LncRNA CCAT2, involving miR-34a/TGF-ß1/Smad4 signaling, regulate hepatic stellate cells proliferation.

miR-34a targeting on Smad4 plays important role in TGF-ß1 pathway which is a dominant factor for balancing collagen production and degradation in hepatic stellate cells. TGF-ß1/Smad4 regulated collagen deposition is a hallmark of hepatic fibrosis. The potential regulation on miR-34a by LncRNAs in hepatic stellate cells (HSCs) is still reserved to be revealed. In current study, it was hypothesized that a miR-34a interactor, lncRNA CCAT2 may regulate TGF-ß1 pathway in liver fibrotic remodeling. The interaction between CCAT2 and miR-34a-5p was checked by dual luciferase assay. the effects of CCAT2 and miR-34a-5p on cell proliferation and apoptosis were verified by MTT assay, colony formation assay, and flow cytometry assay. Dual luciferase activity showed CCAT2 are targets of miR-34a-5p. Sh-CCAT2 transfection prohibit HSCs proliferation and induce HSCs apoptosis, also inhibited ECM protein synthesis in HSCs. Decreased miR-34a-5p enhanced HSCs proliferation, blocked HSCs apoptosis and promoted ECM protein production. miR-34a-5p inhibitor undo protective regulation of sh-CCAT2 in liver fibrosis. Furthermore, clinical investigation showed that CCAT2 and Smad4 expression level were significantly induced, while miR-34a-5p was significantly decreased in HBV related liver fibrosis serum. In conclusion, activated HSCs via TGF-ß1/Smad4 signaling pathway was successfully alleviated by CCAT2 inhibition through miR-34a-5p elevation.

METTL16 regulates m6A methylation on chronic hepatitis B associated gene HLA-DPB1 involved in liver fibrosis.

The role of genetic factors in the occurrence and progression of CHB (CHB) is still not fully explored. In recent years, genome-wide association studies on CHB patients have demonstrated that a large number of CHB-associated single nucleotide polymorphisms exist in the gene intron, which may regulate expression at the transcriptional level. Modification of RNA m6A methylation is one of the key mechanisms regulating gene expression. Here we show that METTL16, an m6A regulator involved in mRNA intron splicing, is differentially expressed in CHB the tissue of patients who has definite diagnosis of mild and severe fibrosis. At the same time, there are also significant differences in the expression of CHB-associated genes such as HLA-DPA1 and HLA-DPB1. The expression of HLA-DPB1 is related to METTL16. Furthermore, analyses of RNA binding of METTL16 and HLA-DPB1 show that the silencing of METTL16 in astrocytes downregulates m6A and expression of HLA-DPB1. In conclusion, METTL16 participates in the progression of CHB fibrosis by regulating the m6A level and expression of HLA-DPB1.

Identification of PLA2G7 as a novel biomarker of diffuse large B cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma globally, and patients with relapsed or refractory DLBCL typically experience poor long-term outcomes. METHODS: Differentially expressed genes associated with DLBCL were identified using two GEO datasets in an effort to detect novel diagnostic or prognostic biomarkers of this cancer type, after which receiver operating characteristic curve analyses were conducted. Genes associated with DLBCL patient prognosis were additionally identified via WCGNA analyses of the TCGA database. The expression of PLA2G7 in DLBCL patient clinical samples was further assessed, and the functional role of this gene in DLBCL was assessed through in vitro and bioinformatics analyses. RESULTS: DLBCL-related DEGs were found to be most closely associated with immune responses, cell proliferation, and angiogenesis. WCGNA analyses revealed that PLA2G7 exhibited prognostic value in DLBCL patients, and the upregulation of this gene in DLBCL patient samples was subsequently validated. PLA2G7 was also found to be closely linked to tumor microenvironmental composition such that DLBCL patients expressing higher levels of this gene exhibited high local monocyte and gamma delta T cell levels. In vitro experiments also revealed that knocking down PLA2G7 expression was sufficient to impair the migration and proliferation of DLBCL cells while promoting their apoptotic death. Furthmore, the specific inhibitor of PLA2G7, darapladib, could noticeably restrained the DLBCL cell viability and induced apoptosis. CONCLUSIONS: PLA2G7 may represent an important diagnostic, prognostic, or therapeutic biomarker in patients with DLBCL.

Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Outcome of Immune Checkpoint Inhibitors.

A meta-analysis of 14 studies (16 cohorts) incorporating 1751 participants was performed to evaluate the correlation between baseline neutrophil-to-lymphocyte ratio (NLR) and outcome of immune checkpoint inhibitors (ICI). The pooled hazard ratio (HR) suggested elevated pretreatment NLR was associated with poor OS (HR: 2.61, 95% confidence intervals (CI): 1.77-3.86, p < 0.00001) and PFS (HR: 1.74, 95% CI: 1.34-2.27, p < 0.0001). Stratified analyses on tumor types, ICI agents, the cutoff value of NLR and study regions exhibited the similar outcomes. This study demonstrated that elevated NLR was a predictor of poor OS and PFS for ICI.

Laboratory analysis on the surface runoff pollution reduction performance of permeable pavements.

Permeable pavements are used to address the water quality impacts of urbanization. However, few quantitative relations are available on their pollutant removal performance with respect to varying conditions, especially for different components of a permeable pavement. Individually, the water quality performance of the surface pavement layer and gravel layer of a permeable pavement under various conditions was determined in laboratory-scale pavement cells. Our aim was to reveal the manner in which different factors influence the ability of these two layers to remove total suspended solids (TSS), nutrients, including nitrate (NOx-N), ammonia (NH4-N) and phosphorous (TP), chemical oxygen demand (COD), and heavy metals (copper (Cu), lead (Pb), cadmium (Cd), and zinc (Zn)), and to provide quantitative understanding of these influences. The removal efficiencies of most stormwater runoff pollutants showed a significant variation with changing rainfall intensity. NH4-N, NOx-N, TP, and TSS removal exhibited statistically negative linear relationship with rainfall intensity. TSS removal was negatively correlated with TSS concentration for the gravel layer, whereas no obvious trend was observed for the surface pavement layer. The statistical results obtained demonstrate that TSS, NH4-N, NOx-N, TP, and COD were removed mainly by the surface pavement layer. A smaller gravel gradation was more effective for removing most pollutants, except for NOx-N and COD. Positive linear relationships were observed between the gravel layer thickness and pollutant (TSS, TP, NH4-N, Cu, and Cd) removal. More importantly, a simple mathematical model was developed to predict the overall performance of the permeable pavement system. By comparing with the overall measured performance, a good performance was achieved, illustrating its promising application in the design of permeable pavements.

CDK4/6 Inhibitor Palbociclib Amplifies the Radiosensitivity to Nasopharyngeal Carcinoma Cells via Mediating Apoptosis and Suppressing DNA Damage Repair.

BACKGROUND: Radiotherapy is the primary approach for nasopharyngeal carcinoma (NPC). Although high survival rates can be obtained with radiation for early stage lesions, distant metastasis and local recurrence frequently occur. In this study, we pioneeringly investigated the antitumor activity and underlying mechanism of cyclin-dependent kinase 4/6 inhibitor (palbociclib) combined with radiation on NPC cells. METHODS: Evaluation of radiation enhancement with palbociclib was based on results from CCK8 and clonogenicity assays for cell proliferation, flow cytometry for apoptosis, ROS level and cell cycle and immunocytochemistry for DNA double-strand break repair. RESULTS: Palbociclib inhibited cellular growth of RB-proficient CNE-1 and CNE-2 via reducing RB phosphorylation and arresting cell cycle. Combination regimens of palbociclib plus radiation were significantly superior to palbociclib or radiation only through inhibiting cellular growth and inducing apoptosis. Moreover, the antitumor activity of both concurrent palbociclib plus radiation and radiation followed by palbociclib consistently preceded that of palbociclib followed by radiation. Meanwhile, the two preferable combination regimens possessed higher proportion of G2/M phase cells, evidently inhibited DNA double-strand break repair and eventually triggered tumor cell apoptosis. CONCLUSION: Our study demonstrated that palbociclib could provoke a strong antitumor activity as a potential adjuvant to radiation therapy for NPC harboring RB expression.

Predictive value of positron emission tomography for the prognosis of molecularly targeted therapy in solid tumors.

OBJECTIVE: This study aimed at comprehensively exploring the value applying positron emission tomography (PET) to predict the effect of molecularly targeted therapy in solid tumors. MATERIALS AND METHODS: A systematic search was performed for potentially relevant studies from the time of inception to February 2017. The primary endpoints were progression-free survival (PFS), overall survival (OS), and time to progression (TTP). The results were analyzed by Review Manager version 5.3 (RevMan 5.3) statistical software. Subgroup analyses were implemented based on the type of molecularly targeted agents (monoclonal antibodies arm and small molecular targeted agents arm), mechanism (erlotinib/gefitinib arm and bevacizumab arm), radioactive tracers, type of tumor, and reevaluated PET timing. RESULTS: Twenty-six studies incorporating 865 individuals were eligible. Compared with PET nonresponse group, PET response group displayed a decrease in maximal standard uptake value (SUVmax), which was associated with a significantly prolonged PFS (HR =0.41, 95% CI [0.29, 0.59]; P<0.00001), OS (HR =0.52, 95% CI [0.40, 0.67]; P<0.00001), and TTP (HR =0.30, 95% CI [0.14, 0.66]; P=0.003). Similar results were obtained in the subgroup analyses of PFS in erlotinib/gefitinib arm and small molecular targeted agents arm; and OS in lung cancer arm, erlotinib/gefitinib arm, bevacizumab arm, small molecular targeted agents arm, monoclonal antibodies arm, 18F-fluorodeoxythymidine (18F-FLT) arm, 18F-fluorodeoxyglucose (18F-FDG) arm, and early PET timing arm. CONCLUSION: Our study demonstrated that PET was a favorable approach to predict the prognosis of molecularly targeted therapy for solid tumors. PET assessment within 2 weeks could be useful to predict clinical outcome.

Evaluation on Efficacy and Safety of Arsenic Trioxide Plus Transcatheter Arterial Chemoembolization Versus Transcatheter Arterial Chemoembolization alone for Unresectable Primary Liver Cancer

Currently, some clinical trials of arsenic trioxide (As203) plus transcatheter arterial chemoembolization (TACE) in the treatment of unresectable primary liver cancer (PLC) had been conducted, but the results were controversial. Therefore, we performed a meta-analysis on 14 clinical trials (1076 cases) to evaluate efficacy and safety of As203 plus TACE versus TACE alone for unresectable PLC. The primary end points included objective response rate (ORR), karnofsky performance score (KPS) improvement rate, and 1-year survival rate. The second end points were adverse events consisting of leukopenia, liver dysfunction, nausea/vomiting, fever, myelosuppression and pain. Our study showed that, compared with TACE alone, As203 plus TACE appeared a significant benefit on ORR (RR = 1.32, 95% CI: 1.15,1.50, P < 0.0001), KPS improvement rate (RR = 1.24, 95% CI: 1.03,1.48, P = 0.02) and 1-year survival rate (RR = 1.31, 95% CI: 1.15,1.49, P < 0.0001). Additionally, no remarkable difference of adverse events were observed between two arms: leukopenia (RR = 1.44, 95% CI: 0.90,2.32, P = 0.13), liver dysfunction (RR = 0.96, 95% CI: 0.76,1.21, P = 0.71), nausea/vomiting (RR = 1.10, 95% CI: 0.84,1.44, P = 0.48), fever (RR = 1.15, 95% CI: 0.82,1.61, P = 0.43), myelosuppression (RR = 1.07, 95% CI: 0.74,1.56, P = 0.72) and pain (RR = 0.88, 95% CI: 0.57,1.36, P = 0.57). This study demonstrated that As203 plus TACE produced a favorable efficacy without enhancing adverse events and was a promising combination therapy option for unresectable PLC.

Correlation between EGFR mutation status and the incidence of brain metastases in patients with non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Numerous studies have been performed to investigate the correlation between epidermal growth factor receptor (EGFR) mutation status and the incidence of brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC), however, the outcomes were inconsistent. Thus, we performed this study to establish the role of EGFR mutation status in BMs. METHODS: Electronic databases PubMed, Embase, Cochrane Library, CBM, WanFang, CNKI were searched to identify relevant trials. The primary endpoint was the incidence of BMs in EGFR mutations or wild type NSCLC and the secondary endpoint was overall survival calculated from the BMs emerging (BMOS). RESULTS: Twenty-two studies incorporating 8,152 participants were eligible. EGFR mutations group possessed a significantly higher risk of BMs (OR =1.99; 95% CI, 1.59-2.48; P=0.000) than EGFR wild type group. In the stratified analysis, compared with EGFR wild type group, EGFR mutations group had a significant higher incidence (OR =2.01; 95% CI, 1.56-2.59; P=0.000) of subsequent BMs while only a trend of increasing the incidence of initial BMs (OR =1.38; 95% CI, 0.98-1.94; P=0.066). Moreover, exon 19 deletion had a trend of increasing the incidence of BMs than exon 21 mutation (OR =1.44; 95% CI, 0.77-2.68; P=0.252). Compared with EGFR wild type group, EGFR mutations group possessed a prolonged overall BMOS (HR =0.68; 95% CI, 0.47-0.98; P=0.038) and a longer BMOS in initial BMs (HR =0.50; 95% CI, 0.31-0.80; P=0.004) but no significant difference in NSCLC with subsequent BMs (HR =0.95; 95% CI, 0.42-2.15; P=0.901). CONCLUSIONS: Patients with EGFR mutations were more susceptible to develop into BMs than those with EGFR wild type, especially during the course of disease.