Transgelin Promotes Glioblastoma Stem Cell Hypoxic Responses and Maintenance Through p53 Acetylation.

Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin-binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self-renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.

Hypoxia-induced galectin-8 maintains stemness in glioma stem cells via autophagy regulation.

BACKGROUND: Glioma stem cells (GSCs) are the root cause of relapse and treatment resistance in glioblastoma (GBM). In GSCs, hypoxia in the microenvironment is known to facilitate the maintenance of stem cells, and evolutionally conserved autophagy regulates cell homeostasis to control cell population. The precise involvement of autophagy regulation in hypoxic conditions in maintaining the stemness of GSCs remains unclear. METHODS: The association of autophagy regulation and hypoxia was first assessed by in silico analysis and validation in vitro. Glioma databases and clinical specimens were used to determine galectin-8 (Gal-8) expression in GSCs and human GBMs, and the regulation and function of Gal-8 in stemness maintenance were evaluated by genetic manipulation in vitro and in vivo. How autophagy was stimulated by Gal-8 under hypoxia was systematically investigated. RESULTS: Hypoxia enhances autophagy in GSCs to facilitate self-renewal, and Gal-8 in the galectin family is specifically involved and expressed in GSCs within the hypoxic niche. Gal-8 is highly expressed in GBM and predicts poor survival in patients. Suppression of Gal-8 prevents tumor growth and prolongs survival in mouse models of GBM. Gal-8 binds to the Ragulator-Rag complex at the lysosome membrane and inactivates mTORC1, leading to the nuclear translocation of downstream TFEB and initiation of autophagic lysosomal biogenesis. Consequently, the survival and proliferative activity of GSCs are maintained. CONCLUSIONS: Our findings reveal a novel Gal-8-mTOR-TFEB axis induced by hypoxia in the maintenance of GSC stemness via autophagy reinforcement, highlighting Gal-8 as a candidate for GSCs-targeted GBM therapy.

Dendritic cell vaccine of gliomas: challenges from bench to bed.

Gliomas account for the majority of brain malignant tumors. As the most malignant subtype of glioma, glioblastoma (GBM) is barely effectively treated by traditional therapies (surgery combined with radiochemotherapy), resulting in poor prognosis. Meanwhile, due to its "cold tumor" phenotype, GBM fails to respond to multiple immunotherapies. As its capacity to prime T cell response, dendritic cells (DCs) are essential to anti-tumor immunity. In recent years, as a therapeutic method, dendritic cell vaccine (DCV) has been immensely developed. However, there have long been obstacles that limit the use of DCV yet to be tackled. As is shown in the following review, the role of DCs in anti-tumor immunity and the inhibitory effects of tumor microenvironment (TME) on DCs are described, the previous clinical trials of DCV in the treatment of GBM are summarized, and the challenges and possible development directions of DCV are analyzed.

Microsurgical Treatment of Arteriovenous Malformations: A Single-Center Study Experience.

OBJECTIVE: The purpose of the study was to assess the functional outcomes after microsurgical resection of arteriovenous malformations (AVMs) and to compare the results between patients eligible for A Randomized Trial of Unruptured Brain Arteriovenous Malformations in this surgical series to the results reported and the ARUBA study. METHODS: We reviewed the records of 169 patients who underwent microsurgical treatment of arteriovenous malformation (AVMs) in our institution between January 2016 and December 2021. These patients' functional status was assessed using modified Rankin Scale (mRS) scores at the last follow-up and before treatment. The mRS scores at the latest follow-up were classified into good outcomes (mRS < 3) and poor outcomes (mRS ≥ 3). Clinical presentation, patients' demographics, AVM characteristics, follow-up time, and obliteration rate were analyzed. Subgroup analyses were performed on the whole cohort, comparing Spetzler-Martin Grade I and Grade II, and ARUBA-eligible AVMs. RESULTS: The initial hemorrhagic presentation occurred in 71 (42%) out of 169 patients. The majority of the patients presented with headaches (73%). The AVMs were completely obliterated in 166 (98.2%) patients. The series included 65 Spetzler-Martin Grade I (38.5%), 46 Grade II (27.2%), 32 Grade III (18.9%), 22 Grade IV (13%), and 4 Grade V (2.4%) AVMs. There were 98 unruptured and 79 ARUBA-eligible cases. Also, optimal functional outcome was achieved in 145 (85.8%) patients. The overall mortality rate was 5.3% (9/169). The multivariate analysis illustrated that a poor outcome was significantly associated with presurgical mRS ≥3 (p < 0.013; OR, 0.206; 95% CI 0.059-0.713), increasing age (p < 0.045; odds ratio [OR], 1.022; 95% CI 1.000-0.045), and female gender (p < 0.009; OR, 2.991; 95% CI 1.309-6.832). CONCLUSIONS: Our study suggests that better outcomes can be obtained using microsurgical resection in the majority of patients with AVMs. Independent predictors of poor outcomes after surgical resection of AVMs include increasing age at the time of surgery, poor presurgical functional status, and female gender. Supposing that patients are more suitable for microsurgery after presurgical examination, outcomes are normally better in that case than those achieved by multimodal interventions (such as conservative treatment or ARUBA treatment arm). Therefore, we recommend early surgical removal on all surgically accessible AVMs to prevent successive hemorrhages and the consequences of poor neurological outcomes.

Programmed cell death 10 increased blood-brain barrier permeability through HMGB1/TLR4 mediated downregulation of endothelial ZO-1 in glioblastoma.

Dysfunction of blood brain barrier (BBB) contributes to the development of peritumoral edema (PTE) and GBM progression. Programmed cell death 10 (PDCD10) exerts various influence on cancers, especially in glioblastoma (GBM). We previously found that PDCD10 expression was positively correlated with PTE extent in GBM. Thus, the present study aims to investigate the emerging role of PDCD10 in regulating BBB permeability in GBM. Here we found that in vitro indirect co-culture of endothelial cells (ECs) with Pdcd10-overexpressed GL261 cells resulted in a significant increase of FITC-Dextran (MW, 4000) leakage by reducing endothelial zonula occluden-1 (ZO-1) and Claudin-5 expression in ECs respectively. Overexpression of Pdcd10 in GBM cells (GL261) triggered an increase of soluble high mobility group box 1 (HMGB1) release, which in turn activated endothelial toll like receptor 4 (TLR4) and downstream NF-κB, Erk1/2 and Akt signaling in ECs through a paracrine manner. Moreover, Pdcd10-overexpressed GL261 cells facilitated a formation of abnormal vasculature and increased the BBB permeability in vivo. Our present study demonstrates that upregulation of PDCD10 in GBM triggered HMGB1/TLR4 signaling in ECs and significantly decreased endothelial ZO-1 expression, which in turn dominantly increased BBB permeability and contributed to tumor progression in GBM.

Risk Factor and Replacement Therapy Analysis of Pre- and Postoperative Endocrine Deficiencies for Craniopharyngioma.

BACKGROUND: Pituitary hormone deficiency (PHD) is one of the most common symptoms and postoperative complications of craniopharyngiomas (CPs). However, the risk factors for PHD in CPs are little known. The purpose of this study was to analyze the risk factors of pre- and postoperative PHD and to investigate replacement therapy for CP patients. METHODS: A retrospective study of 126 patients diagnosed with CP was performed. Univariate analysis was performed using Pearson's chi-squared test or Fisher's exact test, and a multiple logistic binary regression model was used to identify the influencing factors of pre- and postoperative PHD in craniopharyngioma. RESULTS: Children and patients with hypothalamic involvement were more likely to have preoperative PHD. Patients with suprasellar lesions had a high risk of postoperative PHD, and preoperative PHD was a risk factor for postoperative PHD. CONCLUSION: Children have a high incidence of preoperative PHD. Preoperative PHD can serve as an independent risk factor for postoperative PHD. Preoperative panhypopituitarism can serve as an indication of pituitary stalk sacrifice during surgery. The management of replacement therapy for long-term postoperative endocrine hormone deficiency in patients with craniopharyngioma should be enhanced.

Targeting FGL2 in glioma immunosuppression and malignant progression.

Glioblastoma (GBM) is the most malignant type of glioma with the worst prognosis. Traditional therapies (surgery combined with radiotherapy and chemotherapy) have limited therapeutic effects. As a novel therapy emerging in recent years, immunotherapy is increasingly used in glioblastoma (GBM), so we expect to discover more effective immune targets. FGL2, a member of the thrombospondin family, plays an essential role in regulating the activity of immune cells and tumor cells in GBM. Elucidating the role of FGL2 in GBM can help improve immunotherapy efficacy and design treatment protocols. This review discusses the immunosuppressive role of FGL2 in the GBM tumor microenvironment and its ability to promote malignant tumor progression while considering FGL2-targeted therapeutic strategies. Also, we summarize the molecular mechanisms of FGL2 expression on various immune cell types and discuss the possibility of FGL2 and its related mechanisms as new GBM immunotherapy.

Identification of a Signature for Predicting Prognosis and Immunotherapy Response in Patients with Glioma.

Glioma is a deadly tumor that accounts for the vast majority of brain tumors. Thus, it is important to elucidate the molecular pathogenesis and potential diagnostic and prognostic biomarkers of glioma. In the present study, gene expression profiles of GSE2223 were obtained from the Gene Expression Omnibus (GEO) database. Core modules and hub genes related to glioma were identified using weighted gene coexpression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis of differentially expressed genes (DEGs). After a series of database screening tests, we identified 11 modules during glioma progression, followed by six hub genes (RAB3A, TYROBP, SYP, CAMK2A, VSIG4, and GABRA1) that can predict the prognosis of glioma and were validated in glioma tissues by qRT-PCR. The CIBERSORT algorithm was used to analyze the difference of immune cell infiltration between the glioma and control groups. Finally, Identification VSIG4 for immunotherapy response in patients with glioma demonstrating utility for immunotherapy research.

Prognostic Value and Biological Function of Galectins in Malignant Glioma.

Malignant glioma is the most common solid tumor of the adult brain, with high lethality and poor prognosis. Hence, identifying novel and reliable biomarkers can be advantageous for diagnosing and treating glioma. Several galectins encoded by LGALS genes have recently been reported to participate in the development and progression of various tumors; however, their detailed role in glioma progression remains unclear. Herein, we analyzed the expression and survival curves of all LGALS across 2,217 patients with glioma using The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Rembrandt databases. By performing multivariate Cox analysis, we built a survival model containing LGALS1, LGALS3, LGALS3BP, LGALS8, and LGALS9 using TCGA database. The prognostic power of this panel was assessed using CGGA and Rembrandt datasets. ESTIMATE and CIBERSORT algorithms confirmed that patients in high-risk groups exhibited significant stromal and immune cell infiltration, immunosuppression, mesenchymal subtype, and isocitrate dehydrogenase 1 (IDH1) wild type. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), CancerSEA, and Gene Set Enrichment Analysis (GSEA) showed that pathways related to hypoxia, epithelial-to-mesenchymal transition (EMT), stemness, and inflammation were enriched in the high-risk group. To further elucidate the function of LGALS in glioma, we performed immunohistochemical staining of tissue microarrays (TMAs), Western blotting, and cell viability, sphere formation, and limiting dilution assays following lentiviral short hairpin RNA (shRNA)-mediated LGALS knockdown. We observed that LGALS expression was upregulated in gliomas at both protein and mRNA levels. LGALS could promote the stemness maintenance of glioma stem cells (GSCs) and positively correlate with M2-tumor-associated macrophages (TAMs) infiltration. In conclusion, we established a reliable survival model for patients with glioma based on LGALS expression and revealed the essential roles of LGALS genes in tumor growth, immunosuppression, stemness maintenance, pro-neural to mesenchymal transition, and hypoxia in glioma.

TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvß5-Src-Stat3 signaling.

Rationale: In the glioblastoma (GBM) microenvironment, tumor-associated macrophages (TAMs) are prominent components and facilitate tumor growth. The exact molecular mechanisms underlying TAMs' function in promoting glioma stem cells (GSCs) maintenance and tumor growth remain largely unknown. We found a candidate molecule, transforming growth factor beta-induced (TGFBI), that was specifically expressed by TAMs and extremely low in GBM and GSC cells, and meanwhile closely related to glioma WHO grades and patient prognosis. The exact mechanism of TGFBI linking TAM functions to GSC-driven tumor growth was explored. Methods: Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry staining (IHC) and public datasets were used to evaluate TGFBI origin and level in GBM. The response of GSCs to recombinant human TGFBI was assessed in vitro and orthotopic xenografts were established to investigate the function and mechanism in vivo. Results: M2-like TAMs infiltration was elevated in high-grade gliomas. TGFBI was preferentially secreted by M2-like TAMs and associated with a poor prognosis for patients with GBM. TGFBI promoted the maintenance of GSCs and GBM malignant growth through integrin αvß5-Src-Stat3 signaling in vitro and in vivo. Of clinical relevance, TGFBI was enriched in the serum and CSF of GBM patients and significantly decreased after tumor resection. Conclusion: TAM-derived TGFBI promotes GSC-driven tumor growth through integrin αvß5-Src-Stat3 signaling. High serum or CSF TGFBI may serve as a potential diagnostic and prognostic bio-index for GBMs.

Influence of Different Welding Parameters on the Morphology, Microstructure, and Mechanical Properties of 780 Duplex-Phase Steel Laser Lap Welded Joint.

This paper attempted to establish a relationship between the morphology, microstructure and mechanical properties of a laser lap welded joint (WJ) of 780 duplex-phase (DP) steel under different welding parameters. The experimental results showed that the microstructure of the heat-affected zone (HAZ) of all the WJs were tempered martensite and equiaxed ferrite. The microstructure at the fusion zone (FZ) in all the WJs was dominated by lath martensite and ferrite, and the grain size of the FZ was larger than that in the base materials (BMs). The mechanical properties of the welded joints were tested by a universal testing machine, and the changing law of lap tensile resistance with the laser-welding parameters was analyzed. The results show that there was a linear relationship between the width of the weld and the tensile-shear forces of the weld, and the penetration of the weld had no obvious effect on the tensile-shear forces of the weld. A binary linear-regression equation was established to reveal the degree of influence of welding speed and laser power on the mechanical properties of WJs. It was found that the laser power had a greater influence on the mechanical properties of WJs than the welding speed.

Programmed Cell Death 10 Mediated CXCL2-CXCR2 Signaling in Regulating Tumor-Associated Microglia/Macrophages Recruitment in Glioblastoma.

Background: Programmed cell death 10 (PDCD10) plays a crucial role in regulating tumor phenotyping, especially in glioblastoma (GBM). Glioma-associated microglia/macrophages (GAMs) in tumor pathological microenvironment contribute to GBM progression. We previously found that the infiltration of GAMs was associated with PDCD10 expression in GBM patients. The present study aims to further explore the regulation of PDCD10 on GAMs in GBM. Methods: Overexpression of PDCD10 in human- and murine-GBM cells was established by lentiviral transduction. Cell behaviors and polarization of primary microglia, microglia- and macrophage-like cells were investigated through indirect co-culture with GBM cells in vitro respectively. The PDCD10-induced release of chemokines was identified by a chemokine protein array. The cross-talk between GBM and microglia as well as macrophages was further studied using selective antagonist SB225002. Finally, an orthotopic homograft mouse model was employed to verify the results of in vitro experiments. Results: Indirect co-culture with PDCD10-overexpressed GBM cells promoted proliferation and migration of microglia- and macrophage-like cells, and stimulated pro-tumorigenic polarization of primary microglia, microglia- and macrophage-like cells. Pdcd10-upregulated GBM cells triggered a nearly 6-fold increase of CXC motif chemokine ligand 2 (CXCL2) release, which in turn activated CXC chemokine receptor 2 (CXCR2) and downstream Erk1/2 and Akt signaling in primary microglia, microglia- and macrophage-like cells. The blockage of CXCR2 signaling with specific inhibitor (SB225002) abolished microglia- and macrophage-like cell migration induced by PDCD10-upregulated GBM cells. Moreover, Pdcd10-upregulated GL261 cells promoted GAMs recruitment and tumor growth in vivo. Conclusion: Our study demonstrates that overexpression of PDCD10 in GBM recruits and activates microglia/macrophages, which in turn promotes tumor progression. CXCL2-CXCR2 signaling mediated by PDCD10 is potentially involved in the crosstalk between GBM cells and GAMs.

Targeting the Complement Pathway in Malignant Glioma Microenvironments.

Malignant glioma is a highly fatal type of brain tumor, and its reoccurrence is largely due to the ordered interactions among the components present in the complex microenvironment. Besides its role in immune surveillance and clearance under physiological conditions, the complement system is expressed in a variety of tumor types and mediates the interactions within the tumor microenvironments. Recent studies have uncovered the broad expression spectrum of complement signaling molecules in the tumor microenvironment and various tumor cells, in particular, malignant glioma cells. Involvement of the complement system in tumor growth, immunosuppression and phenotype transition have also been elucidated. In this review, we enumerate the expression and function of complement molecules in multiple tumor types reported. Moreover, we elaborate the complement pathways in glioma cells and various components of malignant glioma microenvironments. Finally, we summarize the possibility of the complement molecules as prognostic factors and therapeutic targets in the treatment of malignant glioma. Specific targeting of the complement system maybe of great significance and value in the future treatment of multi-type tumors including malignant glioma.

Surgical fenestration might not be the best option for very young patients with middle fossa arachnoid cysts.

PURPOSE: Surgical fenestration is widely accepted as a primary treatment for middle fossa arachnoid cysts (MFACs) in pediatric patients. However, postoperative subdural effusion and/or hydrocephalus always affect treatment outcomes. In this study, we presented our experience of treating MFACs with surgical fenestration in pediatric patients and analyzed the cases complicated by postoperative subdural effusion and/or hydrocephalus, to give insight into the clinical characteristics predisposing the complications. METHODS: We retrospectively analyzed 21 pediatric cases with MFACs treated by surgical fenestration suffering postoperative subdural effusion and/or hydrocephalus in our department from November 2011 to April 2019. We reviewed the clinical characteristics and treatment outcomes. RESULTS: A total of 21 patients, among a total of 53 pediatric patients with MFACs treated by surgical fenestration, developed subdural effusion and/or hydrocephalus postoperatively. The mean age at the time of the initial surgery was 49 months. A total of 75% (6/8) of the patients under 2 years old and 13.3% (6/45) of the older patient group sustaining postoperative subdural effusion and/or hydrocephalus required further surgeries, respectively (Fisher's exact test, p = 0.001). Notably, among the 21 cases with postoperative subdural effusion and/or hydrocephalus, all the 6 patients under 2 years old needed additional surgeries, while of the other 15 older patients, only 40% (6/15) needed further surgical interventions (Fisher's exact test, p = 0.019). CONCLUSION: The immature CSF absorption in MFAC patients younger than 2 years old might predispose them to the relatively serious postoperative subdural effusion and/or hydrocephalus. For very young patients with giant MFACs, surgical fenestration might not be the best option.

Prognostic significance of ARL9 and its methylation in low-grade glioma.

This study aimed to determine the value of ARL9 expression or methylation as a biomarker for LGG survival. We investigated the expression, methylation, prognosis and immune significance of ARL9 through bioinformatics analysis. ARL9 is negatively regulated by ARL9 methylation, leading to its low expression in LGG tissues. Both low ARL9 expression and hypermethylation predicted favorable OS and PFS in LGG patients, according to the TCGA database. Cox regression demonstrated that low ARL9 expression and ARL9 hypermethylation were independent biomarkers for OS. Moreover, three other glioma databases were utilized to verify the prognostic role of ARL9 in LGG, and the similar results were reached. A meta-analysis revealed that low ARL9 expression was closely relevant to better OS. Finally, ARL9 expression exhibited a close correlation with some immune cells, especially CD8+ T cells. ARL9 could constitute a promising prognostic biomarker, and probably plays an important role in immune cell infiltration in LGG.

Microsurgical Treatment of Epilepsy with Parenchymal Neurocysticercosis.

Parenchymal neurocysticercosis is the most common form of neurocysticercosis in the central nervous system (CNS), which mainly causes epilepsy and usually responses well to routine medications. However, there are appreciable cases of relapses refractory to medical treatment. We investigated microsurgical treatment of epilepsy with parenchymal neurocysticercosis. Nine cases of epilepsy caused by parenchymal neurocysticercosis from 2002 to 2018 were analyzed retrospectively. Cysts in 7 cases were completely removed. No case died of operation and no new dysfunction of the nervous system was observed after surgery. Among the other 9 cases, 8 cases became seizure-free or controlled by medicine according to the postoperative follow-up for 6 months to 9 years. One case was lost for follow-up. It was suggested that epilepsy with parenchymal neurocysticercosis can usually be controlled after routine medications. However, surgery is still indicated in some cases and careful microsurgery is associated with satisfactory clinical outcomes in appropriately selected cases.

Association of APOE ε4 with progressive hemorrhagic injury in patients with traumatic intracerebral hemorrhage.

OBJECTIVE: The intracranial hematoma volume in patients with traumatic brain injury is a key parameter for the determination of the management approach and outcome. Apolipoprotein E (APOE) ε4 is reported to be a risk factor for larger hematoma volume, which might contribute to a poor outcome. However, whether APOE ε4 is related to progressive hemorrhagic injury (PHI), a common occurrence in the clinical setting, remains unclear. In this study, the authors aimed to investigate the association between the APOE genotype and occurrence of PHI. METHODS: This prospective study included a cohort of 123 patients with traumatic intracerebral hemorrhage who initially underwent conservative treatment. These patients were assigned to the PHI or non-PHI group according to the follow-up CT scan. A polymerase chain reaction and sequencing method were carried out to determine the APOE genotype. Multivariate logistic regression analysis was applied to identify predictors of PHI. RESULTS: The overall frequency of the alleles was as follows: E2/2, 0%; E2/3, 14.6%; E3/3, 57.8%; E2/4, 2.4%; E3/4, 22.8%; and E4/4, 2.4%. Thirty-four patients carried at least one allele of ε4. In this study 60 patients (48.8%) experienced PHI, and the distribution of the alleles was as follows: E2/2, 0%; E2/3, 5.7%; E3/3, 22.8%; E2/4, 2.4%; E3/4, 16.3%; and E4/4, 1.6%, which was significantly different from that in the non-PHI group (p = 0.008). Additionally, the late operation rate in the PHI group was significantly higher than that in the non-PHI group (24.4% vs 11.4%, p = 0.002). Multivariate logistic regression identified APOE ε4 (OR 5.14, 95% CI 2.40-11.62), an elevated international normalized ratio (OR 3.57, 95% CI 1.61-8.26), and higher glucose level (≥ 10 mmol/L) (OR 3.88, 95% CI 1.54-10.77) as independent risk factors for PHI. Moreover, APOE ε4 was not a risk factor for the coagulopathy and outcome of the patients with traumatic intracerebral hemorrhage. CONCLUSIONS: The presence of APOE ε4, an elevated international normalized ratio, and a higher glucose level (≥ 10 mmol/L) are predictors of PHI. Additionally, APOE ε4 is not associated with traumatic coagulopathy and patient outcome.

RCC2 promotes proliferation and radio-resistance in glioblastoma via activating transcription of DNMT1.

Regulator of chromosome condensation 2 (RCC2) is a regulator of cell-cycle progression linked in multiple cancers to pro-tumorigenic phenomena including promotion of tumor growth, tumor metastases and poorer patient prognoses. However, the role of RCC2 in GBM remains under-investigated. Here, we sought to determine the relevance of RCC2 in GBM, as well as its roles in GBM development, progression and prognosis. Initial clinical evaluation determined significant RCC2 enrichment in GBM when compared to normal brain tissue, and elevated expression was closely associated with a poorer prognosis in glioma patients. Via shRNA inhibition, we determined that RCC2 is essential to tumor proliferation and tumorigenicity in vitro and in vivo. Additionally, RCC2 was determined to promote radioresistance of GBM tumor cells. Investigation of the underlying mechanisms implicated DNA mismatch repair, JAK-STAT pathway and activated transcription of DNA methyltransferase 1 (DNMT1). For validation, pharmacologic inhibition via administration of a DNMT1 inhibitor demonstrated attenuated GBM tumor growth both in vitro and in vivo. Collectively, this study determined a novel therapeutic target for GBM in the form of RCC2, which plays a pivotal role in GBM proliferation and radio-resistance via regulation of DNMT1 expression in a p-STAT3 dependent manner.

RETRACTED: Serine/threonine kinase BUB1 promotes proliferation and radio-resistance in glioblastoma.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The article has been retracted for the following reasons: The authors have informed the journal that in the published version, the authors showed that that BUB1 inhibitor confers higher cell killing effect for irradiation treatment. This conclusion was based on two experimental evidences. First, the irradiation treatment showed greater cytotoxicity for in vitro cell growth when combined with BUB1 inhibitor. Second, the FACS data showed that the combination of irradiation and BUB1 inhibitor induced significantly higher apoptosis rate of GBM tumor cells, in comparison with irradiation alone. After the acceptance of the article, the authors reported that they found that it was hard to obtain the same result for the cell apoptosis experiment. Because of the doubtful result, the authors currently do not have enough evidence to support the conclusion (the combination of BUB1 inhibition and irradiation is a potential clinical strategy). However, the overall purpose of this manuscript is to identify potential therapeutic target for GBM and as it stands it may mislead other researchers.