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Byline: Lijian. Xu, Yueqi. Zhu, Ruijian. Zhang, Tingzhun. Zhu, Jieqing. Wan, Fuyou. Liang, Bing. Zhao Background: Small intracranial aneurysms have a low risk of rupture. However, ruptured anterior communicating artery [...]

Background: Microglial polarization is one of the most promising therapeutic targets for multiple central nervous system (CNS) disorders, including ischemic stroke. However, detailed transcriptional alteration of microglia following cerebral ischemic stroke remains largely unclear. Methods: Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) for 60 min in mice. Single-cell RNA sequencing (scRNA-seq) was performed using ischemic brain tissues from tMCAO and sham mice 3 days after surgery. Ch25h−/− mice were used to investigate the role of specific microglia subcluster on post-stroke infarct volume and neuroinflammation. Results: We identified a relatively homeostatic subcluster with enhanced antigen processing and three "ischemic stroke associated microglia" (ISAM): MKI67+, CH25H+ and OASL+ subclusters. We found the MKI67+ subcluster undergo proliferation and differentiation into CH25H+ and OASL+ subclusters. CH25H+ microglia was a critical subcluster of ISAM that exhibited increased phagocytosis and neuroprotective property after stroke. Ch25h−/− mice developed significantly increased infarct volume following ischemic stroke compared to Ch25h+/−. Meanwhile, the OASL+ subcluster accumulated in the ischemic brain and was associated with the evolving of neuroinflammation after stroke, which was further aggravated in the aged mice brain. Conclusions: Our data reveal previously unrecognized roles of the newly defined CH25H+ and OASL+ microglia subclusters following ischemic stroke, with novel insights for precise microglia modulation towards stroke therapy. [ABSTRACT FROM AUTHOR]

Background and Purpose: Drug-eluting stents generally have superior performance to bare metal stents in the treatment of vertebral artery stenosis (VAS). This prospective, multicenter, and single-arm clinical trial was initiated to assess in-stent restenosis (ISR) and midterm outcome after rapamycin-eluting stent placement in patients with symptomatic extracranial VAS. Methods: The subjects underwent angiographic follow-up at 6 months and final clinical follow-up at 12 months. The primary efficacy endpoint was ISR at 6 months. Secondary endpoints included technical success, target lesion-related transient ischemic attack (TIA), stroke, or death, and all-cause TIA, stroke, or death during the 12-month follow-up period. Results: A total of 104 stents were implanted in the 101 patients and 83 patients (82.2%) completed angiographic follow-up at 6 months. The technical success rate was 86.1% (87/101); mean in-stent stenosis rate was 25.1 ± 17.1% and ISR rate was 5.9% (95% CI: 0.8–10.9%). All the patients with ISR were completely asymptomatic and no stent fractures were observed during angiographic follow-up. At the 12-month clinical follow-up, target lesion-related TIA, stroke, or death had occurred in two (2.0%) patients and all-cause TIA, stroke, or death had occurred in six (6.1%) patients. Conclusion: The placement of rapamycin-eluting stents in patients with symptomatic extracranial VAS yields favorable ISR results and showed a trend of favorable safety outcomes including low rates of perioperative complications and late stroke. However, further study is needed to establish the long-term clinical benefits of this stent in the treatment of VA disease. [ABSTRACT FROM AUTHOR]

Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood.Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests.Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery.Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

Background: Unruptured intracranial aneurysm treatment aims to reduce the risk of aneurysm rupture and bleeding, relieves symptoms and improve the quality of life for patients. This study aimed to assess the safety and efficacy of Pipeline Embolization Device (PED, Covidien/Medtronic, Irvine, CA) treatment for intracranial aneurysms presenting with mass effect in real-world settings., Methods: We selected patients from the PED in China Post-Market Multi-Center Registry Study with mass effect presentation. The study endpoints included postoperative mass effect deterioration and mass effect relief at follow-up (3-36 months). We conducted multivariate analysis to identify factors associated with mass effect relief. Subgroup analyses by aneurysm location, size and form were also performed., Results: This study included 218 patients with a mean age of 54.3±11.8 years and a female predominance of 74.0% (162/218). The postoperative mass effect deterioration rate was 9.6% (21/218). During a median follow-up period of 8.4 months, the mass effect relief rate was 71.6% (156/218). Notably, immediate aneurysm occlusion following treatment was significantly associated with mass effect relief (OR 0.392, 95% CI, 0.170 to 0.907, p=0.029). Subgroup analysis demonstrated that adjunctive coiling contributed to mass effect relief in cavernous aneurysms, while dense embolism impeded symptom relief in aneurysms<10 mm and saccular aneurysms., Conclusions: Our data confirmed the efficacy of PED in relieving mass effect. The findings of this study provide support for endovascular treatment to alleviate mass effect in unruptured intracranial aneurysms., Trial Registration Number: NCT03831672., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Intracranial aneurysms pose a significant health issue, affecting 3-5% of the adult population. The pipeline embolization device (PED) has emerged as a promising treatment for these lesions. This study aimed to investigate the impact of operator experience on complication and poor outcome rates, as well as the learning curve for PED., Methods: A total of 217 patients were consecutively enroled from four eligible centres and divided into three groups based on the number of procedures performed: group 1 (first 10 procedures), group 2 (11-20 procedures), and group 3(>20 procedures). Major complications include operation-related ischaemic or haemorrhagic events and mass effect deterioration. Poor outcome was defined as a modified Rankin Scale score greater than 2 at discharge. Cumulative summation (CUSUM) analysis was generated to assess the learning curve according to major complications and poor outcome., Results: The study found that major complications and poor outcomes occurred in 5.1% and 2.3% of cases, respectively. The rate of major complications decreased from 10.0% in group 1 to 2.9% in group 3 ( P =0.053), while the rate of poor outcomes decreased from 7.5% in group 1 to 0.7% in group 3 ( P =0.015). Multivariable regression analysis adjusted for covariates showed that operator experience was associated with a lower rate of poor outcomes ( P =0.034). CUSUM analysis demonstrated that the learning curve for avoiding major complications and poor outcomes required 27 (mean=13) and 40 (mean=20) cases, respectively., Conclusions: These findings suggest that PED treatment requires a learning curve of 40 cases to achieve reproducibility regarding complications and functional results. Additionally, major complications and poor outcomes significantly decreases after the first 20 procedures. CUSUM analysis can serve as a useful tool for monitoring and assessing surgical performance., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The safety outcomes of endovascular therapy for intracranial artery stenosis in a real-world stetting are largely unknown. The Clinical Registration Trial of Intracranial Stenting for Patients with Symptomatic Intracranial Artery Stenosis (CRTICAS) was a prospective, multicentre, real-world registry designed to assess these outcomes and the impact of centre experience., Methods: 1140 severe, symptomatic intracranial arterial stenosis (ICAS) patients treated with endovascular therapy were included from 26 centres, further divided into three groups according to the annual centre volume of intracranial angioplasty and stent placement procedures over 2 years: (1) high volume for ≥25 cases/year; (2) moderate volume for 10-25 cases/year and (3) low volume for <10 cases/year., Results: The rate of 30-day stroke, transient ischaemic attack or death was 9.7% (111), with 5.4%, 21.1% and 9.7% in high-volume, moderate-volume and low-volume centres, respectively (p<0.05). Multivariable logistic regression confirmed high-volume centres had a significantly lower primary endpoint compared with moderate-volume centres (OR=0.187, 95% CI: 0.056 to 0.627; p≤0.0001), while moderate-volume and low-volume centres showed no significant difference (p=0.8456)., Conclusion: Compared with the preceding randomised controlled trials, this real-world, prospective, multicentre registry shows a lower complication rate of endovascular treatment for symptomatic ICAS. Non-uniform utilisation in endovascular technology, institutional experience and patient selection in different volumes of centres may have an impact on overall safety of this treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

MicroRNA (miRNA) dysfunction has been confirmed as a key event of ischemic stroke appearance. This study is aimed at revealing the role of miR-429 in the angiogenesis of HBMECs. The HBMECs were treated with oxygen and glucose deprivation (OGD) to establish the ischemic cell model. The qRT-PCR was used to measure the expression levels of the miR-429 in the serums of the patients or cells, and CCK-8, wound healing assay, and tube formation assay were used to observe the effects of miR-429 on the phenotype of HBMECs. Moreover, the Targetscan, dual-luciferase reporter assay, and Western blot were used to reveal the downstream target and regulation mechanism of miR-429 in OGD-induced HBMECs. The results showed that miR-429 was significantly upregulated in the serums of the patients, and overexpressed miR-429 could extremely inhibit the viability, migration, and tube formation of OGD-induced HBMECs. Furthermore, it was found that SNAI2 was a downstream factor of miR-429, and SNAI2 could rescue the effects of miR-429 on OGD-induced HBMECs. Besides, the Western blot showed that miR-429 could affect the activity of GSK-3 β / β -catenin pathway via inhibiting the expression of SNAI2. In conclusion, this study suggests that miR-429 inhibits the angiogenesis of HBMECs through SNAI2-mediated GSK-3 β / β -catenin pathway., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Yameng Sun et al.)

Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood., Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests., Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery., Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Traumatic injuries to the brain and spinal cord affect a large percentage of the world's population. However, there are currently no effective treatments for these central nervous system (CNS) injuries. In our study, we evaluated the neuroprotective role of functionalized multi-walled carbon nanotubes (MWCNTs) carrying brain derived neurotrophic factor (BNDF), nogo-66 receptor (NgR) and Ras homolog gene family member A (RhoA) in spinal cord injury (SCI). Our results showed that transfection into rat cortical neurons with BDNF-DNA significantly elevated the expression of BDNF both in vitro and in vivo. Meanwhile, transfection with NgR-siRNA and RhoA-siRNA resulted in an obvious down-regulation of NgR and RhoA in neuron cells and in injured spinal cords. In addition, the functionalized MWCNTs carrying BDNF-DNA, NgR-siRNA and RhoA-siRNA exhibited remarkable therapeutic effects on injured spinal cord. Taken together, our study demonstrates that functionalized MWCNTs have a potential therapeutic application on repair and regeneration of the CNS.