Survival Analysis of Patients Undergoing Intraoperative Contrast-enhanced Ultrasound in the Surgical Treatment of Malignant Glioma.

OBJECTIVE: Complete resection of malignant gliomas is often challenging. Our previous study indicated that intraoperative contrast-enhanced ultrasound (ICEUS) could aid in the detection of residual tumor remnants and the total removal of brain lesions. This study aimed to investigate the survival rates of patients undergoing resection with or without the use of ICEUS and to assess the impact of ICEUS on the prognosis of patients with malignant glioma. METHODS: A total of 64 patients diagnosed with malignant glioma (WHO grade HI and IV) who underwent surgery between 2012 and 2018 were included. Among them, 29 patients received ICEUS. The effects of ICEUS on overall survival (OS) and progression-free survival (PFS) of patients were evaluated. A quantitative analysis was performed to compare ICEUS parameters between gliomas and the surrounding tissues. RESULTS: The ICEUS group showed better survival rates both in OS and PFS than the control group. The univariate analysis revealed that age, pathology and ICEUS were significant prognostic factors for PFS, with only age being a significant prognostic factor for OS. In multivariate analysis, age and ICEUS were significant prognostic factors for both OS and PFS. The quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding tissue. CONCLUSION: ICEUS facilitates the identification of residual tumors. Age and ICEUS are prognostic factors for malignant glioma surgery, and use of ICEUS offers a better prognosis for patients with malignant glioma.

A pair of primary colorectal cancer-derived and corresponding synchronous liver metastasis-derived organoid cell lines.

Proper preclinical models for the research of colorectal cancer (CRC) and CRC liver metastases (CLM) are a clear and unmet need. Patient-derived organoids have recently emerged as a robust preclinical model, but are not available to all scientific researchers. Here, we present paired 3D organoid cell lines of CWH22 (CRC-derived) and CLM22 (CLM-derived) with sound background information and the short tandem repeats are identical to those of the normal tissue. Morphological and immunohistochemical staining, along with whole-exome sequencing (WES), confirmed that the organoids exhibited the same differentiation, molecular expression, and mutation status as the corresponding tumor tissue. Both organoids possessed mutated APC/KRAS/SMAD4/CDKN1B/KMT2C genes and wild-type TP53 and PIK3CA; stably secreted the tumor markers CEA and CA19-9, and possessed sound proliferation rates in vitro, as well as subcutaneous tumorigenicity and liver metastatic abilities in vivo. IC50 assays confirmed that both cell lines were sensitive to 5-fluorouracil, oxaliplatin, SN-38, and sotorasib. WES and karyotype analyses revealed the genomic instability status as chromosome instability. The corresponding adherent cultured CWH22-2D/CLM22-2D cells were established and compared with commonly used CRC cell lines from the ATCC. Both organoids are publicly available to all researchers and will be useful tools for specific human CRC/CLM studies both in vitro and in vivo.

Simultaneous inhibition of FAK and ROS1 synergistically repressed triple-negative breast cancer by upregulating p53 signalling.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking effective targeted therapies, necessitating innovative treatment approaches. While targeting ROS proto-oncogene 1 (ROS1) with crizotinib has shown promise, resistance remains a limitation. Recent evidence links focal adhesion kinase (FAK) to drug resistance, prompting our study to assess the combined impact of FAK inhibitor IN10018 and crizotinib in TNBC and elucidate the underlying mechanisms. METHODS: We employed the Timer database to analyze FAK and ROS1 mRNA levels in TNBC and adjacent normal tissues. Furthermore, we investigated the correlation between FAK, ROS1, and TNBC clinical prognosis using the GSE database. We conducted various in vitro assays, including cell viability, colony formation, flow cytometry, EdU assays, and western blotting. Additionally, TNBC xenograft and human TNBC organoid models were established to assess the combined therapy's efficacy. To comprehensively understand the synergistic anti-tumor mechanisms, we utilized multiple techniques, such as RNA sequencing, immunofluorescence, cell flow cytometry, C11-BODIPY staining, MDA assay, and GSH assay. RESULTS: The Timer database revealed higher levels of FAK and ROS1 in TNBC tissues compared to normal tissues. Analysis of GEO databases indicated that patients with high FAK and ROS1 expression had the poorest prognosis. Western blotting confirmed increased p-FAK expression in crizotinib-resistant TNBC cells. In vitro experiments showed that the combination therapy down-regulated cyclin B1, p-Cdc2, and Bcl2 while up-regulating BAX, cleaved-Caspase-3, cleaved-Caspase-9, and cleaved PARP. In TNBC xenograft models, the tumor volume in the combination therapy group was 73% smaller compared to the control group (p < 0.0001). Additionally, the combination therapy resulted in a 70% reduction in cell viability in human TNBC organoid models (p < 0.0001). RNA sequencing analysis of TNBC cells and xenograft tumor tissues highlighted enrichment in oxidative stress, glutathione metabolism, and p53 pathways. The combined group displayed a fivefold rise in the reactive oxygen species level, a 69% decrease in the GSH/GSSG ratio, and a sixfold increase in the lipid peroxidation in comparison to the control group. Western blotting demonstrated p53 upregulation and SCL7A11 and GPX4 downregulation in the combination group. The addition of a p53 inhibitor reversed these effects. CONCLUSION: Our study demonstrates that the combination of IN10018 and crizotinib shows synergistic antitumor effects in TNBC. Mechanistically, this combination inhibits cell proliferation, enhances apoptosis, and induces ferroptosis, which is associated with increased p53 levels.

Targeting LINC01607 sensitizes hepatocellular carcinoma to Lenvatinib via suppressing mitophagy.

Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox status in Lenvatinib-resistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.

FAM129A promotes self-renewal and maintains invasive status via stabilizing the Notch intracellular domain in glioma stem cells.

BACKGROUND: Glioma stem cells (GSCs) are a subpopulation of tumor cells with self-renewal and tumorigenic capabilities in glioblastomas (GBMs). Diffuse infiltration of GSCs facilitates tumor progression and frustrates efforts at effective treatment. Further compounding this situation is the currently limited understanding of what drives GSC invasion. Here we comprehensively evaluated the significance of a novel invasion-related protein, Family with Sequence Similarity 129 Member A (FAM129A), in infiltrative GSCs. METHODS: Western blotting, immunohistochemistry, and gene expression analysis were used to quantify FAM129A in glioma specimens and cancer datasets. Overexpression and knockdown of FAM129A in GSCs were used to investigate its effects on tumor growth and invasion. RNA-seq, qRT-PCR, western blotting, and co-precipitation assays were used to investigate FAM129A signaling mechanisms. RESULTS: FAM129A is preferentially expressed in invasive frontiers. Targeting FAM129A impairs GSC invasion and self-renewal. Mechanistically, FAM129A acted as a positive regulator of Notch signaling by binding with the Notch1 intracellular domain (NICD1) and preventing its degradation. CONCLUSIONS: FAM129A and NICD1 provide a precise indicator for identifying tumor margins and aiding prognosis. Targeting them may provide a significantly therapeutic strategy for GSCs.

LRIG2 promotes glioblastoma progression by modulating innate antitumor immunity through macrophage infiltration and polarization.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor with poor clinical outcomes. Immunotherapy has recently been an attractive and promising treatment of extracranial malignancies, however, most of clinical trials for GBM immunotherapy failed due to predominant accumulation of tumor-associated microglia/macrophages (TAMs). RESULTS: High level of LRIG2/soluble LRIG2 (sLRIG2) expression activates immune-related signaling pathways, which are associated with poor prognosis in GBM patients. LRIG2/sLRIGs promotes CD47 expression and facilitates TAM recruitment. Blockade of CD47-SIRPα interactions and inhibition of sLRIG2 secretion synergistically suppress GBM progression in an orthotropic murine GBM model. CONCLUSIONS: GBM cells with high level LRIG2 escape the phagocytosis by TAM via the CD47-SIRPα axis, highlighting a necessity for an early stage of clinical trial targeting LRIG2 and CD47-SIRPα as a novel treatment for patients with GBM.

Establishment and characteristics of GWH04, a new primary human glioblastoma cell line.

Glioblastoma multiforme (GBM) is a common and fatal disease of the central nervous system. GBM cell lines are fundamental tools used in GBM research. The establishment of novel continuous GBM cell lines with clear genetic backgrounds could facilitate the exploration of molecular mechanisms and the screening and evaluation of antitumor drugs in GBM studies. In the present study, a novel primary glioblastoma cell line was established, named GWH04, from a patient with GBM, and its STR genotype and various tumor parameters were examined. The STR information of GWH04 was identical to that of the original primary tumor tissue. Compared with existing cell lines, GWH04 had a similar in vitro proliferation rate as the U87 cell line, but a faster rate than the GL15 cell line, and substantial soft agar clone­formation capacity and subcutaneous and intracranial tumorigenic capacity. For drug sensitivity test, half maximal inhibitory concentration assays for multiple drugs were performed in these three cell lines, and GWH04 cells were found to be resistant to temozolomide. Aneuploid karyotype with a median of 84 chromosomes was possessed by GWH04, as well as chromosomal structural abnormalities, such as broken chromosomes, double centromere chromosomes, homogeneous staining regions, and double microbodies. Gene sequencing further revealed the mutational status of genes TP53, PTEN, PDGFRA, ERBB2, BRCA1, NF1, and MLH1 and the promoter region of telomerase reverse transcriptase (C228T) in this cell line. Altogether, these results indicated that GWH04 will be a useful tool for human GBM studies both in vitro and in vivo.

Material basis and action mechanism of Euryale Ferox Salisb in preventing and treating diabetic kidney disease.

The aim of this study was to determine the chemical structure and mechanism of action of Euryale ferox Salisb (ES) in the prevention and treatment of diabetic kidney disease (DKD). The TCMSP, SymMap V2, CTD, DisGeNET, and GeneCards databases were searched for ES components, targets, and DKD targets using the network pharmacology method to identify common drug-disease targets. PPI analysis was used to identify hub genes, which were then followed by DKD clinical relevance, GO, KEGG analysis, and transcription factor prediction. Finally, molecular docking was performed. We discovered 24 components of ES and 72 objectives of ES, 9 of which were clinically relevant and primarily regulated by transcription factors such as HNF4A and PPARG. They are involved primarily in signal transduction, inflammatory responses, TNF regulation, apoptosis, MAPK, and other signaling pathways. The main components are oleic acid targeting the protein encoded by PPARA, LPL, FABP1, and vitamin E binding the protein encoded by MAPK1, TGFB1. In general, this approach provides an effective strategy in which ES acts primarily against DKD through oleic acid and vitamin E, targeting the protein encoded by PPARA, LPL, FABP1, MAPK1 to regulate TNF, apoptosis, MAPK, and other signaling pathways. PRACTICAL APPLICATIONS: Euryale ferox Salisb (ES) is well known for its use in medicine and food. Furthermore, ES contains many nutrients, whose pharmacological properties, including antidepressant, antioxidant, and anti-diabetic action, have been extensively demonstrated by numerous studies. In this article, through network pharmacology combined with clinical correlation analysis and molecular docking, the target and mechanism of ES in the treatment of diabetic kidney disease (DKD) were discussed, which clarified its mechanism at the molecular level. Provides a reference for the further development and utilization of ES.

TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvß5-Src-Stat3 signaling.

Rationale: In the glioblastoma (GBM) microenvironment, tumor-associated macrophages (TAMs) are prominent components and facilitate tumor growth. The exact molecular mechanisms underlying TAMs' function in promoting glioma stem cells (GSCs) maintenance and tumor growth remain largely unknown. We found a candidate molecule, transforming growth factor beta-induced (TGFBI), that was specifically expressed by TAMs and extremely low in GBM and GSC cells, and meanwhile closely related to glioma WHO grades and patient prognosis. The exact mechanism of TGFBI linking TAM functions to GSC-driven tumor growth was explored. Methods: Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry staining (IHC) and public datasets were used to evaluate TGFBI origin and level in GBM. The response of GSCs to recombinant human TGFBI was assessed in vitro and orthotopic xenografts were established to investigate the function and mechanism in vivo. Results: M2-like TAMs infiltration was elevated in high-grade gliomas. TGFBI was preferentially secreted by M2-like TAMs and associated with a poor prognosis for patients with GBM. TGFBI promoted the maintenance of GSCs and GBM malignant growth through integrin αvß5-Src-Stat3 signaling in vitro and in vivo. Of clinical relevance, TGFBI was enriched in the serum and CSF of GBM patients and significantly decreased after tumor resection. Conclusion: TAM-derived TGFBI promotes GSC-driven tumor growth through integrin αvß5-Src-Stat3 signaling. High serum or CSF TGFBI may serve as a potential diagnostic and prognostic bio-index for GBMs.

[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].

ALKBH5 Facilitates Hypoxia-Induced Paraspeckle Assembly and IL8 Secretion to Generate an Immunosuppressive Tumor Microenvironment.

The dynamic changes of RNA N6-methyl-adenosine (m6A) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer cell m6A dynamics in the hypoxic tumor niche and its pathological consequences in glioblastoma multiforme (GBM). The m6A demethylase ALKBH5 was induced in GBM models under hypoxic conditions and was associated with a hypoxic gene signature in GBM patient samples. Depletion or inactivation of ALKBH5 in GBM cells significantly suppressed hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in allograft tumors. Expression and secretion of CXCL8/IL8 were significantly suppressed in ALKBH5-deficient tumors. However, ALKBH5 did not regulate CXCL8 m6A directly. Instead, hypoxia-induced ALKBH5 erased m6A deposition from the lncRNA NEAT1, stabilizing the transcript and facilitating NEAT1-mediated paraspeckle assembly, which led to relocation of the transcriptional repressor SFPQ from the CXCL8 promoter to paraspeckles and, ultimately, upregulation of CXCL8/IL8 expression. Accordingly, ectopic expression of CXCL8 in ALKBH5-deficient GBM cells partially restored TAM recruitment and tumor progression. Together, this study links hypoxia-induced epitranscriptomic changes to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. SIGNIFICANCE: Hypoxia induces tumor immune microenvironment remodeling through an ALKBH5-mediated epigenetic and epitranscriptomic mechanism, providing potential immunotherapeutic strategies for treating glioblastoma.

High expression of TXNDC11 indicated unfavorable prognosis of glioma.

BACKGROUND: Thioredoxin domain containing 11 (TXNDC11) has been implicated in numerous cancers. Nevertheless, the function of TXNDC11 in glioma is not well described. This study aimed to assess clinical significance of TXNDC11 in glioma based on bioinformatics analysis and immunohistochemical (IHC) staining. METHODS: GEPIA2, The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases were employed to detect the levels of TXNDC11 transcript in glioma. Gene expression profiles and data from the methylation chip with clinical details from TCGA and Chinese Glioma Genome Atlas (CGGA) of glioma samples were examined. The methylation of TXNDC11 in glioma was evaluated by 450K methylation chip data analysis. The pathways involved in TXNDC11 expression were screened by gene set enrichment analysis (GSEA). The correlation between TXNDC11 and immune cells was analyzed. Protein level of TXNDC11 was detected by IHC staining in glioma specimens. RESULTS: TXNDC11 was highly expressed in glioma, and high TXNDC11 expression was associated with poor overall survival (OS) and worse clinical prognostic variables. The methylation of cg04399632 was statistically different between glioma samples and normal samples, and was negatively correlated with TXNDC11 expression in glioma patients. Survival analysis demonstrated a poorer prognosis in glioma patients with cg04399632 hypomethylation. TXNDC11-high phenotype was associated with certain immune-related pathways and other signaling pathways in glioma. The expression of TXNDC11 was correlated positively with M2 macrophage infiltration and negatively with M0 and M1 macrophage infiltration. IHC staining confirmed that TXNDC11 expression increased in higher-grade glioma. CONCLUSIONS: High expression of TXNDC11 may predict unfavorable prognosis of glioma patients.

Corrigendum: The Prognostic and Therapeutic Potential of LRIG3 and Soluble LRIG3 in Glioblastoma.

[This corrects the article DOI: 10.3389/fonc.2019.00447.].

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.

The Prognostic and Therapeutic Potential of LRIG3 and Soluble LRIG3 in Glioblastoma.

Glioblastoma is a highly lethal type of primary brain tumor that exhibits unrestricted growth and aggressive invasion capabilities, leading to a dismal prognosis despite a multitude of therapies. Multiple alterations in the expression level of genes and/or proteins have been identified in glioblastomas, including the activation of oncogenes and/or silencing of tumor-suppressor genes. Nevertheless, there are still no effective targeted therapies associated with these changes. In this study, we investigated the expression of human leucine-rich repeats and immunoglobulin-like domains protein 3 (LRIG3) in human glioma specimens through immunohistochemical analysis. The results showed that LRIG3 was weakly expressed in high-grade gliomas (WHO [World Health Organization] grades III and IV) compared with that in low-grade gliomas (WHO grade II). Survival analysis of these patients with glioma indicated that LRIG3 is an important prognostic marker for better survival. Moreover, we confirmed the existence of soluble ectodomain of LRIG3 (sLRIG3) in the cell culture supernatant, serum, and in tumor cystic fluid of patients with glioma. Molecular mechanistic investigation demonstrated that both LRIG3 and sLRIG3 inhibit the growth and invasion capabilities of GL15, U87, and PriGBM cells and tumor xenografts in nude mice through regulating the MET/phosphatidylinositol 3-kinase/Akt signaling pathway. Enzyme-linked immunosorbent assay confirmed the positive correlation between serum sLRIG3 protein levels and overall survival time in patients with high-grade gliomas. Taken together, our data for the first time demonstrate the existence of sLRIG3 and that both LRIG3 and sLRIG3 are potent tumor suppressors, which could be used as prognostic markers for better overall survival and therapeutic agents for glioblastoma.

MET in glioma: signaling pathways and targeted therapies.

Gliomas represent the most common type of malignant brain tumor, among which, glioblastoma remains a clinical challenge with limited treatment options and dismal prognosis. It has been shown that the dysregulated receptor tyrosine kinase (RTK, including EGFR, MET, PDGFRα, ect.) signaling pathways have pivotal roles in the progression of gliomas, especially glioblastoma. Increasing evidence suggests that expression levels of the RTK MET and its specific stimulatory factors are significantly increased in glioblastomas compared to those in normal brain tissues, whereas some negative regulators are found to be downregulated. Mutations in MET, as well as the dysregulation of other regulators of cross-talk with MET signaling pathways, have also been identified. MET and its ligand hepatocyte growth factor (HGF) play a critical role in the proliferation, survival, migration, invasion, angiogenesis, stem cell characteristics, and therapeutic resistance and recurrence of glioblastomas. Therefore, combined targeted therapy for this pathway and associated molecules could be a novel and attractive strategy for the treatment of human glioblastoma. In this review, we highlight progress made in the understanding of MET signaling in glioma and advances in therapies targeting HGF/MET molecules for glioma patients in recent years, in addition to studies on the expression and mutation status of MET.

[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].

A Meta-Analysis of Endoscopic Microvascular Decompression versus Microscopic Microvascular Decompression for the Treatment for Cranial Nerve Syndrome Caused by Vascular Compression.

OBJECTIVE: The aim of this study was to compare the efficacy and safety of endoscopic microvascular decompression (E-MVD) and microscopic microvascular decompression (M-MVD) for the treatment for cranial nerve syndrome caused by vascular compression, including primary trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia. METHODS: A systematic search of the online databases, including PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China Biology Medicine disc, and China National Knowledge Infrastructure, was performed from January 1966 to March 2018. The language of the included literature was not limited. Relevant outcomes of perioperative safety and postoperative efficacy were considered for meta-analysis. Single-arm and cumulative meta-analyses were also conducted. All the outcomes were calculated as odds ratios (ORs) with 95% confidence intervals using R language. RESULTS: A total of 9 studies involving 1093 (E-MVD [543] vs. M-MVD [550]) patients were included for analysis in our study. The recent remission rate (92% vs. 86%; OR, 1.71; P = 0.0089), offending vessel discovery rate (99% vs. 95%; OR 2.76, P = 0.0061), and long-term remission rate (97% vs. 87%; OR 4.59, P = 0.0036) were significantly higher in patients who underwent E-MVD than in those who underwent M-MVD, whereas perioperative complications (23% vs. 35%; OR 0.56, P < 0.0001) were significantly lower in patients who underwent E-MVD. CONCLUSIONS: This meta-analysis confirms that E-MVD is superior to M-MVD both in perioperative and postoperative efficacy (short- and long-term), and therefore it should be considered as an appropriate treatment choice for patients with neuralgia and hemifacial spasm.

Inhibition of TAZ contributes radiation-induced senescence and growth arrest in glioma cells.

Glioblastoma (GBM) is the most aggressive brain tumor and resistant to current available therapeutics, such as radiation. To improve the clinical efficacy, it is important to understand the cellular mechanisms underlying tumor responses to radiation. Here, we investigated long-term cellular responses of human GBM cells to ionizing radiation. Comparing to the initial response within 12 hours, gene expression modulation at 7 days after radiation is markedly different. While genes related to cell cycle arrest and DNA damage responses are mostly modulated at the initial stage; immune-related genes are specifically affected as the long-term effect. This later response is associated with increased cellular senescence and inhibition of transcriptional coactivator with PDZ-binding motif (TAZ). Mechanistically, TAZ inhibition does not depend on the canonical Hippo pathway, but relies on enhanced degradation mediated by the ß-catenin destruction complex in the Wnt pathway. We further showed that depletion of TAZ by RNAi promotes radiation-induced senescence and growth arrest. Pharmacological activation of the ß-catenin destruction complex is able to promote radiation-induced TAZ inhibition and growth arrest in these tumor cells. The correlation between senescence and reduced expression of TAZ as well as ß-catenin also occurs in human gliomas treated by radiation. Collectively, these findings suggested that inhibition of TAZ is involved in radiation-induced senescence and might benefit GBM radiotherapy.

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.