Prognostic effect of a novel long noncoding RNA signature and comparison with clinical staging systems for patients with hepatitis B virus-related hepatocellular carcinoma after hepatectomy.

OBJECTIVES: We aimed to establish a novel prognostic long noncoding RNA (lncRNA) signature for hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) patients after hepatectomy and to validate its prognostic efficacy compared with other clinical staging systems. METHODS: Expression data of 374 HCC samples were retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression analyses were performed to develop the lncRNA model. The expression levels of lncRNAs were detected by qualitative real-time polymerase chain reaction (qRT-PCR) in HBV-HCC. Then the qRT-PCR-based signature and nomogram were constructed and compared with those of other clinical staging systems in a clinical cohort and qRT-PCR, RNA fluorescent in situ hybridization and comprehensive bioinformatics analyses were conducted. RESULTS: The signature containing five lncRNAs was constructed through TCGA. This model showed the highest predictive efficacy in patients with HBV-HCC. Compared with normal liver tissues, all lncRNAs were highly expressed in HBV-HCC. A four-lncRNA signature containing LINC01116, DDX11-AS1, LUCAT1 and FIRRE was developed based on the qRT-PCR data in a clinical HBV-HCC patient cohort. A Kaplan-Meier analysis indicated that the low-risk group had significantly longer overall survival than the high-risk group. Additionally, the qRT-PCR-based four-lncRNA formula was an independent prognostic factor and had better predictive efficacy for survival (area under the receiver operating characteristic curve 0.875) compared with other clinical staging systems in HBV-HCC. The lncRNA-mRNA co-expression and enrichment analyses revealed the potential regulatory mechanisms of the lncRNA identified. CONCLUSION: The four-lncRNA model may be an effective prognostic signature and provides potential prognostic biomarkers and therapeutic targets for HBV-HCC.

TRIM31 enhances chemoresistance in glioblastoma through activation of the PI3K/Akt signaling pathway.

Temozolomide (TMZ) resistance is a complication of treatment of glioma, and new strategies are urgently required to overcome chemoresistance in glioma cells. In the present study, it was demonstrated that tripartite motif-containing 31 (TRIM31) was abnormally upregulated in glioma tissues and cell lines compared with normal samples. Furthermore, the role of TRIM31 was assessed by overexpressing and knocking down its expression. Overexpression of TRIM31 increased cell viability, increased TMZ IC50 values and inhibited apoptosis in A172 and U251 cells; whereas overexpression of TRIM31 decreased the expression of the apoptosis-associated protein p53. Knockdown of TRIM31 increased apoptosis in cells treated with TMZ. Additionally, the mechanisms by which TRIM31 affected glioma cells treated with TMZ were determined. Overexpression of TRIM31 increased phosphorylation of AKT and inhibiting the PI3K/AKT signaling pathway abolished the increase in cell viability and decreased phospho-Akt protein expression in TRIM31 overexpressing A172 cells treated with TMZ. Together, the findings suggest that TRIM31 may be a potentially novel target for glioma chemotherapy.

Efficacy and safety of combination therapy of chemoembolization and radiofrequency ablation with different time intervals for hepatocellular carcinoma patients.

BACKGROUND AND OBJECTIVES: Combination of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) has become an effective alternative therapy for hepatocellular carcinoma (HCC). In clinical practice, the choice of time interval between TACE and RFA is a key point for curative effect, but optimal time interval is uncertain in guidelines. We aim to explore the optimal time interval for HCC patients of Child-Pugh classification A or B. METHODS: Two hundred and thirty-three HCC patients of Child A or B who had undergone TACE and RFA were enrolled and divided into seven groups according to different time intervals (1-7weeks). Tumor damage, liver function, complications and survival time of patients after treatment were analyzed. RESULTS: Complete remission rate and total effective rate decreased in groups with the prolonged time interval (p < 0.05). Average Child-Pugh score of patients in first three groups significantly increased one month after combination treatment (p < 0.01). While that not happened in other groups. Complications occurred in 16.7% patients, similarly occurred in groups (p > 0.1). Median survival time in groups four and five were 42 months, longer than other groups (p < 0.01). CONCLUSION: A period of 3-5 weeks is the optimal time interval between TACE and RFA for HCC patients of Child-Pugh classification A or B.

Efficacy and safety of proprotein convertase subtilisin/kexin type 9 monoclonal antibody in adults with familial hypercholesterolemia.

Proprotein convertase-subtilisin/kexin type 9 (PCSK9) monoclonal antibody is a new therapy to reduce low-density lipoprotein cholesterol (LDL-C) level in patients with familial hypercholesterolemia (FH). This pooled analysis aimed to estimate the efficacy and safety of PCSK9 antibody therapy in FH. Reports of randomized controlled trials (RCTs) comparing PCSK9 antibody to placebo were retrieved by a search of MEDLINE via PubMed, EMBASE, the Cochrane Library databases, ClinicalTrials.gov and Clinical Trial Results (up to November 30, 2015) with no language restriction. Data were abstracted by a standardized protocol. We found eight RCTs (1,879 patients with FH) for the pooled analysis. As compared with placebo, PCSK9 antibody therapy remarkably reduced LDL-C level (mean reduction: -48.54 %, 95 % CI: -53.19 to -43.88), total cholesterol (mean reduction: -31.08%, 95 % CI: -35.20 to -26.95), lipoprotein (a) (mean reduction: -20.44%, 95 % CI: -25.21 to -15.66), and apolipoprotein B (mean reduction: -36.32%, 95 % CI: -40.75 to -31.90) and elevated the level of high-density lipoprotein cholesterol (mean change: 6.29 %, 95 % CI: 5.12 to 7.46) and apolipoprotein A1(mean change: 4.86%, 95 % CI: 3.77 to 5.95). Therapy with and without PCSK9 antibodies did not differ in rate of adverse events (pooled rate: 50.86 % vs. 48.63%; RR: 1.03; 95 % CI: 0.92 to 1.15; P = 0.64; heterogeneity P = 0.13; I2= 40%) or serious adverse events (pooled rate: 7.14% vs. 6.74%; RR: 1.05; 95 % CI: 0.70 to 1.58; P = 0.80; heterogeneity P = 0.69; I2= 0%). PCSK9 antibody may be an effective and safe treatment for FH.

Tim-4 Inhibits NO Generation by Murine Macrophages.

OBJECTIVE: T cell immunoglobulin- and mucin-domain-containing molecule-4 (Tim-4) receives much attention as a potentially negative regulator of immune responses. However, its modulation on macrophages has not been fully elucidated so far. This study aimed to identify the role of Tim-4 in nitric oxide (NO) modulation. METHODS: Macrophages were stimulated with 100 ng/ml LPS or 100 U/ml IFN-γ. RT-PCR was performed to detect TIM-4 mRNA expression. Tim-4 blocking antibody and NF-κB inhibitory ligand were involved in the study. NO levels were assayed by Griess reaction. Phosphorylation of NF-κB, Jak2 or Stat1 was verified by western blot. RESULTS: Tim-4 was up-regulated in murine macrophages after interferon-gamma (IFN-γ) stimulation. Tim-4 over-expression decreased NO production and inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS) or IFN-γ-stimulated macrophages. Consistently, Tim-4 blockade promoted LPS or IFN-γ-induced NO secretion and iNOS expression. Tim-4 over-expression decreased LPS-induced nuclear factor kappa B (NF-κB) p65 phosphorylation in macrophages, which was abrogated by NF-κB inhibitory ligand. On the contrary, Tim-4 blocking increased LPS-induced NF-κB signaling, which was also abrogated by NF-κB inhibition. In addition, Tim-4 blockade promoted Jak2 and Stat1 phosphorylation in IFN-γ stimulated macrophages. CONCLUSION: These results indicate that Tim-4 is involved in negative regulation of NO production in macrophages, suggesting the critical role of Tim-4 in immune related diseases.