Biology subjects

Knol, M.

Publications and source records attributed to Knol, M..

6 recordsLinked to original sources

bioRxiv2026

Dosimetric Characterization and Workflow Optimization of the FLASH-SARRP for Reliable Preclinical Radiobiological Studies

ObjectivePreclinical small-animal irradiators such as the FLASH-SARRP can support the advancement of photon-FLASH toward the clinic. This study aimed at characterizing the FLASH-SARRP and established a robust quality assurance (OA) workflow to enable accurate and reproducible preclinical experiments. ApproachCustom 3D-printed spacers were designed to ensure reproducible X-ray tube alignment, sample positioning and mounting of the dosimetric tools. Beam characteristics were evaluated using a combined dosimetric approach. High spatially resolved dose distributions were obtained from Gafchromic films, whereas a plastic scintillating fiber was employed to monitor in real-time the temporal pulse structure and synchronization between the two X-ray tubes. Day-to-day variability of the delivery was evaluated over several sessions. Main resultsThe FLASH-SARRP achieved dose-rates of around 80 Gy/s when both tubes were used simultaneously and provided a homogeneous irradiation field suitable for small-animal studies. A desynchronization between the two tubes was observed with an average delay of 10 ms, resulting in temporal dose-rate heterogeneity. Additionally, a substantial inter-session variability ([~]11%) was found, whereas the intra-session variability was relatively low ([~]4%). Inter-session variability was reduced to 5%, approaching the intra-session variability, by adding Gafchromic films/scintillator-based quality assurance (OA) workflow into the irradiation routine. SignificanceThis work highlights the importance of temporal dosimetry for preclinical FLASH studies. Additionally, a practical OA framework is proposed integrating real-time monitoring with reference dosimetry. The proposed work enables adaptive dose delivery, thereby enhancing the reproducibility of the irradiations, which is crucial for reliable preclinical studies on the FLASH effect.

cancer biology↗

bioRxiv2026

Neuroprotection following FLASH-RT may be mediated by sustained glutamate receptor AMPAR activation in CA3 neurons

To elucidate the early mechanisms underlying the long-term neuroprotective effect of FLASH-RT in the normal brain, spatial transcriptomics (Nanostring) were performed after whole-brain irradiation of C57BL/6J mice with either 1 or 3 fractions of 10 Gy at 5.6x106 Gy/s (1 pulse-FLASH) or at conventional dose-rate 0.1 Gy/s. FLASH -RT induced a distinct transcriptomic signature in the CA3 and DG neurons, with upregulation of genes encoding glutamate receptors, involved in calcium signaling, long-term potentiation and mitochondrial OXPHOS. Early transcriptional upregulation of Gria gene translated into increased AMPAR protein levels at 48h in the DG and CA3 region and sustained higher AMPAR expression at 2 and 4 weeks post-FLASH. These findings support a durable activation of AMPAR. We propose a mechanism to explain FLASH-induced neuroprotection initiated by early calcium influx and subsequent sustained expression of glutamate receptor AMPAR in neurons and/or neural progenitors of the CA3, potentially contributing to long-term cognitive sparing. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/725423v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1ae125forg.highwire.dtl.DTLVardef@138357aorg.highwire.dtl.DTLVardef@13f128dorg.highwire.dtl.DTLVardef@1db1cf6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIFLASH-RT induces a stronger transcriptional response in the hippocampus than the cortex. C_LIO_LIFLASH-RT induces calcium signaling, LTP and mitochondrial OXPHOS genes. C_LIO_LIEarly AMPAR upregulation leads to sustained protein expression. C_LIO_LIFLASH-RT induces a AMPAR-dependent signaling program in CA3 neurons. C_LI

cancer biology↗

bioRxiv2026

Early microglial activation in the TME enables FLASH-RT to eradicate medulloblastoma while promoting neuron-astrocyte crosstalk to minimize toxicity in the hippocampus

BackgroundFLASH-RT defines a promising treatment modality against medulloblastoma, as it minimizes treatment-related complications. To support its clinical translation, we dissected the cellular and molecular determinants of the FLASH response in the tumor-microenvironment (TME) and healthy hippocampus using an orthotopic human medulloblastoma mouse model treated with a hypo-fractionated FLASH regimen. MethodsFive cohorts of 4 weeks-old UW228-MB-bearing female nude mice (n=57) were irradiated, or sham-irradiated using 3x10 Gy (BED=60), delivered 48h apart at 0.1 Gy/s (CONV) or 5.5x106 Gy/s (FLASH) using an electron beam (eRT6). Digital spatial profiling (DSP) was performed 24h after radiotherapy in one cohort, while the four other cohorts were followed for long-term tumor response, cognition, and neuroinflammation. ResultsBoth CONV and FLASH-RT induced a complete and long-lasting anti-tumor response in 100% of animals associated with cognitive decline. However, more mice maintained a very good discrimination score after FLASH exposure (38%) than CONV (7%). DSP revealed a sustained microglial activation in the cerebellar tumor micro-environment, where FLASH enhanced expression of genes with phagocytic and proteolytic activity. In the tumor free hippocampus, FLASH exposure induced a preferential neuron/astrocyte transcriptional crosstalk, which manifested over protracted times to minimize neuroinflammation and cognitive complications. ConclusionThe study shows the tumor-ablative efficacy of hypo-fractionated FLASH-RT in a human medulloblastoma mouse model. It is associated with qualitatively distinct transcriptional signatures prone to tumor and debris clearance mediated by microglial cells of the TME. Moreover, in the hippocampus, FLASH mitigates radiation-induced neurotoxicity by enhancing genes involved in synaptic plasticity, attenuating neuroinflammation, and preserving metabolic function. Key PointsO_LIComplete response of medulloblastoma and reduction of neurotoxicity with hypo-fractionated FLASH regimen. C_LIO_LIClearance-prone phagocytic and proteolytic activity in the microglia of the TME. C_LIO_LINeuron/astrocyte transcriptional crosstalk in the hippocampus. C_LI Importance of the studyThis study constitutes a milestone for the future implementation of FLASH-RT in the treatment of children with brain cancer. It shows that FLASH does not protect medulloblastoma and on the contrary can be ablative when delivered in 3 fractions of 10 Gy. FLASH promotes a metabolically active, phagocytosis-prone phenotype in microglial cells consistent with immune activation and tumor surveillance, in contrast to the proliferative and immunosuppressive signaling programs induced by CONV. It also shows how FLASH may differentially shape long-term brain function in patients with brain tumors by modifying the transcriptional program of hippocampal subregions known to be critical for memory encoding, pattern separation, and consolidation. In summary, this study supports the idea that FLASH has the potential to shift treatment paradigms and change the dismal therapeutic outcome in patients with brain cancer.

cancer biology↗

bioRxiv2019

Grey Matter Age Prediction as a Biomarker for Risk of Dementia: A Population-based Study

Key PointsO_ST_ABSQuestionC_ST_ABSIs the gap between brain age predicted from MRI and chronological age associated with incident dementia in a general population of Dutch adults?\n\nFindingsBrain age was predicted using a deep learning model, using MRI-derived grey matter density maps. In a population based study including 5496 participants, the observed gap was significantly associated with the risk of dementia.\n\nMeaningThe gap between MRI-brain predicted and chronological age is potentially a biomarker for dementia risk screening.\n\nAbstractO_ST_ABSImportanceC_ST_ABSThe gap between predicted brain age using magnetic resonance imaging (MRI) and chronological age may serve as biomarker for early-stage neurodegeneration and potentially as a risk indicator for dementia. However, owing to the lack of large longitudinal studies, it has been challenging to validate this link.\n\nObjectiveWe aimed to investigate the utility of such a gap as a risk biomarker for incident dementia in a general Dutch population, using a deep learning approach for predicting brain age based on MRI-derived grey matter maps.\n\nDesignData was collected from participants of the cohort-based Rotterdam Study who underwent brain magnetic resonance imaging between 2006 and 2015. This study was performed in a longitudinal setting and all participant were followed up for incident dementia until 2016.\n\nSettingThe Rotterdam Study is a prospective population-based study, initiated in 1990 in the suburb Ommoord of in Rotterdam, the Netherlands.\n\nParticipantsAt baseline, 5496 dementia- and stroke-free participants (mean age 64.67{+/-}9.82, 54.73% women) were scanned and screened for incident dementia. During 6.66{+/-}2.46 years of follow-up, 159 people developed dementia.\n\nMain outcomes and measuresWe built a convolutional neural network (CNN) model to predict brain age based on its MRI. Model prediction performance was measured in mean absolute error (MAE). Reproducibility of prediction was tested using the intraclass correlation coefficient (ICC) computed on a subset of 80 subjects. Logistic regressions and Cox proportional hazards were used to assess the association of the age gap with incident dementia, adjusted for years of education, ApoE{varepsilon}4 allele carriership, grey matter volume and intracranial volume. Additionally, we computed the attention maps of CNN, which shows which brain regions are important for age prediction.\n\nResultsMAE of brain age prediction was 4.45{+/-}3.59 years and ICC was 0.97 (95% confidence interval CI=0.96-0.98). Logistic regression and Cox proportional hazards models showed that the age gap was significantly related to incident dementia (odds ratio OR=1.11 and 95% confidence intervals CI=1.05-1.16; hazard ratio HR=1.11 and 95% CI=1.06-1.15, respectively). Attention maps indicated that grey matter density around the amygdalae and hippocampi primarily drive the age estimation.\n\nConclusion and relevanceWe show that the gap between predicted and chronological brain age is a biomarker associated with risk of dementia development. This suggests that it can be used as a biomarker, complimentary to those that are known, for dementia risk screening.

epidemiology↗

bioRxiv2018

Optimizing the use of the Men-ACWY conjugated vaccine to control the developing meningococcal W disease outbreak in the Netherlands, a rapid analysis.

BackgroundThere is a developing outbreak of Neisseria meningitidis serotype W (MenW) in the Netherlands. In response, those aged 14 months and 14 years are vaccinated with the conjugated MenACWY vaccine. In the spring of 2018 we aimed to explore the impact of adding a one-off catch-up campaign targeting those aged 15-18 years on the transmission of MenW and the cost-effectiveness of such a campaign.\n\nMethodsWe estimated the growth rate of the MenW outbreak and quantified the impact of various targeted vaccination strategies on the reproductive number, and subsequently projected the future incidence with and without vaccination. Future cases were expressed in costs and QALYS and the incremental cost-effectiveness ratio was obtained.\n\nResultsWe estimate a reproductive number of around 1.4 (95%CI 1.2-1.7) over the period February 2016-February 2018. Adding the catch-up campaign reduces the reproductive number five years earlier than without a catch-up campaign, to a level around 1.2. The vaccination campaign, including the catch-up, will prevent around 100 cases per year in our base case scenario. Given the projected impact and realistic assumptions on costs and QALYs, adding the catch-up can be considered cost-effective using a threshold of {euro}20,000 per QALY.\n\nConclusionAdding the catch-up campaign targeting those aged 15-18 brings the impact of vaccination on reducing transmission five years forward and directly prevents a high-incidence age group from carriage and disease. Such a campaign can be considered cost-effective. Our study did underpin the decision to introduce a catch-up campaign in spring 2019. Furthermore, our applied method can be of interest for anyone solving vaccine allocation questions in a developing outbreak.

epidemiology↗

bioRxiv2018

Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/{beta}-catenin, TGF-{beta} and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

genetics↗