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Alterations in DNA damage response and repair genes as potential biomarkers for immune checkpoint blockade in gastrointestinal cancer

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Cancer Biology & Medicine 2022年第8期19卷 1139-1149页

作者： Yujiao Wang Xi Jiao Shuang Li Huan Chen Xin Wei Chang Liu Jifang Gong Xiaotian zhang Xicheng Wang Zhi Peng Changsong Qi Zhenghang Wang Yanni Wang Na Zhuo Jianling Zou henghui zhang Jian Li Lin Shen Zhihao Lu Department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer Hospital&InstituteBeijing 100142China Department of Gastric&Colorectal Surgery The First Hospital of Jilin UniversityChangchun 130021China Genecast Precision Medicine Technology Institute Beijing 100192China Life Sciences Institute Zhejiang UniversityHangzhou 310058China Institute of Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China

Objective:Immune checkpoint inhibitors(ICIs)have achieved remarkable results in cancer treatments.However,there is no effective predictive biomarker for gastrointestinal(GI)cancer.Methods:We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort(MSK-GI,n=227),the Janjigian cohort(n=40),and the Peking University Cancer Hospital&Institute cohort(PUCH,n=80)to determine the possible associations between DNA damage response and repair(DDR)gene mutations and clinical outcomes.Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment.Results:In the MSK cohort,the presence of≥2 DDR gene mutations was correlated with prolonged overall survival(OS).The Janjigian and PUCH cohorts further confirmed that subgroups with≥2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit.Furthermore,the DDR gene mutation load could be considered as an independent prognostic factor,and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs.Mechanistically,we showed that the presence of≥2 DDR gene mutations was correlated with higher levels of tumor mutation burden,neoantigen,and T cell infiltration.Conclusions:The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs,which could serve as a potential biomarker to guide patient selection for immunotherapy.

关键词： Gastrointestinal cancer DDR gene mutation immunotherapy biomarker

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The mutational pattern of homologous recombination(HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer

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Cancer Biology & Medicine 2020年第4期17卷 1002-1013页

作者： Yue Fan Haifeng Ying Xueying Wu Huan Chen Ying Hu henghui zhang Lijia Wu Ying Yang Beibei Mao Lan Zheng Department of integrated Traditional Chinese Medicine and Western Medicine Zhongshan HospitalFudan UniversityShanghai 200032China Department of Traditional Chinese Medicine Ruijin HospitalShanghai Jiaotong UniversityShanghai 200025China Genecast Precision Medicine Technology Institute Beijing 100191China Center of Integrative Medicine Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China

Objective:Currently,there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors(ICIs)for patients with gastric cancer(GC).Homologous recombination deficiency(HRD)can modify the tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response.We aimed to analyze the mutational pattern of HR-associated genes in Chinese patients with GC and its relevance to the tumor immune profile and clinical immunotherapeutic response.Methods:A panel of 543 cancer-associated genes was used to analyze genomic profiles in a cohort comprising 484 Chinese patients with GC.Correlations between HR gene mutations and tumor immunity or clinical outcomes were identified via bioinformatic analysis using 2 GC genomic datasets(TCGA and MSK-IMPACT).Results:Fifty-one of the 484(10.54%)patients carried at least one somatic mutation in an HR gene;ATM(16/484,3.31%)was among the most frequently mutated HR genes in the Chinese cohort.Mutations in HR genes were associated with elevated tumor mutational burden,enhanced immune activity,and microsatellite instability status.In the MSK-IMPACT cohort comprising 49 patients with stomach adenocarcinoma or gastroesophageal junction adenocarcinoma treated with ICIs,patients with HR-mut GC(n=12)had significantly better overall survival than those with HR-wt GC(n=37)(log-rank test,P<0.05).Conclusions:Our data suggest that detection of somatic mutations in HR genes might aid in identifying patients who might benefit from immune checkpoint blockade therapy.

关键词： Gastric cancer homologous recombination deficiency immunotherapy biomarker

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紫外线诱变选育高产豆豉纤溶酶菌株及其产酶条件优化

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中国酿造 2024年第3期43卷 177-181页

作者：张文勇张恒慧王晓丽太原工业学院环境与安全工程系山西太原030008

该研究以分离自豆豉样品中产豆豉纤溶酶的枯草芽孢杆菌(Bacillus subtilis)DC-1为出发菌株,采用紫外线诱变选育高产豆豉纤溶酶且稳定遗传的菌株,并以豆豉纤溶酶活力为评价指标,通过单因素试验及正交试验对其发酵条件进行优化。结果表明... 详细信息

该研究以分离自豆豉样品中产豆豉纤溶酶的枯草芽孢杆菌(Bacillus subtilis)DC-1为出发菌株,采用紫外线诱变选育高产豆豉纤溶酶且稳定遗传的菌株,并以豆豉纤溶酶活力为评价指标,通过单因素试验及正交试验对其发酵条件进行优化。结果表明,筛选出一株高产豆豉纤溶酶活力且稳定遗传的诱变菌株DC-V5,其最优发酵条件为:接种量3%、装液量70 mL/250 mL、发酵温度34℃、初始pH 6.5。在此优化发酵条件下,诱变菌株DC-V5产豆豉纤溶酶活力最高达到(451.26±11.09)IU/mL,是优化前出发菌株DC-1的1.74倍。

关键词：枯草芽孢杆菌豆豉纤溶酶紫外线诱变产酶条件优化

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Prognostic impact of gene copy number instability and tumor mutation burden in patients with resectable gastric cancer

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Cancer Communications 2020年第1期40卷 63-66页

作者： Lisheng Cai Linhai Li Dandan Ren Xue Song Beibei Mao Bo Han henghui zhang Department of General Surgery Zhangzhou Afiliated Hospital of Fujian Medical UniversityZhangzhouFujian363000P.R.China Department of General Surgery The First People's Hospital of Yunnan ProvinceThe Affliated Hospital of Kunming University of Science and TechnologyKunmingYunan650032P.R.China Genecast Precision Medicine Technology Institute Beijing100191P.R.China The Second Ward of Oncology Department The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongiang150086P.R.China Institute of Infectious Diseases Bejing Ditan HospitalCapital Medical UniversityBeijing100015P.R.China

Dear Editor,Gastric cancer(GC)is a leading cause of cancer-related deaths worldwide,especially in China and other East Asian countries[1,2].Although considerable achievements have been made in its treatment[3]and predictive biomarkers[4]in past decades,the prognosis of GC remains poor[5].Therefore,more effective prognostic markers are needed to improve the prognosis prediction of GCs.Small panels based on next-generation sequencing,such as FoundationOne CDx and MSK-IMPACT,are widely used for selecting appropriate treatment approaches(such as targeted therapies,immunotherapies,and chemotherapies)with the advantages of a higher sequencing depth and more cost-effectiveness than whole-exome sequencing(WES).Previous studies have demonstrated that molecular characteristics based on the designed cancer-related gene panel were consistent with those determined by WES and could be prognostic markers for various cancer types[6-8].As such,we analyzed the molecular features with the designed panel to investigate probable prognostic biomarkers for Chinese patients with GC.

关键词： patients Gastric treatment

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Partial recovery of disturbed V-J pairing profiles of T-cell receptor in people living with HIV receiving long-term antiretroviral therapy

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Science China(Life Sciences) 2021年第1期64卷 152-161页

作者： Guoli Li Jiarui Li henghui zhang Yu zhang Di Liu Yu Hao Junyan Han Juan Du Liuluan Zhu Yongqin Zeng Bei Li Rui Li Chuan Song Fujie zhang Chen Chen Hongxin Zhao Hui Zeng Institute of Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijing100015China Beijing Key Laboratory of Emerging Infectious Diseases Beijing100015China Clinical and Research Center of Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijing100015China Computational Virology Group Center for Bacteria and Virus Resources and ApplicationWuhan Institute of VirologyChinese Academy of SciencesWuhan430071China University of Chinese Academy of Sciences Beijing101408China

Chronic human immunodeficiency virus(HIV) infection not only causes a gradual loss of CD4~+T cells but also leads to a disturbance of the T cell receptor(TCR) repertoire. In people living with HIV(PLWH), monitoring TCR repertoire is challenged by the inconsistency of complementarity determining region 3(CDR3) and limited cell numbers in clinical samples. Thus, a quantitative method is necessary for monitoring the TCR repertoire in PLWH.We characterized the TCR V-J pairing profile of na?ve and memory CD4~+T cells in healthy donors, HIV-infected antiretroviral therapy(ART)-na?ve patients and long-term(over5 years) ART-experienced patients by performing TCR sequencing. We developed a V-J index with 18 parameters which were subdivided into five categories(expression coverage, cumulative percentage of the top tenth percentile, diversity, intra-individual similarity and inter-individual similarity). In ART-na?ve patients, 14 of the 18 parameters were significantly altered.Long-term ART recovered ten parameters. The four unrecovered parameters were related to inter-individual similarity.Therefore, these findings indicate that long-term ART could only partially recover TCR V-J pairs and introduce newly impacted V-J pairs. Moreover, these results provide new insights into the V-J pairing of the TCR and into the disturbance of TCR repertoire in HIV infection.

关键词： acquired immune deficiency syndrome human immunodeficiency virus antiretroviral therapy T cell receptor V-J pairing

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Storm of soluble immune checkpoints associated with disease severity of COVID-19

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Signal Transduction and Targeted Therapy 2020年第1期5卷 881-883页

作者： Yaxian Kong Yu Wang Xueying Wu Junyan Han Guoli Li Mingxi Hua Kai Han henghui zhang Ang Li Hui Zeng Institute of Infectious Diseases Beijing Key Laboratory of Emerging Infectious DiseasesBeijing Ditan HospitalCapital Medical UniversityBeijing 100015China Department of Respiratory Medicine Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Immupeutics Medicine Institute Beijing 100191China Department of Intensive Care Medicine Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China

Dear Editor,As the outbreak of coronavirus disease 2019(COVID-19)turns into a pandemic,it has literally caused a worldwide public health crisis.Progressive lymphopenia,especially in T cells,was a prominent clinical feature of severe COVID-19 in addition to dyspnea,hypoxemia,acute respiratory distress,and cytokine release syndrome.1 Recently,several studies revealed a correlation between T cell depletion and increased expression levels of several inhibitory checkpoint molecules on T cells in severe COVID-19 cases.2 Classically,inhibitory checkpoint molecules have been documented as key factors for regulating T cell exhaustion in a variety of chronic viral infections and tumors.Recent studies further implied a pivotal role of inhibitory checkpoint molecules in the pathophysiology of acute viral infections,such as Ebola virus or hantavirus infection.Of note,soluble isoforms of checkpoints can be produced by cleavage of membrane-bound proteins or by alternative splicing of mRNA and competitively regulate the functions of their membrane-bound counterparts.3 Thus it is of great interest to determine whether soluble checkpoint molecules are involved in immune regulation and severity of COVID-19.

关键词： severity acute distress

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Molecular analysis of cell-free DNA identifies distinct molecular features in patients with chemosensitive and chemorefractory small cell lung cancer

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Cancer Communications 2019年第1期39卷 188-192页

作者： Jie zhang Chen Tian Fang Lv Jianfei Wang Wenbo Han Jun Nie Ling Dai Weiheng Hu Xiaoling Chen Xiangjuan Ma Guangming Tian Di Wu Sen Han Yang Wang Jieran Long Ziran zhang Jian Fang henghui zhang Department of Thoracic Oncology II Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer Hospital&InstituteBeijing 100142P.R.China Institute of Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijing 100011P.R.China Beijing Genecast Biotechnology Co. Beijing 100191P.R.China

Dear Editor,Lung cancer is the predominant cause of cancer-related death worldwide[1].Non-small cell lung cancer accounts for 80%-85%and small cell lung cancer(SCLC)accounts for 15%-20%of all lung cancer cases[2].Patients with SCLC,a highly aggressive and poorly differentiated malignancy,have an alarming average 5-year overall sur-vival rate of less than 10%[3].Most patients with SCLC already show clinically detectable metastases at diag-nosis and have extremely poor prognoses,even when treated with multimodality therapy[4].Before the addi-tion of atezolizumab to chemotherapy became the first-line treatment of extensive-stage SCLC,chemotherapy is the primary treatment of SCLC[5].

关键词： chemotherapy lung patients

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2195铝锂合金火箭贮箱焊接接头强度分析

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机械制造与自动化 2024年第1期53卷 66-72,77页

作者：马佳琳张恒珲李磊童明波王芳丽南京航空航天大学航空学院江苏南京210016 金陵科技学院机电工程学院江苏南京211169

为确定火箭贮箱搅拌摩擦焊(FSW)焊接接头疲劳寿命,完成对贮箱结构的疲劳分析,对2195铝锂合金母材标准试件与搅拌摩擦焊焊接接头标准试验件进行静力试验与常幅疲劳试验,得出母材与FSW焊接接头的拉伸强度等力学性能参数,同时绘制其S-N曲... 详细信息

为确定火箭贮箱搅拌摩擦焊(FSW)焊接接头疲劳寿命,完成对贮箱结构的疲劳分析,对2195铝锂合金母材标准试件与搅拌摩擦焊焊接接头标准试验件进行静力试验与常幅疲劳试验,得出母材与FSW焊接接头的拉伸强度等力学性能参数,同时绘制其S-N曲线。在试验数据基础上,应用ABAQUS软件对贮箱进行静力分析,联合NCODE软件估算贮箱模型在给定工况载荷下的疲劳寿命。结果表明:应力最严重位置为筒段焊缝处,最先破坏位置发生在筒段横竖焊缝交接处。在疲劳寿命分析的基础上应用ABAQUS-FRANC3D软件联合仿真,在焊缝破坏位置处插入角裂纹,模拟三维裂纹扩展,当裂纹扩展为穿透裂纹时,计算终止。计算了三维表面裂纹的应力强度因子和裂纹扩展寿命,为贮箱损伤容限提供了评估思路。

关键词：搅拌摩擦焊疲劳裂纹扩展疲劳试验

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TBM刀具岩石磨蚀性CAI值调整系数的应用

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隧道建设(中英文) 2022年第2期42卷 231-236页

作者：张恒辉吴炜中铁隧道局集团有限公司中国铁路经济规划研究院有限公司

为研究TBM掘进不同岩层的刀具消耗规律,解决川藏铁路隧道TBM施工概预算定额刀具消耗量的适用问题,根据岩石磨蚀性指数特性,结合引汉济渭、高黎贡山TBM掘进现场实测数据成果,分析等效石英含量、单轴抗压强度、完整性等不同条件下刀具磨... 详细信息

为研究TBM掘进不同岩层的刀具消耗规律,解决川藏铁路隧道TBM施工概预算定额刀具消耗量的适用问题,根据岩石磨蚀性指数特性,结合引汉济渭、高黎贡山TBM掘进现场实测数据成果,分析等效石英含量、单轴抗压强度、完整性等不同条件下刀具磨蚀消耗量的变化规律,并结合应用案例研究推导其与岩石磨蚀性CAI指数的对应关系。在此基础上,推导并验证不同CAI值条件下刀具消耗量调整系数,证明通过石英含量、单轴抗压强度等相关参数推导CAI指数的可行性,为概预算定额中岩石磨蚀性CAI值调整系数的应用提供了理论基础。

关键词： TBM 刀具消耗规律岩石磨蚀性CAI值掘进机刀具定额调整系数

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紫苏粕蛋白抗氧化活性肽的制备、分离纯化及序列鉴定

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中国食品学报 2023年第9期23卷 347-355页

作者：张恒慧张志军陈士国叶兴乾张国华太原工业学院生物与食品教研室太原030008 中北大学化学工程与技术学院太原030051 浙江大学生物系统工程与食品科学学院杭州310058 山西大学生命科学学院太原030006

以紫苏粕粉为原料,使用碱性蛋白酶进行水解反应,制备抗氧化活性肽。采用超滤离心、凝胶过滤色谱和反相色谱等分离纯化手段对其富集。结果表明,相较其它3种蛋白酶,碱性蛋白酶Alcalase对紫苏粕蛋白的水解程度最高,约为(25.94±0.21)%;碱... 详细信息

以紫苏粕粉为原料,使用碱性蛋白酶进行水解反应,制备抗氧化活性肽。采用超滤离心、凝胶过滤色谱和反相色谱等分离纯化手段对其富集。结果表明,相较其它3种蛋白酶,碱性蛋白酶Alcalase对紫苏粕蛋白的水解程度最高,约为(25.94±0.21)%;碱性蛋白酶作用紫苏蛋白后的酶解产物的抗氧化活性最好,对DPPH自由基清除率约为(91.01±0.73)%。酶解上清液经超滤离心分离后最小分子质量组分F1(小于3 ku)抗氧化活性最强,F1组分经Sephadex G-25凝胶过滤色谱分离后按照分子质量大小依次得到P1、P2、P33个组分,其中分子质量最小的P3组分抗氧化活性最高。P3组分经反相色谱分离所得4个组分中,最后被洗脱出来的P3-4组分疏水性最强且DPPH·自由基清除率最高,质量浓度为3μg/mL的P3-4溶液的DPPH·清除率为(58.8±0.78)%。通过LC-MS-MS鉴定,抗氧化活性肽P3-4组分为十二肽,其氨基酸序列为Lys-Leu-Lys-Asp-Ser-Phe-Glu-Arg-Gln-Gly-Met-Val,分子质量为1437.8 u。本研究结果为深入开发紫苏蛋白资源,研发紫苏抗氧化活性肽提供理论参考。

关键词：紫苏粕蛋白抗氧化分离纯化生物活性肽氨基酸序列

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