Cancer neoantigens that arise from tumor mutations are drivers of tumor-specific T cell responses, but identification of T cell-recognized neoantigens in individual patients is challenging.... Show moreCancer neoantigens that arise from tumor mutations are drivers of tumor-specific T cell responses, but identification of T cell-recognized neoantigens in individual patients is challenging. Previous methods have restricted antigen discovery to selected HLA alleles, thereby limiting the breadth of neoantigen repertoires that can be uncovered. Here, we develop a genetic neoantigen screening system that allows sensitive identification of CD4+ and CD8+ T cell-recognized neoantigens across patients’ complete HLA genotypes. Show less
Fischer, K.; Tieskens, J.M.; Luijten, M.A.J.; Zijlmans, J.; Oers, H.A. van; Groot, R. de; ... ; Popma, A. 2022
The aim of the study was to assess internalizing problems before and during the pandemic with data from Dutch consortium Child and adolescent mental health and wellbeing in times of the COVID-19... Show moreThe aim of the study was to assess internalizing problems before and during the pandemic with data from Dutch consortium Child and adolescent mental health and wellbeing in times of the COVID-19 pandemic, consisting of two Dutch general population samples (GS) and two clinical samples (CS) referred to youth/psychiatric care. Measures of internalizing problems were obtained from ongoing data collections pre-pandemic (N-GS = 35,357; N-CS = 4487) and twice during the pandemic, in Apr-May 2020 (N-GS = 3938; clinical: N-CS = 1008) and in Nov-Dec 2020 (N-GS = 1489; N-CS = 1536), in children and adolescents (8-18 years) with parent (Brief Problem Monitor) and/or child reports (Patient-Reported Outcomes Measurement Information System (R)). Results show that, in the general population, internalizing problems were higher during the first peak of the pandemic compared to pre-pandemic based on both child and parent reports. Yet, over the course of the pandemic, on both child and parent reports, similar or lower levels of internalizing problems were observed. Children in the clinical population reported more internalizing symptoms over the course of the pandemic while parents did not report differences in internalizing symptoms from pre-pandemic to the first peak of the pandemic nor over the course of the pandemic. Overall, the findings indicate that children and adolescents of both the general and clinical population were affected negatively by the pandemic in terms of their internalizing problems. Attention is therefore warranted to investigate long-term effects and to monitor if internalizing problems return to pre-pandemic levels or if they remain elevated post-pandemic. Show less
Metastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. As only a subset of... Show moreMetastatic renal cell carcinoma (RCC) has a poor prognosis. Recent advances have shown beneficial responses to immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies. As only a subset of RCC patients respond, alternative strategies should be explored. Patients refractory to anti-PD-1 therapy may benefit from autologous tumor-infiltrating lymphocyte (TIL) therapy. Even though efficient TIL expansion was reported from RCC lesions, it is not well established how many RCC TIL products are tumor-reactive, how well they produce pro-inflammatory cytokines in response to autologous tumors, and whether their response correlates with the presence of specific immune cells in the tumor lesions. We here compared the immune infiltrate composition of RCC lesions with that of autologous kidney tissue of 18 RCC patients. Tcell infiltrates were increased in the tumor lesions, and CD8(+) Tcell infiltrates were primarily of effector memory phenotype. Nine out of 16 (56%) tested TIL products we generated were tumor-reactive, as defined by CD137 upregulation after exposure to autologous tumor digest. Tumor reactivity was found in particular in TIL products originating from tumors with ahigh percentage of infiltrated Tcells compared to autologous kidney, and increased CD25 expression on CD8(+) Tcells. Importantly, although TIL products had the capacity to produce the key effector cytokines IFN-gamma, TNF-alpha or IL-2, they failed to produce significant amounts in response to autologous tumor digests. In conclusion, TIL products from RCC lesions contain tumor-reactive Tcells. Their restricted tumor-specific cytokine production requires further investigation of immunosuppressive factors in RCC and subsequent optimization of RCC-derived TIL culture conditions. Show less
Bussel, L.G.J. van; Haan, N. de; Remme, R.P.; Lof, M.E.; Groot, R. de 2020
Governance is an essential element in land-use decision-making and ecosystem management choices and thus for ecosystem service provisioning. Although a community-based approach, i.e. governance... Show moreGovernance is an essential element in land-use decision-making and ecosystem management choices and thus for ecosystem service provisioning. Although a community-based approach, i.e. governance involving actors from all spheres of society (the state, market and civil society), is considered most appropriate for natural resource management, there is a lack of knowledge about its actual effects on environmental outcomes and ecosystem service supply in particular. To obtain insight in the effect of governance on ecosystem service provision in our study region (Berg en Dal, the Netherlands), we constructed ecosystem service maps for the period 1995 to 2012 using land-use maps. Also an inventory of the implemented governance models was created, based on interviews with stakeholders, supplemented with literature research. Our results show that 1) governance in Berg en Dal changed from top-down to more community-based models during the studied period; and 2) that the potential and actual supply of the majority of the investigated regulating, cultural and habitat ecosystem services increased during the studied period, at the expense of agricultural production. The interviewed local stakeholders also indicated that they have the perception that the landscape has improved during the last two decades. Although there is a clear connection between governance and improved ecosystem service supply, more research is needed to further develop causal relationships explaining the indirect effects and non-linear behavior within ecosystem service governance systems. Show less
Flint, R.B.; Simons, S.H.P.; Andriessen, P.; Liem, K.D.; Degraeuwe, P.L.J.; Reiss, I.K.M.; ... ; DINO Research Group 2020
Background Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of... Show moreBackground Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM (R)). Results A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL(FORMATION KETO-DOXAPRAM)was 0.115 L/h (relative standard error (RSE) 12%) and CL(DOXAPRAM OTHER ROUTES)was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. ImpactCurrent dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure. Show less
Clinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >... Show moreClinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >70 non-small cell lung cancer (NSCLC) samples. We systematically evaluate several methods to identify tumor purity of organoids established from intrapulmonary tumors. Eighty percent of organoids from intrapulmonary lesions have a normal copy number profile, suggesting overgrowth by normal airway organoids (AOs). This is further supported by the failure to detect mutations found in the original tumor in organoids. Histomorphology alone is insufficient to determine tumor purity, but when combined with p63 immunostaining, tumor and normal AOs can be distinguished. Taking into account overgrowth by normal AOs, the establishment rate of pure NSCLC organoids is 17%. Therefore, current methods are insufficient to establish pure NSCLC organoids from intrapulmonary lesions. We discourage their use unless steps are taken to prevent overgrowth by normal AOs. Show less
The resurgence and changing epidemiology of pertussis in high-income countries, the high infant mortality caused by pertussis in low-income countries, and the increasing morbidity in all age groups... Show moreThe resurgence and changing epidemiology of pertussis in high-income countries, the high infant mortality caused by pertussis in low-income countries, and the increasing morbidity in all age groups worldwide call for a concerted effort to both improve the current vaccines and develop new vaccines and vaccination strategies against pertussis. In this Personal View, we identify several key obstacles on the path to developing a durable solution for global control of pertussis. To systematically address these obstacles, the PERtussIS Correlates Of Protection Europe ( PERISCOPE) Consortium was established in March, 2016. The objectives of this consortium are to increase scientific understanding of immunity to pertussis in humans induced by vaccines and infections, to identify biomarkers of protective immunity, and to generate technologies and infrastructure for the future development of improved pertussis vaccines. By working towards the accelerated licensure and implementation of novel, well tolerated, and effective pertussis vaccines, we hope to strengthen and stimulate further collaboration and transparency between the key stakeholders, including the public, the scientific community, public health institutes, regulatory authorities, and vaccine manufacturers. Show less
Oudenhoven, A.P.E. van; Martín-López, B.; Schröter, M.; Groot, R. de 2018
This Editorial of the International Journal of Biodiversity Science, Ecosystem Services & Management (IJBESM) marks the end of this Journal’s publications under Rudolf de Groot. He has been... Show moreThis Editorial of the International Journal of Biodiversity Science, Ecosystem Services & Management (IJBESM) marks the end of this Journal’s publications under Rudolf de Groot. He has been instrumental in bringing the concept of ecosystem services to the fore, through seminal publications, books, lectures, through founding and chairing the Ecosystem Services Partnership (ESP); and finally, through ‘adding the ecosystem services to IJBESM’. After almost 8 years as Editor-in-Chief, he has decided to step down and hand over to a next generation.In the final part of this co-written Editorial, Rudolf de Groot will look back one last time at some highlights of the past years, partly together with his editorial team. The first part of this Editorial introduces the new co-Editors in Chief and how they envision the future of the Journal. Berta Martín-López (Leuphana University of Lüneburg, Germany) and Alexander van Oudenhoven (Leiden University, Netherlands) have gladly accepted to take over as co-Editors in Chief of IJBESM. They are interdisciplinary scientists at the forefront of research on social-ecological systems, ecosystem services, ecosystem management and sustainability transformation. Both are heavily involved in the Intergovernmental science-policy Platform on Biodiversity and Ecosystem Services (IPBES) and both have been actively involved with this Journal for several years. While acknowledging and building on the achievements of the last couple of years, they suggest a way forward for publishing research on human–nature relationships. Show less
The pathogenesis of meningococcal infections involves activation of the complement system, proinflammatory and anti-inflammatory mediators, antimicrobial peptides, and apoptosis. We hypothesized... Show moreThe pathogenesis of meningococcal infections involves activation of the complement system, proinflammatory and anti-inflammatory mediators, antimicrobial peptides, and apoptosis. We hypothesized that variations in genes encoding these products are involved in the susceptibility to and severity of pediatric meningococcal infections. Polymorphisms in poly (adenosine diphosphate-ribose) polymerase (PARP), serine protease C1 inhibitor (C1INH), IL4, IL10 and IL1B, alpha-defensin 4, and beta-defensin 1 (DEFB1) were analyzed in two independent Caucasian case control cohorts from the United Kingdom and the Netherlands and in a family-based transmission disequilibrium test cohort from the UK. In the UK case control cohort, the DEFB1 -44 G/G homozygous genotype was overrepresented in patients with meningococcal disease compared with the G/C and C/C genotypes when combined (odds ratio, 1.57; 95% confidence interval, 1.12-2.20). The transmission disequilibrium test analysis did not confirm this, but did find an association and linkage of the IL4-524 and the C1INH 480 polymorphisms with susceptibility to meningococcal infection. Hematological failure was present more often in UK patients with the DEFB1 -44 G/G genotype compared with the C allele carriers (odds ratio, 2.17; 95% confidence interval, 1.22-3.85). Additional studies are necessary to elucidate the conflicting results obtained for the DEFB1, IL4, and C1INH polymorphisms and their role in susceptibility to and severity of meningococcal disease. Show less
Haan, L.J. de; Groot, R. de; Rijsbergen, P. van 1982
