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Molecular heterogeneity of anti-PD-1/PD-L1 immunotherapy efficacy is correlated with tumor immune microenvironment in East Asian patients with non-small cell lung cancer

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Cancer Biology & Medicine 2020年第3期17卷 768-781页

作者： Runsen Jin Chengming Liu Sufei Zheng Xinfeng Wang Xiaoli Feng Hecheng Li Nan Sun Jie He Department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Thoracic Surgery Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Objective:The aim of this study was to investigate how the tumor immune microenvironment differs regarding tumor genomics,as well as its impact on prognoses and responses to immunotherapy in East Asian patients with non-small cell lung cancer(NSCLC).Methods:We performed an integrated analysis using publicly available data to identify associations between anti-programmed death 1(PD-1)/programmed death-ligand 1(PD-L1)immunotherapy efficacy and classic driver oncogene mutations in East Asian NSCLC *** pooled and clinical cohort analyses were used to correlate driver oncogene mutation status and tumor microenvironment based on PD-L1 and CD8+tumor-infiltrating lymphocytes(TILs).immune infiltrating patterns were also established for genomic NSCLC subgroups using the CIBERSORT ***:Based on East Asian NSCLC patients,TIDE analyses revealed that for anti-PD-1/PD-L1 immunotherapy,epidermal growth factor receptor(EGFR)-mutant and anaplastic lymphoma kinase(ALK)-rearranged tumors yielded inferior responses;however,although Kirsten rat sarcoma viral oncogene homolog(KRAS)-mutant tumors responded better,the difference was not statistically significant(EGFR:P=0.037;ALK:Pimmune microenvironment heterogeneities correlated with oncogenic *** results showed remarkably higher PD-L1-and TIL-positive KRAS-mutant tumors,suggesting KRAS mutations may drive an inflammatory phenotype with adaptive immune ***,the EGFR-mutant or ALK-rearranged groups showed a remarkably higher proportion of PD-L1-/TIL-tumors,suggesting an uninflamed phenotype with immunological ***,similar to triple wild-type NSCLC tumors,EGFR L858R-mutant tumors positively correlated with an inflammatory phenotype,suggesting responsiveness to anti-PD-1/PD-L1 immunotherapy(P<0.05).Furthermore,the CIBERSORT algorithm results revealed that EGFR-mutant and ALK-rearranged tumors were characterize

关键词： NSCLC East Asian oncogene mutations PD-1/PD-L1 inhibitors immune microenvironment

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Ultrasound-triggered biomimetic ultrashort peptide nanofiber hydrogels promote bone regeneration by modulating macrophage and the osteogenic immune microenvironment

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Bioactive Materials 2024年第1期31卷 231-246页

作者： Fan Zhang Mingchen Lv Siyuan Wang Mengyao Li Yu Wang Congjiao Hu Wei Hu Xuekui Wang Xiaogang Wang Zhiduo Liu Zhen Fan Jianzhong Du Yao Sun Department of Oral Implantology Stomatological Hospital and Dental School of Tongji UniversityShanghai Engineering Research Center of Tooth Restoration and Regeneration200072China Department of Gynaecology and Obstetrics Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai200434China Department of Polymeric Materials School of Materials Science and EngineeringTongji University201804China Department of Immunology and Microbiology The Minister of Education Key Laboratory of Cell Death and DifferentiationShanghai Institute of ImmunologyShanghai Jiao Tong University School of MedicineChina Key Laboratory of Big Data-Based Precision Medicine School of Engineering MedicineBeihang UniversityChina

The immune microenvironment plays a vital role in bone defect *** create an immune microenvironment that promotes osteogenesis,researchers are exploring ways to enhance the differentiation of M2-type *** peptides have been discovered to effectively improve this process,but they are limited by low efficiency and rapid degradation in *** overcome these issues,peptide with both M2 regulatory and self-assembly modules was designed as a building block to construct an ultrasound-responsive nanofiber *** nanofibers can be released from hydrogel in a time-dependent manner upon ultrasound stimulation,activating mitochondrial glycolytic metabolism and the tricarboxylic acid cycle,inhibiting reactive oxygen species production and enhancing M2 macrophage *** hydrogel exhibits advanced therapeutic potential for bone regeneration by triggering M2 macrophages to secrete BMP-2 and IGF-I,accelerating the differentiation of bone marrow mesenchymal stem cells(BMSCs)into ***,modularly designed biomimetic ultrashort peptide nanofiber hydrogels provide a novel strategy to rebuild osteogenic immune microenvironments for bone repair.

关键词： Peptide Nanofiber hydrogel immune microenvironment Bone tissue regeneration

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Novel agents targeting leukemia cells and immune microenvironment for prevention and treatment of relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

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Acta Pharmaceutica Sinica B 2020年第11期10卷 2125-2139页

作者： Wei Shi Weiwei Jin Linghui Xia Yu Hu Institute of Hematology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Fred Hutchinson Cancer Research Center SeattleWA 98109-1024USA Department of Cardiovascular Optical Valley School DistrictHubei Provincial Hospital of Traditional Chinese MedicineWuhan 430061China Hubei Province Academy of Traditional Chinese Medicine Wuhan 430074China

Relapse remains the worst life-threatening complications after allogeneic hematopoietic stem cell transplantation(allo-HSCT)in patients with acute myeloid leukemia(AML),whose prognosis has been historically *** the rapid development of genomics and immunotherapies,the interference strategies for AML recurrence have been changing these *** and more novel targeting agents that have received the *** and Drug Administration(FDA)approval for de novo AML treatment have been administrated in the salvage or maintenance therapy of post-HSCT *** strategies that regulate the immune microenvironment of and optimize the graft versus leukemia(GVL)effect of immune cells are gradually *** agents not only have been proven to achieve clinical benefits from a single drug,but if combined with classic therapies,can significantly improve the poor prognosis of AML patients who relapse after *** review will focus on currently available and promising upcoming agents and also discuss the challenges and limitations of targeted therapies in the allogeneic hematopoietic stem cell transplantation community.

关键词： AML Targeted therapy Relapse immune microenvironment Allogeneic hematopoietic stem cell transplantation Oncogenic effectors Metabolism Surface markers

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Action of circulating and infiltrating B cells in the immune microenvironment of colorectal cancer by single-cell sequencing analysis

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2683-2696页

作者： Jing-Po Zhang Bing-Zheng Yan Jie Liu Wei Wang Department of Hepatobiliary and Pancreatic Surgery First Hospital of Hebei Medical UniversityShijiazhuang 050032Hebei ProvinceChina Department of Hepatobiliary Surgery Hunan Provincial People’s HospitalChangsha 410002Hunan ProvinceChina

BACKGROUND The complexity of the immune microenvironment has an impact on the treatment of colorectal cancer(CRC),one of the most prevalent malignancies *** this study,multi-omics and single-cell sequencing techniques were used to investigate the mechanism of action of circulating and infiltrating B cells in *** revealing the heterogeneity and functional differences of B cells in cancer immunity,we aim to deepen our understanding of immune regulation and provide a scientific basis for the development of more effective cancer treatment *** To explore the role of circulating and infiltrating B cell subsets in the immune microenvironment of CRC,explore the potential driving mechanism of B cell development,analyze the interaction between B cells and other immune cells in the immune microenvironment and the functions of communication molecules,and search for possible regulatory pathways to promote the anti-tumor effects of B *** A total of 69 paracancer(normal),tumor and peripheral blood samples were collected from 23 patients with CRC from The Cancer Genome Atlas database(https://***/).After the immune cells were sorted by multicolor flow cytometry,the single cell transcriptome and B cell receptor group library were sequenced using the 10X Genomics platform,and the data were analyzed using bioinformatics tools such as *** differences in the number and function of B cell infiltration between tumor and normal tissue,the interaction between B cell subsets and T cells and myeloid cell subsets,and the transcription factor regulatory network of B cell subsets were explored and *** Compared with normal tissue,the infiltrating number of CD20+B cell subsets in tumor tissue increased *** them,germinal center B cells(GCB)played the most prominent role,with positive clone expansion and heavy chain mutation level increasing,and the trend of differentiation into memory B cells ***,the

关键词： Colorectal cancer Multi-omics analysis Single-cell sequencing analysis immune microenvironment Infiltrating B cells

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Annexin A2 promotion of hepatocellular carcinoma tumorigenesis via the immune microenvironment

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World Journal of Gastroenterology 2020年第18期26卷 2126-2137页

作者： Li-Wei Qiu Yi-Fei Liu Xiao-Qing Cao Yan Wang Xiao-Hong Cui Xian Ye Shuo-Wen Huang Hong-Jun Xie Hai-Jian Zhang Research Center of Clinical Medicine Affiliated Hospital of Nantong UniversityNantong 226001Jiangsu ProvinceChina Department of Pathology Affiliated Hospital of Nantong UniversityNantong 226001Jiangsu ProvinceChina Department of Thoracic Surgery Beijing Chest HospitalCapital Medical University(Beijing Tuberculosis and Thoracic Tumor Research Institute)Beijing 101149China Emergency Department Affiliated Hospital of Nantong UniversityNantong 226001Jiangsu ProvinceChina Department of General Surgery Shanghai Electric Power HospitalShanghai 200050China Medical School of Nantong University Nantong 226001Jiangsu ProvinceChina

Hepatocellular carcinoma(HCC) is the most common primary liver cancer with a dismal prognosis, especially when diagnosed at advanced stages. Annexin A2(ANXA2), is found to promote cancer progression and therapeutic ***, the underlining mechanisms of ANXA2 in immune escape of HCC remain poorly understood up to now. Herein, we summarized the molecular function of ANXA2 in HCC and its relationship with prognosis. Furthermore, we tentatively elucidated the underlying mechanism of ANXA2 immune escape of HCC by upregulating the proportion of regulatory T cells and the expression of several inhibitory molecules, and by downregulating the proportion of natural killer cells and dendritic cells and the expression of several inhibitory molecules or effector molecules. We expect a lot of in-depth studies to further reveal the underlying mechanism of ANXA2 in immune escape of HCC in the future.

关键词： Annexin A2 Hepatocellular carcinoma immune microenvironment Overall survival Chemotherapy resistance Checkpoint

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Prognostic and predictive role of immune microenvironment in colorectal cancer

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 643-652页

作者： Olesya Kuznetsova Mikhail Fedyanin Larisa Zavalishina Larisa Moskvina Olga Kuznetsova Alexandra Lebedeva Alexey Tryakin Galina Kireeva Gleb Borshchev Sergei Tjulandin Ekaterina Ignatova Department of Chemotherapy Federal State Budgetary Institution(N.N.Blokhin National Medical Research Center of Oncology)of the Ministry of Health of the Russian FederationMoscow 115478Russia Department of Pathology Russian Medical Academy of Continuous Professional EducationMoscow 123242Russia OncoAtlas LCC Moscow 115478Russia Federal State Budgetary Institution“National Medical and Surgical Center named after N.I.Pirogov”of the Ministry of Health of the Russian Federation Moscow 105203Russia STOONCO:Science and Technology in Oncology Moscow 115478Russia

Colorectal cancer(CRC)represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death *** traditional classification of CRC is based on pathomorphological and molecular character-istics of tumor cells(mucinous,ring-cell carcinomas,etc.),analysis of mechanisms of carcinogenesis involved(chromosomal instability,microsatellite instability,CpG island methylator phenotype)and mutational statuses of commonly altered genes(KRAS,NRAS,BRAF,APC,etc.),as well as expression signatures(CMS 1-4).It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in *** to the latest data,the immune microenvironment can also be predictive of the response to immune checkpoint *** this review,we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

关键词： Immunoscore immune microenvironment Colorectal cancer Gastrointestinal cancers Predictive biomarkers Digital pathology

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Profiling of hepatocellular carcinoma neoantigens reveals immune microenvironment and clonal evolution related patterns

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Chinese Journal of Cancer Research 2021年第3期33卷 364-378页

作者： Zhenli Li Geng Chen Zhixiong Cai Xiuqing Dong Lei He Liman Qiu Yongyi Zeng Xiaolong Liu Jingfeng Liu The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou 350025China Mengchao Med-X Center Fuzhou UniversityFuzhou 350116China Liver Disease Center the First Affiliated Hospital of Fujian Medical UniversityFuzhou 350005China

Objective: Neoantigens derived from tumor-specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of hepatocellular carcinoma(HCC) neoantigens and their complex interplay with immune microenvironment and tumor evolution have not been fully ***: Here we integrated whole exome sequencing data, transcriptome sequencing data and clinical information of 72 primary HCC patients to characterize the HCC neoantigen profile, and systematically explored its interactions with tumor clonal evolution, driver mutations and immune ***: We observed that higher somatic mutation/neoantigen load was associated with better clinical outcomes and HCC patients could be further divided into two subgroups with distinct prognosis based on their neoantigen expression patterns. HCC subgroup with neoantigen expression probability high(NEP-H) showed more aggressive pathologic features including increased incidence of tumor thrombus(P=0.038), higher recurrence rate(P=0.029),more inclined to lack tumor capsule(P=0.026) and with more microsatellite instability sites(P=0.006). In addition,NEP-H subgroup was also characterized by higher chance to be involved in tumor clonal evolution [odds ratio(OR)=46.7, Pimmune responses, leading to elevated neoantigen expression proportion in tumor cells. Furthermore, we discovered an immune escape mechanism that tumors could become more inconspicuous by evolving subclones with less immunogenicity. We observed that smaller clonal mutation clusters with higher immunogenicity in tumor were more likely to involve in clonal evolution. Based on identified neoantigen profiles, we also discovered series of neoantigenic hotspot genes, which could serve as potential actionable targets in ***: Our results revealed the landscape of HCC

关键词： immune microenvironment immune escape MYC regulation neoantigen tumor clonal evolution

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Ginsenoside Rh1 regulates the immune microenvironment of hepatocellular carcinoma via the glucocorticoid receptor

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Journal of Integrative Medicine 2024年第6期22卷 709-718页

作者： Xiong-hui Wang Ya-lan Fu Yan-nan Xu Peng-cheng Zhang Tian-xiao Zheng Chang-quan Ling Ying-lu Feng Department of Traditional Chinese Medicine First Affiliated Hospital of Naval Medical University PLA Joint Logistics Support Force No.967 Hospital Department of Integrated Traditional Chinese and Western Medicine Medical College of Qingdao University PLA Joint Logistics Support Force No.920 Hospital First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine) Zhejiang Chinese Medical University Department of Traditional Chinese Medicine PLA Navy No.971 Hospital

Objective:Ginsenoside Rh1 （G-Rh1） has been confirmed to inhibit the growth of breast cancer and colon cancer,but its therapeutic effect on hepatocellular carcinoma （HCC） is *** study investigates the therapeutic effect of G-Rh1 on HCC as well as the underlying ***:Bioinformatics methods were used to analyze glucocorticoid receptor （GR） expression and the tumor microenvironment in HCC tissues from HCC *** effect of G-Rh1 on HCC cells was investigated in vitro using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide *** therapeutic effect of G-Rh1 was investigated in vivo using subcutaneous transplantation models in C57BL/6J and nude ***,the proportion of infiltrating immune cells in tumors was analyzed using flow cytometry,the GR and major histocompatibility complex class-I （MHC-I） expression of HCC cells after G-Rh1 treatment was analyzed using Western blotting,and G-Rh1-treated Hepa1-6 cells were cocultured with bone marrow-derived dendritic cells and B3Z T cells to further analyze the ability of G-Rh1 to induce dendritic cell （DC） maturation and CD8+T cell ***:GR expression was upregulated in HCC tissues,and high GR expression was associated with a worsened immune *** vitro studies showed that G-Rh1 had no significant effect on the proliferation of HCC cells,while in vivo studies showed that G-Rh1 exerted antitumor effects in C57BL/6J mice but not in nude *** research revealed that G-Rh1 ameliorated the immunosuppressive tumor microenvironment,thereby enhancing the antitumor effects of lenvatinib by increasing the infiltration of CD8+T cells,mature DCs,and MHC-I-positive ***-I was upregulated by G-Rh1 via GR ***,overexpression of GR abolished the G-Rh1-mediated promotion of MHC-I expression in Huh7 cells,as well as the maturation of DCs and the activation of CD8+T ***:G-Rh1 can regulate the immune microenvironment of HCC by

关键词： Ginsenoside Rh1 Glucocorticoid receptor Hepatocellular carcinoma immune microenvironment MHC-I

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Role of the immune microenvironment in bone,cartilage,and soft tissue regeneration:from mechanism to therapeuticopportunity

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Military Medical Research 2023年第4期10卷 499-528页

作者： Yuan Xiong Bo‑Bin Mi Ze Lin Yi‑Qiang Hu Le Yu Kang‑Kang Zha Adriana CPanayi Tao Yu Lang Chen Zhen‑Ping Liu Anish Patel Qian Feng Shuan‑Hu Zhou Guo‑Hui Liu Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan 430022China Department of Chemical and Biomolecular Engineering Ohio UniversityAthensOH 45701USA Key Laboratory of Biorheological Science and Technology Ministry of Education College of BioengineeringChongqing UniversityShapingbaChongqing 400044China Department of Plastic Surgery Brigham and Women’s HospitalHarvard Medical SchoolBostonMA 02152USA Department of Orthopaedics Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Physics Center for Hybrid Nanostructure(CHyN)University of HamburgHamburg 22761Germany Joint Laboratory of Optofluidic Technology and System National Center for International Research on Green OptoelectronicsSouth China Academy of Advanced OptoelectronicsSouth China Normal UniversityGuangzhou 510006China Skeletal Biology Laboratory Department of Orthopedic SurgeryBrigham and Women’s HospitalHarvard Medical SchoolBostonMA 02120USA Harvard Stem Cell Institute Harvard UniversityCambridgeMA 02138USA.

Bone,cartilage,and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types,whose activity and interplay must be precisely mediated for effective healing *** extensive strides have been made in the understanding of the immune microenvironment processes governing bone,cartilage,and soft tissue regeneration,effective clinical translation of these mechanisms remains a *** of the immune microenvironment is increasingly becoming a favorable target for bone,cartilage,and soft tissue regeneration;therefore,an in-depth understanding of the communication between immune cells and functional tissue cells would be ***,we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone,cartilage,and soft tissue repair and *** discuss the roles of various immune cell subsets in bone,cartilage,and soft tissue repair and regeneration processes and introduce novel strategies,for example,biomaterial-targeting of immune cell activity,aimed at regulating *** the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone,cartilage,and soft tissue regeneration through regulation of the immune microenvironment.

关键词： immune microenvironment Regeneration Cell-cell interaction Tissue engineering Biomaterials

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Effect of antiallergic herbal agents on chloride channel-3 and immune microenvironment in nasal mucosal epithelia of allergic rhinitis rabbits

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Chinese Medical Journal 2010年第8期123卷 1034-1038页

作者： WANG Li-feng XU Li-juan GUO Feng-hua WANG Li-na SHEN Xiao-hong Medical College of Nankai University Tianjin 300071 China

Background Allergic rhinitis （AR） is a Th2 dominant cytokine response. Chloride channel-3 （CIC-3） plays an important role in nasal mucosal edema and inflammatory pathologic changes in AR. Antiallergic herbal agents （AHA） are antiallergic herbal products. In the previous study, we have demonstrated that AHA clearly inhibited allergic medium and relieved allergic reaction of AR. The aim of this study was to evaluate the function of CIC-3 and discuss the possible therapeutic effects of AHA on immune microenvironment in AR. Methods AHA were produced and used to treat AR. An animal model of an AR rabbit was established by ovalbumin （OVA）. The rhinitis rabbits were randomly divided into three groups： AHA treated group （AHATG）, model group （MG） and healthy control group （HCG）. The expressions of CIC-3 protein were examined by immunohistochemical method. The mucosal epithelial cells of all the rabbit groups were primarily cultured with tissue culture method in vitro with or without rhlL-4 or rhlL-2. Furthermore, the expressions of CIC-3 mRNA were detected by real-time PCR. The levels of monocyte chemotactic factor-1 （MCP-1） and vascular cell adhesion molecule-1 （VCAM-1） protein in culture supernatants were measured by ELISA. Results The expressions of CIC-3 mRNA increased more in mucosal epithelial cells of MG than those in AHATG and HCG （P 〈0.01）. The levels of CIC-3 mRNA, MCP-1 and VCAM-1 protein in culture supernatants of MG were significantly higher than those in the other two groups （P 〈0.01）. Those were significantly increased in MG untreated 12 hours later than those in other two groups （P 〈0.01）. The expressions of CIC-3 mRNA, MCP-1 and VCAM-1 protein in culture supernatants of MG and HCG treated with rhlL-4 were significantly higher than those in the AHATG treated with rhlL-4 （P 〈0.01）. The levels of CIC-3 mRNA, MCP-1 and VCAM-1 protein in culture supernatants of all groups treated with rhlL-2 showed no significant changes （P 〉0.05）. Conclusions AHA can inhibit the

关键词： chloride channel-3 antiallergic herbal agents allergic rhinitis immune microenvironment

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