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Development of preoperative prognostic models including radiological features for survival of singular nodular HCC patients

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hepatobiliary & Pancreatic Diseases International 2023年第1期22卷 72-80页

作者： Dong-Yang Ding Lei Liu He-Lin Li Xiao-Jie Gan Wen-Bin Ding Fang-Ming Gu Da-Peng Sun Wen Li Ze-Ya Pan Sheng-Xian Yuan Wei-Ping Zhou Third department of Hepatic surgery Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghai 200438China department of Radiodiagnosis Eastern Hepatobiliary Surgery HospitalNaval Medical UniversityShanghai 200438China

Background:Early singular nodular hepatocellular carcinoma(HCC)is an ideal surgical indication in clinical practice.However,almost half of the patients have tumor recurrence,and there is no reliable prognostic prediction tool.Besides,it is unclear whether preoperative neoadjuvant therapy is necessary for patients with early singular nodular HCC and which patient needs it.It is critical to identify the patients with high risk of recurrence and to treat these patients preoperatively with neoadjuvant therapy and thus,to improve the outcomes of these patients.The present study aimed to develop two prognostic models to preoperatively predict the recurrence-free survival(RFS)and overall survival(OS)in patients with singular nodular HCC by integrating the clinical data and radiological features.Methods:We retrospective recruited 211 patients with singular nodular HCC from December 2009 to January 2019 at Eastern hepatobiliary surgery Hospital(EHBH).They all met the surgical indications and underwent radical resection.We randomly divided the patients into the training cohort(n=132)and the validation cohort(n=79).We established and validated multivariate Cox proportional hazard models by the preoperative clinicopathologic factors and radiological features for association with RFS and OS.By analyzing the receiver operating characteristic(ROC)curve,the discrimination accuracy of the models was compared with that of the traditional predictive models.Results:Our RFS model was based on HBV-DNA score,cirrhosis,tumor diameter and tumor capsule in imaging.RFS nomogram had fine calibration and discrimination capabilities,with a C-index of 0.74(95%CI:0.68-0.80).The OS nomogram,based on cirrhosis,tumor diameter and tumor capsule in imaging,had fine calibration and discrimination capabilities,with a C-index of 0.81(95%CI:0.74-0.87).The area under the receiver operating characteristic curve(AUC)of our model was larger than that of traditional liver cancer staging system,Korea model and Nomograms in Hepatectomy Patients with Hepatitis

关键词： Early-stage hepatocellular carcinoma Singular nodular Radiological features Preoperative prognostic model Recurrence-free survival,Overall survival,Linear equation Neoadjuvant treatment

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Inhibition of pancreatic stellate cell activity by adipose-derived stem cells

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hepatobiliary & Pancreatic Diseases International 2015年第2期14卷 215-221页

作者： Fu-Xiang Yu Long-Feng Su Chun-Lei Dai Yang Wang Yin-Yan Teng Jun-Hui Fu Qi-Yu Zhang Yin-He Tang department of hepatobiliary and Pancreatic surgery FirstAffiliatedHospital WenzhouMedicalCollege department of hepatobiliary and Pancreatic surgery FirstAffiliatedHospitalWenzhouMedicalCollege

BACKGROUND：Pancreatic stellate cells（PSCs）play a critical role in the development of pancreatic fibrosis.In this study we used a novel method to isolate and culture rat PSCs and then investigated the inhibitory effects of adipose-derived stem cells（ADSCs）on activation and proliferation of PSCs.METHODS：Pancreatic tissue was obtained from SpragueDawley rats for PSCs isolation.Transwell cell cultures were adopted for co-culture of ADSCs and PSCs. PSCs prolifera- tion and apoptosis were determined using CCK-8 and flow cytometry, respectively, a-SMA expressions were analyzed using Western blotting. The levels of cytokines [nerve growth factor （NGF）, interleukin-10 （IL-10） and transforming growth factor-ill （TGF-[31）] in conditioned medium were detected by ELISA. Gene expression （MMP-2, MMP-9 and TIMP-1） was analyzed using qRT-PCR. RESULTS： This method produced 17.6_＋6.5 ~ 103 ceils per gram of the body weight with a purity of 90%-95% and a viability of 92%-97%. Co-culture of PSCs with ADSCs significantly inhib- ited PSCs proliferation and induced PSCs apoptosis. Moreover, a-SMA expression was significantly reduced in PSCs＋ADSCs compared with that in PSC-only cultures, while expression of fibrinolytic proteins （e.g., MMP-2 and MMP-9） was upregulated and anti-fibrinolytic protein （TIMP-1） was downregulated. In addition, NGF expression was up-regulated, but IL-10 and TGF-β1 expressions were down-regulated in the coculture conditioned medium compared with those in the PSC- only culture medium. CONCLUSIONS： This study provided an easy and reliable technique to isolate PSCs. The data demonstrated the inhibitory effects of ADSCs on the activation and proliferation of PSCs in vitro.

关键词： pancreatic stellate cells isolation mesenchymal stem cells pancreatic fibrosis fibrinolytic protein

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TOX deficiency facilitates the differentiation of IL-17A-producingγδT cells to drive autoimmune hepatitis

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Cellular & Molecular Immunology 2022年第10期19卷 1102-1116页

作者： Qifeng He Yijun Lu Wenfang Tian Runqiu Jiang Weiwei Yu Yong Liu Meiling Sun Fei Wang Haitian Zhang Ning Wu Zhongjun Dong Beicheng Sun department of hepatobiliary surgery Affiliated Drum Tower HospitalMedical School of Nanjing UniversityNanjingChina department of hepatobiliary surgery The First Affiliated Hospital of Anhui Medical UniversityHefeiChina

The specification of theαβ/γδlineage and the maturation of medullary thymic epithelial cells(mTECs)coordinate central tolerance to self-antigens.However,the mechanisms underlying this biological process remain poorly clarified.Here,we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation,promoted thymic IL-17A-producingγδT-cell(Tγδ17)lineage commitment,and led to the development of fatal autoimmune hepatitis(AIH)via different mechanisms.Transfer ofγδT cells from TOX-deficient mice reproduced AIH.TOX interacted with and stabilized the TCF1 protein to maintain the balance ofγδT-cell development in thymic progenitors,and overexpression of TCF1 normalizedαβ/γδlineage specification and activation.In addition,TOX expression was downregulated inγδT cells from AIH patients and was inversely correlated with the AIH diagnostic score.Our findings suggest multifaceted roles of TOX in autoimmune control involving mTEC and Tγδ17 development and provide a potential diagnostic marker for AIH.

关键词： Autoimmune hepatitis γδT cell IL-17A Immune tolerance TOX

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Conversion therapy in liver transplantation for hepatocellular carcinoma:What's new in the era of molecular and immune therapy?

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hepatobiliary & Pancreatic Diseases International 2023年第1期22卷 7-13页

作者： Chao Jiang Xiao-Dong Sun Wei Qiu Yu-Guo Chen Da-Wei Sun Guo-Yue Lv General surgery Center Department of Hepatobiliary and Pancreatic Surgerythe First Hospital of Jilin UniversityChangchun 130021China

Background:Hepatocellular carcinoma(HCC)is the sixth most common cancer globally,with limited therapies and unsatisfactory prognosis once in the advanced stages.With promising advances in locoregional and systematic treatments,fast development of targeted drugs,the success of immunotherapy,as well as the emergence of the therapeutic alliance,conversion therapy has recently become more well developed and an effective therapeutic strategy.This article aimed to review recent developments in conversion therapy in liver transplantation(LT)for HCC.Data sources:We searched for relevant publications on Pub Med before September 2022,using the terms“HCC”,“liver transplantation”,“downstaging”,“bridging treatment”and“conversion therapy.”Results:Conversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT.Although combining various local and systematic treatments in conversion therapy is still controversial,growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time,which ultimately increases the opportunities for LT.Moreover,the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors.Conclusions:In the era of targeted therapy and immunotherapy,applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients.With the expansion of conversion therapy concepts,further investigation and research is required to realize the full potential of conversion treatment strategies,including accurately selecting candidates,determining the timing of surgery,improving the conversion rate,and guaranteeing the safety and long-term efficacy of treatment.

关键词： Liver transplantation Hepatocellular carcinoma Conversion therapy Targeted therapy Immunotherapy Combination therapy

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Associations of cholecystectomy with the risk of colorectal cancer: a Mendelian randomization study

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Chinese Medical Journal 2023年第7期136卷 840-847页

作者： Lanlan Chen Zhongqi Fan Xiaodong Sun Wei Qiu Wentao Mu Kaiyuan Chai Yannan Cao Guangyi Wang Guoyue Lv department of hepatobiliary and Pancreatic surgery General Surgery CenterFirst Hospital of Jilin UniversityChangchunJilin 130021China

Background:Cholecystectomy is a standard surgery for patients suffering from gallbladder diseases,while the causal effects of cholecystectomy on colorectal cancer(CRC)and other complications are still unknown.Methods:We obtained genetic variants associated with cholecystectomy at a genome-wide significant level(P value<5×10^(-8))as instrumental variables(IVs)and performed Mendelian randomization(MR)to identify the complications of cholecystectomy.Furthermore,the cholelithiasis was also treated as the exposure to compare its causal effects to those of cholecystectomy,and multivariable MR analysis was carried out to judge whether the effect of cholecystectomy was independent of cholelithiasis.The study was reported based on Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization guidelines.Results:The selected IVs explained 1.76%variance of cholecystectomy.Our MR analysis suggested that cholecystectomy cannot elevate the risk of CRC(odds ratio[OR]=1.543,95%confidence interval[CI]:0.607–3.924).Also,it was not significant in either colon or rectum cancer.Intriguingly,cholecystectomy might decrease the risk of Crohn’s disease(OR=0.078,95%CI:0.016-0.368)and coronary heart disease(OR=0.352,95%CI:0.164–0.756).However,it might increase the risk of irritable bowel syndrome(IBS)(OR=7.573,95%CI:1.096–52.318).Cholelithiasis could increase the risk of CRC in the largest population(OR=1.041,95%CI:1.010–1.073).The multivariable MR analysis suggested that genetic liability to cholelithiasis could increase the risk of CRC in the largest population(OR=1.061,95%CI:1.002–1.125)after adjustment of cholecystectomy.Conclusions:The study indicated that cholecystectomy might not increase the risk of CRC,but such a conclusion needs further proving by clinical equivalence.Additionally,it might increase the risk of IBS,which should be paid attention to in clinical practice.

关键词： Cholelithiasis Irritable bowel syndrome Inflammatory bowel disease Causal inference Colorectal cancer Cholecystectomy Mendelian randomization

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Efficacy and safety of low-dose cyclophosphamide combined with lenvatinib, pembrolizumab and TACE for unresectable hepatocellular carcinoma:A single-center, prospective,single-arm clinical trial

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Chinese Journal of Cancer Research 2024年第2期36卷 114-123页

作者： Yupeng Ren Yuxuan Li Mingbo Cao Yongchang Tang Feng Yuan Gaoyuan Yang Zhiwei He Zheng Shi Xiaorui Su Zhicheng Yao Meihai Deng department of hepatobiliary surgery the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China department of General surgery Qilu HospitalShandong UniversityJinan 250012China department of hepatobiliary surgery the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China department of hepatobiliary and Pancreatic surgery the Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China

Objective: Unresectable hepatocellular carcinoma(uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenvatinib, pembrolizumab and transarterial chemoembolization(TACE) for the treatment of uHCC.Methods: From February 2022 to November 2023, a total of 40 patients diagnosed with uHCC were enrolled in this small-dose, single-center, single-arm, prospective study. They received a combined treatment of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE. Study endpoints included progression-free survival(PFS), objective response rate(ORR), and safety assessment. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors(mRECIST), while survival analysis was conducted through KaplanMeier curve analysis for overall survival(OS) and PFS. Adverse events(AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events(version 5.0).Results: A total of 34 patients were included in the study. The median follow-up duration was 11.2 [95% confidence interval(95% CI), 5.3-14.6] months, and the median PFS(mPFS) was 15.5(95% CI, 5.4-NA) months.Median OS(mOS) was not attained during the study period. The ORR was 55.9%, and the disease control rate(DCR) was 70.6%. AEs were reported in 27(79.4%) patients. The most frequently reported AEs(with an incidence rate >10%) included abnormal liver function(52.9%), abdominal pain(44.1%), abdominal distension and constipation(29.4%), hypertension(20.6%), leukopenia(17.6%), constipation(17.6%), ascites(14.7%), and insomnia(14.7%). Abnormal liver function(14.7%) had the most common grade 3 or higher AEs.Conclusions: A combination of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE is safe and effective for u HCC, showcasing a promising therapeutic strategy for managing uHCC.

关键词： Hepatocellular carcinoma lenvatinib low-dose cyclophosphamide pembrolizumab transarterial chemoembolization

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基于植物光合系统赋予人体细胞能量的再生医学

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Science Bulletin 2023年第4期68卷 370-372,M0003页

作者：王经琳黄丹青赵远锦 department of hepatobiliary surgery The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolHepatobiliary Institute of Nanjing UniversityNanjing 210008China

To fulfill the long-held dream of human beings to stay health and extend life,regenerative medicine has merged as the future medical direction.Generally,the regenerative medicine aims to repairing or replacing the dysfunctional organs caused by diseases or aging[1].The phenomenon of regeneration is widespread among natural species[2].Many animals are born with the ability to repair severely defected tissues or regenerate partially damaged organs.For example,geckoes can grow back their severed tails without leaving any scars;earthworms are able to regenerate new bodies on the cut surface after being chopped.

关键词：再生医学 organs 光合系统

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Combination of renoportal anastomosis and inferior mesenteric vein-portal anastomosis in liver transplantation:A new portal reconstruction technique

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hepatobiliary & Pancreatic Diseases International 2022年第2期21卷 182-185页

作者： Guo-Ling Lin Min Xiao Li Zhuang Yu Yang Qi-Yong Li Jian-Fang Lu Meng-Xia Li Shu-Sen Zheng Division of hepatobiliary and Pancreatic surgery Department of SurgeryShulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical CollegeHangzhouChina Division of hepatobiliary and Pancreatic surgery Department of NursingShulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical CollegeHangzhouChina Division of hepatobiliary and Pancreatic surgery Department of SurgeryZhejiang University School of MedicineHangzhouChina Division of hepatobiliary and Pancreatic surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina

Liver transplantation (LT) is the only way to cure end-stage liver disease with or without tumors in the last few decades [1].However,critical issues such as how to rebuild portal flow in patients with portal vein thrombosis (PVT) or superior mesenteric vein (SMV) thrombosis have been challenging for surgeons.Adequate portal flow is critical in LT because more than 75%of the liver’s blood supply comes from the portal vein and the rest comes from the hepatic artery.PVT is a universal problem in LT.

关键词： anastomosis portal Liver

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TPX2 knockdown suppressed hepatocellular carcinoma cell invasion via inactivating AKT signaling and inhibiting MMP2 and MMP9 expression

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Chinese Journal of Cancer Research 2014年第4期26卷 410-417页

作者： Qingquan Liu Pinghua Yang Kangsheng Tu Hongyong Zhang Xin Zheng Yingmin Yao Qingguang Liu department of hepatobiliary surgery The First Affiliated Hospital of Xi'an Jiaotong University department of Hepatic surgery Eastern Hepatobiliary Surgery Hospital

Objective： Targeting protein for Xenopus kinesin-like protein 2 （TPX2） is a nuclear proliferation-related protein that plays a critical role in the formation of mitotic spindle. High expression of TPX2 has been observed in several types of tumors. However, the role of TPX2 in hepatocellular carcinoma （HCC） remains unclear. Our study aimed to investigate the effect of TPX2 on HCC cell invasion. Methods： The immortalized normal human liver cell line L02 and six HCC cell lines including SMMC- 7721, BEL-7402, Huh-7, HepG2, Hep3B and SKHepl were subjected to qRT-PCR and western blot for TPX2 mRNA and protein, respectively. Furthermore, TPX2 small interfering RNA （siRNA） was used to knock down TPX2 expression in SMMC-7721 and HepG2 cells. Cell proliferation and invasion were determined by MTT and transwell assays. Otherwise, expression of p-AKT, MMP2 and MMP9 were evaluated by western blot in SMMC-7721 cells. Results： The expression of TPX2 in HCC cell lines was markedly higher than that in normal human liver cell line. TPX2 knockdown using a specific TPX2-siP, NA reduced the number of invaded cells and inhibited cell proliferation in SMMC-7721 and HepG2 cells. Furthermore, TPX2 knockdown resulted in inactivation of AKT signaling and down-regulation of MMP2 and MMP9 expression in SMMC-7721 cells. Conclusions： Our study identified that TPX2 might contribute to tumor cell invasion through activating AKT signaling and subsequently increasing MMP2 and MMP9 in HCC.

关键词： Targeting protein for Xenopus kinesin-like protein 2 （TPX2） hepatocellular carcinoma MMP2 MMP9

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Research progress of lncRNA and miRNA in hepatic ischemia-reperfusion injury

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hepatobiliary & Pancreatic Diseases International 2023年第1期22卷 45-53页

作者： Shan-Fei Zhu Wei Yuan Yong-Liang Du Bai-Lin Wang department of hepatobiliary surgery Guangzhou Red Cross Hospital of Jinan UniversityGuangzhou 510220China

Background:Hepatic ischemia-reperfusion injury(HIRI)is a common complication of liver surgeries,such as hepatectomy and liver transplantation.In recent years,several non-coding RNAs(nc RNAs)including long non-coding RNAs(lnc RNAs)and micro RNAs(mi RNAs)have been identified as factors involved in the pathological progression of HIRI.In this review,we summarized the latest research on lnc RNAs,mi RNAs and the lnc RNA-mi RNA regulatory networks in HIRI.Data sources:The Pub Med and Web of Science databases were searched for articles published up to December 2021 using the following keywords:“hepatic ischemia-reperfusion injury”,“lnc RNA”,“long noncoding RNA”,“mi RNA”and“micro RNA”.The bibliography of the selected articles was manually screened to identify additional studies.Results:The mechanism of HIRI is complex,and involves multiple lnc RNAs and mi RNAs.The roles of lnc RNAs such as AK139328,CCAT1,MALAT1,TUG1 and NEAT1 have been established in HIRI.In addition,numerous mi RNAs are associated with apoptosis,autophagy,oxidative stress and cellular inflammation that accompany HIRI pathogenesis.Based on the literature,we conclude that four lnc RNA-mi RNA regulatory networks mediate the pathological progression of HIRI.Furthermore,the expression levels of some lnc RNAs and mi RNAs undergo significant changes during the progression of HIRI,and thus are potential prognostic markers and therapeutic targets.Conclusions:Complex lnc RNA-mi RNA-m RNA networks regulate HIRI progression through mutual activation and antagonism.It is necessary to screen for more HIRI-associated lnc RNAs and mi RNAs in order to identify novel therapeutic targets.

关键词： ncRNA lncRNA miRNA Hepatic ischemia-reperfusion injury Research progress

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