Characterization and Phylogenetic Implications of the Complete Mitogenomes of Two Species in the Genus Zhangixalus(Anura:Rhacophoridae)

Mitochondrial genomes(mitogenomes)in frogs are essential for reconstructing the phylogenetic relationships and shedding light on the molecular evolution in these animals.However,there are only seven complete Rhacophoridae genomes that have been reported to date.In this paper,two complete mitogenomes of the Chinese whipping frog(Zhangixalus chenfui)and Emei tree frog(Z.omeimontis)were described,each of which was 20520 and 19782 bp in size,and had A+T contents of 64.26%and 63.83%.The two mitogenomes each included two non-coding control region(D-loop,CR),two ribosomal RNA genes(rRNAs),13 protein-coding genes(PCGs),and 22 transfer RNA genes(tRNAs),and it was found that the mitogenome of Z.chenfui also includes three tandem tRNAMet gene sequences.A typical clover-leaf structure was found for all tRNAs except for tRNASer1(AGN),which showed a reduced DHU arm.The putative D-loop region contains multiple types of tandem repeats regions.Both of these two mitogenomes showed similar pattern of gene rearrangement(tRNA-Ser-ND6-tRNA-Glu-CytbCR1-ND5-CR2-tRNA-Thr-tRNA-Leu-tRNA-Pro).Additionally,three consecutive tRNAMet genes were found for the first time in Z.chenfui,a species in the Rhacophoridae family.For all phylogenetic analyses,which were based on 13 protein-coding genes from 91 Ranoidea mitogenomes,the same phylogenetic trees were observed using either maximum likelihood or Bayesian approaches.These results suggest that the phylogenetic hypotheses for the Ranoidea(including Rhacophoridae,Mantellidae,Ranidae and Dicroglossidae)derived from these mitogenomic data could provide substantiation for the relationships of(Dicroglossidae(Ranidae,(Mantellidae,Rhacophoridae))),and support the presence of a monophyletic group in four families.Moreover,Z.omeimontis and Z.dennysi were found to cluster on the same branch,indicating that they were more closely related as a group.This group may in turn form sister groups with Z.arboreus and Z.schlegelii.However,Z.chenfui is located on the base of other species in the genera.Increased mitogenome sampling should be conducted to provide a more satisfactory resolution to the phylogeny of the Rhacophorus,Rhacophoridae,and Mantellidae.

Tumor Microenvironment Cascade‑Responsive Nanodrug with Self‑Targeting Activation and ROS Regeneration for Synergistic Oxidation‑Chemotherapy

Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions.Herein,we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop.The di-selenide-bridged prodrug synthesized from vitamin E succinate and methotrexate(MTX)self-assembles into nanoparticles(VSeM);decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time.Upon reaching tumor sites,acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake.Afterward,the VSeM could be dissociated in response to intracellular ROS to trigger VES/MTX release;then the released VES could produce extra ROS to accelerate the collapse of VSeM.Finally,the excessive ROS produced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy.Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.

Profiling of hepatocellular carcinoma neoantigens reveals immune microenvironment and clonal evolution related patterns

Objective: Neoantigens derived from tumor-specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of hepatocellular carcinoma(HCC) neoantigens and their complex interplay with immune microenvironment and tumor evolution have not been fully addressed.Methods: Here we integrated whole exome sequencing data, transcriptome sequencing data and clinical information of 72 primary HCC patients to characterize the HCC neoantigen profile, and systematically explored its interactions with tumor clonal evolution, driver mutations and immune microenvironments.Results: We observed that higher somatic mutation/neoantigen load was associated with better clinical outcomes and HCC patients could be further divided into two subgroups with distinct prognosis based on their neoantigen expression patterns. HCC subgroup with neoantigen expression probability high(NEP-H) showed more aggressive pathologic features including increased incidence of tumor thrombus(P=0.038), higher recurrence rate(P=0.029),more inclined to lack tumor capsule(P=0.026) and with more microsatellite instability sites(P=0.006). In addition,NEP-H subgroup was also characterized by higher chance to be involved in tumor clonal evolution [odds ratio(OR)=46.7, P<0.001]. Gene set enrichment analysis revealed that upregulation of MYC and its targets could suppress immune responses, leading to elevated neoantigen expression proportion in tumor cells. Furthermore, we discovered an immune escape mechanism that tumors could become more inconspicuous by evolving subclones with less immunogenicity. We observed that smaller clonal mutation clusters with higher immunogenicity in tumor were more likely to involve in clonal evolution. Based on identified neoantigen profiles, we also discovered series of neoantigenic hotspot genes, which could serve as potential actionable targets in future.Conclusions: Our results revealed the landscape of HCC neoantigens and discovered two clinically relevant subgroups with distinct neoantigen expression patterns, suggesting the neoantigen expression should be fully considered in future immunotherapeutic interventions.

A novel BODIPY-based nano-photosensitizer with aggregation-induced emission for cancer photodynamic therapy

The discovery of aggregation induced enmission(AIE)effect provides opportunities for the rapid development of fuorescence imaging-guided photodynamic therapy(PDT).In this work,a boron dipyrromethene(BODIPY)-based photosensitizer(ET-BDP-O)with AIE characteristics was developed,in which the two linear arms of BODIPY group were linked with triphenylamine to form an electron Donor-Acceptor-Donor(D-A-D)architecture while side chain was equipped with triethylene glycol group.ET-BDP-O was able to directly self-assemble into nanoparticles(NPs)without supplement of any other matrices or stabilizers due to its amphiphilic property.The as-prepared ET-BDP-O NPs had an excellent colloid stability with the size of 125 nm.Benefiting from the AIE property,ET-BDP-O NPs could generate strong fluorescence and reactive oxygen species under light-emitting diode light rradiation(60mW/cm^(2)).After inter-nalized in cancer cells,ET-BDP-O NPs were able to emit bright red fuorescence signal for bioimaging.In addition,the cell viability assay demonstrated that the ET-BDP-O NPs exhibited excellent photocytotoxicity against cancer cells,while negligible cytotoicity under dark envi-ronment.Thus,ET-BDP-O NPs might be regarded as a promising photosensitizer for fluores-cence imaging-guided PDT in future.

Role of post-hepatectomy portal hypertension in predicting the outcome of hepatocellular carcinoma after curative resection

Aims:Portal venous pressure frequently increases after a major hepatectomy.We aimed to assess the outcomes of patients with hepatocellular carcinoma(HCC)with different post-hepatectomy portal pressure statuses and the predictive factors correlated with prognosis and post-hepatectomy portal hypertension(PHPH).Methods:Data from consecutive patients who underwent curative-intent hepatectomy for HCC at the Eastern Hepatobiliary Surgery Hospital and Mengchao Hepatobiliary Hospital of Fujian Medical University between January 2008 and December 2016 were retrospectively analyzed.Patients were followed up until March 1,2022.PHPH was defined as new-onset portal hypertension(PH)in patients without preoperative PH within 1 month of hepatectomy.Patients were classified into two groups according to the presence or absence of PHPH:non-PH and PHPH.The clinicopathological characteristics were compared between the two groups.Univariate and multivariate analyses were used to identify independent risk factors for early and late recurrence of HCC,overall survival(OS),and PHPH.Results:Disease-free survival rates were significantly higher in the non-PH group(n=1068)than those in the PHPH group(n=423)(62.0%,39.0%,and 31.0%vs.46.2%,24.5%,and 19.3%at 1,3,and 5 years,respectively;all p<0.001).The 1-,3-,and 5-year OS rates were 91.0%,66.4%,and 51.4%in the non-PH group and 80.0%,48.9%,and 32.6%in the PHPH group,respectively(all p<0.001).Multivariate analysis revealed that PHPH was independently associated with early recurrence of HCC and poor OS(hazard ratio[HR]1.476,95%confidence interval[CI]1.279–1.704,p<0.001 and HR 1.601,95%CI 1.383–1.853,p<0.001,respectively).Furthermore,hepatitis B virus infection,cirrhosis,preoperative alanine aminotransferase>40 U/L,and major hepatectomy were identified as independent risk factors for PHPH.Conclusions:PHPH was associated with early recurrence of HCC and poor OS but not with late recurrence.Therefore,PHPH may be an attractive target for therapeutic interventions and follow-up surveillance to improve prognosis.

3D printing CO_(2)-activated carbon nanotubes host to promote sulfur loading for high areal capacity lithium-sulfur batteries

Lithium-sulfur batteries(LSBs)have emerged as a promising high energy density system in miniaturized energy storage devices.However,serious issues rooted in large volume change(80%),poor intrinsic conductivity,“shuttle effect”of S cathode,and limited mass loading of traditional electrode still make it a big challenge to achieve high energy density LSBs in a limited footprint.Herein,an innovative carbon dioxide(CO_(2))assisted three-dimensional(3D)printing strategy is proposed to fabricate threedimensional lattice structured CO_(2)activated single-walled carbon nanotubes/S composite thick electrode(3DP S@CNTs-CO_(2))for high areal capacity LSBs.The 3D lattice structure formed by interwoven CNTs and printed regular macropores can not only act as fast electron transfer networks,ensuring good electronic conductivity of thick electrode,but is beneficial to electrolyte infiltration,effectively boosting ion diffusion kinetics even under a high-mass loading.In addition,the subsequent hightemperature CO_(2)in-situ etching can induce abundant nanopores on the wall of CNTs,which significantly promotes the sulfur loading as well as its full utilization as a result of shortened ion diffusion paths.Owing to these merits,the 3DP S@CNTs-CO_(2)electrode delivers an impressive mass loading of 10 mg·cm^(−2).More importantly,a desired attribute of linearly scale up in areal capacitance with increased layers is observed,up to an outstanding value of 5.74 mAh·cm^(−2),outperforming most reported LSBs that adopt strategies that physically inhibit polysulfides.This work provides a thrilling drive that stimulates the application of LSBs in new generation miniaturized electronic devices.

Acceptor modulation for improving thermally activated delayed fluorescence emitter in through-space charge transfer on spiroskeletons

Through-space charge transfer(TSCT)is regarded as an effective way to develop thermally activated delayed fluorescence(TADF)emitters.Based on this strategy,many molecular frameworks have been proposed,among which spirobased scaffolds have been extensively studied due to their unique advantages.In this work,we developed three emitters SPS,SPO,and SPON,which were constructed with the same donor and various acceptors to explore the influence of acceptor modulation at the C9 position of fluorene for spirostructure TSCT emitters.The results show that the acceptor with too weak electronwithdrawing ability will cause the emitter to not have TADF properties,while the acceptor with too much steric hindrance will weaken the face-to-faceπ-πstacking interaction between donor/acceptor(D/A).Since SPO balances the electron-withdrawing strength and steric hindrance of the acceptor,it achieves the highest external quantum efficiency(EQE)of 17.75%.This work shows that appropriate acceptor selection is essential for the TADF properties and high efficiency of the spirobased scaffold TSCT emitter.

42,573 cases of hepatectomy in China： a multicenter retrospective investigation

Hepatectomy is currently routinely performed in most hospitals in China. China owns the largest population of liver diseases and the biggest number of liver resection cases. A nationwide multicenter retrospective investigation involving 112 hospitals was performed, and focused on liver resection for patients with hepatocellular carcinoma(HCC). 42,573 cases of hepatectomy were enrolled, and 18,275 valid cases of liver resection for HCC patients were selected for statistical analysis. The epidemiology of HCC, distribution of hepatectomy, postoperative complications and prognosis were finally analyzed. In the 18,275 HCC patients,81% had hepatitis B virus infection and 10% had hepatitis C virus infection. 38% of the HCC patients had normal Alphafetoprotein(AFP) level, and other 35% had an AFP level lower than 400 ng mL^(-1). In the study period, 97% of the hepatectomy for HCC were treated with open surgery, and 23.81% had vascular exclusion techniques. The operation time was(191.7±105.6) min,the blood loss was(546.0±562.8) m L, and blood transfusion was(543.0±1,035.2) m L. The median survival for HCC patients was 631 days, with 1-, 3-, and 5-year overall survival of 73.2%, 28.8% and 19.6%, respectively. Liver cirrhosis, multiple nodules,tumor thrombosis and high AFP level were risk factors that affect postoperative survival.

CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway

With its high efficiency for site-specific genome editing and easy manipulation,the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR associated protein 9(CAS9)system has become the most widely used gene editing technology in biomedical research.In addition,significant progress has been made for the clinical development of CRISPR/CAS9 based gene therapies of human diseases,several of which are entering clinical trials.Here we report that CAS9 protein can function as a genome mutator independent of any exogenous guide RNA(gRNA)in human cells,promoting genomic DNA double-stranded break(DSB)damage and genomic instability.CAS9 interacts with the KU86 subunit of the DNA-dependent protein kinase(DNA-PK)complex and disrupts the interaction between KU86 and its kinase subunit,leading to defective DNA-PK-dependent repair of DNA DSB damage via non-homologous end-joining(NHEJ)pathway.XCAS9 is a CAS9 variant with potentially higher fidelity and broader compatibility,and dCAS9 is a CAS9 variant without nuclease activity.We show that XCAS9 and dCAS9 also interact with KU86 and disrupt DNA DSB repair.Considering the critical roles of DNA-PK in maintaining genomic stability and the pleiotropic impact of DNA DSB damage responses on cellular proliferation and survival,our findings caution the interpretation of data involving CRISPR/CAS9-based gene editing and raise serious safety concerns of CRISPR/CAS9 system in clinical application.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma(2021 edition)

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.

Functions of p53 in pluripotent stem cells

Pluripotent stem cells(PSCs)are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body,and thus hold great promise for regenerative medicine.To achieve their clinical potential,it is critical for PSCs to maintain genomic stability during the extended proliferation.The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells.In response to DNA damage or oncogenic stress,p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest,apoptosis,and senescence to prevent the passage of genetic mutations to the daughter cells.p53 is also required to maintain the genomic stability of PSCs.However,in response to the genotoxic stresses,a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency,providing mechanisms to maintain the genomic stability of the self-renewing PSCs.In addition,the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress.In summary,the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

Development of a machine learning model to predict early recurrence for hepatocellular carcinoma after curative resection

Background:Early recurrence is common for hepatocellular carcinoma(HCC)after surgical resection,being the leading cause of death.Traditionally,the COX proportional hazard(CPH)models based on linearity assumption have been used to predict early recurrence,but predictive performance is limited.Machine learning models offer a novel methodology and have several advantages over CPH models.Hence,the purpose of this study was to compare random survival forests(RSF)model with CPH models in prediction of early recurrence for HCC patients after curative resection.Methods:A total of 4,758 patients undergoing curative resection from two medical centers were included.Fifteen features including age,gender,etiology,platelet count,albumin,total bilirubin,AFP,tumor size,tumor number,microvascular invasion,macrovascular invasion,Edmondson-Steiner grade,tumor capsular,satellite nodules and liver cirrhosis were used to construct the RSF model in training cohort.Discrimination,calibration,clinical usefulness and overall performance were assessed and compared with other models.Results:Five hundred survival trees were used to generate the RFS model.The five highest Variable Importance(VIMP)were tumor size,macrovascular invasion,microvascular invasion,tumor number and AFP.In training,internal and external validation cohort,the C-index of RSF model were 0.725[standard errors(SE)=0.005],0.762(SE=0.011)and 0.747(SE=0.016),respectively;the Gönen&Heller’s K of RSF model were 0.684(SE=0.005),0.711(SE=0.008)and 0.697(SE=0.014),respectively;the time-dependent AUC(2 years)of RSF model were 0.818(SE=0.008),0.823(SE=0.014)and 0.785(SE=0.025),respectively.The RSF model outperformed early recurrence after surgery for liver tumor(ERASL)model,Korean model,American Joint Committee on Cancer tumor-node-metastasis(AJCC TNM)stage,Barcelona Clinic Liver Cancer(BCLC)stage and Chinese stage.The RSF model is capable of stratifying patients into three different risk groups(low-risk,intermediate-risk,high-risk groups)in the training and two validation cohorts(all P<0.0001).A web-based prediction tool was built to facilitate clinical application(https://recurrenceprediction.shinyapps.io/surgery_predict/).Conclusions:The RSF model is a reliable tool to predict early recurrence for patients with HCC after curative resection because it exhibited superior performance compared with other models.This novel model will be helpful to guide postoperative follow-up and adjuvant therapy.

Pluripotent Stem Cell-derived Strategies to Treat Acute Liver Failure: Current Status and Future Directions

Liver disease has long been a heavy health and economic burden worldwide.Once the disease is out of control and progresses to end-stage or acute organ failure,orthotopic liver transplantation(OLT)is the only therapeutic alternative,and it requires appropriate donors and aggressive administration of immunosuppressive drugs.Therefore,hepatocyte transplantation(HT)and bioartificial livers(BALs)have been proposed as effective treatments for acute liver failure(ALF)in clinics.Although human primary hepatocytes(PHs)are an ideal cell source to support these methods,the large demand and superior viability of PH is needed,which restrains its wide usage.Thus,a finding alternative to meet the quantity and quality of hepatocytes is urgent.In this context,human pluripotent stem cells(PSC),which have unlimited proliferative and differential potential,derived hepatocytes are a promising renewable cell source.Recent studies of the differentiation of PSC into hepatocytes has provided evidence that supports their clinical application.In this review,we discuss the recent status and future directions of the potential use of PSC-derived hepatocytes in treating ALF.We also discuss opportunities and challenges of how to promote such strategies in the common applications in clinical treatments.

Clear mortality gap caused by graft macrosteatosis in Chinese patients after cadaveric liver transplantation

Background:Liver transplantation(LT)is one of the most effective surgical treatment for patients with end-stage liver disease.Steatosis is a contributor for inferior graft quality.But its impact and safety on transplantation was less assessed in Chinese patients.Methods:Graft steatosis and related information involved in recipients,donors and surgical procedures were retrospectively collected from 239 patients.Results:Donor macrosteatosis(MaS)caused about 2.14 and 2.80 folds of increment on patient and graft mortality.Dose-response analysis revealed prominent risk of grafts on overall patient/organ mortality when MaS content exceeded 10%(P<0.05).Noteworthy,deaths were only observed in MaS group when concurrent with extremely higher post-transplant alanine aminotransferase(ALT,64%).However,microsteatosis(MiS)grafts didn’t affect outcomes after LT.In a cohort of Chinese patients,MaS had comprehensive effects on post-transplant outcomes with relatively lower safety threshold at 10%.Mortality gap caused by MaS grafts was observed in patients with severer ischemia reperfusion injury.Conclusions:Our study revealled the graft MaS affected the post-transplant outcomes in lower risk cutoff in Chinese patients.Further study is worthy to validate these results and investigate inner mechanism under the phenomenon.

HIF-1αand HDAC1 mediated regulation of FAM99AmiR92a signaling contributes to hypoxia induced HCC metastasis

Dear Editor,Hypoxic microenvironment is clinically associated with metastasis and poor prognosis of numerous cancers.Previous studies have shown that many protein-coding genes and microRNAs are regulated upon hypoxia and involved in the progression of cancer.However,the roles of lncRNAs in the hypoxia-responsive gene networks and how lncRNA-related signaling network regulates hypoxia induced tumor metastasis is still not clear.

Variations in stable hydrogen and oxygen isotopes in atmospheric water vapor in the marine boundary layer across a wide latitude range

The newly-developed cavity ring-down laser absorption spectroscopy analyzer with special calibration protocols has enabled the direct measurement of atmospheric vapor isotopes at high spatial and temporal resolution. This paper presents real-time hydrogen and oxygen stable isotope data for atmospheric water vapor above the sea surface, over a wide range of latitudes spanning from 38°N to 69°S. Our results showed relatively higher values of 8180 and 82H in the subtropical regions than those in the tropical and high latitude regions, and also a notable decreasing trend in the Antarctic coastal region. By combining the hydrogen and oxygen isotope data with meteoric water line and backward trajectory model analysis, we explored the kinetic fractionation caused by subsiding air masses and related saturated vapor pressure in the subtropics, and the evaporation-driven kinetic fractionation in the Antarctic region. Simultaneous observations of meteorological and marine variables were used to interpret the isotopic composition characteristics and influential factors, indicating that d-excess is negatively correlated with humidity across a wide range of latitudes and weather conditions worldwide. Coincident with previous studies, d-excess is also positively correlated with sea surface temperature and air temperature （Tair）, with greater sensitivity to Tair. Thus, atmospheric vapor isotopes measured with high accuracy and good spatial- temporal resolution could act as informative tracers for exploring the water cycle at different regional scales. Such monitoring efforts should be undertaken over a longer time period and in different regions of the world.

Expert consensus on organizing the multidisciplinary team(MDT) diagnosis and treatment of hepato-pancreato-biliary diseases in China

Multidisciplinary team(MDT) discussion has been well established in some European countries and widely carried out in various clinical professional fields(Festen et al.,2021;Fleissig et al.,2006).Many studies have reported the benefits of MDT,including improving survival and quality of cancer care(Munro et al.,2015;Nixon et al.,2021;Tsai et al.,2020).

A combined Cox and logistic model provides accurate predictive performance in estimation of time-dependent probabilities for recurrence of intrahepatic cholangiocarcinoma after resection

HepatoBiliary Surg Nutr 2021;10(4):464-475|http://dx.doi.org/10.21037/hbsn.2020.01.07 Original Article A combined Cox and logistic model provides accurate predictive performance in estimation of time-dependent probabilities for recurrence of intrahepatic cholangiocarcinoma after resection Seogsong Jeong1,2#,Guijuan Luo2,3#,Qiang Gao4#,Jing Chen2,3#,Xiaolong Liu5,Liangqing Dong4,Yongjie Zhang6,Feng Shen7,Qingbao Cheng8,Chengjun Sui9,Jingfeng Liu5,Hongyang Wang2,3,Qiang Xia1,Lei Chen2,101Department of Liver Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China;2International Cooperation Laboratory on Signal Transduction,Eastern Hepatobiliary Surgery Institute,Second Military Medical University,Shanghai,China;3National Center for Liver Cancer,Shanghai,China;4Department of Liver Surgery and Transplantation,Liver Cancer Institute,Zhongshan Hospital,and Key Laboratory of Carcinogenesis and Cancer Invasion(Ministry of Education),Fudan University,Shanghai,China;5Mengchao Hepatobiliary Hospital,Fujian Medical University,Fuzhou,China;6Biliary Tract Department II,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China;7Department of Hepatobiliary Surgery,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China;8Biliary Tract Department I,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China;9Department of Special Medical Care&Liver Transplantation,Eastern Hepatobiliary Surgery Hospital,Second Military Medical University,Shanghai,China;10Shanghai Cancer Center,Shanghai Medical College,Fudan University;Shanghai,China Contributions:(I)Conception and design:S Jeong,G Luo,Q Gao,J Chen,J Liu,H Wang,Q Xia,L Chen;(II)Administrative support:All authors;(III)Provision of study materials or patients:S Jeong,G Luo,Q Gao,J Chen,J Liu,H Wang,Q Xia,L Chen;(IV)Collection and assembly of data:All authors;(V)Data analysis and interpretation:S Jeong,G Luo,Q Gao,J Chen,J Liu,H Wang,Q Xia,L Chen;(VI)Manuscript writing:All authors;(VII)Final approval of manuscript:All authors.#These authors contributed equally to this work.Correspondence to:Lei Chen;Hongyang Wang.International Cooperation Laboratory on Signal Transduction,Eastern Hepatobiliary Surgery Institute,Second Military Medical University,225 Changhai Road,Shanghai 200438,China.Email:chenlei@smmu.edu.cn;hywangk@vip.sina.com;Qiang Xia.Department of Liver Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,160 Pujian Road,Shanghai 200127,China.Email:xiaqiang@shsmu.edu.cn.