Long non-coding RNA MEG3 regulates autophagy after cerebral ischemia/reperfusion injury.

Severe cerebral ischemia/reperfusion injury has been shown to induce high-level autophagy and neuronal death. Therefore, it is extremely important to search for a target that inhibits autophagy activation. Long non-coding RNA MEG3 participates in autophagy. However, it remains unclear whether it can be targeted to regulate cerebral ischemia/reperfusion injury. Our results revealed that in oxygen and glucose deprivation/reoxygenation-treated HT22 cells, MEG3 expression was obviously upregulated, and autophagy was increased, while knockdown of MEG3 expression greatly reduced autophagy. Furthermore, MEG3 bound miR-181c-5p and inhibited its expression, while miR-181c-5p bound to autophagy-related gene ATG7 and inhibited its expression. Further experiments revealed that mir-181c-5p overexpression reversed the effect of MEG3 on autophagy and ATG7 expression in HT22 cells subjected to oxygen and glucose deprivation/reoxygenation. In vivo experiments revealed that MEG3 knockdown suppressed autophagy, infarct volume and behavioral deficits in cerebral ischemia/reperfusion mice. These findings suggest that MEG3 knockdown inhibited autophagy and alleviated cerebral ischemia/reperfusion injury through the miR-181c-5p/ATG7 signaling pathway. Therefore, MEG3 can be considered as an intervention target for the treatment of cerebral ischemia/reperfusion injury. This study was approved by the Animal Ethics Committee of the First Affiliated Hospital of Zhengzhou University, China (approval No. XF20190538) on January 4, 2019.

Computational systematic selectivity of the Fasalog inhibitors between ROCK-I and ROCK-II kinase isoforms in Alzheimer's disease.

Human Rho-associated coiled-coil forming kinase (ROCK) is a class of essential neurokinases that consists of two structurally conserved isoforms ROCK-I and ROCK-II; they have been revealed to play distinct roles in the pathogenesis of Alzheimer's disease (AD) and other neurological disorders. Selective targeting of the two kinase isoforms with small-molecule inhibitors is a great challenge due to the surprisingly high homology in kinase domain (92 %) and the full identity in kinase active site (100 %). Here, we describe a computational protocol to systematically profile the selectivity of Fasudil and its 25 analogs (termed as Fasalogs) between the two kinase isoforms. It is suggested that the substitution of Fasudil's 1,4-diazepane moiety with rigid ring such as Ripasudil and Dimehtylfasudil would render the resulting inhibitors of ROCK-II over ROCK-I (II-o-I) selectivity, while the substitution with long, flexible group such as H-89 and BDBM92607 tends to have I-o-II selectivity. Structural analysis reveals that the inhibitor affinity is not only determined by the identical active site, but also contributed from the non-identical first and second shells of the site as well as other non-conserved kinase regions, which can indirectly influence the active site and inhibitor binding through allosteric effect. A further kinase assay basically confirms the computational findings, which also exhibits a good consistence with theoretical selectivity over 10 tested samples (Rp = 0.89). In particular, the Fasalog compounds Dimehtylfasudil and H-89 are identified as II-o-I and I-o-II selective inhibitors. They can be considered as promising lead molecular entities to develop new specific ROCK isoform-selective Fasalog inhibitors.

Serum D-dimer as a potential new biomarker for prognosis in patients with thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease, and its mortality rate is 10% to 20%. However, there are currently only a few markers to predict the prognosis in patients with TTP. We aimed to identify several clinical indices and laboratory parameters for predicting the prognosis of TTP at admission.A single-centre observational cohort study that included patients with TTP from the First Affiliated Hospital of Zhengzhou University in China was conducted from January 1, 2012 to November 30, 2018. The primary outcome was prognosis, including in-hospital mortality, major thromboembolic events, or failure to achieve remission at discharge. We used the random forest method to identify the best set of predictors.Eighty-seven patients with TTP were identified, of whom 12 died during the treatment. The total number of patients within-hospital mortality, major thromboembolic events, and failure to achieve remission at discharge was 58. The machine learning method showed that the D-dimer level was the strongest predictor of the primary outcome. Receiver operating characteristic (ROC) analysis demonstrated that the sensitivity and specificity of the D-dimer level alone for identifying high-risk patients were 78% and 81%, respectively, with an optimum diagnostic cut-off value of 770 ng/mL. The area under the ROC curve (AUC) was 0.80, and the 95% confidence interval (CI) was 0.70 to 0.90.This study found that the D-dimer level exhibited a good predictive ability for prognosis in patients with TTP. These findings may aid in the development of new and intensive treatment strategies to achieve remission among high-risk patients. However, external validation is necessary to confirm the generalizability of our approach across populations and treatment practices.

LncRNA FTX Involves in the Nogo-66-Induced Inhibition of Neurite Outgrowth Through Regulating PDK1/PKB/GSK-3ß Pathway.

Nogo-66 can inhibit neurite outgrowth, while its regulation mechanisms have not been fully elucidated. Recent studies prove that lncRNAs are involved in neurite outgrowth. This study was aimed to investigate whether lncRNA FTX was involved in Nogo-66-induced inhibition of neurite outgrowth and explore the potential mechanism. The expression of relative genes was detected by qRT-PCR and western blot. The function of FTX was determined by overexpression and knockdown techniques. The interaction between FTX and PDK1 was evaluated by RIP and RNA pull-down assays. FTX expression was downregulated by Nogo-66 in PC12 cells. Nogo-66-induced inhibition of neurite outgrowth was relieved by FTX overexpression. FTX bound to PDK1 protein to disturb the interaction between PDK1 and E3 ubiquitin ligase RNF126, thereby blocked the ubiquitination degradation of PDK1 and elevated PDK1 protein level. Mechanically, FTX involved in the Nogo-66-induced inhibition of neurite outgrowth through the PDK1/PKB/GSK-3ß pathway. In SCI rats, FTX knockdown inhibited neurite outgrowth induced by the receptor antagonist of Nogo-66. The present results suggested that FTX took part in Nogo-66-inhibited neurite outgrowth, and FTX exerted its function through regulating PDK1/PKB/GSK-3ß pathway.

PAS Domain Containing Repressor 1 (PASD1) Promotes Glioma Cell Proliferation Through Inhibiting Apoptosis In Vitro.

BACKGROUND PAS domain containing repressor 1 (PASD1), the cancer-testis antigen (CTA), has been reported to be aberrantly expressed in various cancer tissues and cancer cell lines; however, normal PASD1 expression can be detected in normal tissue, excluding testicular tissue. Moreover, PASD1 is reported to be abnormally expressed in various malignant tumors. However, it remains unclear whether PASD1 participates in tumorigenesis of glioma. MATERIAL AND METHODS PASD1 expression was detected by immunohistochemistry in 155 glioma tissue specimens in this study. Furthermore, the relationship of PASD1 expression with clinicopathological features in glioma cases was statistically analyzed. In addition, PASD1 was knocked down by small interference RNA (shRNA) in glioma cell line (LN229), so as to assess the potential to use it as the target for treating glioma. RESULTS Our findings suggested that PASD1 expression in glioma patients was extremely upregulated compared with that in normal tissue samples and cell lines. Moreover, PASD1 expression was found to be markedly correlated with gender, The World Health Organization grade and p53 expression; in addition, high PASD1 expression indicated poor prognosis for glioma patients. Additionally, downregulation of PASD1 inhibited the proliferation ability of cells and resulted in cell arrest at the G2/M phase, which was achieved through accelerating apoptosis. Furthermore, our results indicated that PASD1 downregulation could upregulate some apoptosis-modulating proteins at the same time it downregulated some cycle-regulating proteins. CONCLUSIONS Taken together, our findings demonstrated that PASD1, an oncogene, can potentially serve as an independent prognostic factor for glioma patients.

Long non-coding RNA LINC00473 promotes glioma cells proliferation and invasion by impairing miR-637/CDK6 axis.

LINC00473 has been reported to be aberrantly expressed in diverse kinds of human malignancy. However, the function and underlying mechanisms of LINC00473 in glioma still remain unclear. In the present study, LINC00473 was notably elevated in glioma tissues and cell lines. High LINC00473 expression was associated with advanced WHO grade (III-IV), low Karnofsky performance score (KPS), and poor prognosis. Loss function assays showed that LINC00473 knockdown decreased glioma cell proliferation, invasion and epithelial-mesenchymal transition (EMT) processes in vitro, and reduced tumor growth in vivo. Mechanistic analysis indicated that LINC00473 regulated CDK6 expression by competitively binding to miR-637. Moreover, rescue assays revealed that miR-637 inhibitors abolished the effects of LINC00473 suppression on glioma cells progression. Thus, we demonstrated that LINC00473 could act as a ceRNA of miR-637 to promote glioma progression through regulating CDK6 expression, which provided a potential therapeutic target for treatment of glioma patients.

Clinical analysis of syringomyelia resulting from spinal hemangioblastoma in a single series of 38 consecutive patients.

OBJECTIVE: Syringomyelia was predominantly caused by Chiari malformation or intramedullary ependymoma. The goal of this study was to identify factors related to clinical outcomes and spinal hemangioblastoma (SH)-induced syringomyelia formation in a single series of patients. PATIENT AND METHODS: Thirty-eight patients with SH were treated with microsurgery from January 2013 to December 2018. Clinical features and related factors were retrospectively analyzed in SH patients with and without syringomyelia. RESULTS: Out of the total number of SH patients, 21 presented with remarkable syringomyelia, resulting in an incidence of 55.26% (21/38).Gross total resection was achieved in 36 cases (94.73%), and subtotal resection was obtained in 2 patients (5.27%). Neurological symptoms improved in 34 patients, remained stable in 2 patients and were aggravated in 2 cases during follow-up. In addition, there was a notable difference between the location of tumors and syringomyelia (P < 0.05). Syringomyelia occurred more frequently in the cervical segment than in any other spinal segment. Moreover, there was an association between symptom duration and clinical prognosis (P < 0.05). Ordinal regression analysis showed that the prognosis of middle duration groups (6-12 months) was better than early groups (0-6 months, p < 0.05, OR 20.21, 95%CI 2.34-336.97) and late groups (>12 months, p < 0.05, OR 11.54, 95%CI 1.30-102.21). Syringomyelia collapse or reduction occurred between two weeks and 15 months after surgery. An improvement of spinal function grade after surgery was more significant in syringomyelia reduction groups (p < 0.05). CONCLUSIONS: The prevalence of syringomyelia due to SH is considerably high, and the initial clinical presentation of syringomyelia resulting from SH should be emphasized. Satisfactory outcomes were achieved by effective surgery in affected patients.

Corrigendum: HAX-1 Protects Glioblastoma Cells From Apoptosis Through the Akt1 Pathway.

[This corrects the article DOI: 10.3389/fncel.2017.00420.].

Pro-apoptotic effect of TRAIL-transfected endothelial progenitor cells on glioma cells.

Glioma is one of the most common aggressive neuroepithelial malignant tumors in the central nervous system. It has a high recurrence rate and poor prognosis, primarily due to the fact that novel therapeutic agents cannot penetrate the blood-brain barrier (BBB). Endothelial progenitor cells (EPCs) have been reported to move across the BBB and access the tumor site. However, whether EPCs expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce glioma cell apoptosis requires further investigation. In the present study, EPCs were transfected and stably expressed with TRAIL through lentiviral infection. The pro-apoptotic effect of these TRAIL-expressing EPCs on the SHG44 glioma cell line was investigated. The migration ability of TRAIL-expressing EPCs toward SHG44 cells through the Transwell culture system was investigated via a high-content screening assay. The apoptotic rate and the expression of cleaved caspase-8 and -3 in addition to the cleaved poly(ADP-ribose) polymerase in SHG44 cells significantly increased in the TRAIL-overexpressing EPC treatment group compared with the controls. The increased apoptotic rate was reversed using a caspase inhibitor. The findings suggested that the TRAIL-expressing EPCs induced apoptosis in the SHG44 cells by activating the death receptor pathway, indicating that the TRAIL-expressing EPCs may be a useful strategy for glioma treatment.

Clinical study on microsurgical treatment for craniopharyngioma in a single consecutive institutional series of 335 patients.

OBJECTIVES: The optimal management of craniopharyngioma is still controversial. The aim of this study is to explore microsurgical outcomes of craniopharyngioma in 335 cases. PATIENTS AND METHODS: Clinical data of 335 consecutive patients with craniopharyngioma between March 2011 and March 2017 were retrospectively analyzed. RESULTS: Gross total resection (GTR) was achieved in 265 cases (79.1%), subtotal resection (STR) was obtained in 70 cases (20.9%). The GTR rate was 81.93% in pediatric group and 78.17% in adult group respectively, no significant difference regarding the GTR rate was found in adult group compared with in pediatric group (p > 0.05). However, there was a noticeable difference in the elevated hypothalamic obesity in children group compared with in adult group after operation (p < 0.05). Multivariate analysis indicated that the tumor recurrence and surgical times played a negative role in the resection extent, the odds ratio and 95% confidence interval of the tumor recurrence and surgical times is [0.306 (0.155-0.603), (p < 0.01)] and [2.135 (1.101-4.142), (p < 0.05)] respectively. There was significant difference on panhypopituitarism between GTR and STR group (p < 0.05). However, No significant difference regarding the postoperative visual dysfunction and indepent quality of life respectively between GTR and STR group was found (p > 0.05). Additionally, there were no statistically significant differences for recurrence-free curves between GTR and STR plus adjuvant radiotherapy (p > 0.05). CONCLUSIONS: Present findings demonstrated that tumor recurrence and surgical times contribute to negative total resection for craniopharyngioma. Postoperative precise adjuvant radiotherapy was considered in selected cases if pursuit of GTR was rather dangerous under disadvantageous removal factors.

MicroRNA-21 promotes glioma cell proliferation and inhibits senescence and apoptosis by targeting SPRY1 via the PTEN/PI3K/AKT signaling pathway.

AIMS: Our study aims to investigate the effect of microRNA-21 (miR-21) on the proliferation, senescence, and apoptosis of glioma cells by targeting SPRY1 via the PTEN/PI3K/AKT signaling pathway. METHODS: Glioma tissues and brain tissues were collected for this study after surgical decompression for traumatic brain injury. RT-qPCR was employed to measure mRNA levels of miR-21, SPRY1, PTEN, PI3K, and AKT, and Western blotting was conducted to determine protein levels of SPRY1, PTEN, PI3K, AKT, p-AKT, Caspase-3, Caspase-9, P53, GSK3, and p-GSK3. Human glioma U87 cells were assigned into the blank, negative control (NC), miR-21 mimics, miR-21 inhibitors, siRNA-SPRY1, and miR-21 inhibitors + siRNA-SPRY1 groups, with human HEB cells serving as the normal group. Cell proliferation, cell cycle, and apoptosis were determined by MTT and flow cytometry, respectively. RESULTS: Compared with control group, an increased expression of miR-21, PI3K, AKT, p-AKT, P53, and p-GSK3, and a decreased expression of SPRY1, PTEN, Caspase-3, and Caspase-9 were observed in the glioma group, and no significant differences were found in the expression of GSK3. SPRY1 was verified to be the target gene of miR-21. Compared with the blank and NC groups, levels of PI3K, AKT, p-AKT, P53, and p-GSK3 increased while levels of SPRY1, PTEN, Caspase-3, and Caspase-9 decreased in the miR-21 mimics and siRNA-SPRY1 groups; the miR-21 inhibitors group reversed the tendency; furthermore, the miR-21 inhibitors group showed decreased cell proliferation but promoted apoptosis, which were opposite to the results of the miR-21 mimics and siRNA-SPRY1 groups. CONCLUSION: MicroRNA-21 might promote cell proliferation and inhibit cell senescence and apoptosis of human glioma cells by targeting SPRY1 via the PTEN/PI3K/AKT signaling pathway.

Chemokine receptor CXCR7 is an independent prognostic biomarker in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and most fatal primary brain cancer in adults. Due to the complex nature of GBM, its pathogenesis still remain unclear. Accumulating evidence suggest that chemokine receptor CXCR7 contribute to the development of various types of tumors. OBJECTIVE: We aim to examine the prognostic significance of CXCR7 in GBM. METHODS: CXCR7 were first detected by Immunohistochemistry. The association between CXCR7 and overall survival (OS) were examined. Moreover, multivariate analyses were conducted to evaluate the prognostic factors in GBM. RESULTS: Of all 146 GBM patients recruited, 77 were in the high-expression subgroup, the rest 69 were in low-expression subgroup. There are no differences between these two subgroups in terms of age, gender, family history of cancer, extent of surgery, chemotherapy, radiotherapy, KPS, MGMT methylation status and tumor size. However, high CXCR7 expression was robustly correlated with poor OS in GBM. Multivariate analysis confirmed age, KPS scores, chemotherapy, IDH1 mutation, MGMT methylation and CXCR7 were independent factors in survival prognosis. CONCLUSIONS: CXCR7 may involve in the clinical GBM progression, and CXCR7 could be a valuable prognostic marker in the treatment of GBM.

Analysis of the expression of HAX-1 gene in human glioma.

Glioma, as the most common aggressive malignant tumor in the central nervous system, is still an insurmountable issue in neural diseases. The proliferation and survival mechanism of glioma cells need to be explored further for the development of glioma treatment. Hematopoietic cell-specific protein 1 associated protein X-1 (HAX-1) is well known for its anti-apoptotic effect. It was reported to play an important role in several malignant tumors. However, the effect of HAX-1 in glioma still remains unknown. This study aimed to investigate the expression of HAX-1 in glioma and the correlation between HAX-1 and the clinicopathological characteristics and prognosis of glioma. Quantitative reverse transcription polymerase chain reaction and Western blot analysis showed that HAX-1 was overexpressed in glioma cell lines compared with normal human astrocytes. This trend was confirmed by comparing the expression of HAX-1 in glioma tissues and nontumorous tissues. The study also analyzed the correlation between the expression of HAX-1 and clinicopathological characteristics of glioma and found the expression of HAX-1 to be highly related to the differentiation and World Health Organization stage of glioma tissues. The survival analysis revealed that HAX-1 was an independent prognostic factor. In conclusion, this novel study suggested that the overexpression of HAX-1 might contribute to the malignant progression of glioma.

Function of PD-L1 in antitumor immunity of glioma cells.

Human glioma is a highly fatal tumor with a significant feature of immune suppression. The functions of PD-L1 refer to co-simulation and immune regulation. To investigate expression and functional activity of PD-L1 in human glioma cell in vivo and in vitro. Expressions of PD-L1mRNA and protein in the human glioma cell line were analyzed with quantitative RT-PCR and flow cytometer; and then expression of PD-L1 in tissue specimens of 10 glioma patients was treated with immunohistochemical analysis; glioma cell and allogeneic CD4+ and CD8+ T cells were co-cultured, and cytokine IFN-γ, IL-2 and IL-10 in cultured supernatant fluid were determined with ELISA; upon blocking the interaction between glioma cell and the immune cell with PD-L1 monoclonal antibody (5H1), surface markers on immune cells were analyzed using flow cytometer. All human glioma cell lines constitutively expressed PD-L1, and IFN-γ induced glioma cell to highly express PD-L1. It was shown through immunohistochemical analysis that glioma specimen expressed PD-L1, while expression of PD-L1 was not observed in normal tissue and normal human brain near the tumor location. The release of IFN-γ and IL-2 was inhibited, while IL-10 was increased slightly. Glioma cell may escape from immune recognition and injury with the help of PD-L1, which is a significant pathogenic mechanism of glioma.

HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway.

Glioblastoma is the most common malignant tumor in central nervous system (CNS), and it is still insurmountable and has a poor prognosis. The proliferation and survival mechanism of glioma cells needs to be explored further for the development of glioma treatment. Hematopoietic-substrate-1 associated protein X-1 (HAX-1) has been reported as an anti-apoptosis protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 in glioblastomas remains unknown. This study aimed to investigate the effect of HAX-1 in glioblastoma cells and explore the mechanism. The results of clone formation and Edu proliferation assay showed slower multiplication in HAX-1 knock-out cells. Flow cytometry showed cell cycle arrest mainly in G0/G1 phase. Apoptosis due to oxidative stress was increased after HAX-1 was knocked out. Western-blot assay exhibited that the levels of p21, Bax, and p53 proteins were significantly raised, and that the activation of the caspase cascade was enhanced in the absence of HAX-1. The degradation rate and ubiquitination of p53 declined because of the decrease in phosphorylation of proteins MDM2 and Akt1. Co-immunoprecipitation (Co-IP) and immunefluorescent co-localization assays were performed to test the influence of HAX-1 on the interaction between Akt1 and Hsp90, which is crucial for the activity of Akt1. In conclusion, this novel study suggested that HAX-1 could affect the Akt1 pathway through Hsp90. The knock-out of HAX-1 leads to the inactivity of the Ak1t/MDM2 axis, which leads to increased levels of p53, and finally generates cell cycle arrest and results in the apoptosis of glioblastoma cells.

Expression of p16 and Survivin in gliomas and their correlation with cell proliferation.

The survival rate of glioma patients is very low, and a lack of effective diagnostic techniques are available at present. The current study aimed to investigate the expression of p16 and Survivin and their association with proliferation and apoptosis in gliomas, as well as patient characteristics and prognosis. In total, 62 glioma specimens were surgically resected and pathologically confirmed at the Zhumadian Central Hospital (Zhumadian, China) between June 2008 and February 2014. Clinical data, including the gender and age of the patients, as well as the location, infiltration degree, size and pathological stage of the glioma, was collected. In order to evaluate the expression of p16 and Survivin in the gliomas, the Ki-67 labeling index was used to evaluate cell proliferation activity. The number of argyrophilic nucleolar organizer regions and the rate of cellular apoptosis was examined using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. The results were analyzed using SPSS 14.0 statistical software. The positive rate of p16 gene expression in the gliomas was 46.77% (29 cases), and p16 gene expression was positively correlated with the differentiation status, tumor size and pre-operative symptoms. The positive rate of Survivin expression in the gliomas was 69.88% (58 cases), and Survivin expression was positively correlated with tumor size, differentiation status and clinical stage. The proliferation activity of the gliomas was enhanced with increasing p16 and Survivin expression, while apoptosis was inhibited. In conclusion, the overexpression of p16 and Survivin was closely associated with uncontrolled cell proliferation and the inhibition of apoptosis in gliomas. The combined analysis of the expression of p16 and Survivin in gliomas may provide guidance with respect to the clinical diagnosis, evaluation, treatment and prognosis of patients with glioma.

The expression of ATF3, MMP-2 and maspin in tissue chip of glioma.

This paper tested and analyzed the expression of ATF3 (activating transcription factor), MMP-2 (matrix metalloprotease) and maspin in tissue chip of glioma and its correlation with glioma advancement. Based on immunohistochemical staining, this paper selected 100 patients with glioma and 13 healthy persons to test the relative expression of ATF3, MMP-2 and maspin. The result witnessed 72.0% of ATF3 expression in glioma and 15.4% in healthy brain tissues with P<0.05; glioma had 76.0% of MMP-2 expression while healthy brain tissues only had 7.7% (P<0.05); but maspin expression with 53.0% in glioma was much lower than that with 100% in healthy tissues with P<0.05. If the pathological stage of glioma rose up, the expression of ATF3 and MMP-2 accordingly increased while maspin expression decreased. The correlation between ATF3 expression and MMP-2 expression was positive with r=0.553 and p<0.01; negative correlation between ATF3 expression and maspin expression was found with r=-0.457 and p<0.01; and the expression of MMP-2 and maspin were negatively related with r=-0.551 and p<0.01. According to the above results, it could be concluded that the expression of ATF3, MMP-2 and maspin did relate with each other. Besides, the high expression of ATF3 and MMP-2 as well as the low expression of maspin had great influence on glioma, playing a key role in glioma's occurrence, advancement, invasion and metastasis.

Activating transcription factor 3 is overexpressed in human glioma and its knockdown in glioblastoma cells causes growth inhibition both in vitro and in vivo.

Glioblastomas are highly malignant gliomas that are extremely invasive with high rates of recurrence and mortality. It has been reported that activating transcription factor 3 (ATF3) is expressed in elevated levels in multiple malignant tumors. The purpose of this study was to investigate the function of ATF3 in the development of glioma and its clinical significance. Immunohistochemical staining, western blot analysis and RT-qPCR revealed that the mRNA and protein levels of ATF3 and matrix metalloproteinase 2 (MMP2) were higher in the glioma than in the normal human brain tissues, and that their levels were proportional to the pathological grades. By contrast, the mRNA and protein levels of mammary serine protease inhibitor (maspin; SERPINB5) were significantly lower in the glioma than in the normal brain tissue, and maspin expression was inversely proportional to the glioma pathological grade. The transfection of U373MG glioblastoma cells with ATF3-siRNA induced a number of changes in cell behavior; the cell proliferative activity was decreased and flow cytometry revealed an increased proportion of cells arrested in the G0/G1 phase of the cell cycle. In addition, TUNEL staining indicated an increased proportion of cells undergoing apoptosis and Transwell assays revealed impaired cell mobility. The sizes of the tumors grown as xenografts in nude mice were also significantly reduced by treatment of host mice with ATF3-siRNA. Taken together, these results suggest that ATF3 promotes the progression of human gliomas.

HMGB1-induced autophagy in Schwann cells promotes neuroblastoma proliferation.

Neuroblastoma inflicts mostly on children, and the pathogenesis remains elusive. Clinical diagnosis and therapeutic approaches are still on the incipient stage, so further understanding of the molecular and cellular mechanisms of the disease is necessary. Inflammation has been commonly regarded as a hallmark in tumorigenesis and development, and we identified a new inflammatory factor, HMGB1, is considerably increased in neuroblastoma. Our study shows that HMGB1 induces autophagy in Schwann cells through activation of TLR4, and knockdown of TLR4 obviates the HMGB1-induced autophagy. The HMGB1-induced autophagy is through classical pathway, as deficiency of Beclin 1 deprived autophagy in Schwann cells. Coculture of neuroblastoma with Schwann cells pretreated with HMGB1 promoted the proliferation of neuroblastoma cells, and if Beclin 1 is knocked down in Schwann cells, no promotion effects is observed. Taken together, our study demonstrates that HMGB1-induced autophagy in Schwann cells contributes to neuroblastoma cell proliferation, thus providing a potential therapeutic approach on neuroblastoma development.

Clinical features and risk factor analysis for lower extremity deep venous thrombosis in Chinese neurosurgical patients.

BACKGROUND: Deep venous thrombosis (DVT) contributes significantly to the morbidity and mortality of neurosurgical patients; however, no data regarding lower extremity DVT in postoperative Chinese neurosurgical patients have been reported. MATERIALS AND METHODS: From January 2012 to December 2013, 196 patients without preoperative DVT who underwent neurosurgical operations were evaluated by color Doppler ultrasonography and D-dimer level measurements on the 3(rd), 7(th), and 14(th) days after surgery. Follow-up clinical data were recorded to determine the incidence of lower extremity DVT in postoperative neurosurgical patients and to analyze related clinical features. First, a single factor analysis, Chi-square test, was used to select statistically significant factors. Then, a multivariate analysis, binary logistic regression analysis, was used to determine risk factors for lower extremity DVT in postoperative neurosurgical patients. RESULTS: Lower extremity DVT occurred in 61 patients, and the incidence of DVT was 31.1% in the enrolled Chinese neurosurgical patients. The common symptoms of DVT were limb swelling and lower extremity pain as well as increased soft tissue tension. The common sites of venous involvement were the calf muscle and peroneal and posterior tibial veins. The single factor analysis showed statistically significant differences in DVT risk factors, including age, hypertension, smoking status, operation time, a bedridden or paralyzed state, the presence of a tumor, postoperative dehydration, and glucocorticoid treatment, between the two groups (P < 0.05). The binary logistic regression analysis showed that an age greater than 50 years, hypertension, a bedridden or paralyzed state, the presence of a tumor, and postoperative dehydration were risk factors for lower extremity DVT in postoperative neurosurgical patients. CONCLUSIONS: Lower extremity DVT was a common complication following craniotomy in the enrolled Chinese neurosurgical patients. Multiple factors were identified as predictive of DVT in neurosurgical patients, including the presence of a tumor, an age greater than 50 years, hypertension, and immobility.