Elekta's Monaco (Elekta AB, Stockholm, Sweden) treatment planning system (TPS) introduces script-based automation functionality. This study developed and validated a fully script-based automated radiotherapy planning solution for whole-brain radiotherapy (WBRT) based on the Monaco TPS. This approach not only enables complete automation of the planning workflow but also effectively enhances plan quality while meeting clinical dose requirements. To systematically compare dosimetric, radiobiological, and operational performance between script-generated automated plans and clinically approved manual WBRT plans on the Monaco TPS. A retrospective analysis of 20 WBRT patients was conducted. A custom C# ASP.NET script was programmed in Visual Studio 2022 for end-to-end automated template optimization. Plan quality was assessed against clinical manual plans based on a RapidPlan scoring system. Paired t-tests or Wilcoxon signed-rank tests were used to compare planning target volume (PTV) and organ-at-risk (OAR) dosimetry, beam delivery parameters, equivalent uniform dose (EUD), tumor control probability (TCP), and normal tissue complication probability (NTCP). No statistically significant inter-group differences were detected for PTV coverage metrics, majority OAR dose-volume endpoints, beam delivery parameters, or total plan quality scores (p > 0.05). Manual plans yielded significantly lower optic nerve D0.03cc (2874.42 vs 3014.61 cGy, p < 0.05), while automated plans produced significantly reduced mean doses to bilateral parotid glands (566.84 vs 675.30 cGy, p < 0.001) and cochleae (2687.25 vs 2819.73 cGy, p < 0.05). PTV EUD and TCP were nearly identical between 2 planning strategies. For radiobiological indices, automated plans demonstrated statistically elevated NTCP for hippocampi, brainstem, eyes, and optic nerves (p < 0.05). Automated batch processing drastically reduced recorded planning workflow time, though retrospective manual timestamps carry inherent measurement bias. The proposed Monaco scripting workflow reliably generates WBRT plans meeting all institutional clinical dose criteria, with favorable automated sparing of parotid and cochlear tissues. This script tool delivers consistent baseline planning and batch-processing efficiency; multicenter large-cohort validation across variable cranial anatomy is required before universal routine clinical deployment.

Mucopolysaccharidosis type I (MPS-I) is a hereditary lysosomal storage disorder caused by deficiency in the lysosomal enzyme α-L-iduronidase (IDUA) leading to pathogenic over-accumulation of glycosaminoglycans (GAGs), major constituent of connective tissue and mediators of cell signaling. We tested the therapeutic efficacy of the autolysosomal activator GHF201 in the Idua -/- mouse model of MPS-I. We show that GHF201 reduced GAGs and increased cathepsin activity in Idua -/- mouse embryonic fibroblasts (MEFs) and brain cells. In vivo GHF201 improved aberrant locomotion and behavior, reduced interstitial cathepsins in joints and liver, increased systemic catabolism, corrected bone dysplasia, increased autophagic flux, and ameliorated CNS neurodegeneration and neuroinflammation. GHF201 also reduced brain N-glycans, which are degraded in lysosomes. In conclusion, the lysosomal and autophagic activator GHF201 was demonstrated to improve various pathophysiological parameters in MPS-I-modeling Idua -/- female mice. Our results suggest that GHF201 can complement the inadequate Aldurazyme enzyme replacement therapy as an add-on therapy.

MRI-guided focused ultrasound (MRgFUS) thalamotomy is an effective ablative procedure for medication-refractory essential tremor (ET). However, limited data exist regarding its safety in patients with coexisting intracranial disease such as cerebral cavernous malformations. We present a man in his late 60s with medication-refractory ET who underwent staged bilateral MRgFUS thalamotomy. Preoperative MRI demonstrated heterogeneously T1-hyperintense and T2-hyperintense lesions in the left caudate head and basal ganglia consistent with cavernous malformations, with an associated developmental venous anomaly and no prior haemorrhage. After individualised counselling regarding unknown procedural risks, the patient underwent right-sided thalamotomy, followed 1 year later by left-sided thalamotomy. MRI after each procedure demonstrated expected treatment-related changes without acute intracranial haemorrhage around the cavernous malformations. This case demonstrates successful staged bilateral MRgFUS thalamotomy in a patient with cerebral cavernous malformations, suggesting they may not uniformly preclude MRgFUS in carefully selected patients. Preoperative planning, counselling and MRI surveillance remain essential.

The pharmacological actions of anesthetic agents extend far beyond neurodepression, encompassing complex immunomodulatory effects with implications for perioperative immune function, surgical outcomes, infection risk, and cancer biology. This review critically evaluates current evidence on how different anesthetic classes influence innate and adaptive immunity, examining cellular targets and signaling mechanisms. Rather than viewing anesthesia as monolithically immunosuppressive, current evidence supports a nuanced understanding in which immunological effects vary according to anesthetic agent, dose, timing, and clinical context. Volatile anesthetics (isoflurane, sevoflurane) attenuate natural killer cell cytotoxicity and neutrophil function, promote lymphocyte apoptosis with T helper 2 cell skewing, and exhibit context-dependent anti-inflammatory properties. Propofol preserves immune function by attenuating ROS-mediated cellular damage and maintaining Th1/Th2 balance. Ketamine exerts concentration-dependent immunomodulatory effects including anti-inflammatory actions on macrophages and biphasic lymphocyte modulation. We discuss clinical implications in oncological surgery, sepsis, and autoimmune disorders, emphasizing strengths and limitations of current evidence. Emerging frontiers include personalized anesthesia guided by immune phenotyping, novel targeted agents, and the gut microbiome as a modulator of anesthetic-immune interactions, though these remain promising directions rather than established practice. This review integrates mechanistic insights with clinical evidence and identifies priorities for translational research.

MECP2 encodes a methyl-DNA-binding chromatin protein whose dosage is critical for nervous system function: loss-of-function variants cause Rett syndrome, whereas increased dosage causes MECP2 duplication syndrome. Despite extensive research on MECP2 in neurodevelopmental diseases, its unexplored evolutionary history, which we derived from comparative genomic analysis of hundreds of species, provides a novel evolutionary framework for understanding the profound consequences of MECP2 perturbation on brain and behavior. In this review, we analyze the phylogenetic profile of MECP2 and discuss how comparative, molecular, and developmental evidence supports the idea that MECP2 gained significant importance in vertebrate nervous systems. This is because broad CpG methylation, postnatal accumulation of neuronal non-CpG methylation, and long-lived post-mitotic circuits created a growing need for stable yet flexible interpretation of methylation states. We further discuss evidence that MECP2 is functionally anchored to a conserved chromatin-repression axis, particularly the NCoR/SMRT corepressor machinery, while also showing signs of more lineage-restricted integration with mammalian dosage-sensitive regulatory networks. We propose that MECP2 is best understood as a vertebrate-specialized regulator that helps preserve transcriptional homeostasis in mature neurons while allowing experience-dependent plasticity. This framework links methylome interpretation to behavioral adaptation and may help explain why MECP2 dysregulation produces such profound and dosage-sensitive consequences for brain function and behavior.

A current methodological challenge in radiation epidemiology is to account for dose uncertainty in risk estimation. An important preliminary step can be to identify the most influential input parameters involved in dose estimation, before modelling and accounting for their related uncertainty in radiation-induced health risk estimates. In this work, a variance-based global sensitivity analysis (GSA) was performed with Shapley effects and, for the first time in radiation dosimetry, to rank by influence the input parameters of a software conventionally used to estimate organ doses arising from computed tomography (CT) scan exposure: NCICT (National Cancer Institute Dosimetry System for CT) (version 1.0). We focused on brain and red bone marrow (RBM) dose estimation in the French CT cohort and our GSA was performed for three types of examination, classified according to the scanned body region: head, chest, and abdominopelvic. Among the eight uncertain input parameters involved in dose estimation, different influential parameters were highlighted depending on both the scan type and the considered organ dose: these are consistent with the underlying dose calculation methodology. For head CT examinations, technical parameters used for image acquisition including x-ray tube current-time product (mAs) and tube potential (kVp), as well as the end of the scanned body area contributed to about 70% of the variance of the brain dose estimate, while mAs, kVp, the start and end of the scanned body area, and age influenced the RBM dose. The brain and RBM doses delivered during chest CT examinations were mainly influenced by mAs, pitch, and kVp. Finally, kVp was the only input parameter with a significant influence on both the RBM and the brain dose for abdominopelvic CT examinations: it explained more than 30% of the variance of these organ doses. From a clinical perspective, our findings may support optimization of pediatric CT protocols.

Accurate differentiation between moyamoya disease (MMD) and intracranial atherosclerotic disease (ICAD) remains clinically challenging yet crucial for guiding effective therapeutic strategies. Here, we developed a novel nanomaterial platform (SCs-ZIF-8@Au) to perform high-resolution serum metabolic fingerprinting using nanoparticle-assisted laser desorption/ionization mass spectrometry. By integrating machine learning algorithms with metabolic profiling, we established a robust diagnostic model that accurately distinguished MMD from ICAD and healthy controls (HCs). In a cohort comprising 178 MMD patients, 75 ICAD patients, and 103 HCs, our classifier achieved area under the curve (AUC) values of 0.97 (MMD vs HCs), 0.98 (ICAD vs HCs), and 0.88 (MMD vs ICAD). Beyond diagnostics, mechanistic exploration of key metabolic biomarkers revealed that reduced mevalonic acid in MMD impairs endothelial tube formation and migration by disrupting tight junction integrity, attenuating VEGF signaling, and altering calcium homeostasis in human endothelial cells. These findings link dysregulated mevalonate metabolism to pathological angiogenesis in MMD and support its role in endothelial dysfunction. Together, our study provides a clinically applicable, noninvasive diagnostic tool for MMD and ICAD, while uncovering a previously unrecognized pathogenic mechanism that connects systemic metabolic alterations to cerebrovascular remodeling in MMD.

Myocyte enhancer factor 2C (MEF2C) is a transcription factor critical for brain circuit development and cognitive behavior. The loss of one copy of MEF2C leads to MEF2C haploinsufficiency syndrome (MCHS), a neurodevelopmental disorder characterized by intellectual disability, epilepsy, and behavioral phenotypes associated with autism spectrum disorders. Given that numerous genes are regulated by MEF2C, the neuronal and behavioral deficits in MCHS are complex, and there is currently no effective disease-modifying strategy for this disorder. Here, we show that MEF2C haploinsufficiency in forebrain excitability neurons led to an elevation of postsynaptic density protein 95 (PSD-95) in mice. This elevation of PSD-95 coincided with an increased number of structural synapses, facilitated surface expression of N-methyl-D-aspartate (NMDA) receptors, augmented neuronal excitability, and increased susceptibility to seizures. Knocking down PSD-95 or inhibiting the interaction between PSD-95 and NMDA receptors efficiently reduced hyperexcitability phenotypes in MEF2C haploinsufficiency. Most importantly, knocking down PSD-95 significantly improved cognitive behaviors in mice with MEF2C haploinsufficiency. In summary, our study revealed a mechanism underlying hyperexcitability and cognitive defects associated with MCHS and suggests PSD-95 as a therapeutic target for MCHS.

Glioblastoma (GBM) is among the most aggressive and lethal brain tumors, and standard treatment offers only modest survival benefits. Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic cancers, but its efficacy in GBM remains limited. Here we develop a CAR-engineered microglia (CAR-MG) platform and an organoid-based framework to test whether programmable microglial phagocytosis can be directed against GBM. We isolate microglia (MG) from human cortical organoids and engineer them to express a CAR targeting EGFRvIII, a recurrent tumor-specific EGFR deletion variant in GBM. In a 2D co-culture, CAR-MG selectively eliminates GBM cells through phagocytosis. In a 3D GBM-cortical organoid model, CAR-MG infiltrates tumor sites and depletes GBM cells over extended culture. Single-cell RNA sequencing (scRNA-seq) shows elevated phagocytic pathways in CAR-MG and detects internalized tumor-derived transcripts, which resolve phagocytosis-resistance programs. These results support CAR-MG as a myeloid CAR modality for human brain organoid models.

Diffuse gliomas are the most common malignant brain tumors in adults, stratified by isocitrate dehydrogenase (IDH1/IDH2) mutation status. While the median age for central nervous system (CNS) World Health Organization (WHO) grade 2 to 3 IDH-mutant astrocytomas is 38 years, older patients of >55 years predominantly exhibit IDH-wildtype gliomas and confer a poorer prognosis. To examine the clinicopathologic spectrum of IDH-mutant astrocytomas in older adults, we retrospectively reviewed all astrocytic tumors diagnosed at our institution between 2021 and 2024 in patients >55 years. Twenty-two IDH-mutant astrocytomas (median age: 63 years; range: 56-79; male:female = 9:13) were identified and compared descriptively to a historical cohort of 179 IDH-mutant astrocytomas in younger patients. Grade distribution among older patients paralleled that of younger adults: CNS WHO grade 2 (55%), grade 3 (18%), and grade 4 (27%). Magnetic resonance imaging (MRI) showed T2/FLAIR mismatch sign in 25% of grade 2 tumors and in none of the higher grades; 50% of grade 2 tumors demonstrated contrast enhancement. IDH1 p.R132H accounted for 95% of mutations, with 1 p.R132G variant. ATRX loss was seen in 71% and strong p53 immunoreactivity in 83% of evaluable tumors. Copy-number analysis (n = 10) revealed CDKN2A/B homozygous deletion in 10% and heterozygous loss in 20%. Despite their rarity, IDH-mutant astrocytomas in older adults are more prevalent than historically appreciated and maintain imaging and molecular profiles akin to tumors in younger adults. Accordingly, IDH1 p.R132H-specific immunohistochemistry remains a cost-effective first-line screening tool irrespective of age.