Acta Neuropathologica Communications最新文献

{"title":"Ovarian central nervous system-type tumors: integrated neuropathological and methylation-based classification reveals site-related features.","authors":"Martin Raby, Alexis Trécourt, Euphrasie Servant, Anne-Sophie Lebre, Sabrina Croce, Isabelle Treilleux, Tatiana Franceschi, Gerlinde Averous, Catherine Genestie, Margot Bucau, Yassine Bouchoucha, Dominique Berrebi, Raphaël Saffroy, Romain Appay, Pierre-Alexandre Just, Lauren Hasty, Farah Sassi, Alice Métais, Pascale Varlet, Mojgan Devouassoux-Shisheboran, Arnault Tauziède-Espariat","doi":"10.1186/s40478-026-02302-1","DOIUrl":"https://doi.org/10.1186/s40478-026-02302-1","url":null,"abstract":"<p><p>Central nervous system (CNS)-type tumors may occur in the ovary, often associated with a mature teratomatous component. Because of their rarity, little is known about the tumor types historically designated within the primitive neuroectodermal tumors (PNET) terminology and whether they share histopathological and molecular features akin to those of their CNS counterparts. Herein, we retrospectively investigated data from 13 ovarian tumors, initially diagnosed as either \"PNETs\" or CNS-type neoplasms. For each tumor we performed comprehensive histopathologic, genetic and epigenetic analyses and retrieved clinical data when available. Integrated diagnoses were established after a central review of histopathological and molecular data, the following entities were identified: four embryonal tumors with multilayered rosettes (non C19MC-altered), three medulloblastomas, SHH-activated, three ependymomas not elsewhere classified, one Ewing sarcoma, one sarcoma, DICER1-mutant, and one peripheral neuroblastoma. Interestingly, none of the ETMRs harbored a C19MC amplification or DICER1 mutation. The three medulloblastomas, SHH-activated were histopathologically and molecularly similar to their CNS counterparts. Ependymomas did not show any classifying molecular alteration and presented a distinct epigenetic profile when compared with CNS ependymomas. These results indicate that ovarian \"PNETs\" comprise a heterogeneous spectrum of CNS and extra-CNS embryonal or non-embryonal tumor types, and that brain tumor methylation classifiers may be used to classify these tumors. Moreover, these components are characterized by distinct molecular alterations from primary CNS tumors, without C19MC alterations for ETMRs, with an overrepresented SHH-subgroup for medulloblastomas, and with an epigenetic profile distinct from CNS counterparts in ovarian ependymomas. These data need to be confirmed before they can be incorporated into future patient personalized treatment.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial associations between neuronal membrane damage and vasculature after repetitive diffuse TBI in pigs.","authors":"Kathryn L Wofford, Erin M Purvis Conway, Victor P Acero, Jerry Gao, Olivia M Rivellini, Emory Kuo, Constance J Mietus, Kevin D Browne, John C O'Donnell, D Kacy Cullen","doi":"10.1186/s40478-026-02309-8","DOIUrl":"https://doi.org/10.1186/s40478-026-02309-8","url":null,"abstract":"<p><p>Closed-head traumatic brain injury (TBI) generally results in diffusely distributed neuropathology. However, factors influencing the micro-scale distribution of this neuropathology remain unknown. Because neurovasculature exhibits different mechanical properties from the surrounding parenchyma, we postulated that these material transitions would increase the likelihood of biophysical damage and resultant neuropathology. Accordingly, we measured the incidence of neuronal plasmalemmal damage in perivascular domains using an established porcine model of single or repetitive closed-head rotational acceleration induced TBI. We found a significant increase in the proportion of regions containing permeabilized neurons in the cortex, thalamus, and midbrain following a single head rotation. We next employed an unbiased sampling methodology that mapped the distribution of vasculature (location, size, and directionality) and permeabilized neurons to determine if neuronal permeability increased based on proximity to vasculature. We identified an increase in the number of permeabilized neurons and a significant decrease in the number of larger (> 100 μm) vessels in the midbrain after repetitive TBI separated by 3 days. Furthermore, we identified that perivascular areas exhibited an increased density of neuronal permeability relative to more distal, extraperivascular spaces but only when excluding blood vessels that had no associations with permeabilized neurons. Neuronal permeability distribution was not affected by vessel size. These data suggest that vascular changes and neuronal damage may be unique consequences based on injury biomechanics, timing between repetitive injuries, and neuroanatomical features. While neuroanatomical features such as distance to the nearest vessel contribute to the distribution of neuronal mechanoporation, our findings indicate that perivascular proximity is a secondary, not primary, factor influencing this distribution. More research is needed to identify other factors that affect the susceptibility and distribution of neuronal plasmalemmal pathology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling.","authors":"Anna Maria Haschke, Anja von Renesse, Eugenio Graceffo, Susanne Morales-Gonzalez, Alessandro Prigione, Christoph Hübner, Werner Stenzel, Markus Schuelke","doi":"10.1186/s40478-026-02313-y","DOIUrl":"https://doi.org/10.1186/s40478-026-02313-y","url":null,"abstract":"<p><p>During muscle contraction, increased influx of calcium from the myocyte cytosol into the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) links calcium homeostasis with high ATP provision. The MCU is located at the inner mitochondrial membrane and one of its structural components, the mitochondrial calcium uniporter regulator 1 (MCUR1), promotes its activity. Although MCUR1 function has been studied in cell models, mutations have not yet been associated with human disease. Here, we present a patient with proximal muscle weakness and atrophy, showing histological features of autophagic vacuoles with sarcolemmal features, who carries a homozygous MCUR1 nonsense mutation. To investigate the underlying mechanisms of muscle pathology, we examined patient fibroblasts and quadriceps muscle specimens. MCUR1 deficiency compromised mtCa²⁺ uptake, that had been stimulated both by histamine or rising extracellular calcium exposure. Autophagic flux and histologic markers for autophagy (LAMP2, LCB3) were increased in the patient. However, the MCUR1 mutation did not alter MCU-complex assembly or its subcellular location, nor the resting mitochondrial membrane potential. Our study associates MCUR1 deficiency with mitochondrial dysfunction and autophagic vacuolar myopathy, thereby highlighting the crucial role of mtCa²⁺ uptake in regulating mitochondrial function and expanding the spectrum of mitochondrial disorders in humans.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adult-onset Sandhoff disease presenting with a motor neuron disease phenotype: clinical and mechanistic insights from patient-derived models.","authors":"Yao Tang, Didi Shan, Hongxu Wang, Xinbo Ji, Yichang Jiao, Jianing Li, Zexin Zhan, Shuangwu Liu, Xiaohan Sun, Pengfei Lin, Jingwen Xu, Dongdong Wang, Xiulian Sun, Chuanzhu Yan, Yuying Zhao, Fuchen Liu","doi":"10.1186/s40478-026-02308-9","DOIUrl":"https://doi.org/10.1186/s40478-026-02308-9","url":null,"abstract":"<p><p>Sandhoff disease (SD) is a subtype of GM2 gangliosidosis caused by pathogenic variants in Hexosaminidase B (HEXB). It most frequently presents in infancy or early childhood, whereas adult-onset disease is rare and remains incompletely characterized. Here, we describe an adult-onset case of SD presenting as motor neuron disease and provide clinical and mechanistic insights using patient-derived models. The patient was a 34-year-old man with compound heterozygous HEXB variants (c.1598G > A, p.Arg533His and c.1645G > A, p.Gly549Arg) who developed progressive lower limb weakness. Muscle biopsy demonstrated neurogenic changes consistent with denervation, and sural nerve biopsy revealed mild peripheral neuropathy. Nerve conduction studies and electromyography showed widespread neurogenic changes with mildly reduced sensory nerve action potential amplitudes, and leukocyte β-hexosaminidase activity was decreased. To investigate disease mechanisms, we generated induced pluripotent stem cells (iPSCs) from the patient and an isogenic CRISPR-Cas9-corrected control (ISO), and differentiated both lines into motor neurons (MNs). In the SD patient (SDHF)-derived MNs, we observed lysosomal expansion, increased apoptosis, reduced neuronal network excitability, and dysregulated lipidomic profiles. These phenotypes were attenuated in MNs derived from the ISO line, with multiple measures shifting toward those of control (CTL) MNs. Collectively, our findings expand the clinical spectrum of adult-onset SD and support an association between HEXB deficiency and the vulnerability of MNs, while underscoring the value of patient-derived iPSC models for mechanistic studies of lateonset SD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.","authors":"Nikki S Harper, Joanne L Sharpe, Jasmine Speranza, Ravinder Gulia, Jeffrey X Chen, Scott P Allen, Manpreet S Atwal, Stuart Pickering-Brown, Matthew R Livesey, Craig L Bennett, Andreas Prokop, Albert R La Spada, Ryan J H West","doi":"10.1186/s40478-026-02301-2","DOIUrl":"https://doi.org/10.1186/s40478-026-02301-2","url":null,"abstract":"<p><p>Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2α phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2α phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative BRAF p.V600E mutation monitoring in cerebrospinal fluid cell-free DNA reflects therapeutic response to BRAF/MEK inhibitors in papillary craniopharyngioma: a report of two cases.","authors":"Hirotaka Fudaba, Masayuki Yanagida, Kumpei Takao, Kouhei Onishi, Hiroyuki Matsuta, Yasutomo Momii, Mitsuhiro Anan, Nobuhiro Hata, Tsuyoshi Etoh, Minoru Fujiki","doi":"10.1186/s40478-026-02314-x","DOIUrl":"https://doi.org/10.1186/s40478-026-02314-x","url":null,"abstract":"<p><p>Papillary craniopharyngioma (PCP), molecularly defined by the BRAF p.V600E mutation in > 90% of cases, is a highly specific target for BRAF/MEK inhibitor therapy, based on dramatic radiologic responses observed in clinical trials. However, the utility of real-time molecular monitoring remains largely unexplored. Here, we present two patients with BRAF p.V600E-mutant PCP who achieved exceptional tumor volume reductions of 95% and 98% following targeted therapy with dabrafenib and trametinib. To monitor molecular burden, cerebrospinal fluid samples collected longitudinally through preexisting access devices, including Ommaya reservoirs and shunt valves, were quantitatively analyzed for the BRAF p.V600E mutation burden in cell-free DNA (cfDNA). In both cases, the BRAF p.V600E mutation copy number in the CSF rapidly declined and became undetectable, in parallel with radiologic tumor shrinkage. Notably, Case 1 maintained the negative mutation status and did not experience recurrence during the 9-month follow-up period. These findings demonstrate that digital polymerase chain reaction-based monitoring of CSF-derived cfDNA is a sensitive and objective tool for assessing molecular response in PCP, reflecting the real-time efficacy of targeted treatment and providing a framework for individualized management and early detection of recurrence in precision neurooncology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM21 autoantibodies are associated with blood-brain barrier dysfunction in a subgroup of neuromyelitis optica spectrum disorder.","authors":"Fumitaka Shimizu, Chihiro Kadono, Masatoshi Yuri, Hirotada Fujita, Yoichi Mizukami, Kenji Watanabe, Nanami Yamanaka, Masayuki Nakamori","doi":"10.1186/s40478-026-02307-w","DOIUrl":"https://doi.org/10.1186/s40478-026-02307-w","url":null,"abstract":"<p><p>We previously reported that glucose-regulated protein 78 autoantibodies (GRP78 Ab) cause breakdown of the blood-brain barrier (BBB) in neuromyelitis optica spectrum disorder (NMOSD) patients. Objective of the present study is to identify novel antibodies associated with the breakdown of the BBB in NMOSD patients negative for anti-GRP78 Ab. Human brain microvascular endothelial cells (BMECs) were incubated with purified NMOSD-IgG from 4 patients. RNA-seq, a high-content imaging, living cell-based antibody binding assay, and mass spectrometry were used to evaluate molecular changes and identify the target protein of BMECs after exposure to NMOSD-IgG. The anti-tripartite motif-containing protein 21 (TRIM21) autoantibody was detected using an enzyme-linked immunosorbent assay. The clinical data of patients with NMOSD with anti-TRIM21 antibodies were verified. Changes in permeability were evaluated using three in vitro BBB models, including monolayer, spheroid and microfluidic tri-culture models. TRIM21, TROVE2 and SS-B were identified as the target antigens of NMOSD-IgG in GRP78 Ab-negative NMOSD patients using proteomics. NF-κB and tight junctions (claudin-5) in BMECs were identified as important signaling pathways after stimulation with TRIM21 Ab-positive NMOSD-IgG by RNA-seq and high-content imaging at the mRNA and protein levels. TRIM21 Abs from NMOSD patients reacted with TRIM21 in the cytoplasm of BMECs using double immunostaining. Stimulation with some commercial TRIM21 Abs, but not TROVE2 Abs or SS-B Abs, caused the nuclear translocation of NF-κB and an increase in 10- and 150-kDa dextran permeability. Removal of anti-TRIM21 Abs from NMOSD-IgG leads to a significant decrease in the biological effect of NMOSD-IgG on the increased permeability of 10-kDa dextran in BMECs. The positive rate of anti-TRIM21 Abs was 27% (13 of 48) in NMOSD patients, 27% (4 of 15) in myelin oligodendrocyte glycoprotein-antibody associated disease patients, 0% (0 of 43) in multiple sclerosis patients, 5% (2 of 43) in disease controls, and 0% (0 of 16) in healthy controls. Pooled NMOSD-IgG with anti-TRIM21 Abs negative for anti-GRP78 Abs decreased the barrier function more than HC-IgG using three in vitro BBB tri-culture models. In conclusion, anti-TRIM21 Abs in NMOSD may contribute to the breakdown of the BBB in patients with NMOSD via the activation of NF-κB and reduction in claudin-5 in BMECs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune landscape characterization of neurofibromas with atypical features in Neurofibromatosis1 reveals PD-1 and the Tim-3/Galectin-9 pathway as potential therapeutic targets.","authors":"Anaïs Brunet, Fanny Coulpier, Audrey Onfroy, Nouhoum Sako, Katarzyna J Radomska, Valérie Aftimos, Laetitia Lacroix, Audrey Briand-Suleau, Pascale Maille, Oana Hermeziu, Ingrid Laurendeau, Eric Pasmant, Pierre Wolkenstein, Piotr Topilko, Nicolas Ortonne","doi":"10.1186/s40478-026-02310-1","DOIUrl":"https://doi.org/10.1186/s40478-026-02310-1","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to the development of plexiform neurofibromas (pNF), benign tumors of the nerve sheath that can progress to malignant peripheral nerve sheath tumors (MPNST). Some pNFs exhibit atypical characteristics, particularly atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP), which meet recently defined criteria. These are pNFs with concerning histological and/or molecular features and uncertain behavior, leading to their consideration as potential precursors of MPNSTs. In this study, we characterized the immune landscape of a series of atypical neurofibromas (exhibiting increased cellularity or atypical cells) and ANNUBPs (ANF/ANNUBP) compared to cutaneous neurofibromas (cNF), pNFs, and MPNSTs, all from patients with NF1, using immunohistochemistry and single-cell RNA sequencing (scRNA-seq). Our findings revealed that ANF/ANNUBPs are heavily infiltrated with CD3+ T-lymphocytes and CD163+ macrophages. Transcriptomic profiling using the NanoString technology demonstrated that ANF/ANNUBPs exhibit a distinct immune signature compared to both pNFs and MPNSTs. This includes overexpression of two inhibitory immune checkpoints (ICs): HAVCR2 (encoding the IC receptor Tim-3) and its primary ligand Galectin-9 (Gal9). Subsequent analyses of scRNA datasets corroborated these findings with Prss56^Cre/+, Nf1^fl/fl, R26^tdTom/+ mouse model-derived tumors. Using multiplex immunofluorescence, we showed that CD3+ T-cells express the inhibitory IC PD-1, while CD163+ macrophages express both Tim-3 and Gal9. Furthermore, tumor cells within ANF/ANNUBPs were positive for activated caspase-3, suggesting a possible role of the immune microenvironment in controlling tumor growth or inducing cell death. Through deep-targeted DNA sequencing, we detected loss of cell cycle regulators (especially CDKN2A) in ANF/ANNUBPs but no somatic alteration of polycomb repressor complex components EED and SUZ12, the latter typically associated with MPNSTs, even at low frequencies. Additionally, loss of H3K27me3 was associated with even lower densities of CD3+ T-cells and CD163+ macrophages in MPNSTs, and the loss of p16 seemed to act synergistically. Taken together, these findings suggest that an immune response involving both T-lymphocytes and macrophages may play a role in controlling or delaying the malignant transformation of ANF/ANNUBPs into MPNSTs and point to IC molecules as novel immunopreventive strategies in NF1 patients with ANF/ANNUBPs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-plex spatial protein profiling of skeletal muscle biopsies in inflammatory myopathies using the MACSima™ imaging platform: A pilot study.","authors":"Monica Sciacco, Daniele Velardo, Letizia Bertolasi, Patrizia Ciscato, Giuseppe Castellano, Deborah Mattinzoli, Masami Ikehata, Stefania Corti, Giacomo Pietro Comi, Simona Zanotti","doi":"10.1186/s40478-026-02306-x","DOIUrl":"https://doi.org/10.1186/s40478-026-02306-x","url":null,"abstract":"<p><p>Inflammatory myopathies represent a heterogeneous group of autoimmune disorders affecting skeletal muscle, with distinct pathological features. While muscle biopsy remains a key diagnostic tool, conventional immunohistochemical approaches are limited in both number of available markers and spatial resolution. To explore the feasibility and potential of the MACSima™ Imaging Platform for high-dimensional, spatially resolved analysis of skeletal muscle tissue in inflammatory myopathies, we applied a panel of antibodies targeting immune cells, extracellular matrix components, blood vessels, and lymphatic markers to skeletal muscle cryosections from patients with different inflammatory myopathies and age-matched controls. Using the MACSima™ platform, we performed iterative immunofluorescence staining and imaging cycles to generate multiplexed protein maps. The platform enabled robust signal acquisition and preserved tissue morphology throughout all cycles. Preliminary spatial analysis revealed distinct immune cell infiltration patterns, ECM remodeling signatures, and vascular changes across disease subtypes. This pilot study demonstrates the feasibility of applying high-dimensional multiplex imaging to skeletal muscle using the MACSima™ system. Our results represent a first partial spatial profiling of muscle pathology in autoimmune myopathies using an innovative methodological approach.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for coordinate CTCF and histone H3.3 activities in K27M diffuse midline gliomas.","authors":"Rachel H Klein, Jennifer Q Yee, Paul S Knoepfler","doi":"10.1186/s40478-026-02290-2","DOIUrl":"https://doi.org/10.1186/s40478-026-02290-2","url":null,"abstract":"<p><p>Up to 80% of diffuse midline gliomas (DMGs) are characterized by a lysine to methionine driver mutation (K27M) in the tail of histone variant H3.3, pointing to likely roles for epigenetic mechanisms in K27M-driven tumorigenesis. Understanding the effects of mutant histone H3.3 on the complex patterns of histone modifications and interactions with chromatin structure and modifying enzymes is essential to developing effective combination treatment therapies for K27M DMG such as targeting multiple epigenetic enzymes at once. Here, using a genomics approach, we identified combinatorial patterns of epigenetic modifications that are affected by mutant H3.3 in DMG. We also characterized a strong association between H3.3 and the structural chromatin regulator CTCF, finding that mutant H3.3 leads to ectopic binding of CTCF at many additional sites across the genome in DMG. Notably, a number of these ectopic CTCF binding events occur within the HOX gene loci and are associated with an increase in H3K27me3 levels at bivalent domains and a decrease in HOX gene expression. We also find an association of H3.3 and CTCF at genomic sites adjacent to regions with active or repressive modifications, suggesting a potential role for these two factors in segmenting the chromatin and regulating, perhaps insulating, different types of domains. Together our data suggest that H3.3 K27M both affects epigenetic marks and chromatin organization in part through interaction with CTCF and point to a potentially novel contributory role for CTCF in promoting oncogenesis in DMG. These findings could have potential implications for designing therapy regimens to more effectively target the chromatin changes and genomic instability observed in H3.3K27M glioma cells.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}