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One-step synthesis of site-specific antibody-drug conjugates by reprograming IgG glycoengineering with LacNAc-based substrates

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2417-2428页

作者： Wei Shi Wanzhen Li Jianxin Zhang Tiehai Li Yakai Song Yue zeng Qian Dong zeng Lin Likun Gong Shuquan Fan Feng Tang Wei Huang CAS Key Laboratory of Receptor Research CAS Center for Excellence in Molecular Cell ScienceCenter for Biotherapeutics Discovery ResearchShanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China School of Pharmaceutical Science and Technology Hangzhou Institute of Advanced StudyHangzhou 310024China University of Chinese Academy of Sciences Beijing 100049China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China School of Life Science Liaocheng UniversityLiaocheng 252059China

Glycosite-specific antibody-drug conjugatess(gsADCs), harnessing Asn297 N-glycan of IgG Fc as the conjugation site for drug payloads, usually require multi-step glycoengineering with two or more enzymes, which limits the substrate diversification and complicates the preparation ***, we report a series of novel disaccharide-based substrates, which reprogram the IgG glycoengineering to one-step synthesis of gsADCs, catalyzed by an endo-N-acetylglucosaminidase(ENGase) of Endo-S2. IgG glycoengineering via ENGases usually has two steps: deglycosylation by wild-type(WT) ENGases and transglycosylation by mutated ENGases. But in the current method, we have found that disaccharide LacNAc oxazoline can be efficiently assembled onto IgG by WT Endo-S2 without hydrolysis of the product, which enables the one-step glycoengineering directly from native *** studies on substrate specificity revealed that this approach has excellent tolerance on various modification of 6-Gal motif of LacNAc. Within 1 h, one-step synthesis of gsADC was achieved using the LacNAc-toxin substrates including structures free of bioorthogonal groups. These gsADCs demonstrated good homogeneity, buffer stability, in vitro and in vivo anti-tumor activity. This work presents a novel strategy using LacNAc-based substrates to reprogram the multi-step IgG glycoengineering to a one-step manner for highly efficient synthesis of gsADCs.

关键词： Site-specific ADCs ENGase LacNAc One-step assembly Potent in vivo efficacy

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Mesenchymal stem cell-derived extracellular vesicles:a possible therapeutic strategy for orthopaedic diseases:a narrative review

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Biomaterials Translational 2022年第3期3卷 175-187页

作者： Zhao-Lin zeng Hui Xie Department of Orthopaedics Movement System Injury and Repair Research CentreXiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Department of Metabolism and Endocrinology The First Affliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyangHunan ProvinceChina Department of Clinical Medicine The First Affliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyangHunan ProvinceChina

Accumulating evidence suggests that the therapeutic role of mesenchymal stem cells(MSCs)in bone diseases is closely related to paracrine-generated extracellular vesicles(EVs).MSC-derived EVs(MSC-EVs)carry proteins,nucleic acids,and lipids to the extracellular space and affect the bone *** have similar biological functions to MSCs,such as the ability to repair organ and tissue *** addition,MSC-EVs also have the advantages of long half-life,low immunogenicity,attractive stability,ability to pass through the blood-brain barrier,and demonstrate excellent performance with potential practical applications in bone *** this review,we summarise the current applications and mechanisms of MSC-EVs in osteoporosis,osteoarthritis,bone tumours,osteonecrosis of the femoral head,and fractures,as well as the development of MSC-EVs combined with materials science in the field of ***,we explore the critical challenges involved in the clinical application of MSC-EVs in orthopaedic diseases.

关键词： exosomes extracellular vesicles mesenchymal stem cells orthopaedic diseases regenerative medicine

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Measurements of Laser Absorption and Ion Energy in Femtosecond Laser-Cluster Interaction

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Chinese Physics Letters 2001年第2期18卷 211-213页

作者： LIN Jing-Quan ZHANG Jie LI Ying-Jun chen Li-Ming LÜTie-Zheng TENG Hao MAN Bao-Yuan ZHAO Li-zeng Laboratory of Optical Physics Institute of PhysicsChinese Academy of SciencesBeijing 100080

Laser absorption is measured in Xe,Ar and He clusters irradiated by 5 mJ laser pulses in 150 *** measurements show that the absorption efficiency strongly depends on the backing pressure of the gas jets,the laser pulse duration and the atomic number Z of the working *** laser absorption for Xe clusters is found to be as high as 45%at a backing pressure of 20 atm and a laser intensity of 1×10^(15) W/cm^(2).Significant numbers of ions with energies up to 100 keV are detected from Xe cluster *** variation trend of the average ion energy at different backing pressures is consistent with that of the laser energy absorption.

关键词： laser Femto Laser

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业务过程模型的Petri网形式化检查方法

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计算机集成制造系统 2011年第5期17卷 1110-1119页

作者：邓建陈智曾家智电子科技大学计算机科学与工程学院四川成都610054 电子科技大学通信抗干扰国家级重点实验室四川成都610054

为解决企业间业务协同模型形式化检查的问题,将采用标准业务过程建模符号的业务模型转换为Pe-tri网,构造出一种可建模企业间复杂业务协同的业务过程流网。采用过程定义可扩展标记语言2.1版本,开发了一种具有通用性的业务过程模型转换和... 详细信息

为解决企业间业务协同模型形式化检查的问题,将采用标准业务过程建模符号的业务模型转换为Pe-tri网,构造出一种可建模企业间复杂业务协同的业务过程流网。采用过程定义可扩展标记语言2.1版本,开发了一种具有通用性的业务过程模型转换和检查工具。采用业务过程流网对供应链中企业间采购订单过程进行了建模。实验结果表明,业务过程流网能将符合过程定义可扩展标记语言规范的业务模型完整地转换为Petri网,得到的Petri网易于化简和分析。

关键词：企业间协同业务建模模型检查业务过程建模符号可扩展标记语言 Petri网

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Radiotherapy enhances efficacy of PD-1 inhibitors in advanced hepatocellular carcinoma:A propensity-matched real-world study

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Chinese Medical Journal 2024年第11期137卷 1332-1342页

作者： Shujung Hsu Yencheng Chao Yong Hu Yang Zhang Weifeng Hong Yixing chen Rongxin chen Zhaochong zeng Shisuo Du Department of Radiation Oncology Zhongshan HospitalFudan UniversityShanghai 200032China Department of Pulmonary Medicine Zhongshan HospitalFudan UniversityShanghai 200032China Department of Liver Cancer Institute Zhongshan HospitalFudan UniversityShanghai 200032China

Background:To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma(HCC),combination with radiotherapy(RT)has emerged as a promising *** preclinical studies,irradiated tumors released tumor antigens to synergistically increase the antitumor effect of ***,we investigated whether RT enhances the efficacy of anti-programmed death receptor-1(PD-1)inhibitors in advanced HCC in real-world ***:Between August 2018 and June 2021,172 patients with advanced primary HCC were enrolled in the tertiary center(Zhongshan Hospital of Fudan University);95 were treated with a combination of RT and the inhibitor of PD-1(RT-PD1 cohort),and 77 were administered anti-PD-1 therapy(PD1 cohort).The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with *** score matching for bias reduction was used to evaluate the clinical ***:Among 71 propensity-matched pairs,median progression-free survival was 5.7 months in the RT-PD1 cohort vs.2.9 months in the PD1 cohort(P<0.001).Median overall survival was 20.9 months in the RT-PD1 cohort vs.11.2 months in the PD1 cohort(P=0.018).Compared with patients in the PD1 cohort,patients in the RT-PD1 cohort had significantly higher objective response rates(40.8%,29/71 vs.19.7%,14/71,P=0.006)and disease control rates(62.0%,44/71 vs.31.0%,22/71,P<0.001).The incidences of toxic effects were not significantly different between the two ***:RT plus anti-PD-1 therapy is well *** enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.

关键词： Radiotherapy Immune checkpoint inhibitor Programmed cell death receptor-1 Hepatocellular carcinoma Propensity score matching Treatment outcome Adverse effects

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Synergistic sulfonamides plus clindamycin as an alternative therapeutic regimen for HIV-associated Toxoplasma encephalitis: a randomized controlled trial

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Chinese Medical Journal 2022年第22期135卷 2718-2724页

作者： Yao Li Yanming zeng Yanqiu Lu Xuejiao He Yushan Wu Wei Zhang Yanqun Huang Hui chen Yaokai chen Department of Infectious Diseases Chongqing Public Health Medical CenterChongqing 400036China School of Biomedical Engineering Center for Infectious DiseasesBeijing Youan HospitalCapital Medical UniversityBeijing 100069China

Background: The preferred therapeutic regimen for Toxoplasma encephalitis (TE) is a combination of pyrimethamine and sulfadiazine, and trimethoprim-sulfamethoxazole (TMP-SMX) plus azithromycin is the widespread alternative therapeutic regimen. The synergistic sulfonamides tablet contains TMP, sulfadiazine, and SMX and hypothetically could be used for TE treatment. This study aimed to compare the efficacy and safety of synergistic sulfonamides plus clindamycin (regimen B) with TMP-SMX plus azithromycin (regimen A) for the treatment of human immunodeficiency virus (HIV) associated ***: This was an open-labeled, multi-center randomized controlled trial recruited from 11 centers. Each recruited patient was randomly assigned to receive regimen A or regimen B for at least 6 weeks. The overall response was evaluated by assessment of the clinical response of TE-associated clinical features and the radiological response of TE-associated radiological findings. The overall response rate, clinical response rate, radiological response rate, and adverse events were assessed at 2, 6, and 12 weeks. Death events were compared between the two regimens at 6, 12, and 24 ***: A total of 91 acquired immunodeficiency syndrome (AIDS)/TE patients were included in the final analysis (44 in regimen Avs. 47 in regimen B). The overall response rate, which refers to the combined clinical and radiological response, was 18.2% (8/44) for regimen A and 21.3 % (10/47) for regimen B at week 6. The results of clinical response showed that, in comparison with regimen A, regimen B may perform better with regards to its effect on the relief of clinical manifestations (50.0% [22/44]vs. 70.2% [33/47],P = 0.049). However, no significant differences in radiological response, mortality events, and adverse events were found between the two regimens at week ***: Synergistic sulfonamides plus clindamycin, as a novel treatment regimen, showed no significantly different efficacy and compa

关键词： Clindamycin Efficacy Human immunodeficiency virus/acquired immunodeficiency syndrome Safety Synergistic sulfonamides Toxoplasma encephalitis

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An integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1585-1600页

作者： Yiyue Ge Tingzhong Tian Suling Huang Fangping Wan Jingxin Li Shuya Li Xiaoting Wang Hui Yang Lixiang Hong Nian Wu Enming Yuan Yunan Luo Lili cheng chengliang Hu Yipin Lei Hantao Shu Xiaolong Feng Ziyuan Jiang Yunfu Wu Ying Chi Xiling Guo Lunbiao Cui Liang Xiao zeng Li Chunhao Yang Zehong Miao Ligong chen Haitao Li Hainian zeng Dan Zhao Fengcai Zhu Xiaokun Shen Jianyang zeng Institute for Interdisciplinary Information Sciences Tsinghua UniversityBeijingChina NHC Key laboratory of Emeric Pathogenic Microbiology Jiangsu Provincial Center for Diseases Control and PreventionNanjingJiangsu ProvinceChina Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghaiChina Silexon Al Technology Co. Ltd.NanjingJiangsu ProvinceChina Department of Computer Science University of Illinois at Urbana-ChampaignIllinoisILUSA School of Pharmaceutical Sciences Tsinghua UniversityBeijingChina School of Electronic Information and Communications Huazhong University of Science and TechnologyWuhanHubei ProvinceChina Institute of Pathology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina Department of Automation Tsinghua UniversityBeijingChina Inner Mongolia Alashan League Organization Establishment Committee Office Electronic Support Center AlashanInner MongoliaChina Convalife(Shanghai)Co. Ltd.ShanghaiChina Advanced Innovation Center for Human Brain Protection Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Beijing Advanced Innovation Center for Structural Biology Tsinghua-Peking Joint Center for Life SciencesDepartment of Basic Medical SciencesSchool of MedicineTsinghua UniversityBeijingChina Center for Global Health Nanjing Medical UniversityNanjingJiangsu ProvinceChina

The global spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019(COVID-19).In this study,we developed an integrative drug repositioning framework,which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph,literature and transcriptome data to discover the potential drug candidates against *** in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1(PARP1)inhibitor,CVL218,currently in Phase I clinical trial,may be repurposed to treat *** in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic *** addition,we showed that CVL218 can interact with the nucleocapsid(N)protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.

关键词： prevention respiratory acute

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旋转柔性机械臂的动力学建模

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机械强度 2008年第2期30卷 293-296页

作者：陈先龙何锃华中科技大学力学系武汉430074

首先采用随体坐标系描述变形位移场,用Green应变理论分析耦合变形,在计入系统的转动惯量、弯曲—拉伸耦合变形和粘性阻尼的影响下,采用微元法从应力应变角度得出机械臂的动力学方程。然后在随体坐标系内采用Galerkin方法离散变形位移场... 详细信息

首先采用随体坐标系描述变形位移场,用Green应变理论分析耦合变形,在计入系统的转动惯量、弯曲—拉伸耦合变形和粘性阻尼的影响下,采用微元法从应力应变角度得出机械臂的动力学方程。然后在随体坐标系内采用Galerkin方法离散变形位移场,得出系统的控制方程,分析系统的耦合效应。最后通过数值计算表明,阻尼对于系统的振幅有较大影响。

关键词：柔性机械臂 Green应变粘性阻尼刚柔耦合

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Decellularized optic nerve functional scaffold transplant facilitates directional axon regeneration and remyelination in the injured white matter of the rat spinal cord

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Neural Regeneration Research 2021年第11期16卷 2276-2283页

作者： Yu-Rong Bai Bi-Qin Lai Wei-Tao Han Jia-Hui Sun Ge Li Ying Ding Xiang zeng Yuan-Huan Ma Yuan-Shan zeng Key Laboratory for Stem Cells and Tissue Engineering Ministry of EducationSun Yat-sen UniversityGuangzhouGuangdong ProvinceChina Department of Histology and Embryology Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouGuangdong ProvinceChina Co-innovation Center of Neuroregeneration Nantong UniversityNantongJiangsu ProvinceChina Institute of Spinal Cord Injury Sun Yat-sen UniversityGuangzhouGuangdong ProvinceChina Guangdong Provincial Key Laboratory of Brain Function and Disease Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouGuangdong ProvinceChina

Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord ***,achieving good outcome remains *** previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion ***,it has not been reported whether this material promotes axonal regeneration in *** the present study,a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann *** functional scaffold promoted the directional growth and remyelination of regenerating *** vitro,the porcine decellularized optic nerve contained many straight,longitudinal channels with a uniform distribution,and microscopic pores were present in the channel *** spatial micro topological structure and extracellular matrix were conducive to the adhesion,survival and migration of neural stem *** scaffold promoted the directional growth of dorsal root ganglion neurites,and showed strong potential for myelin ***,we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in *** weeks later,the regenerating axons grew straight,the myelin sheath in the injured/transplanted area recovered its structure,and simultaneously,the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were ***,these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin *** procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University(approval ***-IACUC-2019-B034)on February 28,2019.

关键词： axonal regeneration decellularized optic nerve directional regeneration functional scaffold microenvironment neurotrophin-3 optic nerve remyelination Schwann cells tissue engineering white matter injury

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Continuous purification and culture of rat type 1 and type 2 alveolar epithelial cells by magnetic cell sorting

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Chinese Journal of Traumatology 2022年第3期25卷 138-144页

作者： Di Liu Jian-Hui Sun Hua-Cai Zhang Jian-xin Jiang Ling zeng State Key Laboratory of Trauma Bums and Combined InjuriesDoping HospitalArmy Medical UniversityChongqing400042China Medical Center of Trauma and War Injury Daping HospitalArmy Medical UniversityChongqing400042China

Purpose:The incidence of acute lung injury(ALI)in severe trauma patients is 48%and the mortality rate following acute respiratory distress syndrome evolved from ALI is up to 68.5%.Alveolar epithelial type 1 cells(AEC1 s)and type 2 cells(AEC2s)are the key cells in the repair of injured lungs as well as fetal lung ***,the purification and culture of AECls and AEC2s play an important role in the research of repair and regeneration of lung ***:Sprague-Dawley rats(3-4 weeks,120-150 g)were purchased for *** and DNase I were jointly used to digest lung tissue to obtain a single-cell suspension of whole lung cells,and then magnetic bead cell sorting was performed to isolate Tla positive cells as AECls from the single-cell suspension by using polyclonal rabbit anti-Tla(a specific AECls membrane protein)antibodies combined with anti-rabbit IgG ***,alveolar epithelial cell membrane marker protein EpCAM was designed as a key label to sort AEC2s from the remaining Tla-neg cells by another positive immunomagnetic selection using monoclonal mouse anti-EpCAM antibodies and anti-mouse IgG *** purity was identified by immunofluorescence staining and flow ***沾••The purity of AECls and AEC2s was 88.3%±3.8%and 92.6%±2.7%,*** cell growth was observed as follows:AECls stretched within the 12-16 h,but the cells proliferated slowly;while AEC2s began to stretch after 24 h and proliferated rapidly from the 2nd day and began to differentiate after 3 ***:AECls and AEC2s sorted by this method have high purity and good ***,our method provides a new approach for the isolation and culture of AECls and AEC2s as well as a new strategy for the research of lung repair and regeneration.

关键词： Alveolar epithelial cells type 1 Alveolar epithelial cells type 2 Three-dimensional culture Magnetic activated cell sorting

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