Nicotine suppresses crystalline silica-induced astrocyte activation and neuronal death by inhibiting NF-κB in the mouse hippocampus.

AIMS: Exposure to crystalline silica (CS) in occupational settings induces chronic inflammation in the respiratory system and, potentially, the brain. Some workers are frequently concurrently exposed to both CS and nicotine. Here, we explored the impact of nicotine on CS-induced neuroinflammation in the mouse hippocampus. METHODS: In this study, we established double-exposed models of CS and nicotine in C57BL/6 mice. To assess depression-like behavior, experiments were conducted at 3, 6, and 9 weeks. Serum inflammatory factors were analyzed by ELISA. Hippocampus was collected for RNA sequencing analysis and examining the gene expression patterns linked to inflammation and cell death. Microglia and astrocyte activation and hippocampal neuronal death were assessed using immunohistochemistry and immunofluorescence staining. Western blotting was used to analyze the NF-κB expression level. RESULTS: Mice exposed to CS for 3 weeks showed signs of depression. This was accompanied by elevated IL-6 in blood, destruction of the blood-brain barrier, and activation of astrocytes caused by an increased NF-κB expression in the CA1 area of the hippocampus. The elevated levels of astrocyte-derived Lcn2 and upregulated genes related to inflammation led to higher neuronal mortality. Moreover, nicotine mitigated the NF-κB expression, astrocyte activation, and neuronal death, thereby ameliorating the associated symptoms. CONCLUSION: Silica exposure induces neuroinflammation and neuronal death in the mouse hippocampal CA1 region and depressive behavior. However, nicotine inhibits CS-induced neuroinflammation and neuronal apoptosis, alleviating depressive-like behaviors in mice.

Biomimetic hypoxia-triggered RNAi nanomedicine for synergistically mediating chemo/radiotherapy of glioblastoma.

Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.

A primary Rosai-Dorfman-Destombes disease of the scalp: case report and literature review.

Background: Rosai-Dorfman-Destombes disease (RDD) was first described in 1965 as a benign histiocytic proliferative disorder of unknown cause. Cases of RDD limited to cutaneous tissue have been reported over the past few decades, but single cutaneous RDD of the scalp is rare. Case presentation: We report a 31-year-old male with a lump on the parietal scalp without extranodal lesion lasting 1 month with gradual enlargement. The surgical incision ruptured with purulent after the first resection. Then the patient was treated with plastic surgery after disinfection and antibiotic treatment. Finally, he recovered well and discharged after 20 days. Conclusions: RDD of the scalp is rare. Surgical incision can cure the lesion but it may become infected because of increased lymphocytic infiltration. Early diagnosis and differential diagnosis of RDD are necessary. For treatment, individualized therapy is critical to patient prognosis.

Trigeminal Nerve Isolation Application in Microvascular Decompression for Treating Trigeminal Neuralgia: A Retrospective Study.

This study aimed to compare the outcomes of trigeminal nerve isolation (TNI) with conventional microvascular decompression (CMVD) in cases of trigeminal neuralgia (TN). We retrospectively reviewed 143 TN cases who underwent microvascular decompression from January 2017 to January 2020. The surgical management of TNI or CMVD in all patients was randomized. The cases were divided into two groups, one group underwent a TNI and the other one received CMVD. The general data, postoperative outcomes, and complications were reviewed retrospectively. Cases with a narrow cistern of cerebellopontine, short trigeminal nerve root, and arachnoid adhesion were defined as difficult cases. All of the cases were followed up for at least 1 year. Surgical outcomes were assessed and compared between the two groups. In results, we found no significant differences in the general data, duration of hospitalization and blood loss between the two procedures. However, of the 143 cases, 12 cases (17.1%) recurred after surgery in the CMVD group, and four cases (5.5%) recurred after TNI operation. The rates of pain relief were 69 (94.5%) in the CMVD group, and 58 (82.9%) for TNI ( P =0.027). In the TNI group, there was only one difficult case among four no pain-relief cases, while in the CMVD group, 10 difficult cases were found among the 12 no pain-relief cases ( P =0.008). In conclusion, the TNI technique is more effective than the CMVD procedure and could also be performed on patients with classical TN. Future double-blind and randomized controlled trials are necessary to confirm this result.

Synergistic structural and functional alterations in the medial prefrontal cortex of patients with high-grade gliomas infiltrating the thalamus and the basal ganglia.

Background: High-grade gliomas (HGGs) are characterized by a high degree of tissue invasion and uncontrolled cell proliferation, inevitably damaging the thalamus and the basal ganglia. The thalamus exhibits a high level of structural and functional connectivity with the default mode network (DMN). The present study investigated the structural and functional compensation within the DMN in HGGs invading the thalamus along with the basal ganglia (HITBG). Methods: A total of 32 and 22 healthy controls were enrolled, and their demographics and neurocognition (digit span test, DST) were assessed. Of the 32 patients, 18 patients were involved only on the left side, while 15 of them were involved on the right side. This study assessed the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), gray matter (GM) volume, and functional connectivity (FC) within the DMN and compared these measures between patients with left and right HITBG and healthy controls (HCs). Result: The medial prefrontal cortex (mPFC) region existed in synchrony with the significant increase in ALFF and GM volume in patients with left and right HITBG compared with HCs. In addition, patients with left HITBG exhibited elevated ReHo and GM precuneus volumes, which did not overlap with the findings in patients with right HITBG. The patients with left and right HITBG showed decreased GM volume in the contralateral hippocampus without any functional variation. However, no significant difference in FC values was observed in the regions within the DMN. Additionally, the DST scores were significantly lower in patients with HITBG, but there was no significant correlation with functional or GM volume measurements. Conclusion: The observed pattern of synchrony between structure and function was present in the neuroplasticity of the mPFC and the precuneus. However, patients with HITBG may have a limited capacity to affect the connectivity within the regions of the DMN. Furthermore, the contralateral hippocampus in patients with HITBG exhibited atrophy. Thus, preventing damage to these regions may potentially delay the progression of neurological function impairment in patients with HGG.

Nicotine exposure exacerbates silica-induced pulmonary fibrosis via STAT3-BDNF-TrkB-mediated epithelial-mesenchymal transition in alveolar type II cells.

The addictive substance nicotine, found in cigarettes and some e-cigarettes, plays a vital role in pro-inflammatory and fibrotic processes. However, the part played by nicotine in the progression of silica-induced pulmonary fibrosis is poorly understood. We used mice exposed to both silica and nicotine to investigate whether nicotine synergizes with silica particles to worsen lung fibrosis. The results revealed that nicotine accelerated the development of pulmonary fibrosis in silica-injured mice by activating STAT3-BDNF-TrkB signalling. Mice with a history of exposure to nicotine showed an increase in Fgf7 expression and alveolar type II cell proliferation if they were also exposed to silica. However, newborn AT2 cells could not regenerate the alveolar structure and release pro-fibrotic factor IL-33. Moreover, activated TrkB induced the expression of p-AKT, which promotes the expression of epithelial-mesenchymal transcription factor Twist, but no Snail. In vitro assessment confirmed activation of the STAT3-BDNF-TrkB pathway in AT2 cells, exposed to nicotine plus silica. In addition, TrkB inhibitor K252a downregulated p-TrkB and the downstream p-AKT and restricted the epithelial-mesenchymal transition caused by nicotine plus silica. In conclusion, nicotine activates the STAT3-BDNF-TrkB pathway, which promotes epithelial-mesenchymal transition and exacerbates pulmonary fibrosis in mice with combined exposure to silica particles and nicotine.

Using Nicotine in A Silica-Exposed Mouse Model to Promote Lung Epithelial-Mesenchymal Transition.

Smoking and exposure to silica are common among occupational workers, and silica is more likely to injure the lungs of smokers than non-smokers. The role of nicotine, the primary addictive ingredient in cigarettes, in silicosis development is unclear. The mouse model employed in this study was simple and easily controlled, and it effectively simulated the effects of chronic nicotine ingestion and repeated exposure to silica on lung fibrosis through epithelial-mesenchymal transition in human beings. In addition, this model can help in the direct study of the effects of nicotine on silicosis while avoiding the effects of other components in cigarette smoke. After environmental adaptation, mice were injected subcutaneously with 0.25 mg/kg nicotine solution into the loose skin over the neck every morning and evening at 12 h intervals over 40 days. Additionally, crystalline silica powder (1-5 µm) was suspended in normal saline, diluted to a suspension of 20 mg/mL, and dispersed evenly using an ultrasonic water bath. The isoflurane-anesthetized mice inhaled 50 µL of this silica dust suspension through the nose and were awoken via chest massage. Silica exposure was administrated daily on days 5-19. The double-exposed mouse model was exposed to nicotine and then silica, which matches the exposure history of workers who are exposed to both harmful factors. In addition, nicotine promoted pulmonary fibrosis through epithelial-mesenchymal transformation (EMT) in mice. This animal model can be used to study the effects of multiple factors on the development of silicosis.

A Silicosis Mouse Model Established by Repeated Inhalation of Crystalline Silica Dust.

Silicosis can be caused by exposure to respiratory crystalline silica dust (CSD) in an industrial environment. The pathophysiology, screening, and treatment of silicosis in humans have all been extensively studied using the mouse silicosis model. By repeatedly making mice inhale CSD into their lungs, the mice can mimic the clinical symptoms of human silicosis. This methodology is practical and efficient in terms of time and output and does not cause mechanical injury to the upper respiratory tract due to surgery. Furthermore, this model can successfully mimic acute/chronic transformation process of silicosis. The main procedures were as follows. The sterilized 1-5 µm CSD powder was fully ground, suspended in saline, and dispersed in an ultrasonic water bath for 30 min. Mice under isoflurane-induced anesthesia switched from shallow rapid breathing to deep, slow aspiration for approximately 2 s. The mouse was placed in the palm of a hand, and the thumb tip gently touched the lip edge of the mouse's jaw to straighten the airway. After each exhalation, the mice breathed in the silica suspension drop by drop through one nostril, completing the process within 4-8 s. After the mice's breathing had stabilized, their chest was stroked and caressed to prevent the inhaled CSD from being coughed up. The mice were then returned to the cage. In conclusion, this model can quantify CSD along the typical physiological passage of tiny particles into the lung, from the upper respiratory tract to the terminal bronchioles and alveoli. It can also replicate the recurrent exposure of employees due to work. The model can be performed by one person and does not need expensive equipment. It conveniently and effectively simulates the disease features of human silicosis with high repeatability.

Radiomics-Based Machine Learning to Predict Recurrence in Glioma Patients Using Magnetic Resonance Imaging.

OBJECTIVE: Recurrence is a major factor in the poor prognosis of patients with glioma. The aim of this study was to predict glioma recurrence using machine learning based on radiomic features. METHODS: We recruited 77 glioma patients, consisting of 57 newly diagnosed patients and 20 patients with recurrence. After extracting the radiomic features from T2-weighted images, the data set was randomly divided into training (58 patients) and testing (19 patients) cohorts. An automated machine learning method (the Tree-based Pipeline Optimization Tool) was applied to generate 10 independent recurrence prediction models. The final model was determined based on the area under the curve (AUC) and average specificity. Moreover, an independent validation set of 20 patients with glioma was used to verify the model performance. RESULTS: Recurrence in glioma patients was successfully predicting by machine learning using radiomic features. Among the 10 recurrence prediction models, the best model achieved an accuracy of 0.81, an AUC value of 0.85, and a specificity of 0.69 in the testing cohort, but an accuracy of 0.75 and an AUC value of 0.87 in the independent validation set. CONCLUSIONS: Our algorithm that is generated by machine learning exhibits promising power and may predict recurrence noninvasively, thereby offering potential value for the early development of interventions to delay or prevent recurrence in glioma patients.

Case report: Significance of the large rhomboid lip in microvascular decompression: insights from two clinical cases.

The rhomboid lip (RL) is a layer of neural tissue that extends outside the fourth ventricle and is connected to the lateral recess of the fourth ventricle. Although this anatomical structure has been rigorously studied, it is often overlooked in microvascular decompression (MVD) surgery. In this report, we present two cases, one of hemifacial spasm (HFS) and one of glossopharyngeal neuralgia (GPN), in which a large RL was observed during surgery. We found that a large RL is easily confused with arachnoid cysts, and accurate identification and dissection are important to protect the lower cranial nerves.

Synergetic reorganization of the contralateral structure and function in patients with unilateral frontal glioma.

Objective: This study aimed to investigate the contralateral structural and functional plasticity induced by frontal gliomas. Methods: Patients with left (n = 49) or right (n = 52) frontal diffuse glioma were enrolled along with 35 age- matched healthy controls (HCs). The gray-matter volumes (GMVs) of the contralesional region were measured using the voxel-based morphometry (VBM) analysis. Additionally, the amplitude of low-frequency fluctuation (ALFF) of the contralesional region was calculated via resting state functional magnetic resonance imaging (MRI) to assess functional alterations. Result: The GMV of the contralateral orbitofrontal cortex of the right or left frontal gliomas was significantly larger than the corresponding GMV in the controls. In the patients with right frontal glioma, the GMV and ALFF in the left inferior frontal gyrus were significantly increased compared with those in the controls. Conclusion: Glioma invasion of the frontal lobe can induce contralateral structural compensation and functional compensation, which show synergy in the left inferior frontal gyrus. Our findings explain why patients with unilateral frontal glioma can have functional balance, and offer the possibility of preserving the brain function while maximizing tumor removal.

Does epilepsy always indicate worse outcomes? A longitudinal follow-up analysis of 485 glioma patients.

BACKGROUND: Epilepsy is one of the most common glioma complications, and the two may be connected in more ways than we understand. We aimed to investigate the clinical features of glioma-associated epilepsy and explore the risk factors associated with it. METHODS: We collected clinical information from 485 glioma patients in the Nanjing Brain Hospital and conducted 4 periodic follow-up visits. Based on the collected data, we analyzed the clinical characteristics of glioma patients with or without epilepsy and their relationship with survival. RESULTS: Among glioma patients, younger people were more likely to have epilepsy. However, epilepsy incidence was independent of gender. Patients with grade II gliomas were most likely to develop epilepsy, while those with grade IV gliomas were least likely. There was no difference in Karnofsky Performance Status scores between patients with glioma-associated epilepsy and those without epilepsy. Additionally, epilepsy was independently associated with longer survival in the World Health Organization grade IV glioma patients. For grades II, III, and IV tumors, the 1-year survival rate of the epilepsy group was higher than that of the non-epilepsy group. CONCLUSIONS: Epilepsy did not lead to worse admission performance and correlated with a better prognosis for patients with grade IV glioma.

Stable functional compensation within hippocampal-subregion networks in patients with temporal glioma before and after surgery.

Objective: To identify whether tumor invasion of the temporal lobe induces functional compensation of the hippocampal-subregion (HIPsub) network connectivity before surgery, and to further validate the stability of this functional compensation within the HIPsub network in patients with temporal glioma tumor (TTumor) after surgical resection of the tumor. Methods: In the first cohort, analysis of HIPsub functional connectivity (FC) was conducted to identify the functional compensation of the altered HIPsub connectivity pattern in TTumor through a pattern classification approach. Then, the second cohort investigated whether functional compensation in TTumor patients changed after surgical resection of the tumor. Results: In the first cohort, this study identified altered HIPsub network connectivity patterns and its functional compensation regions (i.e., left parahippocampal gyrus and bilateral cerebellum anterior lobe) in TTumor patients. Second, the altered HIPsub network connectivity patterns had the power to discriminate TTumor patients from healthy controls (CN) on an individual subject basis, with an AUC of 97.0%, sensitivity of 93.5%, and specificity of 90.3%. Finally, in the second cohort, we found that functional connectivities of functional compensation regions within the HIPsub network in TTumor patients did not change between before and after surgery. Conclusion: This study provides novel evidence regarding functional compensation within the HIPsub network in TTumor patients. It has been suggested that the fine hippocampal subregion was more sensitive, which reveals functional compensation induced by tumor invasion of the temporal lobe. Furthermore, this study verified the stability and persistence of this functional compensation in TTumor patients after surgical resection of the tumor.

Differentiation of malignant brain tumor types using intratumoral and peritumoral radiomic features.

Tumor infiltration of central nervous system (CNS) malignant tumors may extend beyond visible contrast enhancement. This study explored tumor habitat characteristics in the intratumoral and peritumoral regions to distinguish common malignant brain tumors such as glioblastoma, primary central nervous system lymphoma, and brain metastases. The preoperative MRI data of 200 patients with solitary malignant brain tumors were included from two datasets for training. Quantitative radiomic features from the intratumoral and peritumoral regions were extracted for model training. The performance of the model was evaluated using data (n = 50) from the third clinical center. When combining the intratumoral and peritumoral features, the Adaboost model achieved the best area under the curve (AUC) of 0.91 and accuracy of 76.9% in the test cohort. Based on the optimal features and classifier, the model in the binary classification diagnosis achieves AUC of 0.98 (glioblastoma and lymphoma), 0.86 (lymphoma and metastases), and 0.70 (glioblastoma and metastases) in the test cohort, respectively. In conclusion, quantitative features from non-enhanced peritumoral regions (especially features from the 10-mm margin around the tumor) can provide additional information for the characterization of regional tumoral heterogeneity, which may offer potential value for future individualized assessment of patients with CNS tumors.

Identification of a novel LATS1 variant associated with familial cerebral cavernous malformations in a Chinese family.

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic or hereditary vascular malformations in the central nervous system. CCM1-3 variants have been identified that are associated with the majority of familial cerebral cavernous malformations (FCCMs). However, there are still a few CCM1-3 wild-type FCCMs. The aim of the present study was to identify an additional pathogenic variant of FCCMs. METHODS: In this study, a large five-generation Chinese Han family affected by CCMs was recruited. Magnetic resonance imaging (MRI) was done for the detection of CCMs. Whole-exome sequencing (WES) was performed, and the identified variants were co-segregation analyzed by Sanger sequencing. The function of candidate variants was predicted in silico and experimental validated by angiogenesis assay in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: Twenty-four family members and one healthy spouse were enrolled. We found that CCMs were exhibited on MRI in nine family members. Overall, twenty-seven candidate variants were identified using WES, and no CCM1-3 variants were detected. The missense variant in LATS1 (c.821C > T, p.Thr274Ile) was verified to be associated with the clinical and pathological phenotype of FCCMs. CONCLUSION: Our findings indicated that the LATS1 variant could be a potential pathogenic factor for FCCMs in this Chinese family.

A novel defined risk signature of interferon response genes predicts the prognosis and correlates with immune infiltration in glioblastoma.

BACKGROUND: Interferons (IFNs) have been implemented as anti-tumor immunity agents in clinical trials of glioma, but only a subset of glioblastoma (GBM) patients profits from it. The predictive role of IFNs stimulated genes in GBM needs further exploration to investigate the clinical role of IFNs. METHODS: This study screened 526 GBM patients from three independent cohorts. The transcriptome data with matching clinical information were analyzed using R. Immunohistochemical staining data from the Human Protein Atlas and DNA methylation data from MethSurv were used for validation in protein and methylation level respectively. RESULTS: We checked the survival effect of all 491 IFNs response genes, and found 54 genes characterized with significant hazard ratio in overall survival (OS). By protein-protein interaction analysis, 10 hub genes were selected out for subsequent study. And based on the expression of these 10 genes, GBM patients could be divided into two subgroups with significant difference in OS. Furthermore, the least absolute shrinkage and selection operator cox regression model was utilized to construct a multigene risk signature, including STAT3, STAT2 and SOCS3, which could serve as an independent prognostic predictor for GBM. The risk model was validated in two independent GBM cohorts. The GBM patients with high risk scores mainly concentrated in the GBM Mesenchymal subtype. The higher risk group was enriched in hypoxia, angiogenesis, EMT, glycolysis and immune pathways, and had increased Macrophage M2 infiltration and high expression of immune checkpoint CD274 (namely PD-L1). CONCLUSIONS: Our findings revealed the three-gene risk model could be an independent prognostic predictor for GBM, and they were crucial participants in immunosuppressive microenvironment of GBM.

Intelligent Nanoparticles With pH-Sensitive Co-Delivery of Temozolomide and siEGFR to Ameliorate Glioma Therapy.

Glioblastoma (GBM) is one of the most lethal forms of human cancer, with very few long-term survivors. In addition to surgery, chemotherapy is still an important strategy. Unfortunately, GBM chemotherapy faces two main challenges: first, in GBM, epidermal growth factor receptor (EGFR) overexpression results in chemoresistance; second, temozolomide (TMZ) lacks target specificity, which can lead to a reduction in the concentration and side effects in GBM. Nowadays, with the development of nanomedicine systems for applications in tumor therapies, increasing anticancer efficacy and reducing side effects with multi-drug delivery are huge advantages. In this study, pH-sensitive and GBM-targeting nanovesicle (Tf-PEG-PAE(SS)) was fabricated. The chemotherapy drug (TMZ) and EGFR inhibitor (EGFR-siRNA) were co-encapsulated in the nanocarrier, and their anticancer outcomes were investigated in detail. In vitro experiments have shown that the nanocarrier transports TMZ and EGFR-siRNA efficiently into U87 cells, causing a vigorous apoptotic response by silencing the proliferative EGFR gene and increasing the drug concentration of TMZ simultaneously. An experimental study in mice bearing orthotropic glioma revealed that the accumulated nanocarriers in the tumor site could inhibit the tumor growth and prolong the mice survival remarkably through the intracranial injection of Tf-PEG-PAE(SS)/TMZ@siEGFR. The drug co-delivery system could extend the blood circulation time and offer a new strategy to treat glioblastoma.

Single-Cell Transcriptomics Revealed Subtype-Specific Tumor Immune Microenvironments in Human Glioblastomas.

Human glioblastoma (GBM), the most aggressive brain tumor, comprises six major subtypes of malignant cells, giving rise to both inter-patient and intra-tumor heterogeneity. The interaction between different tumor subtypes and non-malignant cells to collectively shape a tumor microenvironment has not been systematically characterized. Herein, we sampled the cellular milieu of surgically resected primary tumors from 7 GBM patients using single-cell transcriptome sequencing. A lineage relationship analysis revealed that a neural-progenitor-2-like (NPC2-like) state with high metabolic activity was associated with the tumor cells of origin. Mesenchymal-1-like (MES1-like) and mesenchymal-2-like (MES2-like) tumor cells correlated strongly with immune infiltration and chronic hypoxia niche responses. We identified four subsets of tumor-associated macrophages/microglia (TAMs), among which TAM-1 co-opted both acute and chronic hypoxia-response signatures, implicated in tumor angiogenesis, invasion, and poor prognosis. MES-like GBM cells expressed the highest number of M2-promoting ligands compared to other cellular states while all six states were associated with TAM M2-type polarization and immunosuppression via a set of 10 ligand-receptor signaling pathways. Our results provide new insights into the differential roles of GBM cell subtypes in the tumor immune microenvironment that may be deployed for patient stratification and personalized treatment.

Targeting miR-9 in Glioma Stem Cell-Derived Extracellular Vesicles: A Novel Diagnostic and Therapeutic Biomarker.

BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor with no effective strategies in early diagnosis and treatment. This study was aimed to assess the miRNA expression profiles in EVs from CSF and tissue of glioblastoma patients to identify significantly upregulated miRNAs and investigate the underlying neoplastic mechanisms. METHODS: EVs were measured by TEM and NTA assays. Differentially regulated miRNAs were measured using RNA sequencing in GBM CSF EVs and in GBM tissues compared with controls. RT-qPCR was employed to analyze miRNA and gene expression. Luciferase report assay was used to investigate gene target of miR-9. The proliferation ability was detected by EdU and CCK-8 experiment while cell migration was measured by transwell and wound healing assay. RESULTS: The expression level of miR-9 was significantly higher in GBM CSF EVs and tissues than controls (p = 0.038). The area under curve for CSF EV miR-9 was 0.800 (95% CI: 0.583-1.000, p = 0.033). The expression of miR-9 was significantly higher in Glioma stem cells (GSCs) and GSC-derived EVs than in glioblastoma cells. GSC-derives EVs could promote GBM growth and migration Moreover, inhibition of miR-9 in GSCs showed the reverse anti-tumor effects through secreted EVs. MiR-9 could bind to the 3'UTR region of DACT3 and suppress its expression. The miR-9/DACT3 axis might attribute to GBM malignant phenotype. CONCLUSION: MiR-9 in CSF EVs may act as a novel diagnostic biomarker for GBM and targeting miR-9 by GSC-derived EVs may be a specific and efficient strategy for GBM biotherapy.

Altered Static and Dynamic Voxel-mirrored Homotopic Connectivity in Patients with Frontal Glioma.

Contralateral regions play critical role in functional compensation in glioma patients. Voxel-mirrored homotopic connectivity (VMHC) characterizes the intrinsic functional connectivity (FC) of the brain, considered to have a regional functional basis. We aimed to investigate the alterations of brain regional function and VMHC in patients with frontal glioma, and further investigated the correlation between these alterations and cognition. We enrolled patients with frontal glioma and matched healthy controls (HC). We chose degree centrality (DC), regional homogeneity (ReHo), and VMHC to investigate the alterations of regional function and intrinsic FC in patients. Furthermore, partial correlation analyses were conducted to explore the relationship between imaging functional indicators and cognitions. Compared with HC, patients showed decreased static VMHC within right and left middle frontal gyrus (MFG.R, MFG.L), left superior frontal gyrus (SFG.L), right precuneus (PCUN.R), and left precuneus (PCUN.L), decreased static DC within left cingulate gyrus (CG.L), right superior frontal gyrus (SFG.R), and right postcentral gyrus (POCG.R), decreased static ReHo within CG.L, decreased dynamic ReHo within right inferior parietal lobule (IPL.R), but increased dynamic VMHC (dVMHC) within PCUN.R and PCUN.L. Furthermore, values of decreased VMHC within MFG.R, decreased DC within CG.L, decreased ReHo within CG.L, and increased dVMHC within PCUN.R were significantly positively correlated with cognitive functions. We preliminarily confirmed glioma causes regional dysfunction and disturbs long-distance FC, and long-distance FC showed strong instability in patients with frontal glioma. Meanwhile, the correlation analyses indicated directions for cognitive protection in patients with frontal glioma.