Developing a Cost-Effective Surgical Scheduling System Applying Lean Thinking and Toyota's Methods for Surgery-Related Big Data for Improved Data Use in Hospitals: User-Centered Design Approach.

BACKGROUND: Surgical scheduling is pivotal in managing daily surgical sequences, impacting patient experience and hospital resources significantly. With operating rooms costing approximately US $36 per minute, efficient scheduling is vital. However, global practices in surgical scheduling vary, largely due to challenges in predicting individual surgeon times for diverse patient conditions. Inspired by the Toyota Production System's efficiency in addressing similar logistical challenges, we applied its principles as detailed in the book "Lean Thinking" by Womack and Jones, which identifies processes that do not meet customer needs as wasteful. This insight is critical in health care, where waste can compromise patient safety and medical quality. OBJECTIVE: This study aims to use lean thinking and Toyota methods to develop a more efficient surgical scheduling system that better aligns with user needs without additional financial burdens. METHODS: We implemented the 5 principles of the Toyota system: specifying value, identifying the value stream, enabling flow, establishing pull, and pursuing perfection. Value was defined in terms of meeting the customer's needs, which in this context involved developing a responsive and efficient scheduling system. Our approach included 2 subsystems: one handling presurgery patient data and another for intraoperative and postoperative data. We identified inefficiencies in the presurgery data subsystem and responded by creating a comprehensive value stream map of the surgical process. We developed 2 Excel (Microsoft Corporation) macros using Visual Basic for Applications. The first calculated average surgery times from intra- or postoperative historic data, while the second estimated surgery durations and generated concise, visually engaging scheduling reports from presurgery data. We assessed the effectiveness of the new system by comparing task completion times and user satisfaction between the old and new systems. RESULTS: The implementation of the revised scheduling system significantly reduced the overall scheduling time from 301 seconds to 261 seconds (P=.02), with significant time reductions in the revised process from 99 seconds to 62 seconds (P<.001). Despite these improvements, approximately 21% of nurses preferred the older system for its familiarity. The new system protects patient data privacy and streamlines schedule dissemination through a secure LINE group (LY Corp), ensuring seamless flow. The design of the system allows for real-time updates and has been effectively monitoring surgical durations daily for over 3 years. The "pull" principle was demonstrated when an unplanned software issue prompted immediate, user-led troubleshooting, enhancing system reliability. Continuous improvement efforts are ongoing, except for the preoperative patient confirmation step, which requires further enhancement to ensure optimal patient safety. CONCLUSIONS: Lean principles and Toyota's methods, combined with computer programming, can revitalize surgical scheduling processes. They offer effective solutions for surgical scheduling challenges and enable the creation of a novel surgical scheduling system without incurring additional costs.

CircIQGAP1 regulates RCAN1 and RCAN2 through the mechanism of ceRNA and promotes the growth of malignant glioma.

Circular RNA (circRNA) is one of non-coding RNA with specific circular structure, which has been found to be involved in regulating a series of malignant biological behaviors in many malignant tumors. In this study, based on the IDH1 molecular typing of gliomas, we identified a significant downregulation of circRNA (circIQGAP1) expression in IDH1 mutant gliomas by high-throughput sequencing. In 79 tissue samples, we confirmed that circIQGAP1 expression was significantly downregulated in IDH1 mutant gliomas, and that low circIQGAP1 expression was positively associated with better prognosis. Knockdown of circIQGAP1 in glioma cell lines inhibited glioma cell malignancy and conversely overexpression of circIQGAP1 promoted glioma malignancy. circIQGAP1 regulated glioma cell migration, proliferation, invasion and apoptosis through miR-1256/RCAN1/Bax/Bcl-2/Caspase3 and miR-622/RCAN2/Bax/Bcl-2/Caspase3 axes. These results suggest that circIQGAP1 plays an important role in glioma development, promotes tumor growth, and is a potential therapeutic target for glioma.

Conventional versus hybrid knife endoscopic submucosal dissection in large colorectal laterally spreading tumors: A propensity score analysis.

Background: Colorectal endoscopic submucosal dissection (CR-ESD) has become a promising treatment for laterally spreading tumors (LSTs), but is accompanied by great challenges. .: This study aimed to evaluate the efficacy and safety of CR-ESD with a hybrid knife, versus the conventional technique for LSTs ≥30 mm in diameter, and analyze the risk factors for piecemeal resection and perforation. Methods: Patients eligible for CR-ESD were divided into two groups according to the use of the hybrid knife (HK group) or the use of the conventional technique, with an interchange of injection and hook knife (C-group). We performed propensity score matching (PSM) to compare the HK group and the C-group. Risk predictors for perforation and piecemeal resection were identified. Results: PSM identified 61 (132 patients) and 61 (129 patients) patients in the C-group and the HK group, respectively. Resection speed was significantly faster in the HK group than in the C-group (18.86 vs. 13.33 mm2/min, P < 0.001). The rate of knife exchange was significantly lower in the HK group than in the C-group (1.6% vs. 49.2%, P < 0.001). Multivariate analysis revealed that unfavorable locations, including the splenic flexure, hepatic flexure, or cecum, were predictive of piecemeal resection. The presence of severe fibrosis and a semilunar fold were independent risk factors for perforation. Conclusions: : The use of a hybrid knife appears to increase CR-ESD resection speed. The indicators for piecemeal resection or perforation in CR-ESD identified herein might help to assess the technical difficulties of CR-ESD.

Risk Factors and the Management of Entrapped Temporal Horn following Lateral Ventricular Tumor Surgery.

AIM: To investigate the risk factors and optimize the management of entrapped temporal horn (ETH) following lateral ventricular tumor surgery. MATERIAL AND METHODS: We reviewed 41 cases of lateral ventricular tumors treated at the department of neurosurgery of our institution between January 2012 and September 2020. We summarized and analyzed the preoperative symptoms, intraoperative conditions, postoperative complications of the entrapped temporal horn, treatment measures, and recovery. RESULTS: Of 41 patients, 14 (34.1%) had ETH complications. A univariate analysis revealed that the tumor location, tumor diameter, the intraoperative use of hemostatic materials, no extraventricular drainage (EVD) was placed at the end of the operation, tumor stroke, the exposure mode of the tumor boundary, and postoperative meningitis were potential risk factors for the development of ETH. A multivariate binary logistic stepwise regression analysis revealed that tumor diameter ≥3.2cm(OR=14.808,P=0.037), tumor stroke(OR=50.793,P=0.015), non-EVD (OR=0.023,P=0.033), and the mechanical separation of the tumor boundary (OR=30.617,P=0.045) were risk factors for ETH. CONCLUSION: ETH often occurs following the surgery of lateral ventricle tumors. Large tumor diameter, tumor stroke, non-EVD at the end of operation, and the mechanical separation of the tumor boundary are the risk factors of ETH. The natural exposure of the tumor boundary during surgery, avoiding the use of hemostatic materials, placing an EVD tube at the end of operation, and postoperative infection control can effectively reduce the occurrence of ETH. It is essential to select the appropriate treatment method for patients with postoperative ETH.

HAUS Augmin-Like Complex Subunit 1 Influences Tumour Microenvironment and Prognostic Outcomes in Glioma.

Background: The expression of HAUS Augmin-like complex subunit 1 (HAUS1), a protein-coding gene, is low in normal samples among various cancers with pan-cancer analysis. The depletion of HAUS1 in cells decreases the G2/M cell compartment and induces apoptosis. However, the detailed expression pattern of HAUS1 and its correlation with immune infiltration in glioma (LGG and GBM) (LGG: low-grade glioma; GBM: glioblastoma) remain unknown. Therefore, in this study, we examined the role and prognostic value of HAUS1 in glioma. Methods: Transcriptional expression data of HAUS1 were collected from the CGGA and TCGA databases. The Kaplan-Meier analysis, univariate and multivariate Cox analyses, and receiver operating characteristic (ROC) curves were used to analyse the clinical significance of HAUS1 in glioma. The STRING database was used to analyse protein-protein interactions (PPI), and the "ClusterProfiler" package was used for functional enrichment analysis to examine the possible biological roles of HAUS1. In addition, the HAUS1 promoter methylation modification was analysed using MEXPRESS, and the association between HAUS1 expression and tumour-infiltrating immune cells was investigated using CIBERSORT. Results: Based on the data retrieved from TCGA (703 samples) and CGGA (1018 samples), an elevated expression of HAUS1 was observed in glioma samples, which was associated with poorer survival of patients, unfavourable clinical characteristics, 1p/19q codeletion status, WHO grade, and IDH mutation status. Furthermore, multivariate and univariate Cox analyses revealed that HAUS1 was an independent predictor of glioma. HAUS1 expression level was associated with several tumour-infiltrating immune cells, such as Th2 cells, macrophages, and activated dendritic cells. The outcomes of ROC curve analysis showed that HAUS1 was good to prognosticate immune infiltrating levels in glioma with a higher area under the curve (AUC) value (AUC = 0.974). Conclusions: HAUS1 was upregulated and served as a biomarker for poor prognosis in patients with glioma. High HAUS1 expression was associated with several tumour-infiltrating immune cells such as Th2 cells, macrophages, and activated dendritic cells, which had high infiltration levels. Therefore, these findings suggest that HAUS1 is a potential biomarker for predicting the prognosis of patients with glioma and plays a pivotal role in immune infiltration in glioma.

Phosphatase and Tensin Homology Deleted on Chromosome 10 Inhibitors Promote Neural Stem Cell Proliferation and Differentiation.

Phosphatase and tensin homology deleted on chromosome 10 (PTEN) is a tumor suppressor gene. Its encoded protein has phosphatase and lipid phosphatase activities, which regulate the growth, differentiation, migration, and apoptosis of cells. The catalytic activity of PTEN is crucial for controlling cell growth under physiological and pathological conditions. It not only affects the survival and proliferation of tumor cells, but also inhibits a variety of cell regeneration processes. The use of PTEN inhibitors is being explored as a potentially beneficial therapeutic intervention for the repair of injuries to the central nervous system. PTEN influences the proliferation and differentiation of NSCs by regulating the expression and phosphorylation of downstream molecular protein kinase B (Akt) and the mammalian target of rapamycin (mTOR). However, the role of PTEN inhibitors in the Akt/mTOR signaling pathway in NSC proliferation and differentiation is unclear. Dipotassium bisperoxo (picolinoto) oxovanadate (V) [bpv(pic)] is a biologically active vanadium compound that blocks PTEN dephosphorylation and suppresses its activity, and has been used as a PTEN lipid phosphatase inhibitor. Here, bpv(pic) intervention was found to significantly increase the number of rat NSCs, as determined by bromodeoxyuridine staining and the cell counting kit-8, and to increase the percentage of neurons undergoing differentiation, as shown by immunofluorescence staining. Bpv(pic) intervention also significantly increased PTEN and mTOR expression, as shown by real-time PCR analysis and western blotting. In conclusion, PTEN inhibitor bpv(pic) promotes the proliferation and differentiation of NSCs into neurons.

Endoscopic resection of large subepithelial esophageal lesions via submucosal tunneling endoscopic resection and endoscopic submucosal dissection: a single-center, retrospective cohort study.

BACKGROUND: This study aimed to compare the clinical outcomes between submucosal tunneling endoscopic resection (STER) and endoscopic submucosal dissection (ESD) for large subepithelial esophageal lesions (SELs) and analyze risk factors for perforation and piecemeal resection. METHODS: The clinicopathological features and outcomes of endoscopic treatment of 56 patients with SELs with diameters ≥30 mm, diagnosed between June 2017 and December 2020, were reviewed in this retrospective cohort study. Patients were divided into two groups (ESD group and STER group). RESULTS: The complete resection rates of the STER and ESD groups were 88.1% and 78.6%, respectively (p = .398). The operation time of STER was longer than ESD (p = .03), while the hospital stay of STER was shorter than ESD (p = .02). The rate of major adverse events associated with ESD was considerably higher than STER group (p = .035). The extraluminal growth pattern was a risk factor for piecemeal resection, and ESD was an independent risk factor for perforation. Regarding tumors with extraluminal growth patterns, the ESD group's perforation rate was significantly higher than the STER group (p = .009). There were no recurrence or metastases found during a mean follow-up of 24.4 months. CONCLUSION: The STER technique has advantages of shorter hospital stays and fewer major adverse events than ESD. The extraluminal growth pattern seems to be a risk factor for piecemeal resection in both ESD and STER. STER appears to be a preferable choice for large SELs with extraluminal growth patterns.

AMPK-mTOR-Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells.

Dormant cancer cells that survive anticancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction. Moreover, pharmacologic or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in patients with NPC. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer. SIGNIFICANCE: Pretreatment with an autophagy inhibitor before chemotherapy could prevent formation of therapy-induced dormant polyploid giant cancer cells, thereby reducing recurrence and metastasis of nasopharyngeal carcinoma.

Endoscopy during neurotomy of the nervus intermedius for nervus intermedius neuralgia: a case report.

Nervus intermedius neuralgia (NIN) is a rare craniofacial neuralgia with features of paroxysmal pain in the deep ear. Because of sensory nerves overlap in the ear, the diagnosis of NIN is often difficult and not definitive. Here, we present the case of a 70-year-old woman who had deep-ear pain for more than 4 years and was diagnosed with trigeminal neuralgia and treated with carbamazepine without relief in another hospital. Magnetic resonance tomographic angiography revealed no neurovascular conflict with the trigeminal nerve, whereas the anterior inferior cerebellar artery (AICA) was close to the VII/VIII complex. We performed left-sided suboccipital retrosigmoid craniotomy. Surgical exploration under endoscopy clearly showed that the nervus intermedius was compressed by the AICA from behind. The ear pain was completely relieved immediately after nervus intermedius sectioning. The intraoperative findings and postoperative results confirmed that the compression of the nervus intermedius by the AICA caused the otalgia. A patient's specific pain, combined with preoperative imaging examination, is useful in the diagnosis of NIN. Neuroendoscopy has the advantages of enabling a clear field of view and close observation, thus aiding in the identification and accurate cutting of the nervus intermedius during the operation.

Targeting PTEN to regulate autophagy and promote the repair of injured neurons.

The effects of autophagy on neuronal damage can be positive or detrimental negative. Through establishing a model of fetal rat cortical neuron hydraulic shock injury, dipotassium bisperoxo (picolinoto) oxovanadate (V) [bpv(pic)] was used to inhibit PTEN at different time points post-injury and autophagy level after neuronal injury was assessed. Neurons were divided into several intervention groups according to the time point at which bpv(pic) was used to inhibit autophagy, normal neurons and injuried neurons were set as two control groups. Growth of neurons in each group was assessed through immunofluorescence staining. Expression of the autophagy-related proteins LC3-II and LC3-I was analyzed by western blot. Expression of PTEN, mTOR and Beclin-1 was detected by RT-PCR. The number of autophagosomes in the normal group, injury control group and 24 h, 36 h intervention groups were assessed by electron microscope. We found that autophagy was enhanced after neuronal injury and that the levels of LC3-II was significantly reduced by bpv (pic) intervention. The growth of the injury control groups was worse than normal groups, while improved through bpv(pic) intervention at 24 h and 30 h after injured. Western blot analysis showed that the LC3-II and LC3-II/LC3-I ratios of cells increased post-injury, and autophagy induction was evident by electron microscopy. These effects were confirmed by RT-PCR analysis. Taken together, these data suggest that autophagy is activated after injury in neurons while can be inhibited by bpv(pic) administration and then promote the repair of injured neurons.

Modeling Intensive Polytomous Time-Series Eye-Tracking Data: A Dynamic Tree-Based Item Response Model.

This paper presents a dynamic tree-based item response (IRTree) model as a novel extension of the autoregressive generalized linear mixed effect model (dynamic GLMM). We illustrate the unique utility of the dynamic IRTree model in its capability of modeling differentiated processes indicated by intensive polytomous time-series eye-tracking data. The dynamic IRTree was inspired by but is distinct from the dynamic GLMM which was previously presented by Cho, Brown-Schmidt, and Lee (Psychometrika 83(3):751-771, 2018). Unlike the dynamic IRTree, the dynamic GLMM is suitable for modeling intensive binary time-series eye-tracking data to identify visual attention to a single interest area over all other possible fixation locations. The dynamic IRTree model is a general modeling framework which can be used to model change processes (trend and autocorrelation) and which allows for decomposing data into various sources of heterogeneity. The dynamic IRTree model was illustrated using an experimental study that employed the visual-world eye-tracking technique. The results of a simulation study showed that parameter recovery of the model was satisfactory and that ignoring trend and autoregressive effects resulted in biased estimates of experimental condition effects in the same conditions found in the empirical study.

Hippocampal PPARα is involved in the antidepressant-like effects of venlafaxine in mice.

Although thought as a serotonin and norepinephrine reuptake inhibitor (SNRI), the antidepressant mechanisms of venlafaxine remain unknown. Previous reports have shown the role of peroxisome proliferator activated receptor α (PPARα) in depression. In this study, we investigated whether the antidepressant-like effects of venlafaxine require PPARα. We first examined whether repeated venlafaxine administration reversed the effects of chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) on PPARα in the hippocampus and medial prefrontal cortex (mPFC). Then, the pharmacologcial inhibitors of PPARα, GW6471 and MK886, were used to assay if the protecting effects of venlafaxine against chronic stress were prevented by PPARα blockade. Furthermore, gene knockdown of PPARα by AAV-PPARα-shRNA was also used. It was found that venlafaxine treatment fully restored the decreasing effects of CUMS and CRS on the hippocampal PPARα expression. Pharmacological inhibition of PPARα significantly attenuated the antidepressant-like effects of venlafaxine in mice. Moreover, gene knockdown of hippocampal PPARα also fully abolished the antidepressant-like actions of venlafaxine in mice. Collectively, hippocampal PPARα is an antidepressant target of venlafaxine.

Multilevel Reliability Measures of Latent Scores Within an Item Response Theory Framework.

This paper evaluated multilevel reliability measures in two-level nested designs (e.g., students nested within teachers) within an item response theory framework. A simulation study was implemented to investigate the behavior of the multilevel reliability measures and the uncertainty associated with the measures in various multilevel designs regarding the number of clusters, cluster sizes, and intraclass correlations (ICCs), and in different test lengths, for two parameterizations of multilevel item response models with separate item discriminations or the same item discrimination over levels. Marginal maximum likelihood estimation (MMLE)-multiple imputation and Bayesian analysis were employed to evaluate the accuracy of the multilevel reliability measures and the empirical coverage rates of Monte Carlo (MC) confidence or credible intervals. Considering the accuracy of the multilevel reliability measures and the empirical coverage rate of the intervals, the results lead us to generally recommend MMLE-multiple imputation. In the model with separate item discriminations over levels, marginally acceptable accuracy of the multilevel reliability measures and empirical coverage rate of the MC confidence intervals were found in a limited condition, 200 clusters, 30 cluster size, .2 ICC, and 40 items, in MMLE-multiple imputation. In the model with the same item discrimination over levels, the accuracy of the multilevel reliability measures and the empirical coverage rate of the MC confidence intervals were acceptable in all multilevel designs we considered with 40 items under MMLE-multiple imputation. We discuss these findings and provide guidelines for reporting multilevel reliability measures.

Novel Insights into MSK1 Phosphorylation by MRKß in Intracerebral Hemorrhage-Induced Neuronal Apoptosis.

Neuronal apoptosis is regarded as one of the most important pathophysiological changes of intracerebral hemorrhagic (ICH) stroke-a major public health problem that leads to high mortality rates and functional dependency. Mitogen-and stress-activated kinase (MSK) 1 is implicated in various biological functions in different cell types, including proliferation, tumorigenesis and responses to stress. Our previous study showed that MSK1 phosphorylation (p-MSK1) is related to the regulation of LPS-induced astrocytic inflammation, and possibly acts as a negative regulator of inflammation. In this study, we identified a specific interaction between MSK1 and MRKß (MLK-related kinase)-a member of the MAPK pathway-during neuronal apoptosis. In an ICH rat model, western blotting and immunohistochemical analysis revealed that both MRKß and phosphorylation of MSK1 (p-MSK1 Ser376) were significantly upregulated in cells surrounding the hematoma. Triple-immunofluorescent labeling demonstrated the co-localization of MRKß and p-MSK1 in neurons, but not astrocytes. Furthermore, MRKß was partially transported into the nucleus, and interacted with p-MSK1 in hemin-treated neurons. Immunoprecipitation showed that MRKß and p-MSK1 exhibited an enhanced interaction during the pathophysiology process. Utilizing small interfering RNAs to knockdown MRKß or MSK1, we verified that MSK1 Ser376 is a phosphorylation site targeted by MRKß. We also observed that the phosphorylation of NF-κB p65 at Ser276 was mediated by the MRKß-p-MSK1 complex. Furthermore, it was found that the neuronal apoptosis marker, active caspase-3, was co-localized with MRKß and p-MSK1. In addition, flow cytometry analysis revealed that knockdown of MRKß or MSK1 specifically resulted in increased neuronal apoptosis, which suggested that the MRKß-p-MSK1 complex might exert a neuroprotective function against ICH-induced neuronal apoptosis. Taken together, our data suggest that MRKß translocated into the nucleus and phosphorylated MSK1 to protect neurons via phosphorylation of p65-a subunit of nuclear factor κB.

Matrine Exerts Antidepressant-Like Effects on Mice: Role of the Hippocampal PI3K/Akt/mTOR Signaling.

BACKGROUND: Current antidepressants in clinical use always take weeks or even months to exert full therapeutic effects, and sometimes have serious side effects. Thus, it is very necessary to develop novel antidepressants with better efficacy and fewer adverse effects. The present study focused on investigating the antidepressant potential of matrine and its possible mechanisms of action. METHODS: The forced swim test, tail suspension test, and chronic unpredictable mild stress model of depression were used to reveal the antidepressant-like effects of matrine on mice. Western blotting, immunohistochemistry, and lentivirus were further used together to explore the antidepressant mechanism of matrine. RESULTS: It was found that matrine exhibited significant antidepressant actions in the forced swim test and tail suspension test without affecting the locomotor activity of mice. Chronic matrine administration fully reversed the chronic unpredictable mild stress-induced depressive-like symptoms in forced swim test, tail suspension test, and sucrose preference test. After that, western blotting analysis revealed that chronic matrine treatment restored the decreasing effects of chronic unpredictable mild stress on the PI3K/Akt/mammalian target of rapamycin signaling in hippocampus, but not prefrontal cortex. Furthermore, pharmacological and genetic blockade of the PI3K/Akt/mammalian target of rapamycin signaling in hippocampus abolished the antidepressant actions of matrine on mice. CONCLUSIONS: Taken together, matrine produces antidepressant-like effects on mice via promoting the hippocampal PI3K/Akt/ mammalian target of rapamycin signaling.

IDH1 mutation diminishes aggressive phenotype in glioma stem cells.

The R132H mutation in isocitrate dehydrogenase 1 (IDH1-R132H) is associated with better prognosis in glioma patients. Glioma stem cells (GSCs) in glioma are believed to be responsible for glioma growth and maintenance. However, the relation between the R132H mutation and GSCs is not fully understood. In the present study, GSC markers were detected in patients with IDH1-R132H or wild-type IDH1 (IDH1-wt) by tissue microarray immunohistochemistry (TMA-IHC). The relationship between the expression patterns of GSC markers and the clinicopathological characteristics in glioma were analyzed. To confirm this mutation's role in GSCs, the IDH1-R132H in GSCs isolated from glioblastoma patients with IDH1 mutations was overexpressed by using lentiviral constructs in vitro, and then the proliferation, differentiation, apoptosis, migration and invasion of the transfected GSCs were explored. At the molecular level, we detected Wnt/ß-catenin signaling expression to verify its role in regulating the cellular properties of GSCs. The results showed that the positive rate of GSCs in patients with IDH1-R132H was significantly less than that in patients with IDH1-wt. The positive rate of GSCs was correlated with IDH1 mutation, TNM stage and poor overall survive. After transfection in vitro, IDH1-R132H overexpression led to reduced GSCs proliferation, migration and invasion, inducing apoptosis and improving GSC differentiation, accompanied by a significant reduction in activity of ß-catenin. Several mediators, effectors and targets of the Wnt/ß-catenin signaling were downregulated. The data demonstrate that IDH1 mutation reduces the malignant progression of glioma by causing a less aggressive phenotype of GSCs which are involved in the Wnt/ß­catenin signaling.

O-GlcNAc Glycosylation of nNOS Promotes Neuronal Apoptosis Following Glutamate Excitotoxicity.

Ischemic stroke is a dominant health problem with extremely high rates of mortality and disability. The main mechanism of neuronal injury after stroke is excitotoxicity, during which the activation of neuronal nitric oxide synthase (nNOS) exerts a vital role. However, directly blocking N-methyl-D-aspartate receptors or nNOS can lead to severe undesirable effects since they have crucial physiological functions in the central nervous system. Here, we report that nNOS undergoes O-linked-ß-N-acetylglucosamine (O-GlcNAc) modification via interacting with O-GlcNAc transferase, and the O-GlcNAcylation of nNOS remarkably increases during glutamate-induced excitotoxicity. In addition, eliminating the O-GlcNAcylation of nNOS protects neurons from apoptosis during glutamate stimulation by decreasing the formation of nNOS-postsynaptic density protein 95 complexes. Taken together, our data suggest a novel function of the O-GlcNAcylation of nNOS in neuronal apoptosis during glutamate excitotoxicity, suggesting a novel therapy strategy for ischemic stroke.

Upregulated Expression of SSTR3 is Involved in Neuronal Apoptosis After Intracerebral Hemorrhage in Adult Rats.

Somatostatin which is a multifunctional growth hormone inhibitory neuropeptide shows diverse physiological effects, such as neurotransmission, cell growth, apoptosis, and endocrine signaling as well as exerts inhibitory effects on hormonal products and other secretory proteins. SSTR3 is a member of superfamily of somatostatin receptors (SSTR), which are G-protein-coupled plasma membrane receptors. Previous studies proved that SSTR3 regulates antiproliferative signaling and apoptosis in several cells. Here, we explored a potential role of SSTR3 in the regulation of neuronal apoptosis in the course of intracerebral hemorrhage (ICH). An ICH rat model was established and assessed by behavioral tests. We found SSTR3 was significantly upregulated surrounding the hematoma after ICH by Western blot and immunohistochemistry. Double immunofluorescence-manifested SSTR3 was strikingly increased in neurons, not astrocytes or microglia. Moreover, increasing SSTR3 level was found to be accompanied by the upregulation of p53, Bax, and active caspase-3 in vivo and in vitro studies. Furthermore, we detected that neuronal apoptosis marker active caspase-3 was co-localized with SSTR3 suggesting its potential role in neuronal apoptosis. In addition, in vitro study, revealed that SSTR3 knockdown specifically resulted in reducing neuronal apoptosis in PC12 cells, which further indicated that SSTR3 might exert its pro-apoptotic function on neuronal apoptosis. All our findings suggested that upregulated SSTR3 may be involved in neuronal apoptosis after ICH.