PTEN gene mutations correlate to poor prognosis in glioma patients: a meta-analysis Feng Han,1,* Rong Hu,2,* Hua Yang,1 Jian Liu,1 Jianmei Sui,1 Xin Xiang,1 Fan Wang,1 Liangzhao Chu,1 Shibin Song1 1Department of Neurosurgery, Affiliated Hospital of Guizhou Medical University, 2Department of Histology and Embryology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China *These authors contributed equally to this work Background: We conducted this meta-analysis based on eligible trials to investigate the relationship between phosphatase and tensin homolog (PTEN) genetic mutation and glioma patients’ survival. Methods: PubMed, Web of Science, and EMBASE were searched for eligible studies regarding the relationship between PTEN genetic mutation and glioma patients’ survival. The primary outcome was the overall survival of glioma patient with or without PTEN genetic mutation, and second outcome was prognostic factors for the survival of glioma patient. A fixed-effects or random-effects model was used to pool the estimates according to the heterogeneity among the included studies. Results: Nine cohort studies, involving 1,173 patients, were included in this meta-analysis. Pooled results suggested that glioma patients with PTEN genetic mutation had a significant shorter overall survival than those without PTEN genetic mutation (hazard ratio [HR] =2.23, 95% confidence interval [CI]: 1.35, 3.67; P=0.002). Furthermore, subgroup analysis indicated that this association was only observed in American patients (HR =2.19, 95% CI: 1.23, 3.89; P=0.008), but not in Chinese patients (HR =1.44, 95% CI: 0.29, 7.26; P=0.657). Histopathological grade (HR =1.42, 95% CI: 0.07, 28.41; P=0.818), age (HR =0.94, 95% CI: 0.43, 2.04; P=0.877), and sex (HR =1.28, 95% CI: 0.55, 2.98; P=0.564) were not significant prognostic factors for the survival of patients with glioma. Conclusion: Current evidence indicates that PTEN genetic mutation is associated with poor prognosis in glioma patients. However, this finding is derived from data in observational studies, potentially subject to selection bias, and hence well conducted, high-quality randomized controlled trials are warranted. Keywords: glioma, PTEN genetic mutation, meta-analysis

BACKGROUND AND PURPOSE: Endovascular coiling is an alternative to surgical clipping for ruptured intracranial aneurysms. However, no large multicenter prospective study has compared coiling and clipping in patients with poor-grade ruptured aneurysms. We aimed to determine differences in postoperative complications and clinical outcome between the 2 treatments in this group of patients. MATERIALS AND METHODS: A Multicenter Poor-Grade Aneurysm Study was a prospective, multicenter, observational registry of consecutive patients who presented with poor-grade ruptured aneurysms. Three hundred sixty-six patients were enrolled from October 2010 to March 2012. “Poor-grade aneurysm” was defined as a World Federation of Neurosurgical Societies grade of IV or V at the time of aneurysm treatment. Two hundred sixty-two patients received aneurysm treatment within 21 days and were included. Clinical outcomes were assessed at discharge and at 6 and 12 months by the modified Rankin Scale. RESULTS: One hundred thirty-three (50.8%) patients underwent endovascular coiling. Unadjusted analysis showed that the outcome rate (mRS 0–1 or mRS 0–2) at 6 and 12 months in patients undergoing coiling was higher than that in patients undergoing clipping. In adjusted analyses, there was no statistically significant difference in outcomes at 6 and 12 months between the 2 groups. The risk of radiologic hydrocephalus was higher in patients treated with coiling than that in those treated with clipping (adjusted OR, 3.36; 95% CI, 1.13–10.01; P = .030). CONCLUSIONS: The long-term outcome in selected patients was similar between endovascular coiling and clipping for poor-grade ruptured aneurysms. The risk of radiologic hydrocephalus was higher after endovascular treatment of poor-grade aneurysms.

MicroRNAs (miRNAs) have emerged as key mediators of posttranscriptional gene silencing in both pathogenic and pathological aspects of ischemic stroke biology. Therefore, the purpose of present study was to explore the effect of microRNA-199b-3p (miR-199b-3p) on the cerebral microvascular endothelial cells (CMECs) in middle cerebral artery occlusion-reperfusion (MCAO-R) mice by regulating MAPK/ERK/EGR1 axis. Mice were used to establish MCAO-R models and to measure the expression of miR-199b-3p and the MAPK/ERK/EGR1 axis-related genes. CMECs were extracted from the MCAO-R mice. A series of mimic or inhibitor for miR-199b-3p, or U0126 (an inhibitor for the MAPK/ERK/EGR1 axis) were introduced to treat these CMECs. The levels of miR-199b-3p and MAPK/ERK/EGR1 axis-related genes in tissues and cells were detected. The effects miR-199b-3p on the process of CMECs, including cell viability, cell cycle and cell apoptosis were evaluated. miR-199b-3p expressed poorly in the brain tissues after MCAO-R, along with activated MAPK/ERK/EGR1 axis and increased CMECs apoptosis. CMECs transfected with miR-199b-3p mimics and U0126 manifested with increased cell viability, more cells arrested at the S stage, and inhibited apoptosis of CMECs. In conclusion, these key results demonstrated up-regulated miR-199b-3p could protect mice against ischemic stroke by inhibiting the apoptosis of CMECs through blockade of MAPK/ERK/EGR1 axis.

Background: Macrophage infiltration and polarization are crucial for the pathogenesis of intracranial aneurysm (IA) rupture. Axl, a receptor tyrosine kinase, is involved in inflammation and efferocytosis in multiple organs. Upregulated soluble Axl in cerebrospinal fluid (CSF) and plasma is correlated with intracranial aneurysm rupture. This study aimed to investigate the role of Axl in IA rupture and macrophage polarization.Methods: Male C57BL/6J mice were used to induce IA. The level of Axl from control vessels and unruptured and ruptured IA samples was detected. In addition, the relationship between Axl and macrophages was confirmed. The pathway of Axl-mediated macrophage polarization was explored after IA induction in vivo and in bone marrow-derived macrophages (BMDMs) stimulated by LPS/IFN-γ in vitro. The animals were randomized into three groups and treated intraperitoneally with the vehicle, selective AXL antagonist R428, and recombinant mouse growth arrest-specific 6 (rmGas6) for 21 consecutive days. Then, we evaluated the influence of Axl on IA rupture by administrating R428 to inhibit or rmGas6 to activate the Axl receptor in vivo.Results: Compared with that in normal vessels, Axl expression was significantly upregulated in unruptured IA samples. The ruptured IA tissue exhibited significantly higher expression of Axl than the unruptured IA tissue. Axl and F4/80 were coexpressed in IA tissue and LPS/IFN-γ-stimulated BMDMs. R428 treatment significantly reduced the rate of M1-like macrophage infiltration and IA rupture. In contrast, rmGas6 treatment promoted M1 macrophage infiltration and IA rupture. Mechanistically, R428 inhibited the phosphorylation of Axl and STAT1 and the expression of hypoxia-inducible factor-1α (HIF-1α) and decreased the levels of IL-1β, NOS2, and MMP9 in LPS/IFN-γ-stimulated BMDMs. rmGas6 promoted the phosphorylation of Axl and STAT1 and the expression of HIF-1α. In addition, STAT1 knockdown abolished Axl-mediated M1 macrophage polarization.Conclusion: The inhibition of Axl reduced macrophage polarization toward the M1 phenotype via the STAT1/HIF-1α signaling pathway and prevented IA rupture in mice. This finding suggests that pharmacological inhibition of Axl might be used to prevent the progression and rupture of IA.

Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with very high mortality and morbidity. Our limited knowledge on predictors of long-term outcome in poor-grade patients with aSAH definitively managed comes from retrospective and prospective studies of small case series of patients in single center. The purpose of the AMPAS is to determine the long-term outcomes in poor-grade patients with different managements within different time after aSAH, and identify the independent predictors of the outcome that help guide the decision on definitive management. The AMPAS study is a prospective, multicenter, observational registry of consecutive hospitalized patients with poor grade aSAH (WFNS grade IV and V). The aim is to enroll at least 226 poor-grade patients in 11 high-volume medical centers (eg, >150 aSAH cases per year) affiliated to different universities in China. This study will describe poor grade patients and aneurysm characteristics, treatment strategies (modality and time of definitive management), hospitalization complications and outcomes evolve over time. The definitive management is ruptured aneurysm treatment. Outcomes at 3, 6, 12 months after the management were measured using the Glasgow Outcome Scale and the Modified Rankin Scale. The AMPAS is the first prospective, multicenter, observational registry of poor grade aSAH with any management. This study will contribute to a better understanding of significant predictors of outcome in poor grade patients and help guide future treatment of the worst patients after aSAH. Chinese Clinical Trial Registry: ChiCTR-TNRC-10001041 .

The high incidence, mortality, and disability associated with ischemic stroke pose a significant threat to human health. The intestinal microbiota significantly influences the onset, progression, and prognosis of ischemic stroke. Gut flora plays a pivotal role in brain–gut interactions. The reflection of changes in the gut and brain caused by gut microbes facilitates the investigation of early warning biomarkers and potential therapeutic targets for ischemic stroke. In this narrative review of the relationship between gut microbiota and ischemic stroke, we primarily discuss three topics, grounded in real‐world human and animal studies. First, we examined the relationship between ischemic stroke and intestinal microbiota and its metabolites, delineate the overall characteristics of intestinal microbiota dysregulation in ischemic stroke, and assess the potential clinical value, prevailing research controversies, and unique phenomena of intestinal microbiota metabolites such as trimethylamine N‐oxide and short‐chain fatty acids in ischemic stroke. Second, we explored the potential communication pathways between intestinal flora and ischemic stroke based on the brain–gut axis, encompassing metabolic pathways, immune pathways, and neural pathways. Finally, we encapsulated the factors influencing the severity of ischemic stroke via intestinal flora, the pharmacological and nonpharmacological interventions that modulate intestinal flora in treating ischemic stroke, and the current research landscape of intestinal flora in the context of ischemic stroke sequelae.