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Personalized pancreatic cancer therapy:from the perspective of mRNA vaccine

Military Medical Research 2023年第4期10卷 461-477页

作者： Xing Huang Gang Zhang Tian‑Yu Tang Xiang Gao ting‑bo liang Zhejiang Provincial Key Laboratory of Pancreatic Disease the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases Hangzhou 310003China The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province Hangzhou 310009China Cancer Center Zhejiang UniversityHangzhou 310058China

Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and *** therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise *** vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological *** conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains *** with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic *** review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.

关键词： Pancreatic cancer Precise therapy Cancer vaccine mRNA vaccine Tumor antigen Immune subtype

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Immunometabolism:A novel perspective of liver cancer microenvironment and its influence on tumor progression

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World Journal of Gastroenterology 2018年第31期24卷 3500-3512页

作者： Qi Zhang Yu Lou Xue-Li Bai ting-bo liang Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310009Zhejiang ProvinceChina Zhejiang Provincial Key Laboratory of Pancreatic Disease Hangzhou 310009Zhejiang ProvinceChina

The initiation and progression of liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, are dependent on its tumor microenvironment. Immune cells are key players in the liver cancer microenvironment and show complicated crosstalk with cancer cells. Emerging evidence has shown that the functions of immune cells are closely related to cell metabolism. However, the effects of metabolic changes of immune cells on liver cancer progression are largely undefined. In this review, we summarize the recent findings of immunometabolism and relate these findings to liver cancer progression. We also explore the translation of the understanding of immunometabolism for clinical use.

关键词： Cholangiocarcinoma Hepatocellular carcinoma Tumor microenvironment Local immune status Metabolite

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Intratumoral heterogeneity of hepatocellular carcinoma: From singlecell to population-based studies

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World Journal of Gastroenterology 2020年第26期26卷 3720-3736页

作者： Qi Zhang Yu Lou Xue-Li Bai ting-bo liang Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Key Laboratory of Pancreatic Disease of Zhejiang Province Hangzhou 310003Zhejiang ProvinceChina Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province Hangzhou 310003Zhejiang ProvinceChina Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases Hangzhou 310003Zhejiang ProvinceChina

Hepatocellular carcinoma(HCC)is characterized by high heterogeneity in both intratumoral and interpatient *** interpatient heterogeneity is related to personalized therapy,intratumoral heterogeneity(ITH)largely influences the efficacy of therapies in *** contributes to tumor growth,metastasis,recurrence,and drug resistance and consequently limits the prognosis of patients with *** is an urgent need to understand the causes,characteristics,and consequences of tumor heterogeneity in HCC for the purposes of guiding clinical practice and improving ***,we summarize the studies and technologies that describe ITH in HCC to gain insight into the origin and evolutionary process of *** parallel,evidence is collected to delineate the dynamic relationship between ITH and the tumor *** suggest that conducting comprehensive studies of ITH using single-cell approaches in temporal and spatial dimensions,combined with population-based clinical trials,will help to clarify the clinical implications of ITH,develop novel intervention strategies,and improve patient prognosis.

关键词： Hepatocellular carcinoma Tumor heterogeneity Tumor microenvironment Single-cell analysis Local immunity

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mRNA vaccine development for cholangiocarcinoma:a precise pipeline

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Military Medical Research 2023年第2期10卷 262-267页

作者： Tian-Yu Tang Xing Huang Gang Zhang Ming-Hao Lu ting-bo liang Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Zhejiang Provincial Key Laboratory of Pancreatic Disease the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases Hangzhou 310003China Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province Hangzhou 310009China Cancer Center Zhejiang UniversityHangzhou 310058China

Cholangiocarcinoma(CHOL)is one of the most aggressive tumors worldwide and cannot be effectively treated by conventional and novel treatments,including immune checkpoint blockade *** mRNA vaccine-based immunotherapeutic strategy has attracted much attention for various diseases,however,its application in CHOL is limited due to the thoughtlessness in the integration of vaccine design and patient selection.A recent study established an integrated path for identifying potent CHOL antigens for mRNA vaccine development and a precise stratification for identifying CHOL patients who can benefit from the mRNA *** spite of a promising prospect,further investigations should identify immunogenic antigens and onco-immunological characteristics of CHOL to guide the clinical application of CHOL mRNA vaccines in the future.

关键词： Cholangiocarcinoma(CHOL) mRNA vaccine Tumor antigen Immune subtype Immune microenvironment

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Expression of MMP-9 in hepatic sinusoidal obstruction syndrome induced by Gynura segetum

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2013年第1期14卷 68-75页

作者： Xia-zhen YU Tao JI Xue-li BAI liang liang Lin-yan WANG Wei CHEN ting-bo liang Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 China Department of Surgery Changhai Hospital the Second Military Medical University Shanghai 200433 China The Children 's Hospital School of Medicine Zhejiang University Hangzhou 310003 China

Background and objective： Hepatic sinusoidal obstruction syndrome （HSOS） is characterized by painful hepatomegaly, ascites, increased body weight, and jaundice. Gynura segetum （Compositae）, a plant widely used in Chinese traditional medicine, often leads to the development of HSOS. However, the mechanism is unclear. The aim was to study the role of matrix metalloproteinase-9 （MMP-9） in the onset of HSOS induced by Gynura segetum. Methods： Twenty-five male Sprague-Dawley rats were randomly divided into two groups. Twenty were exposed to 600 mg/kg daily Gynura segetum extract solution for three weeks; five control rats were exposed to tap water alone. Liver sections were evaluated by light microscopy with a modified scoring system. Routine transmission electron microscopy （TEM） methods were used to evaluate the ultrastructual features of fixed liver tissue, and blood samples were collected to determine liver enzyme concentrations. MMP-9 expression was assessed by both immunohisto- chemical staining and enzyme-linked immunosorbent assay （ELISA） methods. Results： A stable and reproducible rat model of HSOS was achieved by long-term exposure to Gynura segetum extract. The treated rats presented clinical symptoms and the histopathological manifestation of HSOS, including abnormal liver enzyme concentrations （alanine aminotransferase （ALT）：（84.8＋13.62） vs. （167.0±72.63） U/L, P〈0.05; aspartate aminotransferase （AST）：（27.6±6.31） vs. （232.8±108.58） U/L, P〈0.05）. Hematoxylin and eosin （H＆E） staining and TEM together revealed deposition of red blood cells, the damage and destruction of hepatic sinusoidal endothelial cells, collapse of hepatic sinusoids, hem- orrhage of subendothelial cells, atrophy and destruction of hepatocytes, etc. Compared with controls, the expression of MMP-9 in the blood sample, the lung and liver tissues of HSOS rats was increased. Conclusions： MMP-9 may have an important role in early patholoclical chanqes of HSOS, and thus the onset of the disease.

关键词： Hepatic sinusoidal obstruction syndrome Gynura segetum (Compositae) Sinusoidal endothelial cells Matrix metalloproteinase-9

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Pancreatic cystic neoplasms:a review of preoperative diagnosis and management

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2013年第3期14卷 185-194页

作者： Xue-li BAI Qi ZHANG Noman MASOOD Waqas MASOOD Yun ZHANG ting-bo liang Department of Hepatobiliary-Pancreatic Surgery the Second Affiliated HospitalSchool of MedicineZhejiang University

Pancreatic cystic neoplasms(PCNs) are a diverse group of neoplasms in the pancreas,and are more increasingly encountered with widespread abdominal screening and improved imaging *** most common types of PCNs are serous cystic neoplasms(SCNs),mucinous cystic neoplasms(MCNs),and intraductal papillary mucinous neoplasms(IPMNs).Clinicians frequently feel bewildered in the differential diagnosis and subsequent management among the various types of lesions in the pancreas,which may lead to overtreatment or delayed *** current review provides recent developments in the understanding of the three most common types of PCNs,the latest modalities used in preoperative diagnosis and differential diagnosis,as well as the most up to date *** for diagnosis and differential diagnosis of SCNs,MCNs,and IPMNs are also provided for young *** understanding of these neoplasms is essential for clinicians to make accurate diagnosis and to provide the best management for patients.

关键词： Pancreatic cystic neoplasms Serous cystic neoplasms Intraductal papillary mucinous neoplasms Mucinous cystic neoplasms Diagnosis

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Human development index is associated with mortality-to-incidence ratios of gastrointestinal cancers

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World Journal of Gastroenterology 2013年第32期19卷 5261-5270页

作者： Qi-Da Hu Qi Zhang Wei Chen Xue-Li Bai ting-bo liang Department of Surgery the Second Affiliated HospitalSchool of MedicineZhejiang University

AIM:To identify the role of human development in the incidence and mortality rates of gastrointestinal cancers ***:The age-standardized incidence and mortality rates for gastrointestinal cancers,including cancers of the esophagus,stomach,pancreas,liver,gallbladder,and colorectum,were obtained from the GLOboCAN 2008 database and United States Cancer Statistics(USCS)*** human development index(HDI)data were calculated according to the 2011 Human Development *** estimated the mortality-toincidence ratios(MIRs)at the regional and national levels,and explored the association of the MIR with development levels as measured by the HDI using a modified"drug dose to inhibition response"***,countries were divided into four groups according to the HDI distribution,and the MIRs of the four HDI groups were compared by one-way ANOVA followed by the Tukey-Kramer post-hoc *** MIRs in the United States were predicted from the estimated HDI using the fitted non-linear model,and were compared with the actual MIRs calculated from data in the USCS ***:The worldwide incidence and mortality rates of gastrointestinal cancers were as high as 39.4and 54.9 cases per 100000 individuals,*** and non-linear regression analyses revealed an inverse correlation between the MIR of gastrointestinal cancers and the HDI at the regional and national levels(<0;P=0.0028 for regional level and<0.0001 for national level,ANOVA).The MIR differed significantly among the four HDI areas(very high HDI,0.620±0.033;high HDI,0.807±0.018;medium HDI,0.857±0.021;low HDI,0.953±0.011;P<0.001,oneway ANOVA).Prediction of the MIRs for individual United States states using best-fitted non-linear models showed little deviation from the actual MIRs in the United *** for 28 data points(9.93%of282),the actual MIRs of all gastrointestinal cancers were mostly located in the prediction intervals via the best-fit non-linear regression models.C

关键词： Gastrointestinal neoplasms Mortality-toincidence ratio Human development index Healthcare disparities Socioeconomic factors

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Factors associated with failure of enhanced recovery after surgery program in patients undergoing pancreaticoduodenectomy

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Hepatobiliary & Pancreatic Diseases International 2020年第1期19卷 51-57页

作者： Xiao-Yu Zhang Xiao-Zhen Zhang Fang-Yan Lu Qi Zhang Wei Chen Tao Ma Xue-Li Bai ting-bo liang Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Hepatobiliary and Pancreatic Surgery the Second Affliated HospitalZhejiang University School of MedicineHangzhou 310009China Key Laboratory of Pancreatic Disease of Zhejiang Province Hangzhou 310003China

Background: The enhanced recovery after surgery (ERAS) protocol is an evidence-based perioperative care program aimed at reducing surgical stress response and accelerating recovery. However, a small propor- tion of patients fail to bene t from the ERAS program following pancreaticoduodenectomy. This study aimed to identify the risk factors associated with failure of ERAS program in pancreaticoduodenectomy. Methods: Between May 2014 and December 2017, 176 patients were managed with ERAS program fol-lowing pancreaticoduodenectomy. ERAS failure was indicated by prolonged hospital stay, unplanned read- mission or unplanned reoperation. Demographics, postoperative recovery and compliance were compared of those ERAS failure groups to the ERAS success group. Results: ERAS failure occurred in 59 patients, 33 of whom had prolonged hospital stay, 18 were readmitted to hospital within 30 days after discharge, and 8 accepted reoperation. Preoperative American Society of Anesthesiologists (ASA) score of ≥III (OR = 2.736;95% CI: 1.276 6.939;P=0.028) and albumin (ALB) level of 70 years) were on a high risk of unplanned reoperation (62.5% vs. 23.1%, P=0.026). Patients with prolonged hospital stay and unplanned reoperation had delayed intake and increased intolerance of oral foods. Prolonged stay patients got off bed later than ERAS success patients did (65h vs. 46h, P =0.012). Unplanned reoperation patients tended to experience severer pain than ERAS success patients did (3 score vs. 2 score, P =0.035). Conclusions: Patients with high ASA score, low ALB level or age >70 years were at high risk of ERAS failure in pancreaticoduodenectomy. These preoperative demographic and clinical characteristics are important determinants to obtain successful postoperative recovery in ERAS program.

关键词： Enhanced recovery after surgery ERAS Pancreaticoduodenectomy Failure of ERAS Risk factors

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Probable sirolimus-induced rupture of arterial anastomosis after liver transplantation in a patient intolerant of tacrolimus

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Hepatobiliary & Pancreatic Diseases International 2019年第4期18卷 398-400页

作者： Meng-Yi Lao Tao Ma Xue-Li Bai Xiao-Zhen Zhang Tian-Yu Tang ting-bo liang Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of Medicine79 Qingchun RoadHangzhou 310003China Key Laboratory of Pancreatic Disease of Zhejiang Province Hangzhou 310009China

To the Editor:Liver transplantation remains the only cure for end-stage liver *** is widely used as a first-line immunosuppressive drug to prevent organ rejection after liver transplantation[1–3].However,tacrolimus has a narrow therapeutic index and wide inter-individual variability in pharmacokinetics,which can result in underimmunosuppression or *** administered tacrolimus is rapidly absorbed from the distal gastrointestinal tract and extensively metabolized in the liver and intestinal walls by cytochrome P450(CYP)3A4 and 3A5[2,4,5].

关键词： rupture liver arterial

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Combined targeted therapy and immunotherapy for cancer treatment

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World Journal of Clinical Cases 2021年第26期9卷 7643-7652页

作者： Cheng-Xiang Guo Xing Huang Jian Xu Xiao-Zhen Zhang Yi-Nan Shen ting-bo liang Xue-Li Bai Department of Hepatobiliary and Pancreatic Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

Although targeted therapies and immunotherapies have been effective againstseveral malignancies, the respective monotherapies are limited by low and/orshort-term responses. Specific inhibitors of oncogenic signaling pathways andtumor-associated angiogenesis can activate the anti-tumor immune responses byincreasing tumor antigen presentation or intratumor T cell infiltration. Additionalinsights into the effects and mechanisms of targeted therapies on the induction ofanti-tumor immunity will facilitate development of rational and effective combinationstrategies that synergize rapid tumor regression and durable response. Inthis review, we have summarized the recent combinations of targeted therapiesand immunotherapies, along with the associated clinical challenges.

关键词： Cancer Targeted therapy Immunotherapy Combined treatment

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