BackgroundIsocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.Methodology and Principal FindingsAn electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.ConclusionOur study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.

Rationale Angiogenesis improves perfusion to the ischemic tissue following acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that apoA-I binding protein (AIBP)-regulated cholesterol efflux in endothelial cells (ECs) controls zebrafish embryonic angiogenesis. Objective This study is to determine whether loss of AIBP affects angiogenesis in mice during development and under pathological conditions, and to explore the underlying molecular mechanism. Methods and Results In this paper, we report the generation of AIBP knockout (Apoa1bp−/−) mice, which are characterized of accelerated postnatal retinal angiogenesis. Mechanistically, AIBP triggered relocalization of γ-secretase from lipid rafts to non-lipid rafts where it cleaved Notch. Consistently, AIBP treatment enhanced DLL4-stimulated Notch activation in human retinal ECs. Increasing HDL levels in Apoa1bp−/− mice by crossing them with apoA-I transgenic mice rescued Notch activation and corrected dysregulated retinal angiogenesis. Notably, the retinal vessels in Apoa1bp−/− mice manifested normal pericyte coverage and vascular integrity. Similarly, in the subcutaneous Matrigel plug assay, which mimics ischemic/inflammatory neovascularization, angiogenesis was dramatically upregulated in Apoa1bp−/− mice and associated with a profound inhibition of Notch activation and reduced expression of downstream targets. Furthermore, loss of AIBP increased vascular density and facilitated the recovery of blood vessel perfusion function in a murine hindlimb ischemia model. In addition, AIBP expression was significantly increased in human patients with ischemic cardiomyopathy. Conclusions Our data reveal a novel mechanistic connection between AIBP-mediated cholesterol metabolism and Notch signaling, implicating AIBP as a possible druggable target to modulate angiogenesis under pathological conditions.

The RVOT pacing in AV block patients over 1 year may be superior to RVA pacing in terms of regional LV performance, LV global electromechanical delay, and IVMD, although intraventricular dyssynchrony and LV volumes do not differ. Larger trials with clinical endpoints are warranted to conclusively define the advantages of RVOT or RV septal pacing.

BackgroundMyeloma bone disease (MBD) can cause bone destruction and increase the level of Ca2+ concentration in the bone marrow microenvironment by stimulating osteoclastic differentiation. Nevertheless, the relationships between MBD and highly efficient stimuli of Ca2+ in multiple myeloma (MM) progression, and possible regulatory mechanisms are poorly defined. Here, we reported that the nonselective cation channel transient receptor potential vanilloid 2 (TRPV2) plays a functional role in Ca2+ oscillations and osteoclastogenesis.MethodsTo investigate the expression of TRPV2 in MM, we analyzed publicly available MM data sets and performed immunohistochemistry in MM patients. The correlations between TRPV2 expression levels and osteoclast-related cytokines were analyzed. Fluo-4 staining and ELISA assays were used to assess the regulated function of TRPV2 in intracellular Ca2+ and cytokines. Western blotting and Chromatin immunoprecipitation (ChIP) assays were performed to explore the signaling pathway of TRPV2-induced osteoclastic differentiation. Real-time PCR, Western blotting, ELISA and tartrate-resistant acid phosphatase (TRAP) staining were performed to detect the biological effects of TRPV2 inhibitor on osteoclastogenesis.ResultsThe functional expression of TRPV2, involved in the osteolysis through gating the calcium influx, was changed in the MM cells cultured in a high Ca2+ environment. Mechanistically, TRPV2 modulates nuclear factor-κB ligand (RANKL)-dependent osteoclastic differentiation through the Ca2+-calcineurin-NFAT signaling pathway. Of clinical relevance, systemic administration with SKF96365 could attenuate the MM-induced osteoclast formation in vitro.ConclusionsOur study uncovers the possible roles of TRPV2, which enhances MBD, suggesting that targeting osteocyte-MM cells interactions through blockade of TRPV2 channel may provide a promising treatment strategy in MM.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0280-8) contains supplementary material, which is available to authorized users.

Background/Aims: Long non-coding RNA maternally expressed gene 3 (MEG3) has been reported to play an essential role in cancer progression and metastasis. However, the overall biological role and regulatory mechanism of MEG3 in multiple myeloma (MM) development and progression remains largely ill-defined. Methods: MEG3 and miR-181a expression of MM patients were analyzed by publicly available MM data sets. Cell counting kit-8 and flow cytometry analysis were used to identify the function of MEG3 on MM in vitro. Additionally, we conducted tumor formation experiments in mice models to explain the role of MEG3 on MM in vivo. Then, several mechanism experiments, including dual-luciferase reporter assay and RNA immunoprecipitation were performed to evaluate the emulative relationship between MEG3 and miR-181a. Results: In this research, we found that MEG3 was downregulated in MM patients, which was linked with tumor progression. In addition, we demonstrated that miR-181a was overexpressed in MM patients in consistent with its cancer-promoting function. Importantly, several mechanism experiments revealed that MEG3, acting as an endogenous competitive RNA, could contend with miR-181a to inhibit tumor progression. Furthermore, as the target mRNA of miR-181a, homeobox gene A11(HOXA11) could be positively regulated by MEG3 through sponging miR-181a competitively in vitro. Conclusion: Our present work supplies the first discovery of a MEG3/miR-181a/HOXA11 regulatory network in MM and highlights that MEG3 may serve as a promising target for MM therapy in the future.

RhoA, a member of Rho GTPases family, is known to play an important role in remodeling actin cytoskeleton. During the development of the peripheral nervous system (PNS), Schwann cells undergo proliferation, migration, and radial sorting and finally wrap the related axons compactly to form myelin sheath. All these processes involve actin cytoskeletal remodeling. However, the role of RhoA on Schwann cell during development is still unclear. To address this question, we first used a lentiviral vector-mediated short hairpin (sh) RNA targeting RhoA to knock down the expression of RhoA in the cultured Schwann cells in vitro. Effects of RhoA on Schwann cell proliferation and migration were examined by BrdU assay and transwell assay, respectively. Results of the present study indicated that downregulated RhoA expression in cultured Schwann cells significantly slacked the cells' capabilities of migration and proliferation. Then, we investigated the role of RhoA in the developing rat sciatic nerves. Immunohistology and Western blotting showed that RhoA was mainly expressed in Schwann cells in the sciatic nerves and was peaked at 2 weeks postnatal then kept in low level up to 8 weeks. In the subjected rats whose sciatic nerves were microinjected with lentiviral vectors at postnatal 3 days, we found that the lentiviruses mainly transfected Schwann cells, and the RhoA expression in the transfected Schwann cells was significantly knocked down. Four weeks after lentivirus microinjection, immunohistology and transmission electron microscopy illustrated that RhoA knockdown resulted in hypomyelination and significant decrease of the thickness of myelin in the transfected area. Overall data of current study suggested that RhoA plays a critical role in Schwann cell biology and is essential for myelination in developing peripheral nerve.

PurposeCTLA-4 is one of the most fundamental immunosuppressive cotykines which belongs to the immunoglobulin super-family, and is expressed mainly on activated T cells. Previous studies have reported the existence of CTLA4 60G/A and CTLA4 -1661A/G polymorphism in cancers. However, the effects remain conflicting. Hence, we performed a meta-analysis to investigate the association between these polymorphisms and cancer risk.MethodsWe searched the Pubmed and Web of Science databases until October 24, 2013 to obtain relevant published studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the relationship between CTLA4 gene polymorphisms and cancer susceptibility were calculated by stata 11 software. Heterogeneity tests, sensitivity analyses and publication bias assessments were also performed in our meta-analysis.ResultsA total of 22 articles comprising 31 case-control studies concerning the CTLA-4 60G/A and CTLA-4 -1661A/G polymorphisms were included in the meta-analysis. The pooled results suggested the CTLA-4 60G/A polymorphism was significantly associated with an increased skin cancer risk (AA vs. GG: OR = 1.32, 95%CI = 1.09-1.59; AA vs. GA+GG: OR = 1.26, 95%CI = 1.07-1.48). For CTLA-4 -1661 A/G polymorphism, the results showed that the CTLA-4 -1661A/G polymorphism was significantly associated with an increased cancer risk (GA vs. AA: OR = 1.44, 95%CI = 1.13–1.82; GA+GG vs. AA: OR = 1.35, 95%CI = 1.07–1.69; G vs. A: OR = 1.21, 95%CI = 1.01–1.47), especially in gastric cancer, breast cancer, other cancers and in Asians population subgroups.ConclusionOur meta-analysis suggests that the CTLA-4 -1661A/G polymorphism is a potential factor for the susceptibility of cancer, especially in gastric cancer, breast cancer and other cancers, and the CTLA-4 60G/A polymorphism is significantly associated with increased skin cancer risk. The effect of the CTLA-4 -1661A/G polymorphism on cancer susceptibility especially exists in Asians and population based subjects.

Cervical cancer has the second highest incidence rate among cancers in females, accounting for a majority of cancer-related deaths globally. However, the mechanism of cervical cancer pathogenesis is still unclear. UCA1 is considered an oncogene that can transcribe into a long noncoding RNA (lncRNA). This study aimed to determine the function of UCA1 in cervical cancer. A series of experiments involving BrdU, MTS, scratch-adhesion test, and cell invasion assays were conducted to determine the cellular capabilities of proliferation, viability, migration, and invasion, respectively. Binding sites between UCA1 and miR-143 were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT-PCR and immunoblot, respectively. The results shown that the upregulation of lncRNA UCA1 was found in human cervical cancer. Interference of lncRNA UCA1 inhibited cell proliferation, migration, invasion, and viability. Results of the luciferase reporter assay revealed a binding site between lncRNA UCA1 and miR-206. Knockdown of lncRNA UCA1 could directly upregulate miR-206 expression. VEGF downregulation was also observed after knockdown of lncRNA UCA1. Moreover, co-transfection of anti-miR-206 oligodeoxyribonucleotide (AMO-206) in cervical cancer cells reversed the effect of lncRNA UCA1 on VEGF. Therefore, we concluded that LncRNA UCA1 is upregulated in cervical cancer, and its knockdown can upregulate miR-206, thus, suppressing the growth of cervical cancer cells. LncRNA UCA1 is a potential target in cervical cancer treatment.