Publications by authors named "Castel D"

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed.

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Article Synopsis
  • Constitutional mismatch repair deficiency (CMMRD) leads to a significant cancer risk, primarily resulting in high-grade gliomas in children due to mutations in mismatch repair genes.
  • Analysis of clinical and genetic data from 12 affected children revealed that 50% of their glioma samples expressed PDL1 and exhibited an ultra-hypermutated phenotype, with numerous mutations and specific driver mutations identified.
  • The research indicates that CMMRD gliomas have distinct oncogenic properties, differing from typical glioblastomas, suggesting potential for targeted therapies, particularly those targeting MAPK pathways and PD1 inhibitors.
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Opioid-based medications remain the mainstay of post-operative pain management, even though they are associated with a plethora of adverse effects including addiction, nausea, constipation, cognitive impairment, respiratory depression, and accidental death due to overdose. Local anesthetics are effective at controlling the intense pain after surgery but their short duration of effect limits their clinical utility in post-operative pain management. In this manuscript, an optimized injectable oleogel-based formulation of bupivacaine for multi-day post-operative pain management was characterized on the benchtop and assessed in two clinically-relevant porcine post-operative pain models.

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Background: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established.

Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization.

Results: Median overall survival (OS) was 15.

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  • Pilocytic astrocytomas (PA) are tumors that have unique features based on where they are located in the brain or spine.
  • Doctors face challenges in telling PAs apart from similar tumors, especially in the brain's hemispheric region.
  • A study looked at different types of PAs, and found that they often affect kids and can show various patterns in medical tests, highlighting the need for careful examination for accurate diagnosis.
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  • Diffuse midline gliomas (DMGs) H3 K27-altered are aggressive brain tumors classified into four subtypes, with the H3.3-K27M subgroup exhibiting significant variability in clinical and molecular features.
  • Recent findings suggest that some patients with both H3.3-K27M and BRAF or FGFR1 mutations have a better prognosis, prompting researchers to analyze a cohort of 29 such tumors alongside 31 previously reported cases.
  • Comprehensive analyses reveal that these co-altered DMGs form a unique subtype with distinct DNA methylation profiles, higher occurrence in the thalamus, atypical radiological features, and longer median survival times, highlighting the need for tailored patient management strategies.
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Context: Contusion and soft tissue injuries are common in sports. Photobiomodultion, light and laser therapy, is an effective aid to increase healing rates and improve function after various injury mechanisms. However, it is unclear how well photobiomodulation improves function after a contusion soft tissue injury.

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Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development.

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Article Synopsis
  • - The study identified VRK3 as a specific vulnerability in DMG-H3K27M cells, revealing that its depletion disrupts the cell cycle, especially the G1/S transition, leading to growth arrest.
  • - Knockdown of VRK3 also affected genes related to chromosome segregation and decreased phosphorylation of histone H3, suggesting issues with chromatin regulation during cell division.
  • - Additionally, the research indicated that VRK3 loss causes a metabolic shift towards oxidative phosphorylation, hinting at a potential cell survival mechanism, and proposes therapeutic strategies combining VRK3 depletion with ONC201, a ClpP protease activator.
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Background: Diffuse midline gliomas (DMG) are pediatric tumors with negligible 2-year survival after diagnosis characterized by their ability to infiltrate the central nervous system. In the hope of controlling the local growth and slowing the disease, all patients receive radiotherapy. However, distant progression occurs frequently in DMG patients.

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Myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is a murine model for multiple sclerosis. This model is characterized by chronic and progressive demyelination, leading to impairment of motor function and paralysis. While the outcomes of the disease, including impaired motor function and immunological changes, are well-characterized, little is known about the impact of EAE on the electrophysiology of the motor and sensory systems.

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Ulcerative colitis (UC), Crohn's disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions.

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Pain after surgery remains a significant healthcare challenge. Here, abobotulinumtoxinA (aboBoNT-A, DYSPORT) was assessed in a post-surgical pain model in pigs. Full-skin-muscle incision and retraction surgery on the lower back was followed by intradermal injections of either aboBoNT-A (100, 200, or 400 U/pig), vehicle (saline), or wound infiltration of extended-release bupivacaine.

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Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA.

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Aims: Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non-specific/diffuse form which lacks it, and has unclear phenotype-genotype correlations with numerous differential diagnoses.

Methods: We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large-scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging.

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The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue.

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Pediatric bithalamic gliomas encompass several histomolecular tumoral types from benign to malignant and underlines the central role of a comprehensive neuropathological review, including immunohistochemistry, genetic, and epigenetic analyses, to achieve an accurate diagnosis.

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Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response pathways that operate in pHGGs and the vulnerabilities that these pathways might expose, we sought to identify and characterize a specific DNA repair and cell-cycle gene expression signature of pHGGs.

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Objectives: The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics.

Methods: Twenty-seven treatment-naïve children with histopathologically confirmed DIPG H3K27M mutant were prospectively included.

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