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Enzymatic self-assembly/disassembly turns “ON”/“OFF” the mimetic hydrolytic activity of histidine nanofibers

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Science China Chemistry 2024年第2期67卷 517-522页

作者： xianbao Sun Manli Wang Xiaoyang Liu Wenjun zhan Guangqiong Xu Qiaochu Jiang Hai-Dong Xu Fuqiang Wang Gaolin Liang State Key Laboratory of Digital Medical Engineering School of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China Analysis Center Nanjing Medical UniversityNanjing210029China

Mimetic enzymes are devised as alternates or supplements of natural enzymes in broad fields but regulating their activities in a switchable manner remains ***,we proposed an enzymatic self-assembly/disassembly strategy to address this issue.A peptide molecule Nap FFEYIH(YH) was rationally designed which,after self-assembling into nanofibers,lined up the histidine moieties to form active hydrolysis centers for mimicking hydrolase *** dephosphorylation of Nap FFEYp IH(Yp H) by alkaline phosphatase to yield YH also turned “ON” the hydrolase *** turn,phosphorylation of YH by phosphokinase epidermal growth factor receptor to yield Yp H disassembled the nanofibers and thus turned the activity “OFF”.As such,the “ON”/“OFF” of the mimetic hydrolase activities could be regulated under physiological conditions through ALP/EGFR-mediated self-assembly/disassembly of histidine *** work provides a feasible strategy for the on-demand fabrication of artificial enzymes with controllable and superior activities.

关键词： disassembly hydrolytic activity mimetic enzyme phosphorylation self-assembly

The real-world study of the clinical characteristics,diagnosis,and treatment of advanced pancreatic cancer in China

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Journal of Pancreatology 2024年第1期7卷 1-9页

作者： Jiujie Cui Qihan Fu Xiaobing Chen Yanling Wang Qi Li Feng Wang Zhihua Li Guanghai Dai Yusheng Wang Hongmei zhang Houjie Liang Jun Zhou Liu Yang Fenghua Wang Leizhen Zheng Xiaofeng Chen Ping Gong Jiang Liu Ying Yuan Lin Wang Yuejuan Cheng Jun zhang Yuhong Zhou Weijian Guo xianbao zhan Zhengyun Zou Da Li Shan Zeng Enxiao Li Zhiwei Li Zan Teng Dan Cao Jie Kan Jianping Xiong Ming Quan Jiayu Yao Haiyan Yang Liwei Wang Department of Medical Oncology Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Department of Medical Oncology The First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouChina Department of Medical Oncology Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhouChina Department of Medical Oncology Shanghai General HospitalShanghai Jiao Tong UniversityShanghaiChina Department of Medical Oncology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina Department of Medical Oncology Sun Yat-sen Medical Hospital Sun Yat-sen UniversityGuangzhouChina Medical Oncology Chinese PLA General HospitalBeijingChina Department of Gastrointestinal Oncology Shanxi Provincial Cancer HospitalAffiliated to Shanxi Medical UniversityTaiyuanChina Department of Clinical Oncology Xijing HospitalAir Force Medical UniversityXi’anChina Department of Oncology and Southwest Cancer Center Southwest HospitalThird Military Medical University(Army Military Medical University)ChongqingChina Department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing)Peking University Cancer Hospital&InstituteBeijingChina Cancer Center Department of Medical OncologyZhejiang Provincial People’s HospitalPeople’s Hospital of Hangzhou Medical CollegeHangzhouChina Department of Medical Oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdongChina Oncology Department Xin Hua Hospital Affiliated to Shanghai JiaoTong University School of MedicineShanghaiChina Department of Oncology the First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Department of Oncology The First Affiliated HospitalSchool of MedicineShihezi UniversityShiheziChina Department of Oncology People’s Hospital of Xinjiang Uygur Autonomous RegionXinjiangChina Department of Medical Oncology t

Objective:Real-world diagnostic and treatment data for pancreatic cancer in China are *** such,the present study investigated the clinical characteristics,diagnosis,and treatment of advanced pancreatic cancer(including locally advanced and metastatic disease)in the Hospital-based Advanced Pancreatic Cancer Cohort in China of the China Pancreas Data Center ***:A total of 5349 Chinese patients with advanced pancreatic cancer were identified from a *** entire course of real-world pancreatic cancer management was ***:The proportion of patients with advanced pancreatic cancer was higher among males than females(62.4%vs 37.6%,respectively).Patients typically had a history of hypertension(30.8%),diabetes(21.6%),and cholangitis(20.2%).Abdominal pain(51.6%),abdominal distension(27.1%),jaundice(20.1%),and weight loss(16.3%)were the main symptoms observed in patients with advanced pancreatic cancer in this *** carbohydrate antigen(CA)19-9 is one of the most common tumor *** the present study,2562 patients underwent first-line *** median progression-free survival(PFS)for patients undergoing first-line therapy was 4.1 *** major options for first-line therapy included gemcitabine(GEM)plus S-1(GS/X)(23.4%),nab-paclitaxel plus GEM(AG)(18.1%),oxaliplatin,irinotecan,and leucovorin-modulated fluorouracil(FOLFIRINOX;11.9%),nab-paclitaxel plus S-1(AS)(8.9%),and GEM combined with oxaliplatin/cisplatin(GEMOX/GP)(7.6%).The AS and GS/X regimens were associated with the highest PFS ***:This is the first study to report multicenter,real-world data regarding advanced pancreatic cancer in *** revealed that real-world treatment options differed from guideline recommendations,and PFS was shorter than that in previously reported *** intelligent follow-up systems and standardizing diagnosis and treatment of pancreatic cancer is recommended.

关键词： Advanced pancreatic cancer China Pancreas Data Center Chinese First-line regimens Real-world study

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腹膜转移癌的肿瘤微环境研究进展

中国癌症杂志 2020年第4期30卷 305-309页

作者：陈铃(综述) 湛先保(审校) 海军军医大学(第二军医大学)长海医院肿瘤科上海200433

癌症患者肿瘤出现腹膜转移通常预示预后较差,目前常规的治疗方法是细胞减灭术联合腹腔热灌注化疗(cytoreductive surgery/hyperthermic intraperitoneal chemotherapy,CRS/HIPEC),但是仅适用于少数具备手术条件的患者。现有的研究结果表... 详细信息

癌症患者肿瘤出现腹膜转移通常预示预后较差,目前常规的治疗方法是细胞减灭术联合腹腔热灌注化疗(cytoreductive surgery/hyperthermic intraperitoneal chemotherapy,CRS/HIPEC),但是仅适用于少数具备手术条件的患者。现有的研究结果表明,腹膜转移癌的生物学特征已发生显著改变,腹膜局部免疫微环境也有明显异常,腹膜脂质更是腹膜转移癌微环境中的特殊组分。针对腹膜转移癌局部微环境的深入研究,将有助于揭示腹膜转移的机制,并为开拓新型治疗方法提供有益地探索。

关键词：肿瘤腹膜转移腹水免疫微环境免疫细胞脂肪组织

免疫检查点抑制剂在消化系统恶性肿瘤治疗中的应用

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中国肿瘤生物治疗杂志 2019年第1期26卷 103-108页

作者：陈龙佩湛先保海军军医大学附属长海医院肿瘤科上海200433

消化系统肿瘤是人类常见的恶性肿瘤,其中胃癌、结直肠癌、胰腺癌的发病率和病死率均较高。免疫治疗作为一种新的治疗方法,正逐步成为多种肿瘤的有效治疗策略之一。CTLA-4和PD-1是通过不同机制负调控T细胞活化的关键免疫检查点分子。针... 详细信息

消化系统肿瘤是人类常见的恶性肿瘤,其中胃癌、结直肠癌、胰腺癌的发病率和病死率均较高。免疫治疗作为一种新的治疗方法,正逐步成为多种肿瘤的有效治疗策略之一。CTLA-4和PD-1是通过不同机制负调控T细胞活化的关键免疫检查点分子。针对这些免疫检查点抑制剂,已经显示出临床疗效,并已获美国FDA批准用于多种实体瘤的治疗。其中,纳武单抗在延长晚期肝癌患者生存期方面超过了索拉非尼,派姆单抗在PD-L1阳性晚期食管癌有效率可达30%,纳武单抗与伊匹单抗联合治疗dMMR/MSI-H晚期结直肠癌的客观缓解率达到55%。本文就近年来免疫检查点抑制剂在消化系统肿瘤治疗中的研究进展进行综述。

关键词：消化系统肿瘤免疫检查点抑制剂细胞毒性T淋巴细胞抗原-4(CTLA-4) 程序性死亡分子(PD-1)

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类器官在肿瘤研究中的应用及展望

中国肿瘤生物治疗杂志 2018年第7期25卷 669-673页

作者：徐华炜湛先保第二军医大学长海医院肿瘤科上海200433

过去几十年来在干细胞生物学领域取得的进步,使得一种新型的3D类细胞体外培养技术问世,因其有着类似原器官的空间形态结构,故而称其为类器官。将肿瘤组织用该技术体外培养所形成的肿瘤类器官,极大程度保留了肿瘤细胞在体内的生物特性,... 详细信息

过去几十年来在干细胞生物学领域取得的进步,使得一种新型的3D类细胞体外培养技术问世,因其有着类似原器官的空间形态结构,故而称其为类器官。将肿瘤组织用该技术体外培养所形成的肿瘤类器官,极大程度保留了肿瘤细胞在体内的生物特性,且兼具低成本和便于操作的优点,弥补了以往传统肿瘤实验模型的缺陷。该模型还可用于转化医学研究,可进行包括药敏试验在内的个体化医疗方案的制定,并且具有和多种技术相结合的应用前景。本文重点讨论类器官在肿瘤研究中的应用及其发展潜力。

关键词：类器官肿瘤模型药物筛选个体化医疗转化医学

巨噬细胞在腹膜转移癌免疫微环境中作用的研究进展

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中国肿瘤生物治疗杂志 2020年第3期27卷 333-337页

作者：陈铃(综述) 湛先保(审阅) 海军军医大学长海医院肿瘤科上海200433

腹膜转移癌是临床常见难题,其局部微环境近年来已逐步被关注和研究。腹膜和腹水构成了腹膜转移性癌灶特殊的局部微环境,巨噬细胞是腹膜转移癌微环境中占比最多的免疫细胞群体,具有多种亚型,分泌多种细胞因子,参与多条信号通路,在癌细胞... 详细信息

腹膜转移癌是临床常见难题,其局部微环境近年来已逐步被关注和研究。腹膜和腹水构成了腹膜转移性癌灶特殊的局部微环境,巨噬细胞是腹膜转移癌微环境中占比最多的免疫细胞群体,具有多种亚型,分泌多种细胞因子,参与多条信号通路,在癌细胞存活、血管生成、腹膜侵袭和腹膜转移癌形成的过程中发挥了重要作用。近年来,细胞免疫治疗取得突破性进展,其中靶向肿瘤微环境中肿瘤相关巨噬细胞的免疫治疗逐步开展,多项临床试验正在进行中。本文对巨噬细胞在癌症腹膜转移过程中发挥的作用,以及针对巨噬细胞可能的治疗靶点进行综述。

关键词：肿瘤免疫微环境腹膜转移癌腹水巨噬细胞

嵌合抗原受体T细胞治疗胰腺癌的现状及未来策略

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中国癌症杂志 2019年第7期29卷 481-485页

作者：潘泽雁湛先保海军军医大学附属长海医院肿瘤科

嵌合抗原受体(chimeric antigen receptor,CAR)T细胞作为肿瘤免疫治疗领域的新兴疗法在B细胞系血液系统肿瘤中已经获得了较为满意的疗效,因此,CAR-T细胞疗法也被列为包括胰腺癌在内的实体肿瘤治疗的新探索方向。尽管实体瘤本身的异质性... 详细信息

嵌合抗原受体(chimeric antigen receptor,CAR)T细胞作为肿瘤免疫治疗领域的新兴疗法在B细胞系血液系统肿瘤中已经获得了较为满意的疗效,因此,CAR-T细胞疗法也被列为包括胰腺癌在内的实体肿瘤治疗的新探索方向。尽管实体瘤本身的异质性、微环境的复杂性导致单纯的CAR-T细胞治疗效果不尽如人意,但随着新技术的开发,CAR结构的优化,各种免疫佐剂的联合应用使CAR-T细胞疗法值得进一步研究。该文就CAR-T细胞疗法的特点、治疗胰腺癌的现状及未来方向进行概述。

关键词：嵌合抗原受体T细胞胰腺癌免疫治疗

胰腺黏液性囊腺癌基因突变的检测及其临床意义

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中国肿瘤生物治疗杂志 2019年第4期26卷 440-444页

作者：郭承涛彭小波湛先保海军军医大学附属长海医院肿瘤科上海200433

目的:利用高通量测序平台研究胰腺黏液性囊腺癌(PMCC)组织中基因突变的分布特点及其临床意义。方法:收集2012年1月至2016年12月经外科手术切除的4例PMCC患者癌及癌旁组织石蜡标本,通过Illumina Hiseq 2500平台进行二代基因测序(NGS),结... 详细信息

目的:利用高通量测序平台研究胰腺黏液性囊腺癌(PMCC)组织中基因突变的分布特点及其临床意义。方法:收集2012年1月至2016年12月经外科手术切除的4例PMCC患者癌及癌旁组织石蜡标本,通过Illumina Hiseq 2500平台进行二代基因测序(NGS),结合患者临床病理资料分析PMCC患者癌组织的基因突变特征。结果:在4个PMCC样本中,均检测到7个高频突变基因(SMG),分别是KRAS、AHNAK2、MUC16、MUC17、MUC19、MUC3A和MUC4。3个样本中检测到24个SMG,分别为ADAMTS9、ALDH3B1、CARD14、CSMD3、MKI67、OR1N2、PKHD1、PLCE1、RTL1、SIGLEC12、CCDC168、CEP295、CUBN、DST、HRNR、LAMA5、OR10G4、OR2T4、PLEKHG4B、RP1L1、SLC15A5、SVEP1、TAS1R1和TNRC18。所有样本中均检测到KRAS驱动基因突变,其中3例检测到KRAS的K12热点突变,另1例检测到KRAS的D33E非热点突变。结论:PMCC患者的高突变KRAS和MUC家族,可能成为PMCC精准治疗的潜在靶点和生物标志物。

关键词：胰腺黏液性囊腺癌高通量测序基因突变 KRAS基因

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CAR-T细胞治疗消化系统肿瘤的研究进展

中国肿瘤生物治疗杂志 2020年第7期27卷 813-819页

作者：王一然(综述) 陈铃湛先保(审阅) 海军军医大学附属长海医院肿瘤科上海200433

嵌合抗原受体基因修饰T细胞(chimeric antigen receptor gene modified T lymphocyte,CAR-T cell)治疗血液肿瘤显示了良好的效果,也为治疗食管癌、胃癌、肝细胞癌、胆管癌、胰腺癌和结直肠癌等消化系统肿瘤提供了新选择。消化系统不同... 详细信息

嵌合抗原受体基因修饰T细胞(chimeric antigen receptor gene modified T lymphocyte,CAR-T cell)治疗血液肿瘤显示了良好的效果,也为治疗食管癌、胃癌、肝细胞癌、胆管癌、胰腺癌和结直肠癌等消化系统肿瘤提供了新选择。消化系统不同部位肿瘤的细胞特征和肿瘤微环境存在差异,故靶向抗原的选择和CAR-T细胞的设计也相应地有所不同。CAR-T细胞治疗与其他免疫治疗联合使用也取得了一定的进展,但主要体现在细胞实验和小鼠体内实验。目前存在的脱靶效应、细胞因子释放综合征等副作用严重阻碍了CAR-T细胞的研究进展,限制了其在实体瘤中的应用。本文就近年来CAR-T细胞治疗消化系统肿瘤的研究进展作一阐述。

关键词：嵌合抗原受体基因修饰T细胞食管癌胃癌肝细胞癌胆管癌胰腺癌结直肠癌