Microplastics in three types of human arteries detected by pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS).

Microplastics are ubiquitous in the environment. Human body can be exposed to microplastics through inhalation and ingestion and some microplastics can enter the blood and accumulate in various tissues and organs throughout the body. Animal experiments have suggested that microplastics may promote atherosclerosis. However, data on microplastics in human arteries and clinical evidence supporting a link between microplastics and atherosclerosis are currently lacking. Pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) was used in this study to detect microplastics in three types of human arteries: coronary and carotid arteries with atherosclerotic plaques, as well as the aorta without plaques. Microplastics were detected in all 17 arterial samples, with an average concentration of 118.66 ± 53.87 µg/g tissue. Four types of microplastics were identified: polyethylene terephthalate (PET, 73.70%), polyamide-66 (PA-66, 15.54%), polyvinyl chloride (PVC, 9.69%), and polyethylene (PE, 1.07%). Most importantly, the concentration of microplastics in arteries containing atherosclerotic plaques, both coronary arteries (156.50 ± 42.14 vs. 76.26 ± 14.86 µg/g tissue, P = 0.039), and carotid arteries (133.37 ± 60.52 vs. 76.26 ± 14.86 µg/g tissue, P = 0.015), was significantly higher than that in aortas which did not contain atherosclerotic plaques, suggesting that microplastics might be associated with atherosclerosis in humans. This study provides valuable data for further hazard assessments of microplastics on human cardiovascular health.

Mutational Landscape and Evolutionary Pattern of Liver and Brain Metastasis in Lung Adenocarcinoma.

INTRODUCTION: A comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships among diverse metastatic lesions from cancer remains limited. METHODS: We performed whole-exome sequencing in 84 tissue and blood samples from 26 patients with lung adenocarcinoma having liver metastases (LiM) or brain metastases (BrM) before any systemic therapy, with the goal to molecularly characterize the metastatic process. Mutational landscape and evolutionary patterns were compared between paired primary lesions (primary lesion of LiM or BrM) and metastases (metastatic site of LiM or BrM). RESULTS: We found that common driver mutations, including TP53 and EGFR, were highly consistent between paired primary and metastatic tumors. Although tumor mutational burden was comparable among groups, the LiM group had significantly higher mutational and copy number variational similarity than the BrM group between paired primary lesions and metastases (p = 0.019 and p = 0.035, respectively). Phylogenetic analysis further revealed that LiM-competent disseminations had a higher level of genetic similarity to their paired primary lesions and were genetically diverged from their primary tumors at a relatively later stage than those of BrM. These results suggest that LiM favorably followed the linear progression model, whereas BrM was more consistent with the parallel progression model. CONCLUSIONS: This study suggests that the mutational landscape and evolutionary pattern was distinctly different between the LiM and BrM of lung adenocarcinoma.

Integrin Beta 1 Promotes Glioma Cell Proliferation by Negatively Regulating the Notch Pathway.

In this study, genes associated with the Notch signaling pathway in gliomas were analyzed using bioinformatics and in vitro experiments. The dataset GSE22772 was downloaded from the Gene-Cloud of Biotechnology Information database. Differentially expressed genes (DEGs) between short hairpin RNA (shRNA) intervening glioma cells and control cells were screened using the unpaired t test. Functional enrichment analysis was performed, and coexpression network was analyzed to identify the most important genes associated with the Notch signaling pathway. Integrin beta 1 (ITGB1) mRNA and protein levels in clinical glioma tumor samples and tumor adjacent normal tissue samples were analyzed using quantitative real-time PCR and immunohistochemistry, respectively. The relationship between ITGB1 expression and the prognosis of patients with gliomas was analyzed using the Kaplan-Meier curve. ITGB1 interference expression cell line U87 and ITGB1 overexpressing cell line were established using sh-ITGB1 and oe-ITGB1 plasmids, respectively. MTT and colony formation assays were used to detect changes in the proliferation of glioma cells. Moreover, western blotting was used to detect the expression of Notch and Hey1. A total of 7,962 DEGs were screened between shRNA intervening glioma cells and control cells, which were mainly associated with spliceosome, proteoglycans in cancer, focal adhesion, and the Notch signaling pathway. ITGB1 showed the highest expression in the coexpression network. The mRNA and protein expression of ITGB1 in glioma tumor samples was significantly higher than that in tumor adjacent normal tissue samples (p < 0.05). Overall survival time of patients in the ITGB1 low-expression group was significantly longer than that in the ITGB1 high-expression group, indicating that ITGB1 expression negatively correlated with the prognosis. Fluorescence microscopy, qRT-PCR, and western blotting confirmed the transfection efficiency of ITGB1 overexpression and interference expression in U251 and U87 cells. The MTT and colony formation assays indicated that U87 cell proliferation was significantly inhibited after intervention with ITGB1 (p < 0.05), and overexpression of ITGB1 significantly promoted U251 cell proliferation (p < 0.05). In addition, the expression of Notch and Hey1 proteins was significantly decreased after ITGB1 intervention (p < 0.05), and their expression was significantly upregulated after ITGB1 overexpression (p < 0.05). ITGB1 expression in glioma tissues was significantly higher than that in adjacent normal tissues and was negatively correlated with the survival time of patients. Therefore, ITGB1 can significantly promote proliferation of glioma cells via feedback regulation of the Notch signaling pathway.

FOXO1 associated with sensitivity to chemotherapy drugs and glial-mesenchymal transition in glioma.

Mesenchymal subtype of glioblastoma (GBM), identified as one of four clinically relevant molecular subtypes, has worst prognosis because of its close relation with the malignant biological properties induced by glial-mesenchymal transition (GMT). However, the molecular mechanism of GMT and its characterized molecule of GBM have not been studied. Forkhead box protein O1 (FOXO1) is at a convergence point of receptor tyrosine kinase signaling as one of the three core pathways implicated in GBM. Our previous study indicated that the inactivation of FOXO1 involved in the inhibition of GMT is an independent prognosis factor of GBM. In this study, we will further confirm the role of FOXO1 in GMT through cytological experiments to clarify how FOXO1 regulates GMT and its clinical significance. We established virus-infected FOXO1 overexpression and FOXO1 knockdown cells of U373 MG and U251 mediated by lentivirus, based on the effect of which FOXO1-correlated-GMT experiments were performed in vitro and in vivo. Our data suggested that FOXO1 played a crucial role in resistance to TMZ, BCNU, and CDDP; migration and invasion; and stem cell properties of glioma cells. FOXO1 may serve as a targeted biomarker for prediction of sensitivity to chemotherapy drugs, metastasis, and prognosis, which provides a new idea for mesenchymal GBM treatment.

Novel Minimally Invasive Treatment Strategy for Acute Traumatic Epidural Hematoma: Endovascular Embolization Combined with Drainage Surgery and Use of Urokinase.

BACKGROUND: Hematoma evacuation is regular treatment for acute traumatic epidural hematoma (ATEDH) patients meeting with surgery indications. However, it is an invasive approach performed under general anesthesia. Here, a novel minimally invasive method of endovascular embolization with subsequent drainage surgery and use of urokinase was established to treat ATEDH under local anesthesia. METHODS: A novel minimally invasive method of endovascular embolization with subsequent drainage surgery and use of urokinase was established to treat ATEDH under local anesthesia. Firstly, 23 ATEDH patients with hematomas in the temporal area underwent digital subtraction angiography detecting the bleeding point. Next, embolization was performed. After embolization, drainage surgery was taken and urokinase was injected into the hematoma cyst by drainage tube to lyse hematoma twice per day. RESULTS: The results showed that the middle meningeal artery was the bleeding source. Embolization immediately ceased bleeding. Most clots were resolved and drained after treatment. No recurrence of hematoma or infection was observed. CONCLUSION: The findings suggest that the combined treatments can be an alternative minimally invasive option for ATEDHs, especially for elderly patients or those contraindicated for general anesthesia.

Overexpression of leptin receptor in human glioblastoma: Correlation with vasculogenic mimicry and poor prognosis.

Vasculogenic mimicry (VM) was an important tumor blood supply to complement the endothelial cell-dependent angiogenesis, while leptin and receptor (ObR) involved in angiogenesis in glioblastoma has been reported on previous study, but the relationship between ObR expression and VM formation in human glioblastoma tissues, as well as their prognostic significance still remains unclear. In our study, we found that VM recognized by CD31-/PAS+ immunohistochemical staining in glioblastoma tissues showed a positive correlation with leptin expression (r = 0.58, P < 0.01), as well as ObR expression in glioblastoma tissues (r = 0.61, P < 0.01). Association of glial to mesenchymal transition (GMT)-related molecular with ObR expression and VM formation in glioblastoma tissues indicated that ObR-positive glioblastoma cells with GMT phenotype might be more likely to constitute VM, and co-expression of ObR and CD133 or Nestin to constitute the channel impliated that ObR-positive glioblastoma cells displayed glioblastoma stem cells (GSC) properties. Moreover, Kaplan-Meier statistical analysis showed that patients with more VM or ObR expression displayed poorer prognosis for overall survival times than patients with less expression (VMhigh vs. VMlow: P = 0.033; ObRhigh vs. ObRlow: P = 0.009). And ObR+ glioblastoma cells with GSC characteristic were mostly involved in VM formation, whereas a little part of cells were also related to microvascular density (MVD), which suggested that ObR was an important target for anticancer therapy, so further related studies were needed to improve glioblastoma treatment.

Integrated in silico-in vitro characterization, identification and disruption of the intermolecular interaction between SH3 domain-containing protein kinases and human pituitary tumor-transforming gene 1.

The human pituitary tumor-transforming gene-1 (hPTTG1) has been found to be overexpressed in various cancers. Accumulated evidences implicate that some of protein kinases can specifically recognize two PXXP motifs at hPTTG1 C-terminus through their Src homology (SH3) domain and then phosphorylate the protein by their catalytic domain. Here, we integrate in silico analysis and in vitro assay to characterize the intermolecular interaction between the two hPTTG1 motif peptides 161LGPPSPVK168 (M1P) and 168KMPSPPWE175 (M2P) and the SH3 domains of Ser/Thr-specific protein kinases MAP3K and PI3K. It is identified that the two peptides bind to MAP3K SH3 domain with a moderate affinity, but cannot form stable complexes with PI3K SH3 domain. Long time scale molecular dynamics (MD) simulations reveal that the M1P peptide can fold into a standard poly-proline II helix that is bound in the peptide-binding pocket of MAP3K SH3 domain, while the M2P peptide gradually moves out of the pocket during the simulations and finally forms a weak, transient encounter complex with the domain. All these suggest that the MAP3K M1P site is a potential interacting partner of MAP3K SH3 domain, which may mediate the intermolecular recognition between hPTTG1 and MAP3K.

Long Noncoding RNA miR210HG as a Potential Biomarker for the Diagnosis of Glioma.

BACKGROUND: Glioma remains a diagnostic challenge because of its variable clinical presentation and a lack of reliable screening tools. Long noncoding RNAs (lncRNAs) regulate gene function in a wide range of pathophysiological processes and are therefore emerging biomarkers for prostate cancer, hepatic cancer, and other tumor diseases. However, the effective use of lncRNAs as biomarkers for the diagnosis of glioma remains unproven. METHODS: This study included 42 glioma patients and 10 healthy controls. lncRNA and mRNA microarray chips were used to identify dysregulated lncRNAs in tumor tissue and tumor-adjacent normal tissue, and SYBR Green-based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate upregulated lncRNAs. A receiver operating characteristic curve analysis was conducted to evaluate the diagnostic accuracy of the lncRNA identified as the candidate biomarker. RESULTS: miR210HG levels were significantly higher in tumor tissue than in tumor-adjacent normal tissue in participating glioma patients. Serum miR210HG levels were also significantly higher in glioma patients than in healthy controls. The receiver operating characteristic curve showed that serum miR210HG was a specific diagnostic predictor of acute pulmonary embolism with an area under the curve of 0.8323 (95% confidence interval, 0.7347 to 0.9299, p < 0.001). CONCLUSION: Our findings indicate that miR210HG could be an important biomarker for the diagnosis of glioma, and, as such, large-scale investigations are urgently needed to pave the way from basic research to clinical use.

Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor. This study aimed to identify the hub genes and regulatory factors of GBM subgroups by RNA sequencing (RNA-seq) data analysis, in order to explore the possible mechanisms responsbile for the progression of GBM. The dataset RNASeqV2 was downloaded by TCGA-Assembler, containing 169 GBM and 5 normal samples. Gene expression was calculated by the reads per kilobase per million reads measurement, and nor malized with tag count comparison. Following subgroup classification by the non-negative matrix factorization, the differentially expressed genes (DEGs) were screened in 4 GBM subgroups using the method of significance analysis of microarrays. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction (PPI) network was constructed based on the HPRD database. The subgroup-related microRNAs (miRNAs or miRs), transcription factors (TFs) and small molecule drugs were predicted with pre-defined criteria. A cohort of 19,515 DEGs between the GBM and control samples was screened, which were predominantly enriched in cell cycle- and immunoreaction-related pathways. In the PPI network, lymphocyte cytosolic protein 2 (LCP2), breast cancer 1 (BRCA1), specificity protein 1 (Sp1) and chromodomain-helicase-DNA-binding protein 3 (CHD3) were the hub nodes in subgroups 1-4, respectively. Paired box 5 (PAX5), adipocyte protein 2 (aP2), E2F transcription factor 1 (E2F1) and cAMP-response element-binding protein-1 (CREB1) were the specific TFs in subgroups 1-4, respectively. miR­147b, miR­770-5p, miR­220a and miR­1247 were the particular miRNAs in subgroups 1-4, respectively. Natalizumab was the predicted small molecule drug in subgroup 2. In conclusion, the molecular regulatory mechanisms of GBM pathogenesis were distinct in the different subgroups. Several crucial genes, TFs, miRNAs and small molecules in the different GBM subgroups were identified, which may be used as potential markers. However, further experimental validations may be required.

Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis.

Brain metastasis (BM) is the common complication of non-small cell lung cancer (NSCLC) with a poor prognosis and dismal survival rate. This update meta-analysis aimed to derive a more precise estimation of radiotherapy plus epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC patients with BM. PubMed, EMBASE, Web of Science, Google Scholar, and Cochrane Library were searched to identify any relevant publications. After screening the literature and undertaking quality assessment and data extraction, the meta-analysis was performed using STATA Version 12.0. In total, 15 studies involving 1552 participants were included. The results indicated that radiotherapy plus EGFR TKIs was more effective at improving response rate and disease control rate (DCR) (risk ratio (RR) = 1.48, 95% confidence interval [CI]: 1.12-1.96, P = 0.005; RR = 1.29, 95% CI: 1.02-1.60, P = 0.035; respectively) than radiotherapy alone or plus chemotherapy. Moreover, radiotherapy plus EGFR TKIs significantly prolonged the time to central nervous system progression (CNS-TTP) (HR = 0.56, 95% CI [0.33, 0.80]; P = 0.000) and median overall survival (OS) (HR = 0.58, 95% CI [0.42, 0.74]; P = 0.000) but significantly increased adverse events (any grade) (RR = 1.25, 95% CI [1.01, 1.57]; P = 0.009), especially rash and dry skin. These results suggested that radiotherapy plus EGFR TKIs produced superior response rate and DCR and markedly prolonged the CNS-TTP and OS of NSCLC patients with BM. However, combined groups had the higher rate of incidence of overall adverse effects, especially rash and dry skin.

Role of the anti-glioma drug AT13148 in the inhibition of Notch signaling pathway.

OBJECTIVE: To investigate the drug targets related to Notch signaling pathway for glioma treatment. METHODS: Gene expression profiles GSE44561, GSE48079 and GSE22772GSE48079GSE22772 of glioma cells samples with activated Notch signaling pathway and control samples were downloaded from Gene Expression Omnibus database to screen the differentially expressed genes (DEGs) using limma package. GO (Gene Oncology) function and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses were conducted using DAVID tools to predict the underlying function of these DEGs. Sequentially, drug target genes recorded in DrugBank database were collected and matched with the selected DEGs to identify the potential drug targets for glioma. Further, these targets were verified by the screened DEGs in the anti-glioma drug (AT13148) treated samples of microarray data of GSE38008. RESULTS: A total of 75,645,497 DEGs were respectively identified in GSE44561, GSE48079 and GSE22772GSE48079GSE22772 datasets and these DEGs could well distinguish the glioma samples from controls. The DEGs were mainly enriched in classical functions and pathways, such as cell cycle, and DNA replication. A total of 122 DEGs were found to be potential drug targets for glioma, among which GLIPR1 was targeted by drug XL820, PDGFRB and KDR were targeted by SOT-107. Efficacy validation of the other 119 drug targets by GSE38008 data showed that ACSS1, ASL, GCLM, ROCK2, IMPA1, and TFPI may be targeted by the anti-glioma drug of AT13148. CONCLUSION: AT13148 may inhibit glioma progression by suppressing the Notch signaling genes, including GLIPR1, PDGFRB, ACSS1, and ASL.

The association between Salt-inducible kinase 2 (SIK2) and gamma isoform of the regulatory subunit B55 of PP2A (B55gamma) contributes to the survival of glioma cells under glucose depletion through inhibiting the phosphorylation of S6K.

BACKGROUND: PPP2R2C encodes a gamma isoform of the regulatory subunit B55 subfamily consisting PP2A heterotrimeric with A and C subunits. Currently, the precise functions of B55gamma in cancer are still under investigating. In this project, we reported a novel function of B55gamma in the regulation of glucose metabolism in Glioma cells. METHODS: Western blot and immunoprecipitation were performed to determine protein expression and interaction. Cell viability was measured by Typan Blue staining and direct cell counting using hematocytometer. siRNA technology was used to down regulate protein expression. RESULTS: Glucose uptake and lactate product were suppressed by overexpression of B55gamma in Glioma cells. In addition, cancer cells with larger amount of B55gamma showed higher survival advantages in response to glucose starvation through the dephosphorylation of S6K. From proteomic analysis, we found B55gamma binds with and up regulates SIK2 through the stabilization of SIK2 protein which is required for the B55gamma-mediated suppression of S6K pathway. Knocking down of SIK2 in B55gamma over expressing cells recovered the phosphorylation of S6K. CONCLUSION: In summary, our project will provide novel insight into the design and development of therapeutic strategies to target the B55gamma-mediated glucose metabolism for the treatment of human brain tumor patients.

miR-372 regulates glioma cell proliferation and invasion by directly targeting PHLPP2.

MicroRNAs are known to be involved in carcinogenesis and tumor progression in glioma. Recently, microRNA-372 (miR-372) has been proved to play a substantial role in several human cancers, but its functions in glioma remain unclear. In this study, we confirmed that miR-372 was commonly upregulated in glioma cell lines and tissues. Downregulation of miR-372 markedly inhibited cell proliferation and invasion and induced G1/S arrest and apoptosis. Consistently, the xenograft mouse model also unveiled the suppressive effects of miR-372 knockdown on tumor growth. Further studies revealed that miR-372 modulated the expression of PHLPP2 by directly targeting its 3'-untranslated region (3'-UTR) and that miR-372 expression was inversely correlated with PHLPP2 expression in glioma samples. Silencing of PHLPP2 could rescue the inhibitory effect of miR-372 inhibitor. Moreover, miR-372 knockdown suppressed the phosphorylation levels of the major components of PI3K/Akt pathway including Akt, mTOR, and P70S6K. Taken together, our results suggest that miR-372 functions as an oncogenic miRNA through targeting PHLPP2 in glioma.

GAL3 protein expression is related to clinical features of prolactin-secreting pituitary microadenoma and predicts its recurrence after surgical treatment.

BACKGROUND: Previous in vitro study showed that Galectin-3 (Gal-3) protein plays an important role in pituitary tumorigenesis, however, the association of Gal-3 expression with the clinical feature and prognosis of pituitary tumor in a clinical setting remains unknown. METHODS: We enrolled 220 patients with prolactin-secreting pituitary adenomas (PA) who previously had transsphenoidal pituitary surgery. The Gal-3 expression was detected in the patients' PA samples using immunohistochemistry and those patients were followed up. A prolactin-secreting PA cell line, the MMQ cell line, was used to study the in vitro effect of Gal-3 on proliferation, migration and invasion of PA cells using small interfering RNA (siRNA) transfecton technique. The in vivo tumorgenesis in nude mice was also studied. RESULTS: We found that Gal-3 expression was not related to age and sex, but positively associated with tumor invasion (P<0.001), tumor sizes (P<0.001) and pre-operative prolactin levels (P<0.001). The multivariate Cox analysis showed that the Gal-3 expression was closely associated with the recurrence of PA after the surgical treatment (HR =3.15, P=0.002). The in vitro studies showed that Gal-3 knock-down by the siRNA technique significantly inhibited the proliferation, migration and invasion ability of the MMQ cells, whereas Gal-3 siRNA transfection induced apoptosis of the MMQ cells. The in vivo tumorgenesis assay showed that Gal-3 siRNA transfection significantly inhibited the tumor volume in vivo compared to transfection of the control siRNA (P<0.001). CONCLUSION: Gal-3 regulates proliferation, apoptosis, migration and invasion of the MMQ cells. Gal-3 may be used as a tissue marker to evaluate the clinical feature and prognosis of PA patients.

The histone deacetylase SIRT6 suppresses the expression of the RNA-binding protein PCBP2 in glioma.

More than 80% of tumors that occur in the brain are malignant gliomas. The prognosis of glioma patients is still poor, which makes glioma an urgent subject of cancer research. Previous evidence and our present data show that PCBP2 is over-expressed in human glioma tissues and predicts poor outcome. However, the mechanism by which PCBP2 is regulated in glioma remains elusive. We find that SIRT6, one of the NAD(+)-dependent class III deacetylase SIRTUINs, is down-regulated in human glioma tissues and that the level of SIRT6 is negatively correlated with PCBP2 level while H3K9ac enrichment on the promoter of PCBP2 is positively correlated with PCBP2 expression. Furthermore, we identify PCBP2 as a target of SIRT6. We demonstrate that PCBP2 expression is inhibited by SIRT6, which depends upon deacetylating H3K9ac. Finally, our results reveal that SIRT6 inhibits glioma cell proliferation and colony formation in vitro and glioma cell growth in vivo in a PCBP2 dependent manner. In summary, our findings implicate that SIRT6 inhibits PCBP2 expression through deacetylating H3K9ac and SIRT6 acts as a tumor suppressor in human glioma.

Leptin enhances the invasive ability of glioma stem-like cells depending on leptin receptor expression.

Glioma stem-like cells have been demonstrated to have highly invasive activity, which is the major cause of glioma recurrence after therapy. Leptin plays a role in glioma invasion, however, whether and how leptin contributes to the biological properties of glioma stem-like cells, such as invasion, remains to be explored. In the current study, we aimed to explore the role of leptin during glioma stem-like cells invasion as well as the signaling pathway. We found that glioma stem-like cells exhibited high invasive potential, especially in the presence of leptin, Ob-R coexpressed with CD133 in glioma stem-like cells was showed to be responsible for leptin mediated invasion of glioma stem-like cells. Our results indicated that leptin served as a key intermediary linking the accumulation of excess adipokine to the invasion of glioma stem-like cells, which may be a novel therapeutic target for suppressing tumor invasion and recurrence.

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma.

Glioblastoma is a highly aggressive malignant disease with notable resistance to chemotherapy. In this study, we found that leptin receptor (ObR)-positive glioblastoma cells were resistant to temozolomide (TMZ), and TMZ-resistant cells exhibited high expression of ObR. ObR can serve as a marker to enrich glioblastoma cells with some stem/progenitor cell traits, which explained the reason for TMZ resistance of ObR+ cells. STAT3-mediated SOX2/OCT4 signaling axis maintained the stem/progenitor cell properties of ObR+ cells, which indirectly regulated glioblastoma TMZ resistance. These findings gain insight into the molecular link between obesity and glioblastoma, and better understanding of this drug-resistant population may lead to the development of more effective therapeutic interventions for glioblastoma.

Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM.

BACKGROUND: MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive. METHODS: The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation. RESULTS: Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells. CONCLUSIONS: Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

Association between MTHFR 677C>T polymorphism and risk of gliomas: evidence from a meta-analysis.

Folate metabolism plays an important role in carcinogenesis. Methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism is a genetic alteration in an enzyme involved in folate metabolism, but its effect on risk of gliomas is still uncertain. To shed some light on these contradictory results from previous studies, we performed a meta-analysis of published data investigating the association between MTHFR 677C>T polymorphism and risk of gliomas. PubMed, Embase, and Web of Science databases were searched for eligible case-control studies. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of this association. Ten individual case-control studies from six publications with a total of 1,786 cases and 2,076 controls were included into this meta-analysis. There was no obvious heterogeneity under all comparison models of this meta-analysis. Meta-analysis of those ten studies showed that there was no obvious association between MTHFR 677C>T polymorphism and risk of gliomas under all five genetic models (for T versus C, OR = 1.00, 95 % CI 0.90-1.12, P OR = 0.959; for TT versus CC, OR = 1.02, 95 % CI 0.82-1.27, P OR = 0.870; for CT versus CC, OR = 1.02, 95 % CI 0.89-1.18, P OR = 0.733; for TT+CT versus CC, OR = 1.02, 95 % CI 0.90-1.16, P OR = 0.781; for TT versus CT+CC, OR = 0.99, 95 % CI 0.81-1.21, P OR = 0.902). There was also no obvious association between MTHFR 677C>T polymorphism and risk of gliomas in the sensitivity and subgroup analyses of Caucasians. There was no risk of publication bias in this meta-analysis. The evidence from our meta-analysis supports that there is no association between MTHFR 677C>T polymorphism and risk of gliomas.

Gamma-secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function.

The objective of the current study was to investigate the regulation of VEGF signaling and tumor angiogenesis by gamma-secretase inhibitor DAPT in glioblastoma. Effects of DAPT on VEGFR1, VEGFR2, endothelial cell proliferation and vessel function were evaluated using mouse microvascular endothelial H5V cell line and U87MG xenograft mouse models. We found that DAPT efficiently inhibited Notch signaling, increased VEGFR2 expression, but decreased VEGFR1 expression. DAPT treatment enhanced endothelial cell proliferation when used combined with VEGF, but exerted no effect if used alone. In U87MG xenograft mouse models, DAPT treatment increased tumor vessel density but compromised vessel function, as evidenced by poor perfusion and aggravated hypoxia. Therefore, DAPT treatment results in an uncoupling of tumor vessel density from vessel function and suppresses glioblastoma growth; disturbance of angiogenesis with DAPT presents a novel therapeutic approach for glioblastoma.