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BackgroundMacrophage extracellular traps (METs) and tumor-infiltrating macrophages contribute to the progression of several diseases. But the role of METs and tumor-infiltrating macrophages in colon cancer (CC) has not been illuminated. In this study, we aimed to clarify the prognostic value of METs for CC patients and to explore the interaction between CC cells and METs in vitro and in vivo.MethodsA training cohort consisting of 116 patients and a validation cohort of 94 patients were enrolled in this study. Immunofluorescence (IF) staining was conducted to determine METs formation in CC patients. Cox regression was used to perform prognostic analysis and screen out the best prognostic model. A nomogram was established to predict 5-year overall survival (OS). The correlation between METs with clinicopathological features and inflammatory markers was analyzed. The formation of METs in vitro was detected by SYTOX® green and IF staining, and the effect of METs on CC cells was detected by transwell assays. PAD2-IN-1, a selective inhibitor of peptidylarginine deiminase 2 (PAD2), was introduced to destroy the crosstalk between CC cells and METs in vitro and in vivo.ResultsMETs levels were higher in CC tissues and were an independent prognostic factor for CC patients. The prognostic model consisting of age, tumors local invasion, lymph node metastasis and METs were confirmed to be consistent and accurate for predicting the 5-year OS of CC patients. Besides, METs were correlated with distant metastasis and inflammation. Through in vitro experiments, we confirmed that there was a positive feedback loop between CC cells and METs, in that METs promoted the invasion of CC cells and CC cells enhanced the production of METs, in turn. This interaction could be blocked by PAD2-IN-1 inhibitors. More importantly, animal experiments revealed that PAD2-IN-1 inhibited METs formation and CC liver metastasis in vivo.ConclusionsMETs were the potential biomarker of CC patient prognosis. PAD2-IN-1 inhibited the crosstalk between CC cells and METs in vitro and in vivo, which should be emphasized in CC therapy.

Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted.

Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. In our study, ANXA10 upregulation was revealed by exome and transcription sequencing in 5 pairs of PHCCA and adjacent tissues. The clinical significance and prognostic value of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables and survival rates. As a result, ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and unfavorable prognosis. With in vitro and in vivo experiments, we demonstrated that ANXA10 promoted the epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of the PHCCA cell line QBC939. The key molecule in ANXA10-induced CCA progression was screened by mRNA sequencing. Consequently, PLA2G4A expression was regulated by ANXA10 and it was required in ANXA10-induced metastasis. High PLA2G4A expression also predicted poor prognosis in PHCCA and DCCA. With multiple in vivo experiments, we showed that ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. In conclusion, ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the proliferation, migration and invasion of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. Our results suggested that ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA. Funding Statement: Our study was supported by National Natural Science Foundation of China (Grant no. 81601668), Shandong Province Major Research and Design Program (Grant No. 2018GSF118169), Jinan City Science and Technology Development Program(Grant No. 201805017, 201805013), and Hengrui Hepatobiliary and Pancreatic Foundation (Grant No.Y-2017-144). Declaration of Interests: The authors declare no conflicts of interests. Ethics Approval Statement: All experiments were approved by the Ethics Committee of Qilu Hospital of Shandong University.

Durability fatigue tests for full-scale structures are essential to ensure the fatigue reliability and operational safety of high-speed trains. An accelerated life test (ALT) method is first used to predict the fatigue life of a full-scale bogie frame. Three step-up acceleration load spectrum is compiled for an ALT on the basis of the failure mechanism consistency principle. The ALT of a full-scale bogie frame is conducted. Then, the acceleration coefficient and cycle times from the accelerated load level to the working load level are calculated. Based on the equal damage principle, combined with the finite element calculation, the fatigue life of the bogie frame under acceleration load spectrum is extrapolated. The ALT method is used to compile the acceleration load spectrum and to perform fatigue tests to analyze the acceleration coefficients and predict the fatigue life for a full-scale bogie frame, which provides a reference for the reliability evaluation of large structures.

With the wide application of ballastless track on high-speed railway, the load on the structure of the high-speed train exhibits the characteristics of high frequency and small amplitude. It is the...

The welding deformation of a single-side double-pass welding T-joint is simulated by using a thermal elastic-plastic method (TEPM) and inherent strain method (ISM) respectively, and comparisons are made. Consequently, the numerical simulation results using the two methods are approximately consistent; thus, the application of the thermal elastic-plastic method and inherent strain method for predicting the welding deformation of T-joints is validated. Then, the inherent strain method based on empirical formulas is applied to simulate the welding deformation of a shell model and solid model of the side beam of a bogie frame. A comparative analysis of the two models shows that the simulated result of the solid model is more accurate than that of the shell model. However, the two results are basically consistent with the measured welding deformation of the side beam of the frame, further demonstrating the effectiveness of the inherent strain method in predicting the welding deformation of large complex structures. The prediction methods provided in this paper give a reference to the welding deformation correction and the corresponding welding process optimization for large-scale welded structures.

Background Perihilar cholangiocarcinoma (PHCCA) is the most common type of human cholangiocarcinoma with a very dismal prognosis. Tumor markers and target drugs of PHCCA are desperately needed. Protein phosphatase N3 (PTPN3) has dual roles in the progression of human cancers, but its expression and functions in PHCCA have not been elucidated. Materials and methods The expression of PTPN3 in PHCCA was detected with western blotting, qRT-PCR and immunohistochemistry. The clinical significance of PTPN3 was identified by analyzing the correlations between its expression and the clinicopathological variables, and the prognostic value was evaluated by univariate and multivariate analyses. The functions of PTPN3 in the progression of PHCCA were estimated with both in vitro and in vivo experiments. Results PTPN3 expression was down-regulated in PHCCA compared with normal bile duct. Low PTPN3 expression was markedly associated with large tumor size and unfavorable prognosis. After knocking down PTPN3, the percentages of G2/S phase of PHCCA cells were elevated, and the proliferation increased significantly. Moreover, we demonstrated that the phosphorylation of AKT was elevated by PTPN3 knockdown, and it was required in PTPN3-involved proliferation of PHCCA. Within vivo experiments, PTPN3 and AKT inhibitor MK-2206 were demonstrated to suppress tumor size of PHCCA. Conclusion PTPN3 was a favorable prognostic biomarker of PHCCA. PTPN3 suppressed the proliferation of PHCCA by inhibiting AKT phosphorylation and arresting cell cycle. Our results suggested thatpost-operative detection of PTPN3 would be a helpful approach to stratify the PHCCA patients with high-risk.

When two high-speed trains pass through a tunnel, the aerodynamic changes are more complex and drastic than in open air owing to the interference of the tunnel wall and the entry effect. The impact on the carbody fatigue strength is very significant in the fatigue reliability design of the carbody. In this paper, the sequential coupling method was used for the first time to study the effect of pressure waves on the fatigue strength in a large-scale and complex carbody structure. The computational fluid dynamics method was used to calculate and analyze the aerodynamic pressure wave of the intersection of the trains in a long and short tunnel. A full-scale finite element shell model of the carbody structure was established. Then, the time integration method was used to convert the transient pressure wave into the aerodynamic loads bearing by the side wall of the carbody. The inhomogeneous stress concentrations at the restraint points were eliminated by the inertial release method; moreover, a finite element analysis of the carbody was carried out under the combined aerodynamic and mechanical loads. The Goodman fatigue strength curve of the aluminum alloy carbody was drawn. The influence of the aerodynamic load on the fatigue strength of the vehicle body was analyzed and compared under the entry effect of the short tunnel. The results show that the aerodynamic load of the short tunnel has a significant impact on the fatigue strength of the carbody owing to the train's entry effect. The safety factor of the fatigue strength is 15% less than that of the long tunnel aerodynamic load. In this paper, computational fluid dynamics and finite element method were used to analyze and evaluate the impact of the pressure wave on the fatigue strength of the carbody, which is of great reference value in the structural design of the carbody subjected to complex aerodynamic loads.

Ginsengs, has long been used as one medicinal herb in China for more than two thousand years. Many studies have shown that ginsengs have preventive and therapeutic roles for cancer, and play a good complementary role in cancer treatment. Ginsenosides, as most important constituents of ginseng, have been extensively investigated and emphasized in cancer chemoprevention and therapeutics. However, the functional mechanism of Ginsenosides on cancer is not well known. This review will focus on introducing the functional mechanisms of ginsenosides and their metabolites, which regulate signaling pathways related with tumor growth and metastasis. Ginsenosides inhibit tumor growth via upregulating tumor apoptosis, inducing tumor cell differentiation and targeting cancer stem cells. In addition, Ginsenosides regulate tumor microenvironment via suppressing tumor angiogenesis-related proteins and pathways. Structural modification of ginsenosides and their administration alone or combinations with other Chinese medicines or chemical medicines have recently been developed to be a new therapeutic strategy for cancer. Keywords: Functional mechanism, Ginsenosides, Tumor growth, Tumor metastasis

Ethnopharmacological relevance Liangxue Tongyu Prescription (LTP) is a traditional Chinese medicine formula composed of 8 crude drugs that is widely used to treat acute intracerebral hemorrhage (AICH). Aim of the study To verify the efficacy of LTP on the survival time in the treatment of acute intracerebral hemorrhagic rats (AICHs), and to elucidate its network pharmacodynamic mechanism of multi-component, multi-target, and multi-signaling pathways. Materials and methods Survival analysis was used to evaluate the survival time of AICH rats induced by different doses of collagenase and the efficacy of three doses of LTP in the treatment of AICH rats. The Kaplan-Meier curves for survival time were produced and compared with the Log-rank test and Wilcoxon (Gehan) χ2. Differential mRNA-seq combined with network pharmacology was used to disclose the network effect mechanism of LTP on AICH, and the obtained differential genes were mapped into the predictive empirical compound-target network model (ECT network model) and the empirical compound-target-pathogenesis (disease) network model (ECTP network model). Results The median survival time of four different doses of LTP-treated groups (0.00 g/kg, 5.78 g/kg, 11.55 g/kg, 23.10 g/kg) for adult AICH rats by 0.18 U collagenase was 14 h, 37 h, 150 h, and 51 h respectively, and the 7-day survival rates were 33.3%, 41.7%, 50.0%, and 38.5%, of which the medium-dose group (MD) had a longer survival time and higher survival rate. Through further validation experiments, the MD group had a better efficacy trend with a median survival time of 168 h vs 23 h in the model control group (MC) (Wilcoxon Gehan Test, χ2 = 3.478, P = 0.062). The transcriptomic analysis of mRNA showed that 583 significant differential genes were found between the MC and MD group and 7 key therapeutic targets regulated by 29 compounds in LTP on AICH were screened out by VCT and VCTP network model. These targets were involved in 5 regulatory models or pathways. Conclusion Our study confirmed the exact efficacy of the LTP in the treatment of AICH and revealed the potential pharmacodynamic components and mode of action of the LTP on AICH. Using differential transcriptome of mRNA combined with network pharmacology, we screened out 29 chemical compounds as the potential effective ingredients of LTP which acted on 7 targets of AICH involving 5 pathological pathways, mainly including repairing the brain function defect, improving neural function, protecting blood-brain barrier from damage, reducing inflammatory factors, and inhibiting apoptosis. The present study not only provides a new explanation for the ‘multi-component, multi-target, multi-pathway’ effects of the LTP on AICH but also screened out some major compounds of LTP and their potential targets which will facilitate the development of new drugs for AICH.

Background: Perihilar cholangiocarcinoma (PHCC) is the most common type of cholangiocarcinoma with the worst prognosis. Radical resection of PHCC is difficult; thus, few effective biomarkers or useful molecular profiles for PHCC have been reported in recent years. Methods: In this study, we screened potential biomarkers for PHCC using exon and transcriptome sequencing with PHCC tissues and paired normal tissues, and confirmed that transcription factor 7(TCF7) was upregulated in PHCC using qRT-PCR, western blotting and immunohistochemistry. The correlations between TCF7 and clinicopathological factors were analyzed with Chi-square test, and the prognostic significance of TCF7 was evaluated with univariate and multivariate analysis in two independent cohorts. Moreover, the functions of TCF7 and its main effectors in PHCC cells proliferation, invasion, and migration were investigated with in vitro and in vivo experiments. Findings: TCF7 expression was upregulated in PHCC and it was an unfavorable prognostic biomarker. c-Myc was a main effector of TCF7 in PHCC cells and responsible for TCF7-induced proliferation, invasion, and migration of PHCC cells. With qRT-PCR screening, FOSL1 was also identified as a downstream target gene of TCF7 and was required in TCF7-induced PHCC proliferation. Triple-positive expression of TCF7, c-Myc, and FOSL1 predicted a much worse prognosis in patients with PHCC than TCF7 expression alone. Interpretation: TCF7 correlated with poor prognosis of PHCC by promoting proliferation, invasion, and migration of PHCC, which required the participation of its target gene c-Myc and FOSL1. Triple-positive expression of TCF7, c-Myc, and FOSL1 was a more sensitive factor to predict prognosis than TCF7 expression alone in patients with PHCC. These results suggested that postoperative detection of TCF7, c-Myc, and FOSL1 may be useful for stratifying patients with a high risk of unfavorable prognosis and that suppressing TCF7 or its downstream effectors may be a promising strategy for the treatment of PHCC. Funding: Our study was supported by National Natural Science Foundation of China (Grant no. 81601668), Shandong Province Major Research and Design Program (Grant No. 2018GSF118169), Jinan City Science and Technology Development Program (Grant No. 201805017, 201805013), and Hengrui Hepatobiliary and Pancreatic Foundation (Grant No.Y-2017-144). Declaration of Interest: We declare no conflicts of interest. Ethical Approval: This study was approved by the Qilu Hospital of Shandong Univeristy. The Laboratory Animal Care and Use Committees of the hospital approved all experimental procedures. Written informed consents were received from all patients.

A simple design procedure is proposed for seismic retrofitting of existing structures using viscoelastic dampers (VEDs) based on the uniform damping ratio (UDR) concept to make full use of each damper. The UDR concept states that the equivalent damping ratios, which represent the energy dissipation capacities of the dampers, are the same for each installed VED. The stiffness and damping characteristic parameters of the damped structure can be formally decoupled using UDR-based derivations, which simplify the determination of the VEDs’ parameters. The generalized single-degree-of-freedom method and pushover analysis are adopted for a fast estimation of the seismic response of the damped elastoplastic structure. Taking the response reduction ratio as the design target, a seismic retrofit design procedure is proposed based on the UDR concept to meet the performance demand. Finally, a six-story frame is adopted to illustrate the proposed design method. The dynamic analysis results show that the seismic responses of the structure are well-controlled, as expected, and that the installed VEDs are used effectively. The conclusion can be drawn that the UDR-based design method for retrofitting an existing structure using VEDs is rational and effective.

Preparation of new type coal-based carbon nanomaterials and its application in Fenton-like photocatalytic organic pollutant degradation was presented here. The study promoted the high value-added use of coal and extended Fenton-like research system. The coal with high silicon content from Wucaiwan, Xinjiang, China was used as carbon and silicon source. The coal-based graphene oxide (GO) was obtained via the oxidation and exfoliation of crystal graphite in coal under the ultrasonic oxidation treatment by the modified Hummers method. In this way, the natural silicon in coal was converted into the silica dioxide (SiO2) and in situ linked to the surface of the GO sheet by the surface hydroxyl deprotonation bonding to forme GO/SiO2 nanosheet. After all, the composite photocatalyst ZnO/GO/SiO2 was formed by loading the ZnO nanorods on the GO/SiO2 surface via the hydrothermal synthesis. Meanwhile, the photocatalytic Fenton-like system was constructed with H2O2 and ZnO/GO/SiO2. The property and mechanism of the photocatalytic Fenton-like oxidative degradation of methylene blue (MB) was characterized in detail. The results indicating that the photocatalyst can promote the degradation efficiently, with the photogenerated electron replacing the metal ions as activator for H2O2. On account of the property of adsorption and photogenerated electron transfer, the coal-based GO/SiO2 as carrier of ZnO immensely increased the production of active radicals from H2O2, resulting in the promotion of oxidative degradation.

Local buckling may occur in the straight portion of a corrugated steel plate (CSP) pipe-arch with a deep wave section that is used in a buried structure. In this study, the soil support of the pipe-arch structure is considered, and the local buckling of the straight portion of the CSP is investigated. The corresponding theoretical formulae are derived using the Rayleigh-Ritz method. The simplified mechanical model with the soil support is used for derivation. Then, the finite element models for the invert of the pipe-arch with several waves are established to analyze the actual rotational restraints of the straight portion. The influences of plate thickness, corrugation, aspect ratio and curvature on the local buckling load of the invert are investigated. The relationships of plate thickness and local buckling load for three types of deep corrugations are obtained. These relationships reveal that the actual rotational restraints are negative, i.e., the straight portion provides restraint for the corrugated portion. Based on numerical simulations, the theoretical formulae are modified to account for the actual rotational restraints of the straight portion. Then, the finite element model of the global pipe-arch structure is built. The corresponding analysis matches well with the revised formula, which validates the modified derivation. Finally, according to the yield criterion, a reasonable limit value for the width-to-thickness ratio for the straight portion of the CSP is suggested. This limit can be used to prevent local buckling of CSP buried pipe-arch structures in practice.

The calculation of the dynamic stress of a large and complex welded carbody is the key to the fatigue design and the durability evaluation of the carbody. Adopting the advanced structural stress based on the finite element method, a new finite element transformation method between random loads and dynamic stresses is proposed to be applied in carbody for high-speed trains. The multi-axial random dynamic load spectrums of full-scale carbody are obtained by the vehicle system dynamics method, and the shell finite element model of a full-scale carbody is established. Adopting the concept of a surrogate model, the finite element transformation relationship between the random load and the dynamic structural stress at concerned points is constructed by using multidisciplinary methods to compute the dynamic stress spectrums of concerned points at the welding seam, and dynamic structural stresses are compared and validated through carbody rig-test. The analysis methods of dynamic structural stress are performed systematically for a full-scale welded structure, which provides reference methods for the fatigue durability evaluation of large-scale welded structures.