Semantic transparency modulates the semantic perception of morphemes: Evidence from RSA of BOLD signals.

There is no converging evidence on how a word's semantic transparency affects morphemes' potential semantic activation. The inconsistent results may be due to the limitation of traditional univariate analyses, in which the semantic transparency was treated as discrete categories. In the current study, Chinese two-character words were used as stimuli and functional magnetic resonance imaging (fMRI) techniques were combined with a priming paradigm. Unlike most previous studies, the multivariate representation similarity analysis (RSA) was used to treat semantic transparency as a continuous variable. The RSA results showed that widespread regions in the frontal-parietal-temporal network represent the semantic perception of characters in all words and transparent words, but no brain areas were identified in opaque words. Unlike RSA results, univariate analyses showed no significant difference between the opaque and transparent words. These results suggest that RSA is more suitable to examine the neural mechanism related to continuous variables such as semantic transparency.

Effects of sleep deprivation on language-related brain functional connectivity: differences by gender and age.

Sleep deprivation (SD) negatively affects many cognitive functions, such as language performance. However, what remains unclear is whether and how SD affects the language-related brain network based on gender and age differences. The current study of 86 healthy adults used resting-state functional magnetic resonance imaging (rs-fMRI) to measure language-related functional connectivity after full sleep or partial SD. Gender and age differences in functional connectivity were assessed across four linguistic aspects: phonetics, morphology, semantics, and syntax. The results showed that SD can affect the connectivity status of language-related brain networks, especially syntax-related networks. Furthermore, the influence of SD on the functional connectivity in language-related networks differed between male and female groups, and between younger and older groups. Specifically, there were gender differences in the temporal association cortex and age differences in the parietal association cortex, during full sleep versus partial SD. These findings highlight changes in the brain's functional connectivity in response to SD as a potential source of gender and age differences in brain function.

Predictors of tumor progression of low-grade glioma in adult patients within 5 years follow-up after surgery.

Background: Glioma originates from glial cells in the brain and is the most common primary intracranial tumor. This study intends to use a retrospective analysis to explore the factors that can predict tumor progression in adult low-grade gliomas, namely WHO II grade patients, within 5 years after surgery. Methods: Patients with WHO grade II glioma who were surgically treated in our hospital from February 2011 to May 2017 were included. According to the inclusion and exclusion criteria, 252 patients were included in the final analysis. According to the results of the 5-year follow-up (including survival and imaging review results), patients were divided into progression-free group and progression group. Univariate and multivariate analysis were conducted to investigate the related factors of tumor progression during the 5-year follow-up. Results: The results of the 5-year follow-up showed that 111 (44.0%) cases had no progress (progression free group, PFG), 141 (56.0%) cases had progress (progression group, PG), of which 43 (30.5%) cases were operated again, 37 cases (26.2%) received non-surgical treatments. There were 26 (10.3%) all-cause deaths, and 21 (8.3%) tumor-related deaths. Univariate and multivariate analysis showed that age >45 years old (OR = 1.35, 95% CI, 1.07-3.19, P = 0.027), partial tumor resection (OR = 1.66, 95% CI, 1.15-3.64, P = 0.031), tumor diameter >3 cm (OR = 1.52, 95% CI, 1.14-4.06, P = 0.017) and no radiotherapy (OR = 1.37, 95% CI, 1.12-2.44, P = 0.039) were independent predictors of the progression of tumor during the 5-year follow-up period. Conclusion: Age >45 years old, partial tumor resection, tumor diameter >3 cm, no radiotherapy are predictors for tumor progression for glioma patients after surgery.

XGBoost algorithm and logistic regression to predict the postoperative 5-year outcome in patients with glioma.

Background: Glioma is the most common primary intracranial tumor with poor prognosis. The prediction of glioma prognosis has not been well investigated. XGBoost algorithm has been widely used in and data analysis. The predictive value of XGBoost algorithm in glioma remains unclear. This current study used the XGBoost algorithm to construct a predictive model for postoperative outcomes of glioma patients. Methods: Patients with glioma who underwent surgery from January 2006 to April 2017 were retrospectively included in this study. Clinical and follow-up data were collected. The XGBoost model and multivariate logistic regression analysis model were used to screen the factors related to postoperative outcomes, and the results of the two models were compared. The area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, and Youden index were calculated to evaluate the predictive value of the XGBoost model. Results: A total of 638 patients were included. In total, 336 (52.7%) cases died within 5 years after the operation. Multivariate logistic regression analysis showed that age, gender, World Health Organization (WHO) grade, extent of tumor resection, Karnofsy performance score (KPS), tumor diameter, and whether postoperative radiotherapy and chemotherapy were administered, were the most important risk factors for death within 5 years after surgery in glioma patients. The XGBoost model showed that the top 5 factors related to death of glioma patients within 5 years after surgery were WHO grade (30 points), extent of tumor resection (19 points), postoperative radiotherapy and chemotherapy (16 points), KPS (14 points), and age (11 points). The AUC of the XGBoost model for predicting the death of glioma patients within 5 years after surgery was 0.803 [95% confidence interval (CI): 0.718-0.832], and the sensitivity and specificity were 0.894 and 0.581, respectively. The Youden index was 0.475. The AUC of the multivariate logistic regression model was 0.738 (95% CI: 0.704-0.781), the sensitivity and specificity were 0.785 and 0.632, respectively, and the Youden index was 0.417. Conclusions: Compared with multivariate logistic regression model, XGBoost model has better performance in predicting the risk of death within 5 years after surgery in patients with glioma.

Blockage of glioma cell survival by truncated TEAD-binding domain of YAP.

BACKGROUND: Gliomas are highly aggressive and lack of efficient targeted therapy. YAP, as a Hippo pathway downstream effector, plays a key role in promoting tumor development through the interaction with transcription factor TEAD on the NH3-terminal proline-rich domain. Therefore, targeting TEAD-interacting domain of YAP may provide a novel approach for the treatment of gliomas. MATERIALS AND METHODS: We generated a truncated YAP protein which includes the TEAD-binding domain (YAPBD), and supposed YAPBD can interact with endogenous TEAD but lost the function to activate YAP target gene expressions. The association of YAP expression with the malignant characters of glioma tissues were determined by immunohistochemistry. TEAD-binding capacity of YAPBD was determined by co-immunoprecipitation. The cell proliferation and migration were determined by MTT assay, xenograft assay, wound healing assay and transwell assay, respectively. YAP target genes were detected by Western blot. RESULTS: YAP was highly expressed in glioma tissues and associated with tumor malignancy. YAPBD could block the TEAD-YAP complex formation by competing with YAP binding to TEAD. YAPBD could inhibit glioma cell growth both in vitro and in vivo, through the induction of cell cycle arrest and apoptosis. The cell cycle-related gene cyclin D1 and c-myc, and anti-apoptotic gene Bcl-2, Bcl-xL and survivin were inhibited after YAPBD overexpression. Furthermore, YAPBD also decreased cell migration and invasion, and repressed epithelial-mesenchymal transition. CONCLUSION: YAPBD can block glioma cell survival and repress YAP-dependent gene expressions, indicating gene therapy which targets TEAD-YAP complex would be a potential and significant novel approach for human malignant gliomas.

Truncated TEAD-binding protein of TAZ inhibits glioma survival through the induction of apoptosis and repression of epithelial-mesenchymal transition.

Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, promotes tumor progression by serving as a transcriptional coactivator with TEAD. Here, we introduced a new construct which can express the TEAD-binding domain of TAZ protein (TAZBD), and determined its antitumor effect in malignant glioma both in vitro and in vivo. We first observed that TAZ was upregulated in glioma tissues and related to malignant clinicopathologic characteristic, indicating the crucial role of TAZ during glioma progression. In U87 and U251 cells, TAZBD expression increased the proportion of apoptotic cells, and suppressed the colony formation and tumorigenicity. Further, TAZBD also decreased cell metastasis through the repression of epithelial-mesenchymal transition. The mechanistic study showed that TAZBD suppression of glioma cells was predominantly through blocking the TAZ-TEAD complex formation by competing with endogenous TAZ. Thus, the gene therapy of malignant glioma through blocking TAZ-TEAD complex by TAZBD may provide a new way for the targeted therapy of glioma.

Inhibition of eIF4F complex loading inhibits the survival of malignant glioma.

The eukaryotic initiation factor (eIF)4E­binding proteins (4E­BPs) regulate cap­dependent protein translation and control the assembly of the eIF4F complex. In the present study, a phosphorylation­deficient truncated 4E­BP2 (eIF4FD) was constructed into the eukaryotic expression vector pSecTag2, and the in vitro and in vivo effects on malignant glioma survival were determined through inhibiting eIF4F complex assembly. Cell cycle distribution analysis and TUNEL staining show that overexpression of eIF4FD suppressed cell proliferation and induced apoptosis in U251 cells. Western blotting showed that the cell cycle­related genes cyclin D1 and C­myc, and anti­apoptotic genes B­cell lymphoma 2 (Bcl­2), Bcl­extra large and survivin were reduced following the overexpression of eIF4FD. Furthermore, eIF4FD suppressed glioma vascularization via reductions in the expression of ß­catenin and vascular endothelial growth factor. In the orthotopic xenograft model, the stable expression of eIF4FD in U251 cells attenuated cell growth and increased the rate of apoptosis. Accordingly, pSecTag2­PTD­eIF4FD injection via the tail vein of mice also lead to cell growth inhibition and the induction of apoptosis. Therefore, the study showed that phosphorylation­deficient truncated 4E­BP2 efficiently inhibited eIF4E and prevented the formation of the eIF4F complex, which further contributed to the inhibition of cell proliferation and vascularization, and the induction of apoptosis. Therefore, the 4E­BP2­based phosphorylation­deficient truncation designed in the present study may represent a novel approach for the targeted therapy of human malignant glioma though inhibition of the translation initiation complex.

The cap-translation inhibitor 4EGI-1 induces mitochondrial dysfunction via regulation of mitochondrial dynamic proteins in human glioma U251 cells.

Translation initiation factors (eIFs) are over-activated in many human cancers and may contribute to their progression. The small molecule 4EGI-1, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anti-cancer effects in human cancer cells. The goal of the present study was to evaluate the anti-cancer effects of 4EGI-1 in human glioma U251 cells. We found that 4EGI-1 impaired the assembly of the eIF4F complex, and inhibited proliferation of U251 cells via inducing apoptosis. 4EGI-1 treatment induced collapse of mitochondrial membrane potential (MMP) and production of intracellular reactive oxygen species (ROS), which were prevented by the ROS scavenger N-acetyl-cysteine (NAC). In addition, 4EGI-1 inhibited mitochondrial ATP synthesis via suppressing complex I activity, but had no effects on mitochondrial biogenesis. The results of fluorescence staining showed that 4EGI-1 indeed fragmented the mitochondrial network of U251 cells. We found a significant decrease in optic atrophy type 1 (Opa-1) and mitofusin 1 (Mfn-1) related to fusion proteins as well as an increase in fission protein dynamin-related protein 1 (Drp-1). Furthermore, the anti-cancer effects of 4GI-1 were partially nullified by knock down of Drp-1 using siRNA. These data indicate that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for human glioma therapy.