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Background: Surgical treatment of complex giant pituitary adenomas (GPAs) presents significant challenges. The efficacy and safety of combining transsphenoidal and transcranial approaches for these tumors remain controversial. In this largest cohort of patients with complex GPAs, we compared the surgical outcomes between those undergoing a combined regimen and a non-combined regimen. We also examined the differences in risks of complications, costs, and logistics between the two groups, which might offer valuable information for the appropriate management of these patients., Patients and Methods: This was a multicenter retrospective cohort study conducted at 13 neurosurgical centers. Consecutive patients who received a combined or non-combined regimen for complex GPAs were enrolled. The primary outcome was gross total resection, while secondary outcomes included complications, surgical duration, and relapse. A propensity score-based weighting method was used to account for differences between the groups., Results: Out of 647 patients [298 (46.1%) women, mean age: 48.5 ± 14.0 years] with complex GPAs, 91 were in the combined group and 556 were in the noncombined group. Compared with the noncombined regimen, the combined regimen was associated with a higher probability of gross total resection [50.5% vs. 40.6%, odds ratio (OR): 2.18, 95% confidence interval (CI): 1.30-3.63, P = 0.003]. The proportion of patients with life-threatening complications was lower in the combined group than in the non-combined group (4.4% vs. 11.2%, OR: 0.25, 95% CI: 0.08-0.78, P = 0.017). No marked differences were found between the groups in terms of other surgical or endocrine-related complications. However, the combined regimen exhibited a longer average surgery duration of 1.3 h ( P < 0.001) and higher surgical costs of 22,000 CNY (~ 3,000 USD, P = 0.022) compared with the noncombined approach., Conclusions: The combined regimen offered increased rates of total resection and decreased incidence of life-threatening complications, which might be recommended as the first-line choice for these patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type ( Lgmn +/+ ) mice following whole-brain irradiation. Lgmn knockout ( Lgmn -/- ) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn +/+ primary neurons with the conditioned media derived from irradiated Lgmn +/+ or Lgmn -/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation-induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many pre-mRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-Δexon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1-Δexon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets.

Investigations of protein-protein interactions (PPIs) are of paramount importance for comprehending cellular processes within biological systems. The bimolecular fluorescence complementation (BiFC) assay presents a convenient methodology for visualizing PPIs within live cells. While a range of fluorescent proteins have been introduced into the BiFC system, there is a growing demand for new fluorescent proteins to accommodate the expanding requirements of researchers. This study describes the introduction of Tagged blue fluorescent protein 2 (TagBFP2) into the BiFC assay to verify the interaction between two proteins, with Enhanced yellow fluorescent protein (EYFP) employed as a positive control. Both fluorescent proteins demonstrated optimal performance in this study. Compared to EYFP, the BiFC system utilizing TagBFP2 yielded a higher signal-to-noise ratio, which facilitated differentiation of the signal of PPIs from noise and enabled employment of other fluorescent proteins within the BiFC assay. Notably, the utilization of a fluorescent secondary antibody in immunofluorescence applications or the tagging of an interest protein with a fluorescent protein occupied the green or yellow channel. Overall, the present article introduces a BiFC assay that is highly straightforward, reliable, and replicable, with the ability to be completed within 1 week. This method requires neither expensive instrumentation nor technical skills of a high order., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Protein p62 (sequestosome 1) encoded by gene SQSTM1 plays a vital role in mediating protectively selective autophagy in tumor cells under stressed conditions. CircSQSTM1 (hsa&#95;circ&#95;0075323) is a circular transcript generated from gene SQSTM1 (chr5:179260586-179260782) by back-splicing. However, the potential role of hsa&#95;hsa&#95;circ&#95;0075323 in glioblastoma (GBM) remains unclear. Here, we aimed to explore the biological function of hsa&#95;circ&#95;0075323 in GBM and its relationship with autophagy regulation., Results: Hsa&#95;circ&#95;0075323 is highly expressed in GBM cells and mainly locates in the cytoplasm. Inhibition of hsa&#95;circ&#95;0075323 in U87-MG and T98G cells attenuated proliferation and invasion ability significantly, while upregulation of has&#95; circ&#95;0075323 enhanced proliferation and migration of U251-MG and A172 cells. Mechanistically, depletion of hsa&#95;circ&#95;0075323 in GBM cells resulted in impaired autophagy, as indicated by increased expression of p62 and decreased expression of LC3B., Conclusions: Hsa&#95;circ&#95;0075323 regulates p62-mediated autophagy pathway to promote GBM progression and may serve as a prognostic biomarker potentially., (© 2023. The Author(s).)

Introduction: To explore and evaluate the performance of MRI-based brain tumor super-resolution generative adversarial network (MRBT-SR-GAN) for improving the MRI image resolution in brain tumors., Methods: A total of 237 patients from December 2018 and April 2020 with T2-fluid attenuated inversion recovery (FLAIR) MR images (one image per patient) were included in the present research to form the super-resolution MR dataset. The MRBT-SR-GAN was modified from the enhanced super-resolution generative adversarial networks (ESRGAN) architecture, which could effectively recover high-resolution MRI images while retaining the quality of the images. The T2-FLAIR images from the brain tumor segmentation (BRATS) dataset were used to evaluate the performance of MRBT-SR-GAN contributed to the BRATS task., Results: The super-resolution T2-FLAIR images yielded a 0.062 dice ratio improvement from 0.724 to 0.786 compared with the original low-resolution T2-FLAIR images, indicating the robustness of MRBT-SR-GAN in providing more substantial supervision for intensity consistency and texture recovery of the MRI images. The MRBT-SR-GAN was also modified and generalized to perform slice interpolation and other tasks., Conclusions: MRBT-SR-GAN exhibited great potential in the early detection and accurate evaluation of the recurrence and prognosis of brain tumors, which could be employed in brain tumor surgery planning and navigation. In addition, this technique renders precise radiotherapy possible. The design paradigm of the MRBT-SR-GAN neural network may be applied for medical image super-resolution in other diseases with different modalities as well., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Glioblastoma multiforme (GBM) is well known as a highly aggressive brain tumor subtype. Here, we show that overexpression (OE) of dematin actin-binding protein (DMTN) inhibits GBM proliferation and invasion by affecting cell cycle regulation and actin remodeling, respectively. RT-qPCR, western blotting, and immunohistochemical (IHC) staining demonstrated a significant reduction in DMTN expression in gliomas, especially in high-grade gliomas (HGG) compared with normal brains, which correlates with worse survival in HGG patients. Functional studies revealed inhibitory effects of DMTN on tumor proliferation and migratory capacities. The attenuation in tumor proliferative ability upon DMTN OE was accompanied by RhoA suppression and CDK1, CDK2, CDK4, and cyclin D1 downregulation, while RhoA rescue restored the proliferative phenotype. Meanwhile, overexpression of DMTN produced profoundly disorganized stress fibers, which led to impaired tumor invasion. Furthermore, DMTN overexpression produced substantial suppression of tumor growth upon subcutaneous and intracranial implantation in mice, and this was accompanied by significantly reduced vinculin expression and Ki67 positivity. Taken together, these findings demonstrate the role of DMTN in regulating GBM cell proliferation, actin cytoskeleton, and cell morphology and identify DMTN as a vital tumor suppressor in GBM progression., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-small-cell lung cancer (NSCLC) is one of the most fatal malignant tumors harmful to human health. Previous studies report that Platycodin D (PD) exhibits anti-tumor effects in multiple human cancers, including NSCLC, but the underlying mechanisms are largely unknown. Accumulating evidence indicates that non-coding RNAs (ncRNAs) participate in NSCLC disease progression, but the link between PD and the ncRNAs in NSCLC is poorly elucidated. Here, we used whole transcriptome sequencing to systematically investigate the RNAs-associated regulatory network in the PD treating NSCLC cell lines. A total of 942 significantly dysregulated RNAs were obtained. Among those, five circRNAs and six IncRNAs were rigorously selected via database and in vitro validation. In addition, the functional enrichment study of differentially expressed mRNAs, single nucleotide polymorphisms (SNPs) within PD-related mRNA structures, and the interaction between PD and mRNA-related proteins were analyzed through gene set enrichment analysis (GSEA), structural variant analysis, and molecular docking, respectively. With further in vitro validation, the results show that PD inhibits cell proliferation, arrests the cell cycle, and induces cell apoptosis through targeting BCL2-related proteins. We hope these data can provide a full concept of PD-related molecular changes, leading to a new treatment for NSCLC.

Background: Abnormal proliferation and migration of cells are hallmarks of cancer initiation and malignancy. Asparagine endopeptidase (AEP) has specific substrate cleavage ability and plays a pro-cancer role in a variety of cancers. However, the underlying mechanism of AEP in cancer proliferation and migration still remains unclear., Methods: Co-immunoprecipitation and following mass spectrometry were used to identify the substrate of AEP. Western blotting was applied to measure the expression of proteins. Single cell/nuclear-sequences were done to detect the heterogeneous expression of Tmod3 in tumor tissues. CCK-8 assay, flow cytometry assays, colony formation assay, Transwell assay and scratch wound-healing assay were performed as cellular functional experiments. Mouse intracranial xenograft tumors were studied in in vivo experiments., Results: Here we showed that AEP cleaved a ubiquitous cytoskeleton regulatory protein, tropomodulin-3 (Tmod3) at asparagine 157 (N157) and produced two functional truncations (tTmod3-N and tTmod3-C). Truncated Tmod3 was detected in diverse tumors and was found to be associated with poor prognosis of high-grade glioma. Functional studies showed that tTmod3-N and tTmod3-C enhanced cancer cell migration and proliferation, respectively. Animal models further revealed the tumor-promoting effects of AEP truncated Tmod3 in vivo. Mechanistically, tTmod3-N was enriched in the cell cortex and competitively inhibited the pointed-end capping effect of wild-type Tmod3 on filamentous actin (F-actin), leading to actin remodeling. tTmod3-C translocated to the nucleus, where it interacted with Staphylococcal Nuclease And Tudor Domain Containing 1 (SND1), facilitating the transcription of Ras Homolog Family Member A/Cyclin Dependent Kinases (RhoA/CDKs)., Conclusion: The newly identified AEP-Tmod3 protease signaling axis is a novel "dual-regulation" mechanism of tumor cell proliferation and migration. Our work provides new clues to the underlying mechanisms of cancer proliferation and invasive progression and evidence for targeting AEP or Tmod3 for therapy., (© 2022. The Author(s).)

An intracranial aneurysm in a pituitary adenoma (PA) is not uncommon; however, preoperative angiography is not clinically used as a routine screening test for PA patients. Therefore an intracranial aneurysm is often missed while diagnosing PA patients. When an aneurysm is missed in patients with pituitary tumors, the supporting power by the tumor to the blood vessels or aneurysm will disappear when the tumor is removed and patients may suffer intraoperative or postoperative aneurysm rupture, which may lead to fatal, catastrophic hemorrhage. Herein, we report a case of a PA patient with the signal shadow of vessel flow void, observed vaguely in the right internal carotid artery cavernous segment on magnetic resonance imaging, and a small aneurysm was found via digital subtraction angiography. In order to ensure the safety of surgery, we first performed embolization of the aneurysm and then resected the tumor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is one of the most devastating cancers and is characterized by rapid cell proliferation and aggressive invasiveness. Legumain (LGMN), a substrate-specific protease, is associated with poor progression of GBM. Circular RNAs (circRNAs) are aberrantly expressed in various cancers and play crucial roles in tumor progression; however, the functional roles of circRNAs originating from LGMN remain largely unknown in GBM. Herein, we found that hsa&#95;circ&#95;0033009 (circLGMN) was the most abundantly expressed circRNA derived from LGMN. CircLGMN was upregulated in high-grade glioma (HGG), and high expression of circLGMN was associated with poor prognosis in patients with glioma. CircLGMN overexpression promoted GBM cell proliferation and enhanced cell invasion. Mechanistically, circLGMN acts as a sponge for miR-127-3p, and prevents miR-127-3p-mediated degradation of LGMN mRNA, ultimately leading to increased LGMN protein expression. Treatment with miR-127-3p mimic suppressed proliferation and reduced invasion of GBM cells overexpressing circLGMN. Moreover, circLGMN overexpression promoted GBM malignancy in vivo, while miR-127-3p overexpression alleviated this effect. Taken together, circLGMN is a novel tumor-promoting circRNA that acts by sponging miR-127-3p, which ultimately leads to LGMN upregulation. Thus, targeting the circLGMN/miR-127-3p/LGMN axis might be a promising strategy for GBM treatment. More importantly, the discovery of the self-regulatory mechanism of LGMN expression by circLGMN, will facilitate further research on LGMN., (Copyright © 2021. Published by Elsevier B.V.)

Aims: To determine how consistently Chinese glioblastoma multiforme (GBM) patients were treated according to the Stupp regimen. Patients and methods: The proportion of treatments conforming to the Stupp regimen and reasons for nonconformity were evaluated in 202 newly diagnosed GBM patients. Results: Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations were temozolomide dosages >75 mg/m 2 (58/120; 48.3%) and treatment durations <42 days (84/120; 70.0%) in the concomitant phase and temozolomide dosages <150 mg/m 2 (89/101; 88.1%) in the maintenance phase. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments. Conclusion: Increased conformity to the Stupp regimen is needed for GBM patients in China.

Objective: The aim of this study was to establish a nomogram model for predicting the risk of short-term recurrence in glioma patients., Methods: The clinical data of recurrent glioma patients were summarized and analyzed in this study. Univariate and multivariate logistic regression analyses were performed to analyze the correlation between clinical data and the risk of short-term recurrence after operation. A nomogram was established based on the multivariate logistic regression model results., Results: A total of 175 patients with recurrent glioma were enrolled, with 53 patients in the short-term recurrence (STR) group (recurrent time ≤6 months) and 122 patients in the long-term recurrence (LTR) group (recurrent time ≥36 months). Univariate analysis revealed that age at diagnosis, Karnofsky performance scores (KPSs), tumor location, glioma grade, glioma type, extent of resection (EOR), adjuvant chemotherapy (ad-CT), concurrent chemotherapy (co-CT), and isocitrate dehydrogenase (IDH) status were significantly associated with the short-term glioma recurrence. Multivariate analyses revealed that age at diagnosis, KPS, glioma grade, EOR, and IDH were independent risk factors for short-term glioma recurrence. A risk nomogram for the short-term recurrence of glioma was established, with the concordance index (C-index) of 0.971. The findings of calibration and receiver operating characteristic (ROC) curves showed that our nomogram model had good performance and discrimination to estimate short-term recurrence probability., Conclusion: This nomogram model provides reliable information about the risk of short-term glioma recurrence for oncologists and neurosurgeons. This model can predict the short-term recurrence probability and give assistance to decide the interval of follow-up or formulate individualized treatment strategies based on the predicted results. A free online prediction risk tool for this nomogram is provided: https://rj2021.shinyapps.io/Nomogram&#95; recurrence-risk/., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Zhu, Zheng, Liao, Chen, Liao, Yang, Zhou, Bai, Wang, Hou, Qiu and Huang.)

The 2016 World Health Organization classification of central nervous system tumor firstly introduces molecular diagnosis to glioma, while the molecular features of adult thalamic gliomas (ATGs) in a relatively large sample have not been reported. We aimed at exploring molecular characteristics in ATGs. The data of 97 and 575 newly diagnosed ATGs and superficial gliomas (SGs) patients were collected, and we performed a comparative analysis of molecular characteristics between them. We analyzed expressions of molecules as follow: H3 K27M, isocitrate dehydrogenase1 (IDH1), Ki-67, O6-Methylguanine-DNA methyltransferase (MGMT) promoter, EGFR, p53, ATRX, GFAP, Oligo2, PTEN, MGMT, and MMP9 by immunohistochemistry. Direct gene sequencing was performed to test the H3 K27M, IDH1, and TERT promoter mutation. The median age at diagnosis of ATGs was 36.0 years, and majority of them were high-grade glioma. We found a significant difference in H3 K27M mutation (P = 0.003), IDH1 mutation (P < 0.001), MGMT promoter methylation (P = 0.005), and Ki67 > 0.1 (P < 0.001) between ATGs and SGs. The statuses of IDH1 (P < 0.001), MGMT promoter (P < 0.001), and Ki67 (P < 0.001) were significantly different between these two groups in lower-grade gliomas. And statuses of IDH1 (P < 0.001), Ki67 (P < 0.001), and EGFR (P = 0.032) were different between these two groups in high-grade gliomas. Only Ki67 > 0.1 was differentially expressed between lower- and high-grade gliomas in ATGs (P = 0.014). The high occurrence of H3 K27M mutation and Ki67 > 0.1, rare occurrence of IDH1 mutation, and MGMT promoter methylation in ATGs suggested that ATGs may be a distinct type of glioma entity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Objectives: Endoscopic nasopharyngectomy (ENPG) is a promising way in treating recurrent nasopharyngeal carcinoma (rNPC), but sometimes may require therapeutic internal carotid artery (ICA) occlusion beforehand. Balloon test occlusion (BTO) is performed to evaluate cerebral ischemic tolerance for ICA sacrifice. However, absence of neurological deficits during BTO does not preclude occur of delayed cerebral ischemia after permanent ICA occlusion. In this study, we evaluate the utility of near-infrared spectroscopy (NIRS) regional cerebral oxygen saturation (rSO 2 ) monitoring during ICA BTO to quantify cerebral ischemic tolerance and to identify the valid cut-off values for safe carotid artery occlusion. This study also aims to find out angiographic findings of cerebral collateral circulation to predict ICA BTO results simultaneously., Material and Methods: 87 BTO of ICA were performed from November 2018 to November 2020 at authors' institution. 79 angiographies of collateral flow were performed in time during BTO and classified into several Subgroups and Types according to their anatomic and collateral flow configurations. 62 of 87 cases accepted monitoring of cerebral rSO 2 . Categorical variables were compared by using Fisher exact tests and Mann-Whitney U tests. Receiver operating characteristic curve analysis was used to determine the most suitable cut-off value., Results: The most suitable cut-off △rSO 2 value for detecting BTO-positive group obtained through ROC curve analysis was 5% (sensitivity: 100%, specificity: 86%). NIRS rSO 2 monitoring wasn't able to detect BTO false-negative results ( p = 0.310). The anterior Circle was functionally much more important than the posterior Circle among the primary collateral pathways. The presence of secondary collateral pathways was considered as a sign of deteriorated cerebral hemodynamic condition during ICA BTO. In Types 5 and 6, reverse blood flow to the ICA during BTO protected patients from delayed cerebral ischemia after therapeutic ICA occlusion ( p = 0.0357). In Subgroup IV, absence of the posterior Circle was significantly associated with BTO-positive results ( p = 0.0426)., Conclusion: Angiography of cerebral collateral circulation during ICA BTO is significantly correlated with ICA BTO results. Angiographic ICA BTO can be performed in conjunction with NIRS cerebral oximeter for its advantage of being noninvasive, real-time, cost-effective, simple for operation and most importantly for its correct prediction of most rSO 2 outcomes of ICA sacrifice. However, in order to ensure a safe carotid artery occlusion, more quantitative adjunctive blood flow measurements are recommended when angiography of cerebral collateral circulation doesn't fully support rSO 2 outcome among clinically ICA BTO-negative cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BL declared a shared affiliation with the authors to the handling editor at time of review., (Copyright © 2021 Yang, Wu, Chen, Sun, Hu, Wang, Guo, Qiu and Dai.)

Background: This study explored the related factors that influence the recurrence time of glioblastomas (GBM)., Methods: A retrospective study of recurrent GBM patients with surgical resection was performed. Recurrence time was analyzed using Kaplan-Meier survival curves. The Cox regression model was used to investigate the possible factors associated with recurrence time., Results: A total of 176 patients (113 males and 63 females) were enrolled in the study, with a median age of 57 years (range, 19-76 years). From this cohort, 18 patients (10.2%) had gross total resection (GTR), 53 patients (30.1%) had subtotal resection (STR), and 105 patients (59.7%) had partial resection (PR). Postoperatively, all patients received radiotherapy (RT), with 55.1% administered concurrent chemotherapy (CTh) and 59.7% administered adjuvant CTh. The median recurrence time was 10.0 months (range, 1.0-75.0 months). Patients with PR (P=0.004), gliomas that contacted the subventricular zone (SVZ) (P=0.004), isocitrate dehydrogenase 1 (IDH1) wild-type (P=0.048), telomerase reverse transcriptase (TERT) C228T wild-type (P=0.012), and positive glial fibrillary acidic protein (GFAP) expression (P=0.044) had a shortened time to recurrence. Cox regression analysis revealed that PR (P=0.036), SVZ contact (P=0.008), and TERT C228T wild type (P=0.023) were significantly associated with a shortened recurrence time., Conclusions: PR, tumor contacting the SVZ, and TERT C228T wild type were independent risk factors for tumor recurrence in patients with GBM.

Abstract: Chordoid glioma is a rare low-grade tumor that originates almost exclusively in the anterior part of the third ventricle. The diagnosis and treatment of the tumor remain controversial. In this article, the authors present a novel case of chordoid glioma of the third ventricle. The patient was treated with less invasive microsurgery followed by low-dose gamma knife radiosurgery. Magnetic resonance imaging revealed a decrease in tumor size and necrosis in the central region of the tumor, without significant complications at follow-up 14 months later. Based on these findings, the authors suggest that less invasive microsurgical resection followed by low-dose gamma knife radiosurgery is safe and effective for the treatment of chordoid glioma of the third ventricle., (Copyright © 2017 by Mutaz B. Habal, MD.)

Pseudogenes, which are long noncoding RNAs that originate from protein-coding genes, have been suggested to play important roles in disease. Although studies have revealed high expression of legumain (LGMN) in many types of tumors, the regulation of LGMN remains largely unknown. Here, we found that a novel LGMN pseudogene (LGMNP1) was upregulated in glioblastoma (GBM) tissues and high LGMNP1 expression in GBM cells enhanced proliferation and invasion. Biochemical analysis showed that cytoplasmic LGMNP1 functionally targeted miR-495-3p in a manner involving an RNA-induced silencing complex. Dual-luciferase reporter assays demonstrated that LGMN was a target of miR-495-3p, and LGMN was upregulated and positively correlated with LGMNP1 in GBM. Moreover, miR-495-3p was downregulated and negatively correlated with LGMNP1 in GBM tissues. Notably, the tumor-promoting effects of LGMNP1 upregulation could be alleviated by miR-495-3p mimics. Furthermore, GBM cells overexpressing LGMNP1 exhibited more aggressive tumor progression and elevated LGMN expression in vivo. Thus, our data illustrate that LGMNP1 exerts its oncogenic activity, at least in part, as a competitive endogenous RNA (ceRNA) that elevates LGMN expression by sponging miR-495-3p. CeRNA-mediated miRNA sequestration might be a novel therapeutic strategy in GBM., (Copyright © 2020. Published by Elsevier B.V.)

Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood., Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests., Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery., Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: This study aimed to perform a survival analysis of patients with multicentric low-grade gliomas (MLGGs) and to assess the influence of various prognostic factors on progression-free survival (PFS) and overall survival., Methods: A literature search on Web of Science and PubMed was performed for literature in English published from 1963 to September 2018. Detailed information including demographics, clinical characteristics, treatments, critical events, and time to events for survival analysis were extracted from the included articles., Results: A total of 36 cases from published articles were selected for analysis. Univariate analysis showed that age (<31 years or ≥31 years), grade (pure low grade/low and high grade) and glioma type (astrocytoma/oligodendroglioma) had a significant relationship with PFS. Cox regression analysis showed that tumor grade was an independent prognostic factor for PFS. No factors correlated with overall survival., Conclusions: This integrative analysis of MLGGs patients revealed that age younger than 31 years, pure MLGG, and oligodendroglioma were significantly associated with improved PFS, and pure MLGGs was an independent prognostic factors for PFS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Zinc fingers and homeoboxes 1 (ZHX1) is a transcription repressor that has been implicated in the tumorigenesis and progression of diverse tumors. The functional role and regulating mechanism of ZHX1 has not been elucidated in glioblastoma (GBM). Previous reports have suggested that a large number of non-coding RNAs play a vital role in glioma initiation and progression. This study aimed to investigate the functional role and co-regulatory mechanisms of the metastasis-associated lung adenocarcinoma transcript-1 (MALAT1)/ microRNA-199a (miR-199a)/ZHX1 axis in GBM. We analyzed the expression of the MALAT1/miR-199a/ZHX1 axis and its correlation with patients' overall survival using two different glioma gene-expression datasets. A series of in vitro and in vivo studies including dual luciferase reporter assay, fluorescence in situ hybridization (FISH), RNA immunoprecipitation, and pull-down experiments were completed to elucidate the biological significance of the MALAT1/miR-199a/ZHX1 axis in promoting glioma proliferation and progression. Elevated ZHX1 expression correlated with poor prognosis in GBM patients, and in vitro studies demonstrated that ZHX1 attenuated GBM cell apoptosis by downregulation of pro-apoptotic protein (Bax) and upregulation of anti-apoptotic protein (Bcl-2). Furthermore, knockdown of MALAT1 inhibited GBM proliferation and progression in vitro and reduced tumor volume and prolonged survival in an orthotopic GBM murine model. Finally, we demonstrated that MALAT1 promoted ZHX1 expression via acting as a competing endogenous RNA by sponging miR-199a. The MALAT1/miR-199a/ZHX1 axis promotes GBM cell proliferation and progression in vitro and in vivo, and its expression negatively correlates with GBM patient survival. Blocking the MALAT1/miR-199a/ZHX1 axis can serve as a novel therapeutic strategy for treating GBM., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

A 52-year-old male who had chronic hypertension for several years presented with abrupt epistaxis. The CT scan revealed a 40 mm × 40 mm mass in the nasal cavity intended to the maxillary sinus and the base of skull. Nasal endoscope biopsy and serum/urinary catecholamine detection conformed an ectopic noradrenaline-secreting pheochromocytoma. The present research was to discuss the clinical characteristics of the rare pheochromocytoma and the palliative interventional embolization for it.

Background: Malignant glioma is one of the essentially incurable tumors with chemoresistance and tumor recurrence. As a histone methyltransferase, SUV39H2 can trimethylate H3K9. SUV39H2 is highly expressed in many types of human tumors, while the function of SUV39H2 in the development and progression of glioma has never been elucidated., Methods: RT-qPCR and IHC were used to test SUV39H2 levels in glioma tissues and paired normal tissues. The clinical relevance of SUV39H2 in glioma was analyzed in a public database. Colony formation assays, CCK-8 assays, and flow cytometry were conducted to explore the role of SUV39H2 in the growth of glioma cells in vitro. A cell line-derived xenograft model was applied to explore SUV39H2's role in U251 cell proliferation in vivo. Sphere formation assays, RT-qPCR, flow cytometry, and IF were conducted to illustrate the role of SUV39H2 in the stemness and chemosensitivity of glioma. Luciferase reporter assays and WB were applied to determine the function of SUV39H2 in Hh signaling., Results: SUV39H2 was highly expressed in glioma tissues relative to normal tissues. SUV39H2 knockdown inhibited cell proliferation and stemness and promoted the chemosensitivity of glioma cells in vitro. In addition, SUV39H2 knockdown also significantly inhibited glioma cell growth in vivo. Moreover, we further uncovered that SUV39H2 regulated hedgehog signaling by repressing HHIP expression., Conclusions: Our findings delineate the role of SUV39H2 in glioma cell growth and chemosensitivity as a pivotal regulator of the hedgehog signaling pathway and may support SUV39H2 as a potential target for diagnosis and therapy in glioma management., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Background: Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNA, have been proposed to mediate the progression of diverse types of tumors. Systematic studies of circRNAs have just begun, and the physiological roles of circRNAs remain largely unknown. Here, we focused on elucidating the potential role and molecular mechanism of circular forkhead box O3 (circFOXO3) in glioblastoma (GBM) progression., Methods: First, we analyzed circFOXO3 alterations in GBM and noncancerous tissues through real-time quantitative reverse transcription PCR (qRT-PCR). Next, we used loss- and gain-of-function approaches to evaluate the effect of circFOXO3 on GBM cell proliferation and invasion. Mechanistically, fluorescent in situ hybridization, RNA pull-down, dual luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the interaction between circFOXO3 and miR-138-5p/miR-432-5p in GBM. An animal model was used to verify the in vitro experimental findings., Results: CircFOXO3 expression was significantly higher in GBM tissues than in noncancerous tissues. GBM cell proliferation and invasion were reduced by circFOXO3 knockdown and enhanced by circFOXO3 overexpression. Further biochemical analysis showed that circFOXO3 exerted its pro-tumorigenic activity by acting as a competing endogenous RNA (ceRNA) to increase expression of nuclear factor of activated T cells 5 (NFAT5) via sponging both miR-138-5p and miR-432-5p. Notably, tumor inhibition by circFOXO3 downregulation could be reversed by miR-138-5p/miR-432-5p inhibitors in GBM cells. Moreover, GBM cells with lower circFOXO3 expression developed less aggressive tumors in vivo., Conclusions: Our data demonstrate that circFOXO3 can exert regulatory functions in GBM and that ceRNA-mediated microRNA sequestration might be a potential strategy for GBM therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The current study used a rat middle cerebral artery occlusion (MCAO) model with the aim to explore the effects of compound porcine cerebroside and ganglioside injection (CPCGI) on brain ischemia/reperfusion injury in rats. Improvement in the infarct‑side microcirculation and the overall recovery of neurological function were detected by triphenyltetrazolium chloride staining, laser speckle blood flow monitoring, latex perfusion, immunofluorescence and immunoblotting. The results revealed that administration of CPCGI for 7 consecutive days following ischemic stroke contributed to the recovery of neurological function and the reduction of cerebral infarct volume in rats. Blood flow monitoring results demonstrated that the administration of CPCGI effectively promoted cerebral blood flow following stroke, and contributed to the protection of the ischemic side blood vessels. In addition, CPCGI treatment increased the numbers of new blood vessels in the peripheral ischemic region, and upregulated the expression levels of vascular endothelial growth factor, angiopoietin 1 and its receptor TEK receptor tyrosine kinase, fibroblast growth factor and Wnt signaling pathway‑associated proteins. Taken together, the present results indicated that CPCGI improved the blood circulation and neurological function following cerebral ischemia/reperfusion in rats.

The study reported a case of an intrasellar arachnoid cyst with visual disturbances as the main symptom. Arachnoid cyst is a common intracranial benign space-occupying lesion, but rarely seen in intrasellar region with less than 100 cases reported available in English language literature. Therefore, it is still controversial about the diagnosis and treatment of such patients. This article reviewed previous literature and discussed the differential diagnosis and surgical strategies of intrasellar arachnoid cyst in combination with our own case.

Elevated expression of lncRNA H19 ( H19 ) in the setting of hypoxia has been implicated as a promising therapeutic target for various cancers. However, little is known about the impact and underlying mechanism of H19 in ischemic brain stroke. This study found that H19 levels were elevated in the serum of stroke patients, as well as in the ischemic penumbra of rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and neuronal cells with oxygen glucose deprivation (OGD). Further, knockdown of H19 with siRNA alleviated cell apoptosis in OGD neuronal cells, and inhibition of H19 in MCAO/R rats significantly decreased neurological deficit, brain infarct volume and neuronal apoptosis. Lastly, with gain and loss of function studies, dual luciferase reported assay, RNA immunoprecipitation (RIP) and pull-down experiments, we demonstrated the dual competitive interaction of miR-19a with H19 and the 3'-UTR of Id2 mRNA, resulting in the identification of the H19 -miR-19a-Id2 axis. With biological studies, we also revealed that H19 -miR-19a-Id2 axis modulated hypoxia induced neuronal apoptosis. This study demonstrates that the identified H19 -miR-19a-Id2 axis plays a critical role in hypoxia induced neuronal apoptosis, and blocking this axis may serve as a novel therapeutic strategy for ischemic brain injury.

Glioblastoma is a lethal brain tumor type, which is frequently resistant to radiotherapy. The aim of the present study was to explore the function of legumain pseudogene 1 (LGMNP1) on radioresistance in glioblastoma. Reverse transcription‑quantitative PCR was used to detect the relative expression of LGMNP1 in glioma cell lines after radiotherapy. Ectopic expression of LGMNP1 was achieved by transfection of a lentiviral vector. A clonogenic assay was used to determine the colony formation ability following radiotherapy. A comet assay, flow cytometry and western blot analysis were applied to detect DNA damage, the apoptotic rate, and levels of apoptotic proteins, respectively. The results revealed that LGMNP1 was significantly upregulated in glioma cells after radiation. Glioma cells stably overexpressing LGMNP1 were successfully established. Overexpression of LGMNP1 in glioma cells reduced DNA damage processes and the percentage of apoptotic cells after radiotherapy. In addition, overexpression of LGMNP1 in glioblastoma multiforme cells decreased apoptotic protein expression after radiotherapy. The present results indicated that upregulation of LGMNP1 conferred radiotherapy resistance by increasing the ability of DNA damage protection and reducing the apoptotic population in glioma cells.

Drug resistance induced by increasing intracellular levels of detoxifying agents for conventional platinum(II) drugs such as metallothioneins (MTs) and glutathione (GSH) are the major obstacles for widely used platinum-based chemotherapeutic cancer treatment. Here, we developed trans-geometry platinum (II) drugs with sterically hindered bulky ligands PyPt which is able to hind the GSH attack of platinum drug to overcome cisplatin resistance. Moreover, the PyPt can self-assemble with biodegradable copolymer mPEG-PGA into uniform nanoparticles with PyPt drugs in the polymeric core and PEG as the shell, further protecting PyPt from GSH detoxification to further slow the reaction rate with GSH in vivo. This strategy was developed to bring benefit of not only increasing the solubility of sterically hindered platinum drugs but also combating cisplatin resistance. The M(PyPt) exhibited environment controlled releasing of Pt in tumor micro-environment which prohibited the division of cancer cells. Furthermore, due to the increasing solubility of nanoparticle encapsulated PyPt, the cellular uptake and cytotoxicity of M(PyPt) against both cancer resistance cells was enhanced compared to the cisplatin and PyPt through evaluating with flow cytometry and MTT, respectively. Thus, it was concluded that the M(PyPt) was capable to successfully overcome the cisplatin resistance in the drug-resistant cell line, indicating its potential application in the treatment of clinical cancers with strong cisplatin resistance. Hence the M(PyPt) strategy may represent a promising novel drug delivery system for the local treatment of drug resistance cancer., (Copyright © 2018. Published by Elsevier B.V.)

Long non-coding RNAs (lncRNAs) play vital roles in the pathobiology of glioblastoma multiforme (GBM). Though radiotherapy remains the most effective component of multiple therapies for patients with GBM, lncRNAs conferring GBM radioresistance are less unknown. Here, the present study identified that the antisense transcript of hypoxia-inducible factor-1α (AHIF) was upregulated in GBM cells after radiotherapy. The deregulation of AHIF affected GBM cell clonogenic formation, DNA repair and apoptosis. Notably, knockdown of AHIF inhibited tumorigenesis after radiotherapy in vivo. Further biochemical analysis identified that AHIF regulated proteins associated with apoptosis after radiotherapy. Thus, the present data illustrate that suppression of AHIF increases radiosensitivity in GBM cells, which may be a potential diagnostic and therapeutic target for GBM patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) has the highest mortality rate among patients with brain tumors, and radiotherapy forms an important part of its treatment. Thus, there is an urgent requirement to elucidate the mechanisms conferring GBM progression and radioresistance. In the present study, it was identified that antisense transcript of hypoxia‑inducible factor‑1α (AHIF) was significantly upregulated in GBM cancerous tissues, as well as in radioresistant GBM cells. The expression of AHIF was also upregulated in response to radiation. Knockdown of AHIF in GBM cells decreased viability and invasive capacities, and increased the proportion of apoptotic cells. By contrast, overexpression of AHIF in GBM cells increased viability and invasive capacities, and decreased the proportion of apoptotic cells. Furthermore, exosomes derived from AHIF‑knockdown GBM cells inhibited viability, invasion and radioresistance, whereas exosomes derived from AHIF‑overexpressing GBM cells promoted viability, invasion and radioresistance. Further biochemical analysis identified that AHIF regulates factors associated with migration and angiogenesis in exosomes. To the best of our knowledge, the present study is the first to establish that AHIF promotes glioblastoma progression and radioresistance via exosomes, which suggests that AHIF is a potential therapeutic target for GBM.

Objective: Victims of motor vehicle accidents often develop post-traumatic stress disorder, which causes significant social function loss. For the difficulty in treating post-traumatic stress disorder, identification of subjects at high risk for post-traumatic stress disorder is essential for providing possible intervention. This paper aims to examine the cortical structural traits related to susceptibility to post-traumatic stress disorder., Methods: To address this issue, we performed structural magnetic resonance imaging study in motor vehicle accident victims within 48 hours from the accidents. A total of 70 victims, available for both clinical and magnetic resonance imaging data, enrolled in our study. Upon completion of 6-month follow-up, 29 of them developed post-traumatic stress disorder, while 41 of them didn't. At baseline, voxelwise comparisons of cortical thickness, cortical area and cortical volume were conducted between post-traumatic stress disorder group and trauma control group., Results: As expected, several reduced cortical volume within frontal-temporal loop were observed in post-traumatic stress disorder. For cortical thickness, no between-group differences were observed. There were three clusters in left hemisphere and one cluster in right hemisphere showing decreased cortical area in post-traumatic stress disorder patients, compared with trauma controls. Peak voxels of the three clusters in left hemisphere were separately located in superior parietal cortex, insula and rostral anterior cingulate cortex., Conclusion: The finding of reduced surface area of left insula and left rostral anterior cingulate cortex suggests that shrinked surface area in motor vehicle accident victims could act as potential biomarker of subjects at high risk for post-traumatic stress disorder.

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and it is characterized by extremely poor therapeutic response and overall survival. Adjuvant radiotherapy remains the standard of care following surgical resection. Thus, elucidating the mechanisms conferring radioresistance in GBM is extremely urgent. In the present study, miR-96 was demonstrated to be significantly upregulated in radioresistant GBM cells. Knockdown of miR-96 in the radioresistant GBM cells T98G elevated the % of apoptotic cells and reduced their clonogenic formation ability following radiotherapy. By contrast, overexpression of miR-96 in the radiosensitive GBM cells U87-MG reduced the % of apoptotic cells and increased their clonogenic formation ability following radiotherapy. Results from phosphorylated-H2A histone family member X (γH2AX) foci staining and comet assays revealed that miR-96 enhanced the DNA repair processes. Furthermore, miR-96 overexpression conferred radioresistance by downregulating programmed cell death protein 4 (PDCD4). Luciferase assay results revealed that miR-96 bound to the 3'UTR of PDCD4 mRNA. Finally, U87-MG cells regained radiosensitivity following PDCD4 overexpression. Taken together, the present is the first study to establish that upregulation of miR-96 in GBM cells confers radioresistance via targeting PDCD4, which might be a potential therapeutic target for GBM.

Glutamate and γ‑aminobutyric acid (GABA) transporters serve central roles in normal neuronal activity and are associated with numerous pathological brain conditions, including ischemia and epilepsy. However, the interplay between these transporters in ischemia remains unclear. In the present study, the expression levels of the excitatory amino acid carrier 1 (EAAC1) and GABA transporter 1 (GAT1) were analyzed in vivo and in vitro within ischemic models by immunofluorescence, western blot and RT‑qPCR. Cell survival rates were analyzed following altered expression of these transporters within neuronal cells by flow cytometry. Expression levels of EAAC1 were reduced within the cerebrum of focal cerebral ischemic middle cerebral artery occlusion rat models as well as in primary neurons cultured under hypoxia. However, GAT1 expression levels were slightly elevated under ischemic conditions. The altered expression levels of EAAC1 and GAT1 were combined within neuron cells and the effects were investigated. Apoptotic analysis revealed that EAAC1 suppression and overexpression of GAT1 increased neuronal cell apoptosis under hypoxic conditions; however, EAAC1 overexpression combined with GAT1 knockdown reduced neuronal cell apoptosis under hypoxic conditions. The present study detected the expression levels of the glutamate and GABA transporters under hypoxia, in association with ischemia. The results indicated that, increased expression of EAAC1 combined with GAT1 suppression may provide protective effects in the treatment of epilepsy and ischemia.

Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis occasionally affecting central nervous system (CNS), and GPA patients with initial CNS symptoms are even rarer, whose diagnosis is further confused by an absence of positive antineutrophil cytoplasmic antibody. The authors described the characteristics of antineutrophil cytoplasmic antibody -negative GPA with CNS onset in a patient and discussed on its management, which may contribute to future diagnosis and treatment of patients with similar conditions.

With respect to the intriguing biocompatibility and the stealthy functions of poly(ethylene glycol) (PEG), PEGylated nanoparticulates have been intensively engineered for utilities as drug delivery vehicles. To advocate the targeted drug transportation, targeting ligands were strategically installed onto the surface of PEGylated nanoparticulates. The previous in vitro investigations revealed that the ligand-specified cell endocytosis of nanoparticulates was pronounced for the nanoparticulates with adequately high PEG crowdedness. The present study aims to explore insight into the impact of PEGylation degree on in vivo tumor-targeted accumulation activities of cRGD-installed nanoparticulates. The subsequent investigations verified the importance of the PEGylation crowdedness in pursuit of prolonged retention in the blood circulation post intravenous administration. Unprecedentedly, the PEGylation crowdedness was also identified as a crucial important parameter to pursue the tumor-targeted accumulation. A plausible reason is the elevated PEGylation crowdedness eliciting the restricted involvement in nonspecific protein adsorption of nanoparticulates in the biological milieu and consequently pronouncing the ligand-receptor-mediated binding for the nanoparticulates. Noteworthy was the distinctive performance of the class of the proposed systems once utilized for transportation of the mRNA payload to the tumors. The protein expression in the targeted tumors appeared to follow a clear PEGylation crowdedness dependence manner, where merely 2-fold PEGylation crowdedness led to remarkably 10-fold augmentation in protein expression in tumors. Hence, the results provided important information and implications for design of active-targeting PEGylated nanomaterials to fulfill the targeting strategies in systemic applications.

Temozolomide (TMZ), as a kind of alkylating agent, is widely utilized for the treatment of glioblastoma (GBM). However, temozolomide resistance (TR) often develops quickly and results in tumor recurrence and poor outcome. Recent advances have demonstrated that miRNAs exert critical roles in chemoresistance. Downregulation of miR‑146b‑5p promotes glioma cell proliferation, reduces apoptosis, and correlates with poor survival of patients. Nonetheless, the function of miR‑146b‑5p in temozolomide resistance remains unclear. In the present study, we successfully generated U87 and U251‑TR cells, and found that miR‑146b‑5p was downregulated in TR cells. Overexpression of miR‑146b‑5p restored sensitivity of U87/U251‑TR cells to TMZ by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of TRAF6 were inversely related to miR‑146b‑5p levels, and overexpression of TRAF6 in miR‑146b‑5p‑OE cells enhanced the resistance against TMZ. Moreover, temozolomide-resistant GBM cells had a higher level of phosphorylated protein kinase B (AKT) and P65. Overexpression of miR‑146b‑5p or TRAF6 knockdown significantly decreased the level of p‑AKT and p‑p65. Collectively, our data demonstrated that miR‑146b‑5p, as a tumor suppressor, mediated temozolomide resistance in GBM cells through negatively regulating TRAF6 expression, indicating that miR‑146b‑5p and its targeted genes would be potential therapeutic targets for glioma therapy.

Aberrant expression of microRNAs hae been shown to be closely associated with glioblastoma cell proliferation, apoptosis and drug resistance. However, mechanisms underlying the role of mcroRNAs in glioblastoma cell growth and apoptosis are not fully understood. In this study, we report that miR-503 is overexpressed in glioblastoma tissue compared with normal human brain tissue. Mechanistically, miR-503 can be induced by TGF-â1 at the transcriptional level by binding the smad2/3 binding elements in the promoter. Ectopic overexpression of miR-503 promotes cell growth and inhibits apoptosis by targeting PDCD4. In contrast, inhibition of miR-503 reduces cell growth. Furthermore, miR-503 inhibitor augments the growth inhibitory effect of temozolomide in glioblastoma cells. These results establish miR-503 as a promising molecular target for glioblastoma therapy.

Forkhead transcription factor FoxO3a has been reported to have ambiguous functions and distinct mechanisms in various solid tumors, including glioblastoma (GBM). Although a preliminary analysis of a small sample of patients indicated that FoxO3a aberrations in glioma might be related to aggressive clinical behavior, the clinical significance of FoxO3a in glioblastoma remains unclear. We investigated the expression of FoxO3a in a cohort of 91 glioblastoma specimens and analyzed the correlations of protein expression with patient prognosis. Furthermore, the functional impact of FoxO3a on GBM progression and the underlying mechanisms of FoxO3a regulation were explored in a series of in vitro and in vivo assays. FoxO3a expression was elevated in glioblastoma tissues, and high nuclear FoxO3a expression in human GBM tissues was associated with poor prognosis. Moreover, knockdown of FoxO3a significantly reduced the colony formation and invasion ability of GBM cells, whereas overexpression of FoxO3a promoted the colony formation and invasion ability. The results of in vivo GBM models further confirmed that FoxO3a knockdown inhibited GBM progression. More, the pro-oncogenic effects of FoxO3a in GBM were mediated by the activation of c-Myc, microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin1 in a mixed-lineage leukemia 2 (MLL2)-dependent manner. These findings suggest that high FoxO3a expression is associated with glioblastoma progression and that FoxO3a independently indicates poor prognosis in patients. FoxO3a might be a novel prognostic biomarker or a potential therapeutic target in glioblastoma., (© 2017 UICC.)

Elevated circulating asparaginyl endopeptidase (AEP), a novel lysosomal protease, has been found in breast cancer, and AEP is thus considered to be a prognostic factor in this disease. However, the pathological functions of circulating AEP in the development of breast cancer and the potential of AEP-targeted therapy remain unclear. We used MMTV-PyVmT transgenic mice, which spontaneously develop mammary tumors. Western blotting showed overexpression of AEP in both primary tumor tissue and lung metastases compared to their normal counterparts. Moreover, the concentration of circulating AEP gradually increased in the serum during the development of mammary tumors. Purified AEP protein injected through the tail vein promoted tumor growth and mammary tumor metastasis and shortened survival, whereas AEP-specific small compound inhibitors (AEPIs) effectively suppressed tumor progression and prolonged host survival. Further analysis of the molecular mechanism revealed that AEP was important for PI3K/AKT pathway activation. Thus, an elevated serum AEP level was closely related to mammary cancer progression and metastasis, and AEP is a potential target for breast cancer therapy in the clinic.

Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by the presence of multiple congenital melanocytic nevi and the proliferation of melanocytes in the central nervous system. The authors present a 9-year-old Chinese boy whose clinical manifestations are intermittent headache for 2 months and persistent abdominal pain for 10 days. 3D-reconstruction computed tomography angiography image, digital subtraction angiography, and magnetic resonance imaging plus angiography (MRI+MRA) examinations results suggested that cavernoma at left frontal lobe potentially associated with hemorrhage. In addition, miliary abnormal signals were widely scattered on MRA image so that other malignant metastatic diseases cannot be ruled out. GI physical examination had not any abnormal findings, antispasmodic drugs were ineffective but antiepilepsy drugs were effective to abdominal pain. In surgery, no cavernoma was noticed but an accumulation of densely melanocytic mass located at the lesion on radiology images. The lesions spread along with perivascular of sylvian veins and leptomeningeal. Pathology investigation demonstrated brain metastatic malignant melanoma associated with hemosiderosis. The lesion of brain parenchyma was totally removed but the spread lesions could not be treated with surgery. Adjuvant radiotherapy was performed but failed to control the malignant development, still the patient died in 3 months postinitial operation. The authors conclude that abdominal pain was a manifestation of epilepsy related to the frontal lobe lesion. Neurocutaneous melanosis is a rare disease, brain metastases result in abdominal pain is rare even more, and it is worth the attention of clinicians.

Neuroblastoma (NB) is one of the most commonly seen malignancies in childhood and infancy. Cantharidin is a highly potent natural toxin that possesses potent anti-tumor properties on various cancers including NB. However, exposure to cantharidin can cause severe chemical burns and application of cantharidin for cancer therapy is limited. Here we report a strategy of bundling cantharidin within a hybrid platinum (IV) prodrug conjugate. This hydrophobic drug conjugate, ie, CanPt can be further formulated into liposome for drug delivery to minimize the exposure of cantharidin to normal cells for efficient chemotherapeutic agent against NB., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Ischemia stroke is a destructive cerebrovascular disease and a major cause of death and lifelong neurological disability. N-Acetyl-l-aspartyl-l-glutamate (NAAG) is a neurotransmitter in the mammalian brain and involves a variety of physiological and pathological functions including ischemia brain injury. Full understanding of the functions of NAAG peptidase (GCPII) in the pathogenesis of ischemia brain injury is extremely valuable for effective therapies to ischemia stroke., Methods: The expressions of GCPII and NAAG agonist metabotropic glutamate receptor (mGluR3) and TGFb1 were examined by real-time polymerase chain reaction and western blot. Moreover, GCPII knockdown cells were constructed using lentivirus-mediated transfection. Function and molecular mechanisms of GCPII knockdown on apoptosis induced from hypoxic-ischemic-induced injury in neuronal cells were analyzed., Results: In this study, we found that the expressions of GCPII and mGluR3 were upregulated in CoCl2-induced hypoxia environment in neuronal cells. Moreover, knockdown of GCPII in neuronal cells ameliorated apoptosis from hypoxic-ischemic-induced injury through suppressing expressions of caspase 3 and caspase 9., Conclusions: Our results highlighted the roles of GCPII in the ischemia brain injury, and might provide an important target in therapeutic implications., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: A small portion of the Motor vehicle accidents (MVA) survivors would develop post-traumatic stress disorder (PTSD), which would cause substantial social function loss. How to identify those high-risk MVA survivors in the acute phase of the trauma is the first step to prevent the onset of PTSD. In the present study, we studied white matter integrity of subjects post to MVA by diffusional tensor imaging (DTI)., Methods: To investigate whether the integrity of the white matter was impaired in the acute phase of the MVA among survivors who later develop PTSD and whether it could predict the severity of PTSD while being diagnosed. MVA Survivors were recruited to get trauma-specific clinical assessments and received DTI scan within 2 days from the MVA. These survivors were divided into 2 groups, PTSD group and trauma control (TC) group based on the clinical follow-up interview. Tract-Based Spatial Statistics (TBSS) was carried out to investigate difference in white matter integrity between 2 groups within DTI parameter maps. White matter integrity was measured by using fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radical diffusivity (RD)., Results: Compared with TC group, PTSD group showed lower FA value in multiple regions of both hemispheres, mainly involving anterior thalamic radiation, cortico-spinal tract, forceps minor, uncinate, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, cingulum and superior longitudinal fasciculus. Increased RD was also detected in PTSD group in the posterior part of right hemisphere, involving forceps major, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, cingulum, hippocampus and superior longitudinal fasciculus. The baseline FA and RD values correlated with Clinician-Administered PTSD Scale scores at clinical follow up., Conclusion: MVA survivors who later developed PTSD had more abnormalities in white matter integrity in the acute phase than those non-PTSD MVA survivors. Imaging markers of white matter integrity might be helpful in early identification of MVA survivors at high risk of PTSD., Limitations: Larger sample size in our extensive study is needed to confer a robust inference and image data at follow up are needed to observe the longitudinal changes of white matter integrity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Neuroendocrine tumor (NET) is not a common source of brain metastasis and the standard management of intracranial metastatic NET with lung origin remains unclear as a result of its rarity. We aimed to generalize some applicable protocols from our current 2 cases and relevant literature.

Chronic subdural hematoma (CSDH) is still a mysterious disease. Though great success has been has achieved by neuro-surgery treatment, the origin and development of CSDH remains unknown. Tremendous clinical observations have found the correlation of subdural effusion (SDE) and CSDH. However, systematic elucidation of CSDH's origin and progression is lacking while almost all the current hypothesis only explained partial phenomenon. This hypothesis proposes Interleukin (IL)-8 inducing neutrophil respiratory burst is the crucial impact when SDE evolves into CSDH. IL-8 initially secreted by dural border layer cells, accumulates and the concentration of IL-8 rises in the SDE cavity. Accompanied by the formation of neo-membrane under the dura meninges, IL-8 firstly prompts to establish the neo-vasculature in it, and then attracts lymphocytes aggregation in the neo-membrane. Both the newly recruited lymphocytes and endothelial cells assist the further elevation of local IL-8 concentration. When the IL-8 concentration elevated to a particular level, it attracts neutrophils to the inner wall of neo-vessels and primes them to oxidative burst. Lysosomes and superoxide released by these neutrophils make the fragile neo-capillary became leaky, and subsequently the plasma and blood cells run into SDE. However, as long as the erythrocytes come into the cavity, they shall bind large quantity of IL-8 and decrease IL-8 concentration to a lower level relatively that reduce the neutrophils recruit. When this negative feedback is stagnancy, for example, the SDE space is so large in elder man who is experiencing brain atrophy, the neo-vessels have to release more erythrocytes to bind IL-8, the liquid cavity will expand and the high intracranial pressure symptoms appeared. Our hypothesis holds potential for the proper therapeutic intervention of CSDH. IL-8 antagonist and other anti-inflammation drugs like macrolides antibiotics, glucocorticoid and atorvastatin might be optional to resist the liquid cavity expanding as actually occurs obvious bleeding soon., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cerebral ischemic stroke has long been recognized as a prevalent and serious neurological disease that was associated with high mortality and morbidity. However, the current therapeutic protocols remain suboptimal with major mechanisms underlying stroke urgently warranted. Inhibitor of DNA binding/differentiation 2 (Id2) is found to be up-regulated in neuronal cells following hypoxia/ischemia (H/I). This study was aimed to investigate whether knockdown of Id2 in neuronal cells could protect them from hypoxic and ischemic injury both in vitro and in vivo. Flow cytometric analysis was employed to assess neuronal apoptosis in CoCl2-treated neuroblastoma B35 cells engineered to overexpress or knockdown Id2 expression. In vivo knockdown of Id2 was performed in Sprague-Dawley rats by a single intracerebroventricular injection of Cy3-labeled and cholesterol-modified Id2-siRNA. We found that knockdown of Id2 attenuated H/I-induced neuronal apoptosis in vitro while overexpression of Id2 produced an opposite effect. In a rat model of middle cerebral artery occlusion (MCAO), in vivo knockdown of Id2 significantly improved neurological deficits, reduced the volume of ischemic infarction and diminished the neuronal apoptosis in the penumbra area. Double immunofluorescence staining showed less co-localization of retinoblastoma tumor suppressor protein (Rb)-Id2 but greater co-localization of Rb-E2F1 in the penumbra area. Cell cycle assay further demonstrated that Id2 knockdown induced G0/G1 cell cycle arrest in CoCl2-treated B35 cells. The present data support the implication of Id2 in the modulation of H/I-induced neuronal apoptosis and may provide a potential therapeutic option to protect brain tissues from ischemic injury by inhibition of its expression., (Copyright © 2015 Elsevier B.V. All rights reserved.)