinsic properties that are considered of very high concern are ideally identified and regulated before wide-spread use and exposure. The use of in silico tools can help to identify potential substances of very high concern (SVHCs).Earlier, predictive models have been developed that identify potential SVHCs based on global structural similarity to known SVHCs. Here in this study, these read-across similarity models have been extended with other similarity modules, including toxicophore, biological and physicochemical similarity.The newly developed SVHC similarity profiles do individually not outperform the existing global similarity model. However, combining these new modules in an extended similarity approach results in more comprehensive predictions and allows for improved interpretability and applicability to the broader chemical universe. As such, this new approach is thought to support model users in interpretation of the model-prediction, and can thereby contribute to better screening and prioritization of potential SVHCs.Environmental Biolog
How do nature-based solutions contribute to biodiversity in cities?
Get PDFThe multifunctional character of nature-ased solutions (NbS) in cities, benefiting both biodiversity and human well-being, is gaining increasing attention. Designing multifunctional NbS in cities requires insights in how NbS contribute to biodiversity, since biodiversity supports ecosystem stability and resilience, and benefits for people. While knowledge of urban biodiversity has increased, a comprehensive understanding of how NbS contribute to biodiversity is still lacking. We analyzed the outcomes of 185 urban NbS cases in 87 cities across 33 countries, based on data collected in a systematic literature review. Our results show that 78% of NbS cases contribute positively to improving biodiversity when compared to non-NbS. In some cases, their performance was comparable to that of natural reference sites. Twenty-eight NbS cases evaluating multiple outcomes, beyond biodiversity, predominantly demonstrate win–win solutions for biodiversity and human well-being, although the evidence base remains limited. We showed that current evidence is limited to specific taxa (mostly animals), NbS types (e.g., gardens, forests), and commonly used metrics (e.g., species richness, abundance). We also found that only 39% of cases integrated baseline data, highlighting a lack of comparative studies effectively assessing NbS contributions to biodiversity. Our research provides insights for indicator selection to facilitate the evaluation of NbS for biodiversity and beyond, advancing the understanding of multifunctional NbS, and expanding NbS evaluations to provide accessible information for decision-making and policy.NWO17595Environmental Biolog