Dynamic simulation insights into friction weakening effect on rapid long-runout landslides:A case study of the Yigong landslide in the Tibetan Plateau,China

This study proposed a novel friction law dependent on velocity,displacement and normal stress for kinematic analysis of runout process of rapid landslides.The well-known Yigong landslide occurring in the Tibetan Plateau of China was employed as the case,and the derived dynamic friction formula was included into the numerical simulation based on Particle Flow Code.Results showed that the friction decreased quickly from 0.64(the peak)to 0.1(the stead value)during the 5s-period after the sliding initiation,which explained the behavior of rapid movement of the landslide.The monitored balls set at different sections of the mass showed similar variation characteritics regarding the velocity,namely evident increase at the initial phase of the movement,followed by a fluctuation phase and then a stopping one.The peak velocity was more than 100 m/s and most particles had low velocities at 300s after the landslide initiation.The spreading distance of the landslide was calculated at the two-dimension(profile)and three-dimension scale,respectively.Compared with the simulation result without considering friction weakening effect,our results indicated a max distance of about 10 km from the initial unstable position,which fit better with the actual situation.

Origin of the Oligocene Tuolangla porphyry-skarn Cu-W-Mo deposit in Lhasa terrane,southern Tibet

Although some porphyry-skarn deposits occur in post-collisional extensional settings,the post-collisional deposits remain poorly understood.Here the authors describe the igneous geology,and mineralization history of Tuolangla,a newly-discovered porphyry-skarn Cu-W-Mo deposit in southern Tibet that belongs to the post-collisional class.The deposit is associated with Lower Cretaceous Bima Formation.It was intruded by granodiorite porphyry intrusions at about 23.1 Ma.Field investigation indicated that mineralization is spatially and temporally associated with granodiorite porphyry.Molybdenite yielded a Re-Os weighted mean age of 23.5±0.3 Ma and is considered to represent the age of skarn mineralization at the deposit.Theδ^34S values of sulfides,concentrated in a range between 0.6‰to 3.4‰,show that the sulfur has a homogeneous source with characteristics of magmatic sulfur.The Pb isotopic compositions of sulfides indicate that ore-forming metal materials were derived from the mantle and ancient crust.The granodiorite porphyry displays high SiO2(68.78%–69.75%)and K2O(3.40%–3.56%)contents,and relatively lower Cr(2.4×10^-6–4.09×10^-6),Ni(2.79×10^-6–3.58×10^-6)contents,and positiveεHf(t)values(7.7–12.9)indicating that the mineralization porphyry was derived from the partial melting of juvenile lower crust.The Tuolangla deposit is located in the central part of Zedang terrane.This terrane was once considered an ancient terrane.This terrane is in tectonic contact with Cretaceous ophiolitic rocks to its south and Mesozoic continental margin arc volcanics and intrusions of the Gangdese batholith of the Lhasa terrane to its north.Thus,the authors proposed that the Oligocene porphyry skarn Cu-W-Mo mineralization is probably associated with the Zedang terrane.This finding may clarify why the Oligocene(about 23 Ma)deposits are found only in the Zedang area and why mineralization types of the Oligocene mineralization are considerably different from those of the Miocene(17–14 Ma)mineralization.

Mechanisms of trichostatin A inhibiting AGS proliferation and identification of lysine-acetylated proteins

AIM: To explore the effect of lysine acetylation in related proteins on regulation of the proliferation of gastric cancer cells, and determine the lysine-acetylated proteins and the acetylated modified sites in AGS gastric cancer cells. METHODS: The CCK-8 experiment and flow cytometry were used to observe the changes in proliferation and cycle of AGS cells treated with trichostatin A (TSA). Real time polymerase chain reaction and Western blotting were used to observe expression changes in p21, p53, Bax, Bcl-2, CDK2, and CyclinD1 in gastric cancer cells exposed to TSA. Cytoplasmic proteins in gastric cancer cells before and after TSA treatment were immunoprecipitated with anti-acetylated lysine antibodies, separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis gel and silver-stained to detect the proteins by mass spectrometry after removal of the gel. The acetylated proteins in AGS cells were enriched with lysine-acetylated antibodies, and a high-resolution mass spectrometer was used to detect the acetylated proteins and modified sites. RESULTS: TSA significantly inhibited AGS cell proliferation, and promoted cell apoptosis, leading to AGS cell cycle arrest in G0/G1 and G2/M phases, especially G0/G1 phase. p21, p53 and Bax gene expression levels in AGS cells were increased with TSA treatment duration; Bcl-2, CDK2, and CyclinD1 gene expression levels were decreased with TSA treatment duration. Two unknown protein bands, 72 kDa (before exposure to TSA) and 28 kDa (after exposure to TSA), were identified by silver-staining after immunoprecipitation of AGS cells with the lysine-acetylated monoclonal antibodies. Mass spectrometry showed that the 72 kDa protein band may be PKM2 and the 28 kDa protein band may be ATP5O. The acetylated proteins and modified sites in AGS cells were determined. CONCLUSION: TSA can inhibit gastric cancer cell proliferation, which possibly activated signaling pathways in a variety of tumor-associated factors. ATP5O was obviously acetylated in AGS cells following TSA treatment.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma:A single-arm, multicenter, prospective study

Mammalian target of rapamycin(m TOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant(LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival(RFS) in hepatocellular carcinoma(HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specifc for the frst 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefts for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data.

Hepatic differentiation of rat induced pluripotent stem cells in vitro

AIM: To show the efficient generation of hepatocytelike cells(HLCs) differentiated from the induced pluripotent stem cells(iP SCs) of rats.METHODS: Hepatic differentiation was achieved using a three-step protocol with several growth factors. First, rat i PSCs were differentiated into definitive endoderm cells using Activin A and Wnt3 a treatment. Then fibroblast growth factor 4 and bone morphogenetic protein 2 were added to the culture medium and used to induce hepatic differentiation. Finally, hepatocyte growth factor, Oncostatin M and dexamethasone were used for hepatic maturation. The liver-related markers and functions of HLCs were assessed at the gene and protein levels.RESULTS: After endodermal induction, the differentiated cells expressed endodermal markers forkhead box protein A2 and SRY-box containing gene 17 at the m RNA and protein levels. After 20 d of culture, the i PSCs were differentiated into HLCs. These differentiated cells expressed hepatic markers including α-fetoprotein, albumin CK8, CK18, CK19, and transcription factor HNF-4α. In addition, the cells expressed functional proteins such as α1-antitrypsin, cytochrome P450 1A2 and CYP 3A4. They acted like healthy hepatic cells, storing glycogen and taking up indocyanine green and low-density lipoproteins. Also, the rates of urea synthesis(20 d 1.202 ± 0.080 mg/dL vs 0 d 0.317 ± 0.021 mg/d L, P < 0.01) and albuminsecretion(20 d 1.601 ± 0.102 mg/d L vs 0 d 0.313 ± 0.015 mg/d L, P < 0.01) increased significantly as differentiation progressed.CONCLUSION: Rat i PSCs can differentiate into HLCs rapidly and efficiently. These differentiated cells may be an attractive resource for treatment of end-stage liver disease.

Knockdown of Decoy Receptor 3 Impairs Growth and Invasiveness of Hepatocellular Carcinoma Cell Line of HepG2

Background：Decoy receptor 3 （DcR3） binds to Fas ligand （FasL） and inhibits FasL-induced apoptosis.The receptor is overexpressed in hepatocellular carcinoma （HCC）,and it is associated with the growth and metastatic spread of tumors.DcR3 holds promises as a new target for the treatment of HCC,but little is known regarding the molecular mechanisms underlying the oncogenic properties of DcR3.The present work,therefore,examined the role of DcR3 in regulating the growth and invasive property of liver cancer cell HepG2.Methods：HepG2 cells were stably transfected with lentivirus-based short hairpin RNA vector targeting DcR3.After the knockdown of DcR3 was confirmed,cell proliferation,clone formation,ability of migrating across transwell membrane,and wound healing were assessed in vitro.Matrix metalloproteinase-9 （MMP 9） and vascular epithelial growth factor （VEGF）-C and D expressions of the DcR3 knockdown were also studied.Comparisons between multiple groups were done using one-way analysis of variance （ANOVA）,while pairwise comparisons were performed using Student＇s t test.P 〈 0.05 was regarded statistically significant.Results：DcR3 was overexpressed in HepG2 compared to other HCC cell lines and normal hepatocyte Lo-2.Stable knockdown of DcR3 slowed down the growth of HepG2 （P 〈 0.05） and reduced the number of clones formed by 50% compared to those without DcR3 knockdown （P 〈 0.05）.The knockdown also reduced the migration of HepG2 across transwell matrix membrane by five folds compared to the control （P 〈 0.05） and suppressed the closure of scratch wound （P 〈 0.05）.In addition,the messenger RNA levels of MMP 9,VEGF-C,and VEGF-D were significantly suppressed by DcR3 knockdown by 90% when compared with the mock control （P 〈 0.05）.Conclusions：Loss of DcR3 impaired the growth and invasive property of HCC cell line of HepG2.Targeting DcR3 may be a potential therapeutic approach for the treatment of HCC.

Anti-apoptosis Effect of Decoy Receptor 3 in Cholangiocarcinoma Cell Line TFK-1

Background： Decoy receptor 3 （DcR3） is a protein with anti-apoptotic effect that belongs to the tumor necrosis factor receptor superfamily. DcR3 is highly expressed in a variety of malignant tumors including cholangiocarcinoma and its expression was found to be related to the clinical stage, the invasion, and tile metastasis of the tumor. This in vitro study aimed to investigate the effect ofdownregulated expression of DcR3 on cell viability, cell apoptosis, and cell cycle in cholangiocarcinoma cell line TFK-1. Methods： Three different cell lines were cultured： human cholangiocarcinoma TFK-I, human biliary epithelial carcinoma HuCCT-1, and human cholangiocarcinoma RBE. The cholangiocarcinoma cell line with the highest expression of DcR3 was selected for further investigation. The expression of DcR3 was silenced/knocked down by transfection with DcR3-siRNA in the selected cell line. Various biological phenotype parameters such as cell viability, apoptosis, and cell cycle were observed. Results： The mRNA and protein levels of DcR3 were measured in the three cell lines, and TFK-1 was selected. After the treatment with DcR3-siRNA for 48 h, DcR3 mRNA and protein expression in the treatment group were 38.45% （P 〈 0.01 ） and 48.03% （P 〈 0.05） of that of＇the control, respectively. It was found that the cell viability decreased to 61.87% of the control group （P 〈 0.01 ） after the downregulation of DcR3 in cholangiocarcinoma cell line TFK- 1 by transfection with DcR3-siRNA, while tile percentage ofapoptotic cells was 2.98 times as compared with the control group （P 〈 0.05）. Compared with the control group the ratio of G0/G1 increased, and the ratio of G2/M dccreased in the treatment group. However, the differences were not statistically significant. Conclusions： The effect of DcR3 on the growth and apoptosis ofcholangiocarcinoma has been demonstrated. DcR3 is not only a predictive marker for malignant tumor but it is also likely to be a potential target for cancer gene therapy. Further studies should focus on exploring the binding ligand of DcR3, the signaling pathway involved, and the molecular mechanism for the regulation of DcR3 expression in cholangiocarcinoma.

XB130 Knockdown Inhibits the Proliferation, Invasiveness, and Metastasis of Hepatocellular Carcinoma Cells and Sensitizes them to TRAIL-Induced Apoptosis

Background：XB 130 is a recently discovered adaptor protein that is highly expressed in many malignant tumors,but few studies have investigated its role in hepatocellular carcinoma （HCC）.Therefore,this study explored the relationship between this protein and liver cancer and investigated its molecular mechanism of action.Methods：The expression of XB 130 between HCC tissues and adjacent nontumor tissues was compared by real-time polymerase chain reaction,immunochemistry,and Western blotting.XB130 silencing was performed using small hairpin RNA.The effect of silencing XB130 was examined using Cell Counting Kit-8,colony assay,wound healing assay,and cell cycle analysis.Results：We found that XB 130 was highly expressed in HCC tissues （cancer tissues vs.adjacent tissues：0.23 ± 0.02 vs.0.17 ± 0.02,P 〈 0.05） and liver cancer cell lines,particularly MHCC97H and HepG2 （MHCC97H and HepG2 vs.normal liver cell line LO-2：2.35 ± 0.26 and 2.04 ± 0.04 vs.1.00 ± 0.04,respectively,all P 〈 0.05）.The Cell Counting Kit-8 assay,colony formation assay,and xenograft model in nude mice showed that silencing XB130 inhibited cell proliferative ability both in vivo and in vitro,with flow cytometry demonstrating that the cells were arrested in the G0/G1 phase in HepG2 （HepG2 XB130-silenced group [shA] vs.HepG2 scramble group [NA]：74.32 ± 5.86% vs.60.21 ± 3.07%,P 〈 0.05） and that the number of G2/M phase cells was decreased （HepG2 shA vs.HepG2 NA：8.06 ± 2.41% vs.18.36 ± 4.42%,P 〈 0.05）.Furthermore,the cell invasion and migration abilities were impaired,and the levels of the epithelial-mesenchymal transition-related indicators vimentin and N-cadherin were decreased,although the level of E-cadherin was increased after silencingXB130.Western blotting showed that the levels of phosphorylated phosphoinositide 3-kinase （PI3K） and phospho-protein kinase B （p-Akt） also increased,although the level of phosphorylated phosphatase and tensin homolog increased,indicating that XB 130 activated the PI3K/ Akt pathway.Furthermore,we found that a reduction in XB130 increased liver cancer cell sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.Conclusions：Our findings suggest that XB130 might be used as a predictor of liver cancer as well as one of the targets for its treatment.

Graft versus host disease after liver transplantation:A case report

In documenting clinical experience in the diagnosis and treatment of graft versus host disease(GVHD),we retrospectively analyzed data of one case that has developed GVHD after liver transplantation.This patient exhibited fever,skin rash,and diarrhea on day 9 after liver transplantation.His liver function was normal.Skin biopsy showed scattered keratinocytes accompanied by satellite-like lymphocyte infiltration and basal cell liquefaction degeneration.After carefully analyzing the complications,we took the strategy of decreasing the dose of tacrolimus.Thereafter,the patient’s temperature decreased to normal,his skin rashes subsided,and his diarrhea was relieved.This case suggests that reducing the dosage of immunosuppressive agents can be an effective strategy for GVHD after liver transplantation.