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Mice with type I interferon signaling deficiency are prone to epilepsy upon HSV-1 infection

Virologica Sinica 2024年第2期39卷 251-263页

作者： Wei Yang Chong-Yang Tang Dong-Ying Fan Yi-Song Wang Pei-Gang Wang Jing An Guo-Ming Luan beijing Key Laboratory of Epilepsy Sanbo Brain HospitalCapital Medical UniversityBeijing100093China beijing Institute for brain Disorders Capital Medical UniversityBeijing100093China Department of Neurosurgery Epilepsy CenterSanbo Brain HospitalCapital Medical UniversityBeijing100093China Department of Microbiology School of Basic Medical SciencesCapital Medical UniversityBeijing100069China Chinese Institute for brain Research Beijing102206China

Viral encephalitis continues to be a significant public health *** our previous study,we discovered a lower expression of antiviral factors,such as IFN-β,STING and IFI16,in the brain tissues of patients with Rasmussen's encephalitis(RE),a rare chronic neurological disorder often occurred in children,characterized by unihemispheric brain ***,a higher cumulative viral score of human herpes viruses(HHVs)was also found to have a significant positive correlation with the unihemispheric atrophy in *** I IFNs(IFN-I)signaling is essential for innate anti-infection response by binding to IFN-α/βreceptor(IFNAR).In this study,we infected WT mice and IFNAR-deficient A6 mice with herpes simplex virus 1(HSV-1)via periocular injection to investigate the relationship between IFN-I signaling and HHVs-induced brain *** all mice exhibited typical viral encephalitis lesions in their brains,HSV-induced epilepsy was only observed in A6 *** gene expression matrix,functional enrichment analysis and protein-protein interaction network revealed four gene models that were positively related with HSV-induced ***,ten key genes with the highest scores were *** together,these findings indicate that intact IFN-I signaling can effectively limit HHVs induced neural symptoms and brain lesions,thereby confirming the positive correlation between IFN-I signaling repression and brain atrophy in RE and other HHVs encephalitis.

关键词： IFN-I signaling Human herpes viruses(HHVs) Rasmussen's encephalitis(RE)

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Local field potentials,spiking activity,and receptive fields in human visual cortex

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Science China(Life Sciences) 2024年第3期67卷 543-554页

作者： Lu Luo Xiongfei Wang Junshi Lu Guanpeng Chen Guoming Luan Wu Li Qian Wang Fang Fang School of Psychological and Cognitive Sciences and beijing Key Laboratory of Behavior and Mental Health Peking UniversityBeijing 100871China School of Psychology Beijing Sport UniversityBeijing 100084China Department of Neurosurgery Sanbo Brain HospitalCapital Medical UniversityBeijing 100093China beijing Key Laboratory of Epilepsy Epilepsy CenterSanbo Brain HospitalCapital Medical UniversityBeijing 100093China IDG/McGovern Institute for brain Research Peking UniversityBeijing 100871China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100871China beijing Institute for brain Disorders Beijing 100069China State Key Laboratory of Cognitive Neuroscience and Learning and IDG/McGovern Institute for brain Research Beijing Normal UniversityBeijing 100875China

The concept of receptive field(RF) is central to sensory neuroscience. Neuronal RF properties have been substantially studied in animals,while those in humans remain nearly unexplored. Here, we measured neuronal RFs with intracranial local field potentials(LFPs) and spiking activity in human visual cortex(V1/V2/V3). We recorded LFPs via macro-contacts and discovered that RF sizes estimated from lowfrequency activity(LFA, 0.5–30 Hz) were larger than those estimated from low-gamma activity(LGA, 30–60 Hz) and high-gamma activity(HGA, 60–150 Hz). We then took a rare opportunity to record LFPs and spiking activity via microwires in V1 simultaneously. We found that RF sizes and temporal profiles measured from LGA and HGA closely matched those from spiking activity. In sum, this study reveals that spiking activity of neurons in human visual cortex could be well approximated by LGA and HGA in RF estimation and temporal profile measurement, implying the pivotal functions of LGA and HGA in early visual information processing.

关键词： human visual cortex receptive field intracranial EEG local field potential spiking activity

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Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance

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Chinese Medical Journal 2024年第7期137卷 859-870页

作者： Xianlong Wang Chuan Zhao Jincheng Lin Hongxing Liu Qiuhong Zeng Huadong Chen Ye Wang Dapeng Xu Wen Chen Moping Xu En Zhang Da Lin Zhixiong Lin Department of Bioinformatics School of Medical Technology and EngineeringKey Laboratory of Medical BioinformaticsKey Laboratory of Ministry of Education for Gastrointestinal CancerFujian Medical UniversityFuzhouFujian 350122China Department of Neurosurgery Sanbo Brain HospitalCapital Medical UniversityBeijing 100093China

Background:Adamantinomatous craniopharyngioma(ACP)is the commonest pediatric sellar *** effective drug is available and interpatient heterogeneity is *** study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles,imaging findings,and histological features,in order to predict the response to anti-inflammatory treatment and ***:Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled,including 119 ACPs and 23 papillary ***-exome sequencing(151 tumors,including recurrent ones),RNA sequencing(84 tumors),and DNA methylome profiling(95 tumors)were *** clustering and non-negative matrix factorization were used for subgrouping,and Cox regression were utilized for prognostic evaluation,***:Three distinct molecular subgroups were identified:WNT,ImA,and *** WNT subgroup showed higher Wnt/β-catenin pathway activity,with a greater number of epithelial cells and more predominantly solid *** ImA and ImB subgroups had activated inflammatory and interferon response pathways,with enhanced immune cell infiltration and more predominantly cystic ***-activated protein kinases(MEK/MAPK)signaling was activated only in ImA samples,while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group,mostly consisting of *** degree of astrogliosis was significantly elevated in the ImA group,with severe finger-like protrusions at the invasive front of the *** molecular subgrouping was an independent prognostic factor,with the WNT group having longer event-free survival than ImB(Cox,P=0.04).ImA/ImB cases were more likely to respond to immune checkpoint blockade(ICB)therapy than the WNT group(P<0.01).In the preliminary screening of subtyping markers,CD38 was significantly downregulated in WNT compared with ImA and ImB(P=0.01).Conclusions:ACP comprises three molecular subtypes with distinct

关键词： Craniopharyngioma Central nervous system tumor Precision medicine beta Catenin Proto-Oncogene Proteins B-raf

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Glioma-derived ANXA1 suppresses the immune response to TLR3 ligands by promoting an anti-inflammatory tumor microenvironment

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Cellular & Molecular Immunology 2024年第1期21卷 47-59页

作者： Yu Zheng Haihui Jiang Naixue Yang Shaoping Shen Daosheng Huang Lemei Jia Jing Ling Longchen Xu Mingxiao Li Kefu Yu Xiaohui Ren Yong Cui Xun Lan Song Lin Xin Lin Institute for Immunology and School of Medicine Tsinghua UniversityBeijing100084China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityChina.National Clinical Research Center for Neurological DiseasesCenter of Brain TumorBeijing Institute for Brain Disorders and Beijing Key Laboratory of Brain TumorBeijing100070China Department of Neurosurgery Peking University Third HospitalPeking UniversityBeijing100191China Tsinghua-Peking Center for Life Sciences Beijing100084China

A highly immunosuppressive tumor microenvironment(TME)and the presence of the blood‒brain barrier are the two major obstacles to eliciting an effective immune response in patients with high-grade glioma(HGG).Here,we tried to enhance the local innate immune response in relapsed HGG by intracranially injecting poly(I:C)to establish a robust antitumor immune response in this registered clinical trial(NCT03392545).During the follow-up,12/27(44.4%)patients who achieved tumor control concomitant with survival benefit were regarded as responders in our *** found that the T-cell receptor(TCR)repertoire in the TME was reshaped after poly(I:C)*** on the RNA-seq analysis of tumor samples,the expression of annexin A1(ANXA1)was significantly upregulated in the tumor cells of nonresponders,which was further validated at the protein *** vitro and in vivo experiments showed that ANXA1 could induce the production of M2-like macrophages and microglia via its surface receptor formyl peptide receptor 1(FPR1)to establish a Treg cell-driven immunosuppressive TME and suppress the antitumor immune response facilitated by poly(I:C).The ANXA1/FPR1 signaling axis can inhibit the innate immune response of glioma patients by promoting an anti-inflammatory and Treg-driven ***,ANXA1 could serve as a reliable predictor of response to poly(I:C),with a notable predictive accuracy rate of 92.3%.In light of these notable findings,this study unveils a new perspective of immunotherapy for gliomas.

关键词： glioma ANXA1 TLR3 poly(I:C) immunotherapy

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In patients who had a stroke or TIA, enlarged perivascular spaces in basal ganglia may cause future haemorrhagic strokes

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Stroke & Vascular Neurology 2024年第1期9卷 8-17,I0001-I0033页

作者： Yu Tian Mengxing Wang Yuesong Pan Xia Meng Xingquan Zhao Liping Liu Yongjun Wang Yilong Wang Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Chinese Institute for brain Research BeijingChina National Center for Neurological Diseases BeijingChina Advanced Innovation Center for Human brain Protection Capital Medical UniversityBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina

Introduction It remains unclear whether enlarged perivascular spaces(EPVS)predict poor clinical outcomes in patients with acute ischaemic stroke(AIS)or transient ischaemic attack(TIA).Method Data were obtained from the Third China National Stroke Registry *** estimated EPVS in basal ganglia(BG)and centrum semiovale(CSO)using a semiquantified scale(Grade from 0 to 4).Using Cox and logistic regression analyses,the associations of EPVS with 3-month and 1-year adverse outcomes(including recurrent stroke,ischaemic stroke,haemorrhagic stroke,combined vascular event,disability and mortality)were *** analyses of any association of cerebral small vessel disease at baseline and development of a small arterial occlusion(SAO)were *** Among 12603 patients with AIS/TIA,median age was 61.7±11.6 years,and 68.2%were *** adjusting for all potential confounders,frequent-to-severe BG-EPVS was associated with a decreased risk of recurrent ischaemic stroke(HR 0.71,95%CI 0.55 to 0.92,p=0.01)but an increased risk of haemorrhagic stroke(HR 1.99,95%CI 1.11 to 3.58,p=0.02)at 1 year after AIS/TIA,compared with none-to-mild *** with frequent-to-severe CSO-EPVS had a decreased risk of disability(OR 0.76,95%CI 0.62 to 0.92,p=0.004)and all-cause death(HR 0.55,95%CI 0.31 to 0.98,p=0.04)within 3-month but not 1-year follow-ups,compared with those with none-to-mild *** analyses showed that both BG-EPVS(HR 0.43,95%CI 0.21 to 0.87,p=0.02)and CSO-EPVS(HR 0.58,95%CI 0.35 to 0.95,p=0.03)were associated with a decreased risk of subsequent ischaemic stroke in patients with SAO during 1-year *** BG-EPVS increased the risk of haemorrhagic stroke in patients already with AIS/TIA within 1 ***,caution is recommended when selecting antithrombotic agents for secondary stroke prevention in patients with AIS/TIA and more severe BG-EPVS.

关键词： patients haemorrhagic prevention

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Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

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Neural Regeneration Research 2024年第2期19卷 440-446页

作者： Sumei Liu Baoguo Liu Qian Li Tianqi Zheng Bochao Liu Mo Li Zhiguo Chen Cell Therapy Center Beijing Institute of GeriatricsXuanwu HospitalCapital Medical UniversityNational Clinical Research Center for Geriatric Diseasesand Key Laboratory of Neurodegenerative DiseasesMinistry of EducationBeijingChina Center of Neural Injury and Repair Beijing Institute for Brain DisordersBeijingChina Center of Parkinson’s Disease Beijing Institute for Brain DisordersBeijingChina

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate *** a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury ***,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord *** neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury ***,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion *** of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the ***,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion ***-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

关键词： biomaterial fibrinogen functional recovery induced neural stem cell transplantation microenvironment microglia spinal cord injury thrombin

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Sirolimus can promote the disappearance of renal angiomyolipoma associated with tuberous sclerosis complex:a prospective cohort study

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World Journal of Pediatrics 2024年第6期20卷 602-610页

作者： Shuo Dun Yang-Yang Wang Lin Wan Qiu-Hong Wang Qian Lu Xiao-Yan Yang Qi Zhang Hui-Min Chen Lu-Peng Qiu Li-Ping Zou Medical School of Chinese PLA Beijing 100853China Department of Pediatrics The First Medical CenterChinese PLA General HospitalBeijing 100853China Center of Epilepsy Beijing Institute for Brain DisordersBeijing 100069China

Background Renal angiomyolipoma(RAML)is the most common kidney lesion in patients with tuberous sclerosis complex(TSC),affecting about 80%of *** is a benign tumor that grows over time,usually bilaterally,and can easily lead to kidney complications such as acute ***,we investigated the efficacy and safety of sirolimus in children with TSC-associated RAML and explored the factors affecting tumor disappearance under sirolimus treatment through subgroup *** A prospective cohort study was *** was initiated at 1 mg/(m^(2)×day),and dose adjustments were made by a 2-week titration period to attain a trough blood concentration of 5-10 ng/*** disappearance of RAML in chil-dren after sirolimus treatment was observed,and Cox regression was used to screen the factors affecting tumor *** One hundred and twenty-six patients who met the criteria were *** 3 months,6 months,12 months,and 24 months of follow-up,tumors disappeared in 18(14.3%),30(23.8%),39(31.0%),and 42(33.3%)children,*** disappeared in 50(39.7%)children by the last visit of each individual,and 30(60%)of them occurred within 6 *** multivariate Cox regression analysis showed that patients with a smaller maximum tumor diameter at baseline had a higher tumor disappearance ***-six(29%)patients had stomatitis during the entire treatment period,and no serious *** Sirolimus could promote the disappearance of TSC-related *** disappearance rate was correlated with the maximum diameter at baseline,and the smaller the tumor was,the higher the disappearance *** is well tolerated in the treatment of RAML associated with TSC.

关键词： Angiomyolipoma mTOR inhibitor Sirolimus Tuberous sclerosis

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Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction (STRATEGY): protocol for a multicentre, randomised controlled trial

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Stroke & Vascular Neurology 2024年第1期9卷 75-81,I0047-I0052页

作者： Xiaoling Liao Shuo Feng Yicong Wang Yuesong Pan Weiqi Chen Hui Qu Xingquan Zhao Liping Liu Yongjun Wang Yilong Wang Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical Research Center for Neurological Diseases Beijing TiantanHospitalCapital Medical UniversityBeijingChina Chinese Institute for brain Research BeijingChina National Center for Neurological Diseases BeijingChina Advanced Innovation Center for Human brain Protection Capital Medical UniversityBeijingChina beijing Laboratory of Oral Health Capital Medical UniversityBeijingChina

Background Perforating artery territorial infarction(PAI)caused by branch atheromatous disease(BAD)is prone to recurrence and early progression without an effective and well-documented antiplatelet treatment ***,an adjunctive antiplatelet agent,has shown great potential to treat acute ischaemic ***,whether the combination of tirofiban and aspirin can improve the prognosis of PAI remains *** To explore an effective and safe antiplatelet regimen for reducing the risk of recurrence and early neurological deterioration(END)in PAI caused by BAD by comparing the tirofiban and aspirin combination with placebo and aspirin *** Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction(STRATEGY)trial is an ongoing multicentre,randomised,placebo-controlled trial in *** patients shall be randomly assigned to receive standard aspirin with tirofiban or placebo on the first day and standard aspirin from days 2 to *** primary endpoint is a new stroke or END within 90 *** primary safety endpoint is severe or moderate bleeding within 90 *** The STRATEGY trial will assess whether tirofiban combined with aspirin is effective and safe in preventing recurrence and END in patients with *** registration number NCT05310968.

关键词： Aspirin regimen centre

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Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis (BASIS): protocol of a prospective, multicentre, randomised, controlled trial

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Stroke & Vascular Neurology 2024年第1期9卷 66-74页

作者： Xuan Sun Ming Yang Dapeng Sun Guangge Peng Yiming Deng Xingquan Zhao Liping Liu Ning Ma Feng Gao Dapeng Mo Wengui Yu Yongjun Wang Yilong Wang Zhongrong Miao Department of Interventional Neuroradiology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Department of Neurology Beijing Luhe HospitalCapital Medical UniversityBeijingChina Department of Neurology Comprehensive Stroke&Cerebrovascular CenterUniversity of California IrvineIrvineCaliforniaUSA Chinese Institute for brain Research BeijingChina National Center for Neurological Diseases BeijingChina Advanced Innovation Center for Human brain Protection Capital Medical UniversityBeijingChina China National Clinical Research Center for Neurological Diseases BeijingChina beijing Laboratory of Oral Health Capital Medical UniversityBeijingChina

Background The superiority of balloon angioplasty plus aggressive medical management(AMM)to AMM alone for symptomatic intracranial artery stenosis(sICAS)on efficacy and safety profiles still lacks evidence from randomised controlled trials(RCTs).Aim To demonstrate the design of an RCT on balloon angioplasty plus AMM for *** Balloon Angioplasty for Symptomatic Intracranial Artery Stenosis(BASIS)trial is a multicentre,prospective,randomised,open-label,blinded end-point trial to investigate whether balloon angioplasty plus AMM could improve clinical outcome compared with AMM alone in patients with *** eligible in BASIS were 35–80 years old,with a recent transient ischaemic attack within the past 90 days or ischaemic stroke between 14 days and 90 days prior to enrolment due to severe atherosclerotic stenosis(70%–99%)of a major intracranial *** eligible patients were randomly assigned to receive balloon angioplasty plus AMM or AMM alone at a 1:1 *** groups will receive identical AMM,including standard dual antiplatelet therapy for 90 days followed by long-term single antiplatelet therapy,intensive risk factor management and life-style *** participants will be followed up for *** outcomes Stroke or death in the next 30 days after enrolment or after balloon angioplasty procedure of the qualifying lesion during follow-up,or any ischaemic stroke or revascularisation from the qualifying artery after 30 days but before 12 months of enrolment,is the primary *** BASIS trail is the first RCT to compare the efficacy and safety of balloon angioplasty plus AMM to AMM alone in sICAS patients,which may provide an alternative perspective for treating *** registration number NCT03703635;https://***.

关键词： balloon prospective centre

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Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

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Signal Transduction and Targeted Therapy 2024年第1期9卷 326-337页

作者： You Zhai Yicong Du Guanzhang Li Mingchen Yu Huimin Hu Changqing Pan Di Wang Zhongfang Shi Xu Yan Xuesong Li Tao Jiang Wei Zhang Department of Molecular Neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingPR China Department of Urology Peking University First HospitalInstitute of UrologyPeking UniversityNational Urological Cancer CenterBeijingPR China Department of Pathophysiology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China China National Clinical Research Center for Neurological Diseases BeijingPR China Center of brain Tumor Beijing Institute for Brain DisordersBeijingPR China Research Unit of Accurate Diagnosis Treatmentand Translational Medicine of Brain TumorsChinese Academy of Medical SciencesBeijingPR China Chinese Glioma Genome Atlas Network(CGGA)and Asian Glioma Genome Atlas Network(AGGA) BeijingPR China

Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid *** instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance ***,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less ***,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term *** this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented *** mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen *** type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell ***,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol *** mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR ***,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.

关键词： Together instance depletion

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