Minimally invasive endoscopic evacuation with the novel, portable Axonpen neuroendoscopic system for spontaneous intracerebral hemorrhage.

Minimally invasive surgeries have shown potential to improve mortality and clinical outcomes of spontaneous intracerebral hemorrhage (ICH). The present study assessed the first-in-human outcomes of a novel, portable neuroendoscopic system for ICH evacuation at our single center. This neuroendoscopic system integrates real-time visualization into a handpiece which has controllable suction, irrigation, and coagulation to allow a neurosurgeon to conduct minimally invasive ICH evacuation independently with bimanual dexterity. Pre- and postoperative data of ten patients who had spontaneous basal ganglia hemorrhage (mean: 46.5 ± 12.2 mL) and underwent evacuation with the specified neuroendoscopic system were collected prospectively. The mean time to receive surgery was 12.1 ± 7.6 h. Mean operative time was 3.4 ± 0.9 h. The mean hematoma volume decreased to 6.0 ± 3.9 mL at postoperative 6 h, resulting in a mean volume reduction of 86.0 ± 11.2% (P = 0.005). The median length of intensive care unit stay was 3 days (IQR, 3-4 days). At discharge, the median Glasgow Coma Scale (GCS) score significantly improved to 11.5 (IQR, 11-15; P = 0.016), and the median modified Rankin Scale (mRS) score was 4 (IQR, 4-5). Six patients (60%) showed a favorable mRS score of ≤ 3 on their last return visit. Neither death nor rebleeding occurred during the follow-up periods. Integrated design of the innovative device is valuable to optimize minimally invasive endoscopic ICH evacuation procedure. Further studies are needed to clarify long-term benefits from such type of the innovative device to early intervention of ICH.

Middle cerebral artery infarction, A rare complication of intracranial cryptococcoma in an immunocompetent patient: A case report and literature review.

Background: This report presents the first case of intracranial cryptococcoma arising from the right frontal lobe causing right middle cerebral artery infarction. Intracranial cryptococcomas usually occur in the cerebral parenchyma, basal ganglia, cerebellum, pons, thalamus, and choroid plexus; they may mimic intracranial tumors, but seldom cause infarction. Of the 15 cases of pathology-confirmed intracranial cryptococcomas in the literature, no case has been complicated by middle cerebral artery (MCA) infarction. Here, we discuss a case of intracranial cryptococcoma with an ipsilateral middle cerebral artery infarction. Case Description: A 40-year-old man was referred to our emergency room due to progressive headaches and acute left hemiplegia. The patient was a construction worker with no history of avian contact, recent travel, or human immunodeficiency virus (HIV) infection. Brain computed tomography (CT) showed an intra-axial mass, and subsequent magnetic resonance imaging (MRI) delineated a large mass of 53 mm in the right middle frontal lobe and a small lesion of 18 mm in the right caudate head, with marginal enhancement and central necrosis. A neurosurgeon was consulted in view of the intracranial lesion, and the patient underwent en-bloc excision of the solid mass. The pathology report later identified a Cryptococcus infection rather than malignancy. The patient underwent 4 weeks of postoperative treatment with amphotericin B plus flucytosine; he then received subsequent oral antifungal treatment for 6 months, and had neurologic sequelae that manifested as left side hemiplegia. Conclusion: Diagnosis of fungal infections in the CNS remains challenging. This is especially true of Cryptococcus CNS infections that present as a space-occupying lesion in an immunocompetent patient. A Cryptococcus infection should be considered in the differential diagnoses in patients with brain mass lesions, as this infection can be misdiagnosed as a brain tumor.

Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma.

BACKGROUND: This study aimed to validate whether infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells is safe and whether CAR-T cells exert anti-glioblastoma (GBM) activity. METHODS: A total of eight patients with GD2-positive GBM were enrolled and infused with autologous GD2-specific 4SCAR-T cells, either through intravenous administration alone or intravenous combined with intracavitary administration. RESULTS: 4SCAR-T cells expanded for 1-3 weeks and persisted at a low frequency in peripheral blood. Of the eight evaluable patients, four showed a partial response for 3 to 24 months, three had progressive disease for 6 to 23 months, and one had stable disease for 4 months after infusion. For the entire cohort, the median overall survival was 10 months from the infusion. GD2 antigen loss and infiltrated T cells were observed in the tumor resected after infusion. CONCLUSION: Both single and combined infusions of GD2-specific 4SCAR-T cells in targeting GBM were safe and well tolerated, with no severe adverse events. In addition, GD2-specific 4SCAR-T cells partially mediate antigen loss and activate immune responses in the tumor microenvironment. Validation of our findings in a larger prospective trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03170141 . Registered 30 May 2017.

Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.

BACKGROUND: Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC. METHODS: Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models. RESULTS: Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis. CONCLUSION: Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

A Novel Tumor-Promoting Role for Nuclear Factor IX in Glioblastoma Is Mediated through Transcriptional Activation of GINS1.

Our previous study illustrated that nuclear factor IX (NFIX) promotes glioblastoma (GBM) progression by inducing migration and proliferation of GBM cells. However, the underlying mechanism of how NFIX regulates GBM cell proliferation remains obscure. In this study, we uncovered that Go-Ichi-Ni-San 1 (GINS1) is upregulated and positively correlated with NFIX in human GBM specimen. NFIX silencing downregulates the expression of GINS1, which is pivotal for cell-cycle progression and proliferation of GBM cells. Replenishment of GINS1 largely rescues the NFIX-null effect on GBM cell proliferation. Mechanistic investigation revealed that NFIX transcriptionally actives GINS1 expression by directly binding to promoter region (-1779 to -1793bp) of the GINS1 gene. Furthermore, knockdown of NFIX sensitizes GBM cells to DNA damage-inducing agents including doxorubicin and temozolomide, in a GINS1-dependent manner. IMPLICATIONS: Our study highlights that targeting NFIX-GINS1 axis could be a novel and potential therapeutic approach for GBM treatment.

Correlation between initial tumor enlargement and magnetic resonance imaging characteristics following linear accelerator-based stereotactic radiosurgery for acoustic neuromas.

BACKGROUND: Initial tumor enlargement (or pseudoprogression) instead of true tumor progression is a common phenomenon in patients with acoustic neuromas who are treated with stereotactic radiosurgery (SRS). This phenomenon can affect clinical decision-making and patient management. This study assessed the correlation between initial tumor enlargement and magnetic resonance imaging characteristics in patients with acoustic neuromas who were treated with linear accelerator (LINAC)-based SRS. The long-term tumor control outcomes were also analyzed. MATERIALS AND METHODS: In total, 330 patients with sporadic acoustic neuromas who were treated with LINAC SRS between March 2006 and March 2020 were retrospectively evaluated to assess their initial tumor enlargement. The tumors were divided into homogeneously enhanced, heterogeneously enhanced, and cystic types based on the morphological characteristics noted on magnetic resonance images. Tumor control was assessed in 275 patients with a follow-up duration of more than 2 years. RESULTS: Initial enlargement was observed in 137 of 330 (41.5%) tumors as early as 3 months after LINAC SRS. Data analysis revealed that postoperative tumors with a residual volume lower than 2.5 cm3 had a lower incidence of initial enlargement (p = 0.039). No correlation was noted between the initial enlargement and morphological characteristics of tumors. In patients with a mean follow-up duration of 82.8 ± 37.2 months, heterogeneously enhanced tumors exhibited a lower control rate than homogeneously enhanced and cystic tumors (p = 0.045). No correlation was noted between initial enlargement and tumor control. CONCLUSION: Initial enlargement can occur as early as 3 months after SRS. Postoperative residual tumors with a volume lower than 2.5 cm3 exhibit a lower incidence of initial enlargement. Heterogeneously enhanced tumors have a lower local control rate.

The Prognostic Impacts of Body Mass Index and Distance to the Peritoneal Bottom on Laparoscopic Ventriculoperitoneal Shunt Placement.

OBJECTIVE: Laparoscopic ventriculoperitoneal shunt surgery has been reported to have several advantages in selected patients. However, the prognostic factors have been understudied specifically for this surgery. We sought to investigate the factors influencing the complications after the laparoscopic ventriculoperitoneal shunt placement. METHODS: All surgeries in this prospective study were performed by the same team of neurosurgeons and general surgeons. Clinical parameters as well as potential risk factors for postoperative complications were analyzed. The endpoint was overall complications requiring surgical revision within the follow-up period after surgery. RESULTS: Ninety-nine patients (51 male and 48 female) scheduled for laparoscopic-assisted ventriculoperitoneal shunt surgery between 2019 and 2021 were included. Overall shunt complication rate was 9% (9 of 99 cases), and there was 1 patient (1%) who had distal dysfunction among them. Body mass index ≥27 kg/m2 (hazard ratio 4.87; 95% confidence interval 1.05-22.57; P = 0.043), and nonprogrammable shunts (hazard ratio 7.91; 95% confidence interval 1.51-41.50; P = 0.014) were significantly associated with an increased risk of complications. Among 75 patients who received programmable shunts, the vertical distance from the distal tip to the presumed bottom of peritoneal cavity was significant positively associated with the number of pressure adjustments (R2 0.511, adjusted R2 0.504, and P < 0.001). CONCLUSIONS: Ventriculoperitoneal shunt surgery provided benefits with little complication rate, whereas patients treated with nonprogrammable shunts and obese patients had less favorable outcome. A positive correlation between the vertical distance from the distal tip to the bottom of peritoneal cavity and pressure adjustments inferred to the advantage of the laparoscopic method.

Photo-Crosslinked Hyaluronic Acid/Carboxymethyl Cellulose Composite Hydrogel as a Dural Substitute to Prevent Post-Surgical Adhesion.

A dural substitute is frequently used to repair dura mater during neurosurgical procedures. Although autologous or commercially available dural substitutes matched most of the requirements; difficulties during dural repair, including insufficient space for suturing, insufficient mechanical strength, easy tear and cerebrospinal fluid leakage, represent major challenges. To meet this need, a photo-crosslinked hydrogel was developed as a dural substitute/anti-adhesion barrier in this study, which can show sol-to-gel phase transition in situ upon short-time exposure to visible light. For this purpose, hyaluronic acid (HA) and carboxymethyl cellulose (CMC), materials used in abdominal surgery for anti-adhesion purposes, were reacted separately with glycidyl methacrylate to form hyaluronic acid methacrylate (HAMA) and carboxymethyl cellulose methacrylate (CMCMA). The HA/CMC (HC) hydrogels with different HA compositions could be prepared by photo-crosslinking HAMA and CMCMA with a 400 nm light source using lithium phenyl-2,4,6-trimethylbenzoylphosphinate as a photo-initiator. From studies of physico-chemical and biological properties of HC composite hydrogels, they are bio-compatible, bio-degradable and mechanically robust, to be suitable as a dural substitute. By drastically reducing attachment and penetration of adhesion-forming fibroblasts in vitro, the HC hydrogel can also act as an anti-adhesion barrier to prevent adhesion formation after dural repair. From in vivo study in rabbits, the HC hydrogel can repair dural defects as well as protect the dura from post-operative adhesion, endorsing the possible application of this hydrogel as a novel dural substitute.

Hepatic MDM2 Causes Metabolic Associated Fatty Liver Disease by Blocking Triglyceride-VLDL Secretion via ApoB Degradation.

Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.

Delayed Progressive Mass Effect After Secured Ruptured Middle Cerebral Artery Aneurysm: Risk Factors and Outcomes.

Objective: Delayed progressive mass effect (DPME) after securing an aneurysm is uncommon following microsurgical or endovascular repair and leads to a poor clinical outcome. Patients with ruptured middle cerebral artery (MCA) aneurysms have a high risk of postoperative oedema and mass effect, which may require decompressive treatment. Because few studies have discussed the risk and predictive factors, we focused on ruptured MCA aneurysms and evaluated the outcomes of these patients and the necessity of salvage surgery when DPME presented. Methods: Data on 891 patients with aneurysmal subarachnoid haemorrhage (aSAH) treated between January 2011 and February 2020 were extracted from the medical database of a tertiary referral centre. A total of 113 patients with aSAH resulting from at least one MCA aneurysm were identified. After excluding patients with several clinical confounders, we enrolled 80 patients with surgically treated aSAH. We examined the characteristics of aneurysms and hematomas, perioperative contrast pooling patterns, presence of distal hematomas, perisylvian low density, occlusive treatment modality, management strategies, the need for salvage surgical decompression, and postoperative 90-day outcomes to identify possible risk factors. Results: DPME was observed in 27 of the 80 patients (33.7%). The DPME and non-DPME group differed significantly in some respects. The DPME group had a higher risk of salvage surgery (p < 0.001) and poorer outcomes (mRS at day 90; p = 0.0018). The univariate analysis indicated that the presence of hematoma, CTA spot signs, perisylvian low density, and distal hematoma were independent risk factors for DPME. We also noted that DPME remained an independent predictor of a poorer 90-day functional outcome (mRS ≤ 2). Conclusion: DPME can lead to salvage decompression surgery and directly relates to poor outcomes for patients with a ruptured MCA aneurysm. Distal hematoma, perisylvian low density, and CTA spot signs on preoperative images can predict DPME.

Characterisation of Severe Traumatic Brain Injury Severity from Fresh Cerebral Biopsy of Living Patients: An Immunohistochemical Study.

Traumatic brain injury (TBI) is an extremely complex disease and current systems classifying TBI as mild, moderate, and severe often fail to capture this complexity. Neuroimaging cannot resolve the cellular and molecular changes due to lack of resolution, and post-mortem tissue examination may not adequately represent acute disease. Therefore, we examined the cellular and molecular sequelae of TBI in fresh brain samples and related these to clinical outcomes. Brain biopsies, obtained shortly after injury from 25 living adult patients suffering severe TBI, underwent immunohistochemical analysis. There were no adverse events. Immunostaining revealed various qualitative cellular and biomolecular changes relating to neuronal injury, dendritic injury, neurovascular injury, and neuroinflammation, which we classified into 4 subgroups for each injury type using the newly devised Yip, Hasan and Uff (YHU) grading system. Based on the Glasgow Outcome Scale-Extended, a total YHU grade of ≤8 or ≥11 had a favourable and unfavourable outcome, respectively. Biomolecular changes observed in fresh brain samples enabled classification of this heterogeneous patient population into various injury severity categories based on the cellular and molecular pathophysiology according to the YHU grading system, which correlated with outcome. This is the first study investigating the acute biomolecular response to TBI.

Neurological deteriorations in mild brain injuries: the strategy of evaluation and management.

PURPOSE: Most mild traumatic brain injuries (TBIs) can be treated conservatively. However, some patients deteriorate during observation. Therefore, we tried to evaluate the characteristics of deterioration and requirement for further management in mild TBI patients. METHODS: From 1/1/2017 to 12/31/2017, patients with mild TBI and positive results on CT scans of the brain were retrospectively studied. Patients with and without neurological deteriorations were compared. The characteristics of mild TBI patients with further neurological deterioration or the requirement for interventions were delineated. RESULTS: One hundred ninety-two patients were enrolled. Twenty-three (12.0%) had neurological deteriorations. The proportions of deterioration occurring within 24 h, 48 h and 72 h were 23.5, 41.2 and 58%, respectively. Deteriorated patients were significantly older than those without neurological deteriorations (69.7 vs. 60.2; p = 0.020). More associated extracranial injuries were observed in deteriorated patients [injury severity score (ISS): 20.2 vs. 15.9; p = 0.005). Significantly higher proportions of intraventricular hemorrhage (8.7 vs. 1.2%; p = 0.018) and multiple lesions (78.3 vs. 53.8%; p = 0.027) were observed on the CT scans of patients with neurological deteriorations. Subset analysis showed that deteriorated patients who required neurosurgical interventions (N = 7) had significantly more initial GCS defects (13 or 14) (71.4 vs. 12.5%; p = 0.005) and more initial decreased muscle power of extremities (85.7 vs. 18.8%; p = 0.002). CONCLUSION: More attention should be given to mild TBI patients with older age, GCS defects, decreased muscle power of the extremities, multiple lesions on CT scans and other systemic injuries (high ISS). Most deteriorations occur within 72 h after trauma.

The surgical strategy for multilevel massive ossification of the posterior longitudinal ligaments.

Purpose: Creating enough decompression, favorable outcome, less complication, and maintain adequate lordosis and stability in the patients with cervical myelopathy due to multilevel massive ossification of the posterior longitudinal ligament (OPLL) still poses a challenge for surgeons. The aim of our study is to retrospectively evaluate our patients and try to seek a better surgical strategy. Methods: Between 2015 and 2019, 55 consecutive patients with multilevel massive OPLL underwent surgical treatment. Among these, 40 patients were treated with cervical laminectomy and then anterior decompression, fusion, and fixation (ADF), which was defined as group 1, and 15 patients were treated with cervical laminectomy and fixation simultaneously, which was defined as group 2. The patient's radiographic characteristics and postoperative outcomes were evaluated. Results: Better postoperative cervical sagittal lordosis and less long-term axial pain was achieved in group 1 (p < 0.001), though the functional outcome had no significant difference. In the multivariable analysis, anterior fixation accounts for independent factors for better cervical sagittal alignment (p < 0.001). No complications directly associated with cervical laminectomy were observed. Conclusion: In patients with cervical multilevel massive OPLL, laminectomy at compression level and then ADF depended on the severity and range of compression, but corpectomy of not more than two vertebral bodies is suggested, except K-line (+) and long-segment massive OPLL majorly involving the C2 and posterior laminectomy above and below the OPLL-affected levels with posterior fixation simultaneously.

Magnetic nanocomplexes for gene delivery applications.

Gene delivery is an indispensable technique for various biomedical applications such as gene therapy, stem cell engineering and gene editing. Recently, magnetic nanoparticles (MNPs) have received increasing attention for their use in promoting gene delivery efficiency. Under magnetic attraction, gene delivery efficiency using viral or nonviral gene carriers could be universally enhanced. Besides, magnetic nanoparticles could be utilized in magnetic resonance imaging or magnetic hyperthermia therapy, providing extra theranostic opportunities. In this review, recent research integrating MNPs with a viral or nonviral gene vector is summarized from both technical and application perspectives. Applications of MNPs in cutting-edge research technologies, such as biomimetic cell membrane nano-gene carriers, exosome-based gene delivery, cell-based drug delivery systems or CRISPR/Cas9 gene editing, are also discussed.

Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma.

BACKGROUND: High-grade gliomas are rapidly progressing tumors of the central nervous system, and are associated with poor prognosis and highly immunosuppressive microenvironments. Meanwhile, a better understanding of PD-L1, a major prognostic biomarker for checkpoint immune therapy, regulation may provide insights for developing novel immunotherapeutic strategies for treating gliomas. In the present study, we elucidate the functional significance of the orphan nuclear receptor TLX in human glioma, and its functional role in immune suppression through regulation of PD-L1/PD-1 axis. METHODS: TLX and PD-L1 expression patterns, and their association with clinicopathological parameters and immune phenotypes of glioma were analysed using CIBERSORT algorithm and single-sample gene-set enrichment analysis from The Cancer Genome Atlas (n=695) and Chinese Glioma Genome Atlas (n=1018) databases. Protein expression and cellular localization of TLX, PD-L1, and PD-1, as well as the prevalence of cytotoxic tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs), in the glioma immune microenvironment were analyzed via tissue microarray by immunohistochemistry and multiplex immunofluorescence. Glioma allografts and xenografts with TLX manipulation (knockdown/knockout or reverse agonist) were inoculated subcutaneously, or orthotopically into the brains of immunodeficient and immunocompetent mice to assess tumor growth by imaging, and the immune microenvironment by flow cytometry. PD-L1 transcriptional regulation by TLX was analyzed by chromatin immunoprecipitation and luciferase reporter assays. RESULTS: TLX and PD-L1 expression was positively associated with macrophage-mediated immunosuppressive phenotypes in gliomas. TLX showed significant upregulation and positive correlation with PD-L1. Meanwhile, suppression of TLX significantly inhibited in vivo growth of glioma allografts and xenografts (p<0.05), rescued the antitumoral immune response, significantly decreased the PD-L1+, and glioma-associated macrophage population, and increased cytotoxic lymphocyte infiltration (p<0.05). Mechanistically, TLX binds directly to CD274 (PD-L1) gene promoter and activates CD274 transcription. CONCLUSIONS: TLX contributes to glioma malignancy and immunosuppression through transcriptional activation of PD-L1 ligands that bind to PD-1 expressed on both TILs and TAMs. Thus, targeting the druggable TLX may have potential therapeutic significance in glioma immune therapy.

miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities.

The development of glioblastoma (GBM) is typically accompanied by marked changes in lipid metabolism. Oxylipins and their catalyzed enzymes lipoxygenases (LOXs) have been shown to participate in the development of cancers via multiple pathways, while the understanding of LOXs in GBM remains enigmatic. Thus, we aimed to explore the expression and functional roles of LOXs in the development of GBM. Here we showed that ALOXE3 was markedly down-regulated in human GBM. Knockdown of ALOXE3 in GBM cells fostered the orthotopic tumor growth and shortened lifespan in mice. ALOXE3 deficiency rendered GBM cells resistant to p53-SLC7A11 dependent ferroptosis, promoting GBM cell survival. Mechanistically, miR-18a directly targeted ALOXE3 and suppressed its expression and functions in GBM cells. Furthermore, ALOXE3 silencing promoted 12-hydroxyeicosatetraenoic acids (12-HETE) secretion from GBM cells, in turn, 12-HETE enhanced migration of GBM cells by activating Gs-protein-coupled receptor (GsPCR)-PI3K-Akt pathway in an autocrine manner. Altogether, miR-18a/ALOXE3 axis exerts tumor promoting functions by regulating ferroptosis and migration of GBM cells. Targeting miR-18a/ALOXE3 axis may provide novel therapeutic approaches for GBM treatment.

Clinical outcomes of fractionated stereotactic radiosurgery in treating perioptic meningiomas and schwannomas: A single-institutional experience.

Application of radiosurgery to the newly diagnosed or post-operative residual perioptic lesions has been proved to improve tumor control. However, risk of vision injury induced by radiosurgery may increase substantially if the radiation dose is too high or tumor is close to the optic apparatus. The purpose of this study was to evaluate the safety and the effectiveness of fractionated stereotactic radiosurgery (FSRS) for perioptic tumors. We retrospectively analyzed 60 consecutive patients with 53 meningiomas and 7 schwannomas treated with FSRS between October 2007 and February 2020. We administered a marginal dose of 6-7 Gy (mean 6.8 Gy) per fraction and delivered 3 fractions in 3 consecutive days. The median tumor volume was 6.31 cm3 (range 0.3-58.23 cm3). The mean minimum lesion-optic distance (MLOD) is 0.85 mm (range 0-3 mm). After mean follow-up period of 69.6 months (range 6.82-156.32 months; median 58.9 months), the tumor control rates at 1, 3, 5, 8 and 13 years were 98.3%, 93.4%, 90.60%, 88.4% and 88.4%, respectively. Four out of the 60 tumors (6.7%) experienced a transient volume increase after FSRS. None of the patients developed visual impairment related to radiation induced optic neuropathy (RION) after FSRS. In conclusion, FSRS offers an alternative treatment option in treating perioptic meningiomas and schwannomas with acceptable tumor control rates and good visual preservation in the present study.

Nuclear factor IX promotes glioblastoma development through transcriptional activation of Ezrin.

Enhanced migration is pivotal for the malignant development of glioblastoma (GBM), but the underlying molecular mechanism that modulates the migration of the GBM cells remains obscure. Here we show that nuclear factor IX (NFIX) is significantly upregulated in human GBM lesions compared with normal or low-grade gliomas. NFIX deficiency impairs the migration of GBM cells and inhibits the tumor growth in the hippocampus of immunodeficient nude mice. Mechanistically, NFIX silencing suppresses the expression of Ezrin, a protein that crosslinks actin cytoskeleton and plasma membrane, which is also positively correlated with GBM malignancy. NFIX depletion induced migration inhibition of GBM cells can be rescued by the replenishment of Ezrin. Furthermore, we identify a NFIX response element (RE) between -840 and -825 bp in the promoter region of the Ezrin gene. Altogether, our findings show, for the first time that NFIX can transcriptionally upregulate the expression of Ezrin and contribute to the enhanced migration of GBM cells, suggesting that NFIX is a potential target for GBM therapy.

The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders.

Adipose tissue as the largest energy reservoir and endocrine organ is essential for maintenance of systemic glucose, lipid and energy homeostasis, but these metabolic functions decline with ageing and obesity. Adipose tissue senescence is one of the common features in obesity and ageing. Although cellular senescence is a defensive mechanism preventing tumorigenesis, its occurrence in adipose tissue causatively induces defective adipogenesis, inflammation, aberrant adipocytokines production and insulin resistance, leading to adipose tissue dysfunction. In addition to these paracrine effects, adipose tissue senescence also triggers systemic inflammation and senescence as well as insulin resistance in the distal metabolic organs, resulting in Type 2 diabetes and other premature physiological declines. Multiple cell types including mature adipocytes, immune cells, endothelial cells and progenitor cells gradually senesce at different levels in different fat depots with ageing and obesity, highlighting the heterogeneity and complexity of adipose tissue senescence. In this review, we discuss the causes and consequences of adipose tissue senescence, and the major cell types responsible for adipose tissue senescence in ageing and obesity. In addition, we summarize the pharmacological approaches and lifestyle intervention targeting adipose tissue senescence for the treatment of obesity- and ageing-related metabolic diseases.