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Background and purpose: Anti-programmed death-1 (anti-PD-1) adjuvant therapy and targeted therapy have resulted in longer recurrence-free survival (RFS) for malignant melanoma patients in clinical trials. However, the efficacy of adjuvant anti-PD-1 therapy in Chinese melanoma patients has not been previously reported. The purpose of this study was to retrospectively analyze the RFS in Chinese resected stage Ⅲ malignant melanoma patients treated with adjuvant anti-PD-1 therapy and to preliminarily compare it with BRAFV600 inhibitor vemurafenib. Methods: This study retrospectively collected the information of 120 patients with resected stage Ⅲ malignant melanoma from three major cancer centers in China from August 30, 2018 to August 30, 2020. These patients received adjuvant pembrolizumab/toripalimab or vemurafenib. RFS rates were assessed by Kaplan-Meier curves and log-rank tests were used to examined differences. Results: Among the 90 patients with stage Ⅲ malignant melanoma receiving adjuvant anti-PD-1 therapy, the median-RFS (mRFS) was 16 months (95% CI: 14-18 months); the 12-month RFS rate was 69.5% (95% CI: 64.6%-74.4%) and the 24-month RFS rate was 45.8% (95% CI: 40.5%-51.1%). The mRFS for 30 patients who received vemurafenib was 18 months (95% CI: 10-21 months), the 12-month RFS rate was 62.8% (95% CI: 54.0%-71.6%), and the 24-month RFS rate was 32.9% (95% CI: 27.1%-44.7%). In the stratified analysis, firstly, there was no difference in RFS between anti-PD-1 therapy group and vemurafenib group. Secondly, the BRAFV600E mutation status may did not affect the RFS of anti-PD-1 therapy. In addition, in this study, for the patients with BRAFV600E mutation, the RFS showed no difference between these patients received anti-PD-1 therapy or vemurafenib. Finally, although the RFS was better in patients with cutaneous melanoma than in patients with acral and worst in patients of unknown origin, the data for adjuvant therapy in China were still poor. Conclusion: These are the real-world data from adjuvant anti-PD-1 therapy in patients with resected stage Ⅲ cutaneous and acral melanoma patients in China. In our study, adjuvant anti-PD-1 therapy is indistinguishable from vemurafenib indicates more combination therapies are needed to improve outcome in China.

The Duolong porphyry Cu-Au deposit (5.4 Mt at 0.72% Cu, 41 t at 0.23 g/t Au) was recently discovered in the southern Qiangtang terrane, central Tibet. Here, new whole-rock elemental and Sr-Nd-Pb isotope and zircon Hf isotopic data of syn- and post-ore volcanic rocks and barren and ore-bearing granodiorite porphyries are presented for a reconstruction of magmas associated with Cu-Au mineralization. LA-ICP-MS zircon U-Pb dating yields mean ages of 117.0 ± 2.0 and 120.9 ± 1.7 Ma for ore-bearing granodiorite porphyry and 105.2 ± 1.3 Ma for post-ore basaltic andesite. All the samples show high-K calc-alkaline compositions, with enrichment of light rare earth elements (LREE) and large ion lithophile elements (LILE: Cs and Rb) and depletion of high field strength elements (HFSE: Nb and Ti), consistent with the geochemical characteristics of arc-type magmas. Syn- and post-ore volcanic rocks show initial Sr ratios of 0.7045-0.7055, εNd(t) values of −0.8 to 3.6, (206Pb/204Pb)t ratios of 18.408-18.642, (207Pb/204Pb)t of 15.584-15.672 and positive zircon εHf(t) values of 1.3-10.5, likely suggesting they dominantly were derived from metasomatized mantle wedge and contaminated by southern Qiangtang crust. Compared to mafic volcanic rocks, barren and ore-bearing granodiorite porphyries have relatively high initial Sr isotopic ratios (0.7054-0.7072), low εNd(t) values (−1.7 to −4.0), similar Pb and enriched zircon Hf isotopic compositions [εHf(t) of 1.5-9.7], possibly suggesting more contribution from southern Qiangtang crust. Duolong volcanic rocks and granodiorite porphyries likely formed in a continental arc setting during northward subduction of the Bangong-Nujiang ocean and evolved at the base of the lower crust by MASH (melting, assimilation, storage and homogenization) processes. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Skeletal muscles compose about 50% of the body's masses and consider as the largest organ in the body. Skeletal muscle myogenesis is a highly controlled process. During myogenesis, quiescent muscle stem cells are activated and proliferated response to environmental stress, and then differentiated muscle fiber. The specification, proliferation and termination of skeletal muscle cell are coordinated by expression of different transcriptional factors, including Pax3/Pax7, MyoD, Myf5, Myogenin and MRF4, etc.. Epigenetics can be defined as heritable changes in gene function that occur without primary DNA sequence modification. More and more studies indicated that epigenetic modifications of transcriptional factors control a set of genes expression, which further define myogenesis. This review summarized the mechanism of the " epigenetic network ", including histone tails modification, DNA methylation and miRNA in regulating myogenesis. [ABSTRACT FROM AUTHOR]

Background: Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the major swine pathogens. This virus causes immune suppression and other secondary infections, leading to significant economic losses in the swine industry. Tea seed saponins (TS) are a natural extract from tea seeds with anti-cancer, anti-inflammatory and antiviral activity. In this study, we demonstrated that TS possessed anti-PRRSV activity., Methods: MTT assay and trypan blue staining were used to evaluate the cytotoxicity and antiviral ability of TS in cell culture. Apoptosis was measured to assess the safety of TS on Marc-145 cells. Time-of-addition assay, entry inhibition assay and virucidal assay were used to assess the antiviral action of TS. The effect of TS on host cellular gene expression was analysed by real-time PCR. Absolute quantification RT-PCR and western blot were used to study the inhibitory effect of TS on PRRSV N gene and protein expression., Results: Our results showed that 50% cytotoxic concentrations (CC50) and 50% effective concentration (EC50) of TS were 59.86 ±0.3841 µg/ml and 24.29 ±1.194 μg/ml, respectively. The maximum non-cytotoxic concentration of TS on Marc-145 cells was 30 μg/ml. TS inhibited PRRSV-induced cell apoptosis and effectively inhibited PRRSV replication by reducing the expression of host cellular gene PABP, and significantly inhibited virus N gene/protein expression., Conclusions: TS possessed anti-PRRSV activity in vitro and could serve as a potential antiviral drug for PRRSV prevention and control.

There is a global epidemic of obesity, and obesity is known to inhibit AMP-activated protein kinase (AMPK) activity and impairs myogenesis. Myogenin mediates the fusion of myoblasts into myotubes, a critical step in myogenesis. We observed that inhibition of AMPKα1 downregulates myogenin expression and myogenesis, but the underlying mechanisms are unclear. We postulated that AMPK regulates myogenin expression through phosphorlytion of histone deacetylase 5 (HDAC5). In C2C12 cells, HDAC5 knockdown increased while HDAC5 stablization by MC1568 reduced myogenin expression. Consistently, using luciferase assay, we observed that myogenin promoter activity was negatively regulated by HDAC5. Using RNA interference and primary myoblasts prepared from wild-type and AMPKα1 knockout mice, we further demonstrate that AMPKα1 regulates HDAC5 phosphorylation at Ser 259 and 498. Mutation of these two Ser to Ala in HDAC5 abolished the regulatory role of AMPKα1 on myogenin expression, clearly showing the necessity of these phosphorylation sites in mediating myogenin expression. In aggregate, these data show that AMPK inhibition downregulates myogenin transcription and myogenesis through phosphorylation of HDAC5, mediated mainly by AMPKα1. These data demonstrate that AMPK is a key molecular target for promoting myogenesis and muscular regeneration. Because drugs activating AMPK activity, such as metformin, are widely available, our finding has critical clinical implications to ensure proper muscle development and regeneration in obese subjects and under other pathophysiological conditions where AMPK activity is attenuated.

Aim: To investigate the effect of side-stream smoking on gut microflora composition, intestinal inflammation and expression of tight junction proteins., Methods: C57BL/6 mice were exposed to side-stream cigarette smoking for one hour daily over eight weeks. Cecal contents were collected for microbial composition analysis. Large intestine was collected for immunoblotting and quantitative reverse transcriptase polymerase chain reaction analyses of the inflammatory pathway and tight junction proteins., Results: Side-stream smoking induced significant changes in the gut microbiota with increased mouse intestinal bacteria, Clostridium but decreased Fermicutes (Lactoccoci and Ruminococcus), Enterobacteriaceae family and Segmented filamentous baceteria compared to the control mice. Meanwhile, side-stream smoking inhibited the nuclear factor-κB pathway with reduced phosphorylation of p65 and IκBα, accompanied with unchanged mRNA expression of tumor necrosis factor-α or interleukin-6. The contents of tight junction proteins, claudin3 and ZO2 were up-regulated in the large intestine of mice exposed side-stream smoking. In addition, side-stream smoking increased c-Jun N-terminal kinase and p38 MAPK kinase signaling, while inhibiting AMP-activated protein kinase in the large intestine., Conclusion: Side-stream smoking altered gut microflora composition and reduced the inflammatory response, which was associated with increased expression of tight junction proteins.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism; it is inhibited under obese conditions and is activated by exercise and by many anti-diabetic drugs. Emerging evidence also suggests that AMPK regulates cell differentiation, but the underlying mechanisms are unclear. We hypothesized that AMPK regulates cell differentiation via altering β-catenin expression, which involves phosphorylation of class IIa histone deacetylase 5 (HDAC5). In both C3H10T1/2 cells and mouse embryonic fibroblasts (MEFs), AMPK activity was positively correlated with β-catenin content. Chemical inhibition of HDAC5 increased β-catenin mRNA expression. HDAC5 overexpression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular β-catenin content. HDAC5 formed a complex with myocyte enhancer factor-2 to down-regulate β-catenin mRNA expression. AMPK phosphorylated HDAC5, which promoted HDAC5 exportation from the nucleus; mutation of two phosphorylation sites in HDAC5, Ser-259 and -498, abolished the regulatory role of AMPK on β-catenin expression. In conclusion, AMPK promotes β-catenin expression through phosphorylation of HDAC5, which reduces HDAC5 interaction with the β-catenin promoter via myocyte enhancer factor-2. Thus, the data indicate that AMPK regulates cell differentiation and development via cross-talk with the wingless and Int (Wnt)/β-catenin signaling pathway.