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Writing is usually integrated in the curriculum of science studies. However, students often lack the skills to write for various audiences or, to produce a well written manuscript. We developed a concise project of 15 European Credits to improve the writing skills in an early phase of the bachelor study. Students worked on texts from various journals and looked at the writing styles. They rewrote texts in a popular and more scientific way and practiced with clear, vivid language, avoiding clutter and hedge words, considering a proper use of grammar and interpunction. Medical writing was also introduced during the project. Grading was based on rewriting for a non-expert and expert audience. A rewritten text was presented to the public in the form of a student-initiated survey. This project shows an inverted approach creating student ownership and enthusiasm for writing. In addition, we created and tested successfully a concise two-day workshop based on this project. Based on the results we herewith present the work as an idea to explore.

Background Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. Methods We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively. Results ONC201 and paxalisib combination treatment aimed at inducing metabolic distress led to the design of the first DMG-specific platform trial PNOC022 (NCT05009992). Conclusions Here, we expand on the PNOC022 rationale and discuss various considerations, including liquid biome, microbiome, and genomic biomarkers, quality-of-life endpoints, and novel imaging modalities, such that we offer direction on future clinical trials in DMG.

Abstract Increasing evidence exists that the gut microbiome influences toxicity as well as outcomes in a variety of cancers. To investigate the role of the gut microbiome in pediatric neuro-oncology, microbiome analysis has been included in multiple prospective pediatric neuro-oncology clinical trials (NCT05009992, NCT04732065, NCT04775485). In these trials, the OMNIgene-GUTtm preservation tubes are used for the collection of the feces. OMNIgene-GUTtm has demonstrated reliability in preserving the composition of the gut microbiome in adults; however, its validation for use in the pediatric population remains limited. Therefore, we compared the quality of the DNA by 16S rRNA gene sequencing after various methods of stabilizing fecal samples in pediatric populations, from the direct freeze method at − 80 °C to preserving samples with OMNIgene-GUTtm at room temperature for various durations. Our results showed that there were no statistically significant differences between the alpha-diversity, and beta-diversity. However, pairwise differential abundance analyses demonstrated that OMNIgene-GUT™ is superior in maintaining microbial community structure compared to storing samples without any preservation method. With the OMNIgene-GUTtm’s stabilization of the fecal samples being superior and its ease-of-use benefits, it proves to be a valid and ideal method of stabilizing fecal samples for current and future pediatric clinical trials.

Abstract To investigate intestinal health and its potential disruptors in vitro, representative models are required. Human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cells (IECs) more closely resemble the in vivo intestinal tissue than conventional in vitro models like human colonic adenocarcinoma Caco-2 cells. However, the potential of IECs to study immune-related responses upon external stimuli has not been investigated in detail yet. The aim of the current study was to evaluate immune-related effects of IECs by challenging them with a pro-inflammatory cytokine cocktail. Subsequently, the effects of Lactiplantibacillus plantarum WCFS1 were investigated in unchallenged and challenged IECs. All exposures were compared to Caco-2 cells and in vivo data where possible. Upon the inflammatory challenge, IECs and Caco-2 cells induced a pro-inflammatory response which was strongest in IECs. Heat-killed L. plantarum exerted the strongest effect on immune parameters in the IEC model, while L. plantarum in the stationary growth phase had most pronounced effects on immune-related gene expression in Caco-2 cells. Unfortunately, comparison to in vivo transcriptomics data showed limited similarities, which could be explained by essential differences in the study setups. Altogether, hiPSC-derived IECs show a high potential as a model to study immune-related responses in the intestinal epithelium in vitro.

Objective: Children with a supratentorial midline low-grade glioma (LGG) may be at risk for impaired bone health due to hypothalamic-pituitary dysfunction, obesity, exposure to multiple treatment modalities, and/or decreased mobility. The presence of impaired bone health and/or its severity in this population has been understudied. We aimed to identify the prevalence and risk factors for bone problems in children with supratentorial midline LGG. Materials and methods: A retrospective study was performed in children with supratentorial midline (suprasellar or thalamic) LGG between 1 January 2003 and 1 January 2022, visiting the Princess Máxima Center for Pediatric Oncology. Impaired bone health was defined as the presence of vertebral fractures and/or very low bone mineral density (BMD). Results: In total, 161 children were included, with a median age at tumor diagnosis of 4.7 years (range: 0.1–17.9) and a median follow-up of 6.1 years (range: 0.1–19.9). Five patients (3.1%) had vertebral fractures. In 99 patients, BMD was assessed either by Dual Energy X-ray Absorptiometry (n = 12) or Bone Health Index (n = 95); 34 patients (34.3%) had a low BMD (≤ −2.0). Impaired visual capacity was associated with bone problems in multivariable analysis (OR: 6.63, 95% CI: 1.83–24.00, P = 0.004). Conclusion: In this retrospective evaluation, decreased BMD was prevalent in 34.3% of children with supratentorial midline LGG. For the risk of developing bone problems, visual capacity seems highly relevant. Surveillance of bone health must be an aspect of awareness in the care and follow-up of children with a supratentorial midline LGG. Significance statement Patients with supratentorial midline LGG may encounter various risk factors for impaired bone health. Bone problems in survivors of childhood supratentorial midline LGG are, however, understudied. This is the first paper to address the prevalence of bone problems in this specific patient population, revealing visual problems as an important risk factor. Diencephalic syndrome historyand/or weight problems associated with hypothalamic dysfunction were related to bone problems in univariate analyses. The results of this study can be used in the development of guidelines to adequately screen and treat these patients to subsequently minimizing bone problems as one of the endocrine complications.

Abstract Appropriate repair of damaged DNA and the suppression of DNA damage responses at telomeres are essential to preserve genome stability. DNA damage response (DDR) signaling consists of cascades of kinase-driven phosphorylation events, fine-tuned by proteolytic and regulatory ubiquitination. It is not fully understood how crosstalk between these two major classes of post-translational modifications impact DNA repair at deprotected telomeres. Hence, we performed a functional genetic screen to search for ubiquitin system factors that promote KAP1S824 phosphorylation, a robust DDR marker at deprotected telomeres. We identified that the OTU family deubiquitinase (DUB) OTUD5 promotes KAP1S824 phosphorylation by facilitating ATM activation, through stabilization of the ubiquitin ligase UBR5 that is required for DNA damage-induced ATM activity. Loss of OTUD5 impairs KAP1S824 phosphorylation, which suppresses end-joining mediated DNA repair at deprotected telomeres and at DNA breaks in heterochromatin. Moreover, we identified an unexpected role for the heterochromatin factor KAP1 in suppressing DNA repair at telomeres. Altogether our work reveals an important role for OTUD5 and KAP1 in relaying DDR-dependent kinase signaling to the control of DNA repair at telomeres and heterochromatin.

Abstract Maintenance of genome integrity requires tight control of DNA damage response (DDR) signalling and repair, with phosphorylation and ubiquitination representing key elements. How these events are coordinated to achieve productive DNA repair remains elusive. Here we identify the ubiquitin-conjugating enzyme UBE2D3 as a regulator of ATM kinase-induced DDR that promotes non-homologous end-joining (NHEJ) at telomeres. UBE2D3 contributes to DDR-induced chromatin ubiquitination and recruitment of the NHEJ-promoting factor 53BP1, both mediated by RNF168 upon ATM activation. Additionally, UBE2D3 promotes NHEJ by limiting RNF168 accumulation and facilitating ATM-mediated phosphorylation of KAP1-S824. Mechanistically, defective KAP1-S824 phosphorylation and telomeric NHEJ upon UBE2D3-deficiency are linked to RNF168 hyperaccumulation and aberrant PP2A phosphatase activity. Together, our results identify UBE2D3 as a multi-level regulator of NHEJ that orchestrates ATM and RNF168 activities. Moreover, they reveal a negative regulatory circuit in the DDR that is constrained by UBE2D3 and consists of RNF168- and phosphatase-mediated restriction of KAP1 phosphorylation.

Abstract Hepatocellular carcinoma (HCC) comprises 75 to 85% of all primary liver cancers. Current guidelines recommend a biannual HCC surveillance using ultrasound (US) for high-risk patients. However, due to its low sensitivity for detection of early-stage HCC lesions, there is an urgency for more sensitive surveillance tools. Here, we describe the potential of a short MRI surveillance (SMS) protocol for HCC, including axial T1-weighted in-out phase, fat-saturated T2-weighted, and diffusion-weighted sequences. In this prospective, multicenter, patient cohort study, patients will be recruited from existing HCC surveillance cohorts of six medical centers in The Netherlands. Surveillance patients who undergo biannual US, will be invited for SMS on the same day for 3 years. In case of a suspicious finding on either US or SMS, patients will be invited for a full MRI liver protocol including gadolinium-based contrast agent intravenous injection within 2 weeks. To our knowledge, this will be the first study to perform a head-to-head comparison with a paired US-MRI design. We hypothesize that the sensitivity of SMS for detection of early-stage HCC will be higher than that of US leading to improved survival of surveillance patients through timely HCC diagnosis. Furthermore, we hypothesize that the SMS-HCC protocol will prove cost-effective. Relevance statement The US sensitivity for detecting early-stage HCC has been reported to be less than 50%. We expect that the proposed SMS will detect at least twice as many early-stage HCC lesions and therefore prove to be cost-effective. Key points • The low sensitivity of US necessitates better imaging tools for HCC screening. • This is the first study with a paired US-MRI design. • This design will allow a head-to-head comparison in both diagnostics and patient-acceptance. • We expect that SMS can contribute to a higher survival rate. Graphical Abstract

A field campaign was carried out at a sheltered sandy beach with the aim of gaining new insights into the driving processes behind sheltered beach morphodynamics. Detailed measurements of the local hydrodynamics, bed-level changes and sediment composition were collected at a man-made beach on the leeside of the barrier island Texel, bordering the Marsdiep basin that is part of the Dutch Wadden Sea. The dataset consists of (1) current, wave and turbidity measurements from a dense cross-shore array and a 3 km alongshore array; (2) sediment composition data from beach surface samples; (3) high-temporal-resolution RTK-GNSS beach profile measurements; (4) a pre-campaign spatially covering topobathy map; and (5) meteorological data. This paper outlines how these measurements were set up and how the data have been processed, stored and can be accessed. The novelty of this dataset lies in the detailed approach to resolve forcing conditions on a sheltered beach, where morphological evolution is governed by a subtle interplay between tidal and wind-driven currents, waves and bed composition, primarily due to the low-energy (near-threshold) forcing. The data are publicly available at 4TU Centre for Research Data at: https://doi.org/10.4121/19c5676c-9cea-49d0-b7a3-7c627e436541 (Van der Lugt et al., 2023).

It was recently found that the indefinite causal order in the quantum switch can be certified device-independently when assuming the impossibility of superluminal influences. Here we strengthen this result in two ways. First, we give a proof of this fact which is possibilistic rather than probabilistic, i.e. which does not rely on the validity of probability theory at the hidden variable level. Then, returning to the probabilistic setting, we show that the indefinite causal order in the quantum switch is also maximal, in the sense that the observed correlations are incompatible even with the existence of a causal order on only a small fraction of the runs of the experiment. While the original result makes use of quantum theory's violation of a Clauser-Horne-Shimony-Holt inequality, the proofs presented here are based on Greenberger, Horne, and Zeilinger's and Mermin's proofs of nonlocality, respectively.