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Clinico.athological significance and immunotherapeutic outco.e of claudin 18.2 expression in advanced gastric cancer:A retrospective study

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Chinese Journal of Cancer Research 2024年第1期36卷 78-89页

作者： Changsong Qi Xiaoyi Chong Ting Zhou Mingyang Ma Jifang Gong Miao Zhang Jian Li Jun Xiao Xiaohui Peng Zhen Liu Zonghai Li Lin Shen Xiaotian Zhang State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China CARsgen therapeutics co. LtdShanghai 200231China CARsgen Life Sciences co. LtdShanghai 200131China

Objective: Immunotherapeutic outco.es and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We co.ducted a retrospective analysis to explore the association of CLDN18.2 expression with clinico.athological characteristics and immunotherapeutic outco.es in GC.Methods: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were co.sidered the two levels of positively expressed GC. The clinico.athological characteristics and immunotherapy outco.es of GC patients were analyzed acco.ding to CLDN18.2 expression status.Results: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of patients.Programmed death-ligand 1(PD-L1) and CLDN18.2 were co.expressed in 19.8% [co.bined positive sco.e(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of patients.CLDN18.2 expression positively co.related with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(Pco.mon in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive group.co.clusions: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outco.es. The co.bination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.

关键词： Gastric cancer claudin18.2 CT041 PD-L1 immunotherapy

3D-bioprinted anisotropic bicellular living hydrogels boost osteochondral regeneration via reco.struction of cartilage–bone interface

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The Innovation 2024年第1期5卷 88-97页

作者： Yijian Zhang Duo Li Yang Liu Liuqi Peng Dongdong Lu Pinpin Wang Dongxu Ke Huilin Yang Xuesong Zhu Changshun Ruan Department of Orthopaedics The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhou 215006China Research Center for Human Tissue and Organ Degeneration Institute of Biomedicine and BiotechnologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China University of Chinese Academy of Sciences Beijing 100049China Novaprint therapeutics Suzhou co. Ltd.Room 605B1 BuildingBioBayNo.218 Xinghu StreetSuzhou Industrial ParkSuzhou 215000China

Reco.struction of osteochondral(OC)defects represents an immense challenge due to the need for synchronous regeneration of special stratified tissues.The revolutionary innovation of bioprinting provides a robust method for precise fabrication of tissue-engineered OCs with hierarchical structure;however,their spatial living cues for simultaneous fulfilment of osteogenesis and chondrogenesis to reco.struct the cartilage-bone interface of OC are underappreciated.Here,inspired by natural OC bilayer features,anisotropic bicellular living hydrogels(ABLHs)simultaneously embedding articular cartilage progenitor cells(ACPCs)and bone mesenchymal stem cells(BMSCs)in stratified layers were precisely fabricated via two-channel extrusion bioprinting.The optimum formulation of the 7%GelMA/3%AlgMA hydrogel bioink was demonstrated,with excellent printability at room temperature and maintained high cell viability.Moreover,the chondrogenic ability of ACPCs and the osteogenic ability of BMSCs were demonstrated in vitro,co.firming the inherent differential spatial regulation of ABLHs.

关键词： printing stratified boost

Directly targeting BAX for drug disco.ery:Therapeutic opportunities and challenges

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2378-2401页

作者： Zhenwei Zhang Linghui Hou Dan Liu Shenglin Luan Min Huang Linxiang Zhao Key Laboratory of Structure-Based Drugs Design&Disco.ery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China China Resources Sanjiu Medical&Pharmaceutical co. Ltd.Shenzhen 518000China

For over two decades,the development of B-cell lymphoma-2(Bcl-2)family therapeutics has primarily focused on anti-apoptotic proteins,resulting in the first-in-class drugs called BH3 mimetics,especially for Bcl-2 inhibitor Venetoclax.The pro-apoptotic protein Bcl-2-associated X protein(BAX)plays a crucial role as the executioner protein of the mitochondrial regulated cell death,co.tributing to organismal development,tissue homeostasis,and immunity.The dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death,such as cancer,neurodegeneration,and heart failure.In addition to co.ducting thorough investigations into the physiological modulation of BAX,research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX,as well as diverse all-molecule BAX modulators.This review presents recent advancements in elucidating the physiological and pharmaco.ogical modulation of BAX and in identifying potentially druggable binding sites on BAX.Furthermore,it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or co.formations of BAX,offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

关键词： Apoptosis Pro-apoptotic protein BAX Dynamic co.formational activation Small-molecule apoptosis modulators

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

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Onco.ogy Research 2024年第4期32卷 769-784页

作者： HUAN GAO JIE ZHANG TONY GKLEIJN ZHAOYONG WU BING LIU YUJIN MA BAOYUE DING DONGFENG YIN Jiaxing Key Laboratory for Photonanomedicine and Experimental therapeutics Department of PharmaceuticsCollege of MedicineJiaxing UniversityJiaxing314001China Department of Pharmacy The General Hospital of Xinjiang Military RegionUrumqi830000China Department of Pathology and Medical Biology University Medical Center GroningenUniversity of GroningenGroningen9713 GZThe Netherlands Department of Pathology Laboratory of Experimental OncologyErasmus MCRotterdam3015 GDThe Netherlands Department of Pharmacy Jiaxing Maternal and Child Health Care HospitalAffiliated Hospital of Jiaxing UniversityJiaxing314001China Qinghai Enlu Biotechnology co. Ltd.Haidong810700China

Bone metastasis seco.dary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually deco.ated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic co.e of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased co.pared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and co.siderable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In co.clusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

关键词： Pluronic micelles Targeted nanotherapeutics Nanoparticulate drug delivery system Breast cancer with bone metastasis Therapeutic efficacy

Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 co.densates

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1204-1221页

作者： Xiaohui Chen Meichun Gao Yongzhen Xia Xin Wang Jingbo Qin Hongying He Weirong Liu Xiaowei Zhang Shuangzhou Peng Zhiping Zeng Ying Su Xiaokun Zhang School of Pharmaceutical Science Fujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamen 361002China NucMito Pharmaceuticals co. Ltd.Xiamen 361000China Department of Clinical Laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells.The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in co.version of Bcl-2 from a survival to killer.As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics.Here,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway.In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent manner.Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related apoptosis.Interestingly,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 co.densates.Together,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

关键词： XS561 Nur77 Bcl-2 Apoptosis Mitochondria Phase separation TNBC TAMR

Twenty years of Gendicine?rAd-p53 cancer gene therapy:The first-in-class human cancer gene therapy in the era of personalized onco.ogy

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Genes & Diseases 2024年第4期11卷 234-245页

作者： Li Qi Guiqing Li Peipei Li Hongwei Wang Xiaolong Fang Tongchuan He Jingjing Li Affiliated Hospital of Weifang Medical University School of Clinical MedicineWeifang Medical UniversityWeifangShandong 262700China Jinming Yu Academician Workstation of Onco.ogy Affiliated Hospital of Weifang Medical UniversityWeifangShandong 262700China Deco.ding therapeutics co.p Shangha 200000China Yangkun Biogroup co. LtdNanjingJiangsu 210002China The University of Chicago ChicagoIL 60290USA

Genetic mutations in TP53 co.tribute to human malignancies through various means.To date,there have been a variety of therapeutic strategies targeting p53,including gene therapy to restore normal p53 function,mutant p53 rescue,inhibiting the MDM2-p53 interaction,p53-based vaccines,and a number of other approaches.This review focuses on the functions of TP53 and discusses the aberrant roles of mutant p53 in various types of cancer.Reco.binant human p53 adenovirus,trademarked as Gendicine,which is the first anti-tumor gene therapy drug,has made tremendous progress in cancer gene therapy.We herein discuss the biological mechanisms by which Gendicine exerts its effects and describe the clinical re-sponses reported in clinical trials.Notably,the clinical studies suggest that the co.bination of Gendicine with chemotherapy and/or radiotherapy may produce more pronounced efficacy in slowing tumor growth and progression than gene therapy/chemotherapy alone.Finally,we summarize the methods of administration of reco.binant human p53 adenovirus for different cancer types to provide a reference for future clinical trials.

关键词： Gendicine Gene therapy p53 mutation Reco.binant p53 adenovirus TP53

Programmable deaminase-free base editors for G-to-Y co.version by engineered glyco.ylase

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National Science Review 2023年第8期10卷 78-87页

作者： Huawei Tong Nana Liu Yinghui Wei Yingsi Zhou Yun Li Danni Wu Ming Jin Shuna Cui Hengbin Li Guoling Li Jingxing Zhou Yuan Yuan Hainan Zhang Linyu Shi Xuan Yao Hui Yang huidagene therapeutics co. Ltd. Department of Neurology and Institute of Neurology of First Affiliated Hospital Institute of Neuroscience and Fujian Key Laboratory of Molecular Neurology Fujian Medical University Institute of Neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai Center for Brain Science and Brain-Inspired Intelligence

Current DNA base editors co.tain nuclease and DNA deaminase that enables deamination of cytosine(C)or adenine(A), but no method for guanine(G) or thymine(T) editing is available at present. Here we developed a deaminase-free glyco.ylase-based guanine base editor(gGBE) with G editing ability, by fusing Cas9 nickase with engineered N-methylpurine DNA glyco.ylase protein(MPG). By several rounds of MPG mutagenesis via unbiased and rational screening using an intron-split EGFP reporter, we demonstrated that gGBE with engineered MPG co.ld increase G editing efficiency by more than 1500 fold.Furthermore, this gGBE exhibited high base editing efficiency(up to 81.2%) and high G-to-T or G-to-C(i.e. G-to-Y) co.version ratio(up to 0.95) in both cultured human cells and mouse embryos. Thus, we have provided a proof-of-co.cept of a new base editing approach by endowing the engineered DNA glyco.ylase the capability to selectively excise a new type of substrate.

关键词： glyco.ylase base excision repair base editor depurination deaminase-free transversion

Long-co.ID-19: the persisting imprint of SARS-co.-2 infections on the innate immune system

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Signal Transduction and Targeted Therapy 2024年第1期9卷 12-13页

作者： Marianne Boes Pascal Falter-Braun Center for Translational Immunology and Department of Pediatric Immunology University Medical Center UtrechtUtrecht UniversityUtrechtThe Netherlands Institute of Network Biology(INET) Molecular Targets and Therapeutics Center(MTTC)Helmholtz MunichNeuherbergGermany Microbe-Host Interactions Faculty of BiologyLudwig-Maximilians-Universität MünchenPlanegg-MartinsriedGermany

In a recent Cell publication,Cheong et al.unco.er how co.ID-19 causes IL-6 induced epigenetic reprogramming of human immune stem cells,which causes lasting alterations in the co.position and response characteristics of circulating immune cells.1 The study provides important insights into the mechanisms by which SARSco.-2 infections impact the human immune system and is an important hook into unraveling the mechanisms of post-acute sequelae of co.ID-19(PASC)co.monly referred to as longco.ID.

关键词： system co. programming

An engineered xCas12i with high activity,high specificity,and broad PAM range

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Protein & Cell 2023年第7期14卷 540-545页

作者： Hainan Zhang Xiangfeng Kong Mingxing Xue Jing Hu Zikang Wang Yinghui Wei Haoqiang Wang Jingxing Zhou Weihong Zhang Mengqiu Xu Xiaowen Shen Fengcai Yin Zhiyuan Ai Guangyan Huang Junhui Xia Xueqiong Song Hengbin Li Yuan Yuan Jinhui Li Na Zhong Meiling Zhang Yingsi Zhou Hui Yang HuiEdit therapeutics co. Ltd.Shanghai 200120China HuiGene therapeutics co. Ltd.Shanghai 200120China Center for Reproductive Medicine International Peace Maternity and Child Health HospitalInnovative Research Team of High-level Local Universities in ShanghaiSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China

Dear Editor,The clustered regularly interspaced short palindromic repeats-Cas(CRISPR-Cas)systems,including type II Cas9 and type V Cas12 systems,which serve in the adaptive immunity of prokaryotes against viruses,have been developed into genome-editing tools(Anzalone et al.,2020;Doudna,2020).co.pared with type II systems,the type V systems including V-A to V-K showed more functional diversity(Yan et al.,2019).Amongst them,Cas12i has a relatively smaller size(1,033-1,093 aa),co.pared to SpCas9 and Cas12a,and has a 5'-TTN protospacer adjacent motif(PAM)preference(Yan et al.,2019).

关键词： high specificity