MiR196a-5p in extracellular vesicles released from human nasopharyngeal carcinoma enhance the phagocytosis and secretion of microglia by targeting ROCK1.

The microenvironment of the brain has become increasingly recognized as an essential regulator in metastatic and primary brain tumors. Recent studies demonstrate that circulating tumor-derived exosomes are critical for the brain tumor microenvironment. Nasopharyngeal carcinoma (NPC), a malignant tumor of the head and neck, often invades the skull base but infrequently extends to brain parenchyma. Neurobiological communication between microglia and tumor-derived extracellular vesicles (EVs) has been extensively studied, but how NPC cells regulate the immune microenvironment in the brain remains unknown. Here, we report that NPC derived EVs lead to increased microglial phagocytosis and proliferation, and heightened levels of IL-6, IL-8, CXCL1 and TGF-ß1. Analysis of microRNAs in EVs reveal that miR196a-5p is the major effector microRNA. Moreover, we demonstrate an enrichment of miR196a-5p in the plasmatic EVs of NPC patients. Further investigation demonstrated that miR196a-5p was transferred to microglia and regulated microglial structure and functions by downregulating the expression of ROCK1. Therefore, these data indicate that NPC-derived EVs are potent modulators of microglial functions in brain microenvironment. Regardless of brain colonization, EVs-mediated functional changes in microglia may be a universal phenomenon that results in the alteration of the tumor host's microenvironment in the brain.

Increased SERPINB10 Expression in Induced Sputum Was Associated with Airway Type 2 Inflammation in Asthma.

BACKGROUND: Asthma is a common chronic airway inflammation in the world. The aim of this study was to investigate the expression of SERPINB10 in induced sputum and its correlation with airway type 2 inflammation in asthma. METHODS: We recruited 90 subjects and detected SERPINB10 levels in induced sputum by ELISA and analyzed the correlation between SERPINB10 expression levels and FeNO, eosinophils in peripheral blood, lung function, and Th2 cytokines (IL-4, IL-5, and IL-13). RESULTS: The levels of SERPINB10 in induced sputum in asthmatic patients were higher than healthy controls. SERPINB10 levels in induced sputum were positively correlated with FeNO (r = 0.4620, p < 0.0001) and eosinophils in peripheral blood (r = 0.2500, p = 0.0218) and negatively correlated with FEV1 (%predicted) (r = -0.4161, p < 0.0001) and FEV1/FVC% (r = -0.4383, p < 0.0001). SERPINB10 levels were correlated with Th2 cytokines IL-4 (r = 0.6274, p < 0.0001), IL-5 (r = 0.5166, p < 0.0001), and IL-13 (r = 0.5212, p = 0.0003) in asthma. CONCLUSIONS: SERPINB10 levels in induced sputum of asthmatic patients were significantly increased and correlated with asthmatic airway type 2 inflammation. Induced sputum SERPINB10 may be a signature protein for type 2 high asthma and may be a potential target for airway eosinophilic inflammation in asthma.

Correlation between Increased Monocyte Chemotactic Protein 1 Level and Lung Function in Patients with Asthma.

BACKGROUND: The altered expression of monocyte chemotactic protein 1 (MCP1) in bronchoalveolar fluid was observed in patients and animal models of allergic asthma. However, the correlation between induced sputum MCP1 level and asthma clinical features remains poorly understood. OBJECTIVE: This study aims to explore the relationship of MCP1 protein expression in induced sputum with Th2 inflammation and asthma clinical features. METHODS: MCP1 protein expression in induced sputum and serum was detected by ELISA in patients with asthma, and its correlation with Th2 inflammation and lung function was analyzed. The effect of inhaled corticosteroids (ICSs) on MCP1 expression was also evaluated. RESULTS: The MCP1 level in induced sputum (p = 0.0006) and serum (p = 0.0035) was markedly increased and negatively correlated with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)% (r = -0.3674, p = 0.0001) and PC-20 (r = -0.5746, p < 0.0001) in patients with asthma. The area under the curve (AUC) of MCP1 level receiver operating characteristic curve in induced sputum and serum was 0.7134 (p = 0.0007) and 0.7589 (p = 0.0042), respectively. The patients with asthma were grouped into four according to their induced sputum MCP1 level and Th2 signature categories (Th2Hi MCP1Hi, Th2Hi MCP1Low, Th2Low MCP1Hi, and Th2Low MCP1Low). The Th2Low MCP1Hi subgroup had the lowest FEV1/FVC% and histamine concentration required to cause a 20% decline in FEV1. After 4 weeks of ICS treatment, the MCP1 levels in induced sputum and serum were significantly reduced. CONCLUSIONS: The MCP1 level in induced sputum and serum increased in patients with asthma but decreased after ICS treatment. The Th2Low MCP1Hi subgroup had the worst lung function and highest airway hyperresponsiveness. The combination of MCP1 level in induced sputum and Th2 inflammation defines a new phenotype that can be used to predict lung function and treatment response in patients with asthma.

Acute Treatment with Nicotinamide Riboside Chloride Reduces Hippocampal Damage and Preserves the Cognitive Function of Mice with Ischemic Injury.

Nicotinamide adenine dinucleotide (NAD) is a critical cosubstrate for enzymes involved in supplying energy to the brain. Nicotinamide riboside (NR), an NAD+ precursor, emerges as a neuroprotective factor after chronic brain insults. However, researchers have not determined whether it improves cognition after acute ischemia. In the present study, mice with middle cerebral artery occlusion were treated with NR chloride (NRC, 300 mg/kg, IP., 20 min after reperfusion). The results of the Morris water maze test revealed better recovery of learning and memory function in the NRC-treated group. Acute NRC treatment decreased hippocampal infarct volume, reduced neuronal loss and apoptosis in the hippocampus. Western blot and high-performance liquid chromatography assays of hippocampal tissues revealed that the activation of Sirtin-1 and adenosine 5' monophosphate-activated protein kinase was increased, the NAD content was elevated, and the production of adenosine triphosphate was strengthened by NRC. Collectively, acute NRC treatment increased the energy supply, reduced the neuronal loss and apoptosis, protected the hippocampus and ultimately promoted the recovery of cognitive function after brain ischemia.

Microglial Hv1 exacerbates secondary damage after spinal cord injury in mice.

The pathological process of spinal cord injury (SCI) is complex, particularly during secondary damage that triggers a multiphasic glial reaction consisting of both detrimental and beneficial effects. Deletion of a novel voltage-gated proton channel (Hv1) functionally expressed in microglia has been shown to confer neuroprotection during ischemic stroke. Here, we hypothesized that microglial Hv1 may also participate in the process of SCI through modulating glial responses. To test this hypothesis, we employed an SCI model in Hv1-knockout (Hv1-/-) and wild type (WT) mice and assessed resulting microglial polarization, accumulation of pro-inflammatory cytokines, astrocytic activation, oligodendrocytic apoptosis, lesion sizes, and demyelinated areas. Compared with post-SCI results in WT mice, post-SCI Hv1-/- mice exhibited an M2-dominant microglial polarization, decreased accumulation of microglia, and reduced production of pro-inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß). Additionally, Hv1-/- mice had significantly attenuated reactive astrogliosis and reduced expression of chondroitin sulphate proteoglycans (CSPGs) after SCI. Furthermore, Hv1 deficiency reduced SCI-induced oligodendrocytic apoptosis, demyelinated areas, and cavity formation. Collectively, our results provide the first evidence suggesting that microglial Hv1 may be a multi-mechanism therapeutic target for the treatment of SCI.

Deficiency of the microglial Hv1 proton channel attenuates neuronal pyroptosis and inhibits inflammatory reaction after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) causes neurological dysfunction with devastating consequences. SCI pathogenesis is accompanied by inflammasome activation and neuronal damage. But the spatial pattern and the time course of neuronal pyroptosis and apoptosis after SCI should be further elucidated. The microglial voltage-gated proton channel (Hv1) is implicated in reactive oxygen species (ROS)-induced neuronal damage following ischemic stroke. However, there is a lack of quantification on the neuronal pyroptosis and apoptosis associated with microglial Hv1 after SCI. METHODS: We analyzed spatial and temporal characteristics of neuronal pyroptosis and apoptosis following SCI and investigated the effects of Hv1 deficiency on neuronal pyroptosis and the nod-like receptor 3 (NLRP3) inflammasome pathway by using a mouse model of SCI. We tested the effects of Hv1-deficient microglia on ROS production in vivo and examined the relationship between ROS and neuronal pyroptosis in vitro. RESULTS: We observed that apoptosis was detected closer to the injury core than pyroptosis. The incidence of neuronal apoptosis peaked on day 1 after SCI and occurred before pyroptosis. Hv1 deficiency reduced neuronal apoptosis and NLRP3-inflammasome-mediated pyroptosis, improved axonal regeneration, and reduced motor deficits. SCI led to elevated ROS levels, whereas Hv1 deficiency downregulated microglial ROS generation. In vitro, ROS upregulated neuronal pyroptosis and activated the NLRP3 inflammasome pathway, both of which were reversed by addition of a ROS scavenger. Our results suggested that microglial Hv1 regulated neuronal apoptosis and NLRP3-induced neuronal pyroptosis after SCI by mediating ROS production. CONCLUSION: Following SCI, neuronal pyroptosis lasted longer and occurred farther away from the injury core compared with that of neuronal apoptosis. Microglial Hv1 deficiency downregulated microglial ROS generation and reduced apoptosis and NLRP3-induced neuronal pyroptosis. Our findings may provide novel insights into Hv1-associated mechanisms underlying neuronal damage after SCI.

NAD+ precursor nutritional supplements sensitize the brain to future ischemic events.

Nicotinamide adenine dinucleotide (NAD+) is a redox cofactor critical for oxidative phosphorylation. Nicotinamide (NAM) and nicotinamide riboside (NR) are NAD+ precursors widely used as nutritional supplements to augment oxidative phosphorylation. Indeed, NAD+ precursors have been reported to improve outcomes in ischemic stroke when administered as a rescue therapy after stroke onset. However, we have also reported that enhanced reliance on oxidative phosphorylation before ischemia onset might worsen outcomes. To address the paradox, we examined how NAD+ precursors modulate the outcome of middle cerebral artery occlusion in mice, when administered either 20 minutes after reperfusion or daily for three days before ischemia onset. A single post-ischemic dose of NAM or NR indeed improved tissue and neurologic outcomes examined at 72 hours. In contrast, pre-ischemic treatment for three days enlarged the infarcts and worsened neurological deficits. As a possible explanation for the diametric outcomes, a single dose of NAM or NR augmented tissue AMPK, PGC1α, SIRT1, and ATP in both naïve and ischemic brains, while the multiple-dose paradigm failed to do so. Our data suggest that NAD+ precursor supplements may sensitize the brain to subsequent ischemic events, despite their neuroprotective effect when administered after ischemia onset.

Identification of a Signature for Predicting Prognosis and Immunotherapy Response in Patients with Glioma.

Glioma is a deadly tumor that accounts for the vast majority of brain tumors. Thus, it is important to elucidate the molecular pathogenesis and potential diagnostic and prognostic biomarkers of glioma. In the present study, gene expression profiles of GSE2223 were obtained from the Gene Expression Omnibus (GEO) database. Core modules and hub genes related to glioma were identified using weighted gene coexpression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis of differentially expressed genes (DEGs). After a series of database screening tests, we identified 11 modules during glioma progression, followed by six hub genes (RAB3A, TYROBP, SYP, CAMK2A, VSIG4, and GABRA1) that can predict the prognosis of glioma and were validated in glioma tissues by qRT-PCR. The CIBERSORT algorithm was used to analyze the difference of immune cell infiltration between the glioma and control groups. Finally, Identification VSIG4 for immunotherapy response in patients with glioma demonstrating utility for immunotherapy research.

[Corrigendum] LRIG2 promotes the proliferation and cell cycle progression of glioblastoma cells in vitro and in vivo through enhancing PDGFRß signaling.

Subsequently to the publication of the above article and a Corrigendum that addressed the issue of a misspelling of one of the authors' names (DOI: 10.3892/ijo.2019.4769; published online on April 2, 2019), the authors have subsequently discovered that Fig. 7 on p. 1079 contained a duplication in two of the panels that might cause the readers some confusion. The authors were able to re-examine the original data, repeat the experiment, and have decided to revise Fig. 7. The corrected version of Fig. 7, showing replacement data for the p-Akt and Cyclin D1 experiments, is shown on the next page. The authors confirm that these data continue to support the main conclusions presented in their paper, and are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum. They also apologize to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 10.3892/ijo.2018.4482].

Effect of Cerebral Small Vessel Disease Burden on Outcomes in Patients With Acute Ischemic Stroke Receiving Endovascular Treatment.

Background: Cerebral small vessel disease (SVD) is common in the aging population. The study aimed to evaluate the effect of SVD on functional outcomes in patients with acute ischemic stroke (AIS) receiving endovascular treatment (EVT). Methods: From a prospective registry, we selected patients with AIS receiving EVT. SVD features, including white matter hyperintensities (WMH), lacunes and brain atrophy, were assessed on MRI and a validated SVD score was calculated to reflect the total SVD burden. Results: Among 137 patients included, 106 had none-mild SVD burden and 31 had moderate-severe SVD burden. The moderate-severe SVD burden group showed a significantly higher modified Rankin Scale score at 90 d (median, 4 versus 1 points, adjusted common odds ratio 0.32 [95% CI, 0.14-0.69], P < 0.01) and a significantly smaller improvement of NIHSS at 24 h (median, -3 versus -3 points, adjusted ß coefficient 4.02 [95% CI, 0.57-7.48], P = 0.02) and 7 days (median, -4 versus -6 points, adjusted ß coefficient 4.71 [95% CI, 1.06-8.36], P = 0.01) than the none-mild group. There was no significant difference in successful recanalization, death within 90 days, symptomatic intracranial hemorrhage within 24 h between two groups (all P > 0.05). Additionally, for each single SVD feature, brain atrophy and WMH, but not lacunes, were associated with the functional outcome. Conclusion: Moderate-severe SVD burden was associated with poor early and late functional outcomes in patients with AIS receiving EVT. Our results suggest that SVD score may act as a good predictor of outcomes in these patients.

Targeting LRIG2 overcomes resistance to EGFR inhibitor in glioblastoma by modulating GAS6/AXL/SRC signaling.

Epidermal growth factor receptor (EGFR) gene amplification and mutation occurs most frequently in glioblastoma (GBM). However, EGFR-tyrosine kinase inhibitors (TKIs), including gefitinib, have not yet shown clear clinical benefit and the underlying mechanisms remain largely unexplored. We previously demonstrated that LRIG2 plays a protumorigenic role and functions as a modulator of multiple oncogenic receptor tyrosine kinases (RTKs) in GBM. We therefore hypothesized that LRIG2 might mediate the resistance to EGFR inhibitor through modulating other RTK signaling. In this study, we report that LRIG2 is induced by EGFR inhibitor in gefitinib-treated GBM xenografts or cell lines and promotes resistance to EGFR inhibition by driving cell cycle progression and inhibiting apoptosis in GBM cells. Mechanistically, LRIG2 increases the secretion of growth-arrest specific 6 (GAS6) and stabilizes AXL by preventing its proteasome-mediated degradation, leading to enhancement of the gefitinib-induced activation of AXL and then reactivation of the gefitinib-inhibited SRC. Targeting LRIG2 significantly sensitizes the GBM cells to gefitinib, and inhibition of the downstream GAS6/AXL/SRC signaling abrogates LRIG2-mediated gefitinib resistance in vitro and in vivo. Collectively, our findings uncover a novel mechanism in resistance to EGFR inhibition and provide a potential therapeutic strategy to overcome resistance to EGFR inhibition in GBM.

[Corrigendum] LRIG2 promotes the proliferation and cell cycle progression of glioblastoma cells in vitro and in vivo through enhancing PDGFRß signaling.

Following the publication of this article, the authors have realized that the name of the second author was misspelt: "Minghai Dong" should have appeared as "Minhai Dong". The correct information for the authors on this paper is presented above. The authors regret that this error made it into print, andapologize to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 53: 1069­1082, 2018; DOI: 10.3892/ijo.2018.4482].

Pituitary Ependymoma: A Case Report and Review of the Literature.

BACKGROUND: Pituitary ependymoma is exceptionally rare. Its etiology, clinical presentation, radiologic feature, and treatment strategy are still a matter of debate. Only 7 human cases with limited data were reported in the English literature, and now we described another case of pituitary ependymoma. We also systematically reviewed previously reported cases and described its potential etiology, clinical presentation, radiologic features, pathology, immunohistochemical analysis, and ultrastructural examinations. CASE DESCRIPTION: A lesion in pituitary fossa was discovered in a 40-year-old man after suffering a progressive deterioration of vision in his right eye for >1 year with intermittent headache. The lesion was microsurgically resected and proved to be ependymoma upon pathologic and histologic examination. The patient made a fully recovery after surgery. CONCLUSIONS: To our knowledge, only 7 patients with ependymoma in the sellar region have been described in the English literature. We reported 1 more case of pituitary ependymoma and discussed the potential etiology, clinical presentation, radiologic features, pathology, immunohistochemical analysis, ultrastructural examinations, treatment, surgery, radiotherapy, chemotherapy, and prognosis of pituitary ependymoma. The case report may serve as a helpful reference for clinicians and radiologists.

LRIG2 promotes the proliferation and cell cycle progression of glioblastoma cells in vitro and in vivo through enhancing PDGFRß signaling.

The leucine­rich repeats and immunoglobulin­like domains (LRIG) gene family, comprising LRIG1, 2 and 3, encodes integral membrane proteins. It has been well established that LRIG1 negatively regulates multiple growth factor signaling pathways and is considered to be a tumor suppressor; however, the biological functions of LRIG2 remain largely unexplored. It was previously demonstrated that LRIG2 positively regulates epidermal growth factor receptor (EGFR) signaling, the most common aberrant receptor tyrosine kinase (RTK) signaling in glioblastoma multiforme (GBM), which promotes GBM growth. In the present study, the effect of LRIG2 on the proliferation of GBM cells was further addressed, as well as the possible mechanisms underlying the regulatory effect of LRIG2 on platelet­derived growth factor receptor ß (PDGFRß) signaling, another common oncogenic RTK signaling pathway in GBM. First, the expression levels of endogenous LRIG2 and PDGFRß were found to vary notably in human GBM, and the LRIG2 expression level was positively correlated with the expression level of PDGFRß. Furthermore, to the best of our knowledge, this is the first study to demonstrate that LRIG2 promoted the PDGF­BB­induced proliferation of GBM cells in vitro and in vivo through regulating the PDGFRß signaling­mediated cell cycle progression. Mechanistically, LRIG2 has the ability to physically interact with PDGFRß, promoting the total expression and the activation of PDGFRß, and enhancing its downstream signaling pathways of Akt and signal transducer and activator of transcription 3 and the effectors of key regulators of cell cycle progression, resulting in increased GBM cell proliferation. Collectively, these data indicated that LRIG2 may serve as a tumor promoter gene in gliomagenesis by positively regulating PDGFRß signaling, another important oncogenic RTK signaling pathway, in addition to the previously reported EGFR signaling in GBM modulated by LRIG2, and validated LRIG2 as a promising therapeutic target for the treatment of GBM characterized by multiple aberrant RTK signaling.