A novel p55PIK signaling peptide inhibitor alleviates neuroinflammation via the STAT3/NF-kB signaling pathway in experimental stroke.

BACKGROUND: Ischemic stroke remains the predominant contributor to mortality and disability globally. Microglia undergo rapid activation and initiate inflammatory cascade reactions by phenotypic polarization, participating in the regulation of inflammatory injury and tissue repair post-ischemic stroke. Regulating microglia-mediated neuroinflammation is a promising therapeutic strategy for ischemic stroke. Previously, we designed and synthesized a novel p55PIK inhibitor, TAT-N15 polypeptide, which presents inhibitive activity on NF-κB signaling-mediated inflammation in acute conjunctivitis and allergic rhinitis. The present study aimed to explore the therapeutic effect and mechanism of TAT-N15 on ischemia stroke. METHODS: The mouse model of transient cerebral ischemia was made using the intraluminal filament method. After being treated with daily intraperitoneal injections of TAT-N15 (10 mg/kg) for 7 d, the neurological outcomes and the cerebral infarction volume were evaluated. Histopathology of the ischemia cerebral hemisphere was observed by H&E and Nissl staining. Neuronal survival, astrogliosis, and co-labeling of CD86/Iba1 and CD206/Iba1 were detected by immunofluorescence. The cell apoptosis was estimated by TUNEL staining. The expression levels of apoptosis-associated proteins, proinflammatory cytokines, protein markers of M1 and M2 microglia, and the phosphorylation of NF-κB and STAT3 proteins in the ischemic penumbra were detected by Western blot. RESULTS: TAT-N15 treatment significantly decreased the infarct volume and alleviated neurological functional impairment, neuronal injury, and neuron apoptosis. Meanwhile, TAT-N15 treatment restrained the activation of microglia and astrocytes as well as the protein expression of proinflammatory cytokine in ischemic penumbra. Additionally, the administration of TAT-N15 treatment resulted in a significant reduction in the density of M1 phenotype microglia while concurrently increasing the density of M2 phenotype microglia within the ischemic penumbra. Finally, mechanical analysis unveiled that TAT-N15 exerted a substantial inhibitory effect on the protein expression of phosphorylated STAT3 and NF-κB. CONCLUSION: TAT-N15 may inhibit neuroinflammation via regulating microglia activation and polarization through the STAT3/NF-κB pathway, which exhibits the neuroprotection effect in ischemic stroke.

Cross-talk between BCKDK-mediated phosphorylation and STUB1-dependent ubiquitination degradation of BCAT1 promotes GBM progression.

Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.

VEGF165b Mutant Promotes the Apoptosis of Murine Breast Cancer Cells Induced by Paclitaxel by Inducing Tumor Vessel Maturation.

INTRODUCTION: The anti-angiogenic agent vascular endothelial growth factor 165b (VEGF165b) mutant (mVEGF165b), which was developed by our laboratory, has superior antitumor activity to that of native VEGF165b; however, its mechanism of action and druggability need further exploration. METHODS: Using the commercial anti-angiogenic drug bevacizumab as a positive control, the mechanism and developability of mVEGF165b were evaluated and explored. The Cell Counting Kit-8 assay was performed to evaluate the effects of mVEGF165b and bevacizumab alone on the proliferation of human umbilical vein endothelial cells (HUVECs). Meanwhile, the inhibitory effects of mVEGF165b and bevacizumab combined with paclitaxel in a mouse model of breast cancer were assessed. Immunohistochemistry was used to detect their effects on tumor vascular maturation, and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to detect the apoptosis of tumor cells. RESULTS: In vitro cell experiments confirmed that mVEGF165b inhibited the proliferation of HUVECs with an efficacy equivalent to that of bevacizumab. mVEGF165b and bevacizumab combined with paclitaxel significantly delayed the growth of breast cancer in mice. Immunohistochemistry and the TUNEL assay showed that mVEGF165b and bevacizumab combined with paclitaxel-induced higher vascular maturity and more apoptosis than paclitaxel alone. CONCLUSION: mVEGF165b showed similar efficacy and mechanism of action as bevacizumab, indicating its potential to be developed into a safe and effective anti-angiogenic drug.

Survival differences between the USA and an urban population from China for all cancer types and 20 individual cancers: a population-based study.

Background: The systematic comparison of cancer survival between China and the USA is rare. Here we aimed to assess the magnitude of survival disparities and disentangle the impact of the stage at diagnosis between a Chinese metropolitan city and the USA on cancer survival. Methods: We included 11,046 newly diagnosed cancer patients in Dalian Cancer Registry, China, 2015, with the follow-up data for vital status until December 2020. We estimated age-standardised 5-year relative survival and quantified the excess hazard ratio (EHR) of death using generalised linear models for all cancers and 20 individual cancers. We compared these estimates with 17 cancer registries' data from the USA, using the Surveillance, Epidemiology, and End Results database. We further estimated the stage-specific survival for five major cancers by region. Findings: Age-standardised 5-year relative survival for all patients in Dalian was lower than that in the USA (49.9% vs 67.9%). By cancer types, twelve cancers with poorer prognosis were observed in Dalian compared to the USA, with the largest gap seen in prostate cancer (Dalian: 55.8% vs USA: 96.0%). However, Dalian had a better survival for lung cancer, cervical cancer, and bladder cancer. Dalian patients had a lower percentage of stage Ⅰ colorectal cancer (Dalian: 17.9% vs USA: 24.2%) and female breast cancer (Dalian: 40.9% vs USA: 48.9%). However, we observed better stage-specific survival among stage Ⅰ-Ⅱ lung cancer patients in Dalian than in the USA. Interpretation: This study suggests that although the overall prognosis for patients was better in the USA than in Dalian, China, survival deficits existed in both countries. Improvement in cancer early detection and cancer care are needed in both countries. Funding: National Key R&D Program (2021YFC2501900, 2022YFC3600805), Major State Basic Innovation Program of the Chinese Academy of Medical Sciences (2021-I2M-1-010, 2021-I2M-1-046), and Talent Incentive Program of Cancer Hospital of Chinese Academy of Medical Sciences.

Hotspots and difficulties of biliary surgery in older patients.

ABSTRACT: With the accelerated aging society in China, the incidence of biliary surgical diseases in the elderly has increased significantly. The clinical characteristics of these patients indicate that improving treatment outcomes and realizing healthy aging are worthy of attention. How to effectively improve the treatment effect of geriatric biliary surgical diseases has attracted widespread attention. This paper reviews and comments on the hotspots and difficulties of biliary surgery in older patients from six aspects: (1) higher morbidity associated with an aging society, (2) prevention and control of pre-operative risks, (3) extending the indications of laparoscopic surgery, (4) urgent standardization of minimally invasive surgery, (5) precise technological progress in hepatobiliary surgery, and (6) guarantee of peri-operative safety. It is of great significance to fully understand the focus of controversy, actively make use of its favorable factors, and effectively avoid its unfavorable factors, for further improving the therapeutic effects of geriatric biliary surgical diseases, and thus benefits the vast older patients with biliary surgical diseases. Accordingly, a historical record with the highest age of 93 years for laparoscopic transcystic common bile duct exploration has been created by us recently.

ß-Glucan alleviates goal-directed behavioral deficits in mice infected with Toxoplasma gondii.

BACKGROUND: Toxoplasma gondii (T. gondii) is a neuroinvasive parasite causing neuroinflammation, which in turn is associated with a higher risk for several psycho-behavioral disorders. There is an urgent need to identify drugs capable of improving cognitive deficits induced by T. gondii infection. ß-Glucan, an active ingredient in mushrooms, could significantly enhance immunity. However, the effects of ß-glucan against neuroinflammation and cognitive decline induced by T. gondii infection remain unknown. The present study aimed to investigate the neuroprotective effect of ß-glucan on goal-directed behavior of mice chronically infected by T. gondii Wh6 strain. METHODS: A mice model of chronic T. gondii Wh6 infection was established by infecting mice by oral gavage with 10 cysts of T. gondii Wh6. Intraperitoneal injection of ß-glucan was manipulated 2 weeks before T. gondii infection. Performance of the infected mice on the Y-maze test and temporal order memory (TOM) test was used to assess the goal-directed behavior. Golgi-Cox staining, transmission electron microscopy, immunofluorescence, real-time PCR and western blot assays were used to detect prefrontal cortex-associated pathological change and neuroinflammation. RESULTS: The administration of ß-glucan significantly prevented T. gondii Wh6-induced goal-directed behavioral impairment as assessed behaviorally by the Y-maze test and TOM test. In the prefrontal cortex, ß-glucan was able to counter T. gondii Wh6-induced degeneration of neurites, impairment of synaptic ultrastructure and decrease of pre- and postsynaptic protein levels. Also, ß-glucan significantly prevented the hyperactivation of pro-inflammatory microglia and astrocytes, as well as the upregulation of proinflammatory cytokines caused by chronic T. gondii Wh6 infection. CONCLUSIONS: This study revealed that ß-glucan prevents goal-directed behavioral impairment induced by chronic T. gondii infection in mice. These findings suggest that ß-glucan may be an effective drug candidate to prevent T. gondii-associated psycho-behavioral disorders including goal-directed behavioral injury.

Glioma-derived LRIG3 interacts with NETO2 in tumor-associated macrophages to modulate microenvironment and suppress tumor growth.

Tumor-associated macrophages (TAMs) account for 30-50% of glioma microenvironment. The interaction between glioma tumor cells and TAMs can promote tumor progression, but the intrinsic mechanisms remain unclear. Herein, we reported that soluble LRIG3 (sLRIG3) derived from glioma tumor cells can block the M2 polarization of TAMs via interacting with NETO2, thus suppressing GBM malignant progression. The expression or activity of ADAM17 in glioma cells was positively correlated with the expression of sLRIG3 in cell supernatant. Soluble LRIG3 can suppress the M2-like polarity transformation of TAMs and inhibit the growth of tumor. High expression of LRIG3 predicts a good prognosis in patients with glioma. Mass spectrometry and Co-immunoprecipitation showed that sLRIG3 interacts with the CUB1 domain of NETO2 in TAMs. Silencing or knockout of NETO2 could block the effect of sLRIG3, which inhibited the M2-like polarity transformation of TAMs and promoted GBM tumor growth. However, overexpressing His-target NETO2 with CUB1 deletion mutation does not fully recover the suppressive effects of sLRIG3 on the TAM M2-polarization in NETO2-Knockout TAMs. Our study revealed vital molecular crosstalk between GBM tumor cells and TAMs. Glioma cells mediated the M2 polarization of TAM through the sLRIG3-NETO2 pathway and inhibited the progression of GBM, suggesting that sLRIG3-NETO2 may be a potential target for GBM treatment.

Chebulic Acid Prevents Hypoxia Insult via Nrf2/ARE Pathway in Ischemic Stroke.

Excessive reactive oxygen species (ROS) production contributes to brain ischemia/reperfusion (I/R) injury through many mechanisms including inflammation, apoptosis, and cellular necrosis. Chebulic acid (CA) isolated from Terminalia chebula has been found to have various biological effects, such as antioxidants. In this study, we investigated the mechanism of the anti-hypoxic neuroprotective effect of CA in vitro and in vivo. The results showed that CA could protect against oxygen-glucose deprivation/reoxygenation (OGD/R) induced neurotoxicity in SH-SY5Y cells, as evidenced by the enhancement of cell viability and improvement of total superoxide dismutase (T-SOD) in SH-SY5Y cells. CA also attenuated OGD/R-induced elevations of malondialdehyde (MDA) and ROS in SH-SY5Y cells. Nuclear factor-E2-related factor 2 (Nrf2) is one of the key regulators of endogenous antioxidant defense. CA acted as antioxidants indirectly by upregulating antioxidant-responsive-element (ARE) and Nrf2 nuclear translocation to relieve OGD/R-induced oxidative damage. Furthermore, the results showed that CA treatment resulted in a significant decrease in ischemic infarct volume and improved performance in the motor ability of mice 24 h after stroke. This study provides a new niche targeting drug to oppose ischemic stroke and reveals the promising potential of CA for the control of ischemic stroke in humans.

Clinical studies of magnetic resonance elastography from 1995 to 2021: Scientometric and visualization analysis based on CiteSpace.

Background: To assess the knowledge framework around magnetic resonance elastography (MRE) and to explore MRE research hotspots and emerging trends. Methods: The Science Citation Index Expanded of the Web of Science Core Collection was searched on 22 October 2021 for MRE-related studies published between 1995 and 2021. Excel 2016 and CiteSpace V (version 5.8.R3) were used to analyze the downloaded data. Results: In all, 1,236 articles published by 726 authors from 540 institutions in 40 countries were included in this study. The top 10 authors published 57.6% of all included articles. The 3 most productive countries were the USA (n=631), Germany (n=202), and France (n=134), and the 3 most productive institutions were the Mayo Clinic (n=240), Charité (n=131), and the University of Illinois (n=56). The USA and the Mayo Clinic had the highest betweenness centrality among countries and institutions, respectively, and played an important role in the field of MRE. In this study, the 24,347 distinct references were clustered into 48 categories via reasonable clustering using specific keywords, forming the knowledge framework. Among the 294 co-occurring keywords, "hepatic fibrosis", "stiffness", "skeletal muscle", "acoustic strain wave", "in vivo", and "non-invasive assessment" were research hotspots. "Diagnostic performance", "diagnostic accuracy", "hepatic steatosis", "chronic hepatitis B", "radiation force impulse", "children", and "echo" were frontier topics. Conclusions: Scientometric and visualized analysis of MRE can provide information regarding the knowledge framework, research hotspots, frontier areas, and emerging trends in this field.

Neuroprotective Effect of Polyphenol Extracts from Terminalia chebula Retz. against Cerebral Ischemia-Reperfusion Injury.

Current therapies for ischemic stroke are insufficient due to the lack of specific drugs. This study aimed to investigate the protective activity of polyphenol extracts from Terminalia chebula against cerebral ischemia-reperfusion induced damage. Polyphenols of ethyl acetate and n-butanol fractions were extracted from T. chebula. BV2 microglial cells exposed to oxygen-glucose deprivation/reoxygenation and mice subjected to middle cerebral artery occlusion/reperfusion were treated by TPE and TPB. Cell viability, cell morphology, apoptosis, mitochondrial membrane potential, enzyme activity and signaling pathway related to oxidative stress were observed. We found that TPE and TPB showed strong antioxidant activity in vitro. The protective effects of TPE and TPB on cerebral ischemia-reperfusion injury were demonstrated by enhanced antioxidant enzyme activities, elevated level of the nucleus transportation of nuclear factor erythroid 2-related factor 2 and expressions of antioxidant proteins, with a simultaneous reduction in cell apoptosis and reactive oxygen species level. In conclusion, TPE and TPB exert neuroprotective effects by stimulating the Nrf2 signaling pathway, thereby inhibiting apoptosis.

Therapeutic experience of a pancreatic mixed serous neuroendocrine neoplasm invading peripancreatic vessels: A case report.

RATIONALE: Pancreatic mixed serous neuroendocrine neoplasm (PMSNN) is an extremely rare disease. Only a few cases on the surgical treatment of PMSNN have been reported in the literature, and it is unclear whether there is invasion of important peripancreatic vessels. PATIENT CONCERNS: We report the case of a 39-year-old female patient with PMSNN accompanied by invasion of important peripancreatic vessels. She underwent surgery and achieved satisfactory recovery. DIAGNOSIS: Abdominal enhanced CT images showed an enhanced mass with a nonenhanced cyst involving the head and body of the pancreas, which invaded important peripancreatic vessels. The lesion had been misdiagnosed and mistreated as a metastatic carcinoma before admission. INTERVENTIONS: CT 3-dimensional (3D) visualization reconstruction images showed intact peripancreatic vessels. Radical pancreatoduodenectomy was successfully performed and confirmed that the main blood vessels around the pancreas were only compressed or even wrapped by the mass, but not penetrated. OUTCOMES: The patient recovered well and was discharged on the 19th day after surgery. Pathological examination reported the diagnosis of PMSNN with the collision type combination and the well-differentiated grade 2 pancreatic neuroendocrine tumor. She was followed up for 18 months without any abnormalities. LESSONS: This case demonstrates that surgical treatment of PMSNN with invasion of peripancreatic vessels can be successful. Preoperative abdominal CT 3D visualization reconstruction is helpful in determining the degree of invasion of important peripancreatic vessels, and plays a key role in formulating an accurate surgical plan and improving patient outcome.

How to select the quantitative magnetic resonance technique for subjects with fatty liver: A systematic review.

BACKGROUND: Early quantitative assessment of liver fat content is essential for patients with fatty liver disease. Mounting evidence has shown that magnetic resonance (MR) technique has high accuracy in the quantitative analysis of fatty liver, and is suitable for monitoring the therapeutic effect on fatty liver. However, many packaging methods and postprocessing functions have puzzled radiologists in clinical applications. Therefore, selecting a quantitative MR imaging technique for patients with fatty liver disease remains challenging. AIM: To provide information for the proper selection of commonly used quantitative MR techniques to quantify fatty liver. METHODS: We completed a systematic literature review of quantitative MR techniques for detecting fatty liver, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. Studies were retrieved from PubMed, Embase, and Cochrane Library databases, and their quality was assessed using the Quality Assessment of Diagnostic Studies criteria. The Reference Citation Analysis database (https:// www.referencecitationanalysis.com) was used to analyze citation of articles which were included in this review. RESULTS: Forty studies were included for spectroscopy, two-point Dixon imaging, and multiple-point Dixon imaging comparing liver biopsy to other imaging methods. The advantages and disadvantages of each of the three techniques and their clinical diagnostic performances were analyzed. CONCLUSION: The proton density fat fraction derived from multiple-point Dixon imaging is a noninvasive method for accurate quantitative measurement of hepatic fat content in the diagnosis and monitoring of fatty liver progression.

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.

Closed-loop evaluation on potential of three oil crops in remediation of Cd-contaminated soil.

Cd-contaminated farmlands threaten food security and safety by inhibiting crop growth and Cd accumulating in edible parts. Phytoremediation is a promising option to remove Cd from farmland soil. An ideal option is to remediate Cd and produce crops simultaneously on the contaminated soil. Therefore, we chose widely planted oil crops (soybean, sunflower and rape) as experimental materials, cultured in pots filled with soils contaminated with different concentrations (10, 20, 50, and 100 mg kg-1) Cd till harvest, and then took a closed-loop method to evaluate the remediation potential of the three oil crops, including the remediating ability, yield, and quality of seeds and environmental risk of pyrolytic biochar. The results show that the order of Cd accumulation capacity in the three oil crops was sunflower > rape > soybean. The yield and quality of the three oil crops were decreased by being treated with different concentrations of Cd. In addition, the order for a decreased degree in yield of the three oil crops was sunflower < rape < soybean, and the order for a decreased degree in protein and fat content was sunflower < soybean < rape. The potential risk of seeds of the three oil crops as food/feed was sunflower/soybean < soybean/sunflower < rape. After pyrolysis of harvested three oil crops, the order for leaching toxicity/leaching potential was sunflower-biochar < soybean-biochar/rape-biochar < rape-biochar/soybean-biochar. All three oil crops could remediate Cd-contaminated soils, and their seeds could generate economic value. Closed-loop evaluation of sunflower proved it might be a good option for removing Cd from farmland soil.

To Systematically Evaluate and Analyze the Efficacy and Safety of Transcatheter Arterial Chemoembolization (TACE) in the Treatment of Primary Liver Cancer.

The efficacy and safety of transcatheter arterial chemoembolization (TACE) are systematically evaluated in the treatment of primary liver cancer, which provides a reference for clinical practice and more in-depth research. Cochrane Library, PubMed, EMbase, CBM, CNKI, VIP, and WanFang Data, supplemented by other searches, collected all randomized controlled trials (RCT) comparing TACE combined with TACE alone for HCC. The meta-analysis, after selecting the literature, extracting data, and evaluating the methodological quality of the included studies following the inclusion criteria, was performed using RevMan 5.1 software. There was statistical difference in 3-year survival rate of TACE combined with heat treatment for advanced hepatocellular carcinoma (OR = 1.72,95%CI (1.22,2.41), P=0.002, I2 = 0%, and Z = 3.12), total effective rate (OR = 1.91,95%CI (1.31,2.78), P=0.0008, I2 = 0%, and Z = 3.37), quality-of-life improvement rate (OR = 2.29,95%CI (1.62,3.23), P < 0.00001, I2 = 83%, and Z = 3.37), and complication rate (OR = 2.29,95%CI (1.62,3.23), P < 0.00001, I2 = 83%, and Z = 3.37). Compared with TACE alone, TACE combined with hyperthermia can significantly improve the survival rate and recent efficacy of patients, improve the quality of life, and have a trend to reduce the incidence of toxicity. However, its long-term efficacy and more comprehensive safety need to be verified by more sample and high-quality RCT.

Knockdown of STK39 suppressed cell proliferation, migration, and invasion in hepatocellular carcinoma by repressing the phosphorylation of mitogen-activated protein kinase p38.

Hepatocellular carcinoma (HCC) is a serious malignant tumor of the liver. It has been reported that serine/threonine kinase 39 (STK39) participates in tumorigenesis. However, the role of STK39 in HCC remains unknown. In this study, the qRT-PCR and western blot assay demonstrated that STK39 expression was enhanced in HCC patients and tissues. Moreover, CCK-8 and colony formation assays confirmed that knockdown of STK39 suppressed SK-HEP-1 and Huh7 cells proliferation. Furthermore, wound healing assay and transwell assay revealed that knockdown of STK39 repressed SK-HEP-1 and Huh7 cells migration and invasion. Interestingly, knockdown of STK39 reduced p-p38/p38 ratio and levels of c-Myc. Consistently, knockdown of STK39 inhibited the HCC tumor growth in vivo. In summary, knockdown of STK39 suppressed the proliferation, migration, and invasion of HCC cells by inducing the lower levels of p-p38, which might provide a novel therapeutic target for HCC.

Genome-wide profiling of alternative splicing in glioblastoma and their clinical value.

BACKGROUND: Alternative splicing (AS), one of the main post-transcriptional biological regulation mechanisms, plays a key role in the progression of glioblastoma (GBM). Systematic AS profiling in GBM is limited and urgently needed. METHODS: TCGA SpliceSeq data and the corresponding clinical data were downloaded from the TCGA data portal. Survival-related AS events were identified through Kaplan-Meier survival analysis and univariate Cox analysis. Then, splicing correlation network was constructed based on these AS events and associated splicing factors. LASSO regression followed by multivariate Cox analysis was performed to validate independent AS biomarkers and to construct a risk prediction model. Enrichment analysis was subsequently conducted to explore potential signaling pathways of these AS events. RESULTS: A total of 132 TCGA GBM samples and 45,610 AS events were included in our study, among which 416 survival-related AS events were identified. An AS correlation network, including 54 AS events and 94 splicing factors, was constructed, and further functional enrichment was performed. Moreover, the novel risk prediction model we constructed displayed moderate performance (the area under the curves were > 0.7) at both one, two and three years. CONCLUSIONS: Survival-related AS events may be vital factors of both biological function and prognosis. Our findings in this study can deepen the understanding of the complicated mechanisms of AS in GBM and provide novel insights for further study. Moreover, our risk prediction model is ready for preliminary clinical applications. Further verification is required.

Preoperative Fasting Times for Patients Undergoing Elective Surgery at a Pediatric Hospital in Shanghai: The Big Evidence-Practice Gap.

PURPOSE: Preoperative fasting is a necessary experience for pediatric patients undergoing elective surgery. The American Society of Anesthesiologist guideline shows that preoperative fasting times were reduced and safe (no solid food up to 8 hours, no fluid or formula up to 6 hours, no breast milk up to 4 hours, and no clear fluids up to 2 hours before surgery). However, preoperative fasting is usually more prolonged than the suggested time. This study aimed to investigate the duration of preoperative fasting for elective surgery at a pediatric hospital in Shanghai, China, and compare it with the evidence from guidelines. DESIGN: The study used a descriptive cross-sectional design. METHODS: A total of 211 children under anesthesia in a Shanghai's pediatric hospital were included in the study. The preoperative fasting status was assessed using a self-administered record card of preoperative fasting developed by Chinese researchers. FINDINGS: The results indicated that the length of time fasted preoperatively was longer for all participants than that recommended by the American Society of Anesthesiologists. With the long length of fasting time, it is evident that the majority of children experienced hunger (17.5%), thirst (19.4%), and anxiety (16.1%) as indicated with 8 points of the Likert 10-point scale. The degrees of these experiences were relevant to the length of preoperative fasting time. CONCLUSIONS: A big gap was revealed between the recommendation and actual practice, and children underwent an uncomfortable experience before the surgery. These results suggest that evidence-based clinical improvement is required, and the recommended preoperative fasting instruction transform into clinical practice should be promoted.

LRIG3 Suppresses Angiogenesis by Regulating the PI3K/AKT/VEGFA Signaling Pathway in Glioma.

High levels of microvessel density (MVD) indicate poor prognosis in patients with malignant glioma. Leucine-rich repeats and immunoglobulin-like domains (LRIG) 3, a potential tumor suppressor, plays an important role in tumor progression and may serve as a biomarker in many human cancers. However, its role and underlying mechanism of action in glioma angiogenesis remain unclear. In the present study, we used loss- and gain-of-function assays to show that LRIG3 significantly suppressed glioma-induced angiogenesis, both in vitro and in vivo. Mechanistically, LRIG3 inhibited activation of the PI3K/AKT signaling pathway, downregulating vascular endothelial growth factor A (VEGFA) in glioma cells, thereby inhibiting angiogenesis. Notably, LRIG3 had a significant negative correlation with VEGFA expression in glioma tissues. Taken together, our results suggest that LRIG3 is a novel regulator of glioma angiogenesis and may be a promising option for developing anti-angiogenic therapy.

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

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