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An integrative approach of digital image analysis and transcriptome profiling to explore potential predictive biomarkers for TGFβblockade therapy

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3594-3601页

作者： Robert Pomponio Qi Tang Anthony Mei Anne Caron Bema Coulibaly Joachim Theilhaber Maximilian Rogers-Grazado Michele Sanicola-Nadel Souad Naimi Reza Olfati-Saber Cecile Combeau Jack Pollard Tun Tun Lin Rui Wang sanofi translational medicine early development cambridge MA 02142USA sanofi Artificial Intelligence and Deep Analytics Data and Data Sciences CambridgeMA 02142USA sanofi translational Science Vitry sur Seine 94403France sanofi Precision Oncology cambridge MA 02142USA sanofi Oncology early development cambridge MA 02142USA

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes(TILs)is associate with response to *** studies have identified TGFβactivity and signaling as a determinant of T cell exclusion in the tumor microenvironment and poor response to PD-1/PD-L1 *** we coupled the artificial intelligence(AI)-powered digital image analysis and gene expression profiling as an integrative approach to quantify distribution of TILs and characterize the associated TGFβpathway *** of T cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution *** digital image analysis approach achieves 74%concordance with the pathologist assessment for tumor-immune *** transcriptomic profiling suggests that the TIL score was negatively correlated with TGFβpathway activation,together with elevated TGFβsignaling activity observed in excluded and desert tumor *** present results demonstrate that the automated digital pathology algorithm for quantitative analysis of CD8 immunohistochemistry image can successfully assign the tumor into one of three infiltration phenotypes:immune desert,immune excluded or immune *** association between“cold”tumor-immune phenotypes and TGFβsignature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from TGFβblockade.

关键词： Digital pathology Artificial intelligence TGFβ Predictive biomarker Tumor topography T cell infiltration Transcriptomic profiling Machine learning

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Guards at the gate： physiological and pathological roles of tissue-resident innate lymphoid cells in the lung

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Protein & Cell 2017年第12期8卷 878-895页

作者： Hang Cheng Chengyan Jin Jing Wu Shan Zhu Yong-Jun Liu Jingtao Chen Institute of translational medicine The First Hospital Jilin University Changchun 130061 China Department of Pediatrics The First Hospital JUin University Changchun 130021 China Department of Thoracic Surgery The Second Hospital Jilin University Changchun 130041 China sanofi Research and development Cambridge MA 02139 USA

The lung Is an Important open organ and the primary site of respiration. Many *** diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases （COPDs）, pulmonary fibrosis, and lung cancer. In the lung, innate Immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role In containing these pul- monary diseases. Innate lymphoid cells （ILCs）, charac. terized by their strict tissue residence and distinct function in the mucosa, are attracting Increased atten. tion In innate Immunity. Upon sensing the danger slg- nals from damaged epithelium, ILCs activate, proliferate, and release numerous cytoklnes with specific local functions; they also participate in mucosal immune- surveillance, Immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and Induce dis- eases. In this review, we discuss the physiologicel and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the func- tion and plasticity of ILCs.

关键词： lung innate lymphoid cells pulmonarydiseases regional immunity

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Tissue residency of ILC3s in colon cancer microenvironment

Tissue residency of ILC3s in colon cancer microenvironment

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第十三届全国免疫学学术大会

作者： Jing Wu Hang Cheng Tete Li Guoxia Zang Yong-Jun Liu Jingtao Chen Institute of translational medicine The First Hospital Jilin University Department of Pediatrics the First Hospital Jilin University sanofi Research and development

Background and Aims: Colon cancer is one of the most common malignant tumors, effective treatment for metastatic and recurrent are *** system plays an essential role in tumor immune *** lymphoid cells(ILCs) act important tissue-resident innate immune cells, play a critical role in the immune *** has three groups with ILC1s, ILC2s, and *** ILC subsets in human tissues are associated with the pathogenesis and progression of chronic infections and inflammatory *** now, the role of ILCs in colon cancer, especially in the human colon tumor microenvironment remains ***, we collected tissue samples from 58 patients with colon cancer and analyzed the role of ILCs in tumor ***: Mononuclear cells(MNCs) were isolated from colon cancer tissue, then the proportion and number of ILCs were detected by Flow *** sequencing(RNA-Seq) was used to detect the different gene expression of ILC3 in tumor tissues and ***: We found the number of ILC3s and NKP44ILC3s were altered, and negatively correlated with the pathological grade of colon ***-Seq analysis for ILC3s showed thousands of differentially expressed genes, mostly involved in the development of ***: ILC3s in tumor tissue may play a certain role in the development of *** the role of ILCs in colon cancer environment may help to develop new strategies for metastatic and recurrent colon cancer.

关键词： Colon Cancer Innate lymphoid cells RNA-Seq

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Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

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Cellular & Molecular Immunology 2011年第2期8卷 157-163页

作者： Tao You Weiguo Hu Xiaowen Ge Jingnan Shen Xuebin Qin Department of Musculoskeletal Oncology First Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina Laboratory for translational Research Harvard Medical SchoolCambridgeMAUSA Department of medicine Brigham and Women’s HospitalHarvard Medical SchoolBostonMAUSA

Many monoclonal antibodies(mAbs)have been extensively used in the clinic,such as rituximab to treat ***,resistance and non-responsiveness to mAb treatment have been challenging for this line of *** is one of the main mediators of antibody-based cancer therapy via the complement-dependent cytolysis(CDC)***59 plays a critical role in resistance to mAbs through the CDC *** this paper,we attempted to investigate whether the novel CD59 inhibitor,recombinant ILYd4,was effective in enhancing the rituximab-mediated CDC effect on rituximab-sensitive RL-7 lymphoma cells and rituximab-induced resistant RR51.2 ***,the CDC effects,which were mediated by rituximab and anti-CD24 mAb,on the refractory multiple myeloma(MM)cell line ARH-77 and the solid tumor osteosarcoma cell line Saos-2,were respectively *** found that rILYd4 rendered the refractory cells sensitive to the mAb-mediated CDC effect and that rILYd4 exhibited a synergistic effect with the mAb that resulted in tumor cells *** effect on tumor cell lysis was apparent on both hematological tumors and solid ***,rILYd4 may serve as an adjuvant for mAb mediated-tumor immunotherapy.

关键词： CD59 complement lymphoma multiple myeloma rituximab

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Modulating microRNAs in cancer: next-generation therapies

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Cancer Biology & medicine 2022年第3期19卷 289-304页

作者： Nahid Arghiani Khalid Shah Center for Stem Cell and translational Immunotherapy(CSTI) Harvard Medical SchoolBostonMA 02115USA Department of Neurosurgery Brigham and Women’s HospitalHarvard Medical SchoolBostonMA 02115USA Harvard Stem Cell Institute Harvard UniversityCambridgeMA 02138USA

MicroRNAs(miRNAs)are a class of endogenously expressed non-coding regulators of the genome with an ability to mediate a variety of biological and pathological *** is growing evidence demonstrating frequent dysregulation of microRNAs in cancer cells,which is associated with tumor initiation,development,migration,invasion,resisting cell death,and drug *** have shown that modulation of these small RNAs is a novel and promising therapeutic tool in the treatment of a variety of diseases,especially cancer,due to their broad influence on multiple cellular ***,suboptimal delivery of the appropriate miRNA to the cancer sites,quick degradation by nucleases in the blood circulation,and off target effects have limited their research and clinical ***,there is a pressing need to improve the therapeutic efficacy of miRNA modulators,while at the same time reducing their *** delivery vehicles for miRNA modulators have been shown to be effective in vitro and in *** this review,we will discuss the role and importance of miRNAs in cancer and provide perspectives on currently available carriers for miRNA *** will also summarize the challenges and prospects for the clinical translation of miRNAbased therapeutic strategies.

关键词： MiRNAs dysregulation delivery systems cancer therapy clinical translation

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Immunomodulatory properties of mesenchymal stem cells/dental stem cells and their therapeutic applications

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Cellular & Molecular Immunology 2023年第6期20卷 558-569页

作者： Peishan Li Qianmin Ou Songtao Shi Changshun Shao The First Afliated Hospital of Soochow University State Key Laboratory of Radiation Medicine and ProtectionInstitutes for Translational MedicineSoochow UniversitySuzhou PR China South China Center of Craniofacial Stem Cell Research Hospital of StomatologyGuangdong Provincial Key Laboratory of StomatologySun Yat-Sen UniversityGuangzhouPR China

Mesenchymal stem/stromal cells(MsCs)are widely distributed in the body and play essential roles in tissue regeneration and *** can be isolated from discarded tissues,expanded in vitro and used as therapeutics for autoimmune diseases and other chronic *** promote tissue regeneration and homeostasis by primarily acting on immune *** least six different types of MsCs have been isolated from postnatal dental tissues and have remarkable immunomodulatory *** stem cells(DsCs)have been demonstrated to have therapeutic effects on several systemic inflammatory ***,MsCs derived from nondental tissues such as the umbilical cord exhibit great benefits in the management of periodontitis in preclinical ***,we discuss the main therapeutic uses of MSCs/DSCs,their mechanisms,extrinsic inflammatory cues and the intrinsic metabolic circuitries that govern the immunomodulatory functions of MSCs/*** understanding of the mechanisms underpinning the immunomodulatory functions of MSCs/DSCs is expected to aid in the development of more potent and precise MSC/DSC-based therapeutics.

关键词： Mesenchymal stem cells Dental stem cells Immunoregulation Inflammation

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Structure and function of epididymal protein cysteine-rich secretory protein-1

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Asian Journal of Andrology 2007年第4期9卷 508-514页

作者： Kenneth P. Roberts Daniel S. Johnston Michael A. Nolan Joseph L. Wooters Nicole C. Waxmonsky Laura B. Piehl Kathy M. Ensrud-Bowlin David W. Hamilton Department of Urologic Surgery Cell Biology and Development University of Minnesota Minneapolis MN 55455 Contraception Women＇s Health ＆ Musculoskeletal Biology Woman＇s Health Research Institute Wyeth Research Collegeville PA 19426 USA Inflammation Department Molecular Profiling and Biomarker Discovery Wyeth Research Cambridge MA 02140 USA Biological Technologies Molecular Profiling and Biomarker Discovery Wyeth Research Cambridge MA 02140 USA Department of Genetics Cell Biology and Development University of Minnesota Minneapolis MN 55455 USA

Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cysteine residues. In mammals, CRISP-1 inhibits sperm-egg fusion and can suppress sperm capacitation. The molecular mechanism of action of the mammalian CRISP proteins remains unknown, but certain non-mammalian CRISP proteins can block ion channels. In the rat, CRISP-1 comprises two forms referred to as Proteins D and E. Recent work in our laboratory demonstrates that the D form of CRISP-1 associates transiently with the sperm surface, whereas the E form binds tightly. When the spermatozoa are washed, the E form of CRISP-1 persists on the sperm surface after all D form has dissociated. Cross-linking studies demonstrate different protein-protein interaction patterns for D and E, although no binding partners for either protein have yet been identified. Mass spectrometric analyses revealed a potential post-translational modification on the E form that is not present on the D form. This is the only discernable difference between Proteins D and E, and presumably is responsible for the difference in behavior of these two forms of rat CRISP- 1. These studies demonstrate that the more abundant D form interacts with spermatozoa transiently, possibly with a specific receptor on the sperm surface, consistent with a capacitation-suppressing function during sperm transit and storage in the epididymis, and also confirm a tightly bound population of the E form that could act in the female reproductive tract. （Asian J Androl 2007 July; 9： 508-514）

关键词： cysteine-rich secretory protein-1 epididymis sperm capacitation

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Antimicrobial Activity of a Cys-Rich Peptide Derived from a Centrosema virginianum Vicilin

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American Journal of Plant Sciences 2016年第1期7卷 92-107页

作者： Zhongyu Xie Nibedita Saha Caryl Chlan Biology Department The University of Louisiana at Lafayette Lafayette LA USA sanofi Genzyme Corporation Cambridge MA USA

Many antimicrobial peptides (AMPs) have been identified in plants. These peptides are highly divergent at the primary sequence level and vary in their hierarchical structures. Some common biochemical features include the ability to form disulfide bonds, tandemly repeated amino acid sequences and a net charge at pH 7. Unusual Cysteine containing repeats has been identified in several plant seed storage proteins that may act as AMPs. We identified a Cys repeat within a vicilin (seed storage protein) of a wild legume, Centrosema virginianum. Cleavage of the vicilin protein during germination would generate a vicilin derived Cys peptide (VDCP). We investigated the antimicrobial properties of this VDCP and compared its efficacy as an antimicrobial agent to VDCPs from other species. We developed transgenic tobacco plants that expressed cloned sequences encoding the Cysteine repeat unit from C. virginianum, Theobroma cacao and Gossypium hirsutum. Extracts from fully expanded leaves were tested for antimicrobial activity against a fungal pathogen, Botrytis cinerea. The Cys motif from C. virginianum was also expressed in two E. coli cell lines (reducing or oxidizing cytoplasm) and peptide fusion protein fractions were tested for antimicrobial activity against a battery of fungal strains. The unique Cysteine repeat single unit from C. virginianum exhibited antimicrobial properties greater than or equal to the antimicrobial activity associated with expression of the multiple Cys-repeat VDCPs from G. hirsutum or T. cacao in transgenic tobacco. When expressed in bacteria, a C. virginianum VDCP fusion protein exhibited antifungal activity against 3 of the 4 fungi tested. Although the primary role of seed storage proteins is to provide a pool of amino acids and nitrogen for germinating seeds and developing plantlets, it is likely that seed storage protein proteolytic products also provide beneficial antimicrobial properties during germination and young plantlet development.

关键词： Seed Storage Proteins Vicilins Antimicrobial Peptides C. virginianum

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Omics in schizophrenia:current progress and future directions of antipsychotic treatments

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Journal of Bio-X Research 2019年第4期2卷 145-152页

作者： Sun Yidan Zhou Wei Chen Luan Huai Cong Huang Hailiang He Lin Qin Shengying Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghaiChina Analytic and translational Genetics Unit Department of MedicineMassachusetts General Hospital and Harvard Medical SchoolBoston Stanley Center for Psychiatric Research Broad Institute of MIT and HarvardCambridgeMAUSA

Schizophrenia is a life-long,complex mental illness that still lacks satisfactory *** recent years,increasing numbers of candidate biomarkers of schizophrenia occurrences and drug responses to schizophrenia therapies have been successfully identified by many omics *** review discusses the latest discoveries regarding effective drug targets and relevant drug classifications in *** also assesses our understanding of biomarkers for drug efficacy and adverse drug reactions in current schizophrenia treatments using omics *** applications in clinical practice have been proposed based on these new findings,and are now considered highly promising strategies to better treat ***,we explore several novel approaches that aim to reveal additional genetic signatures of schizophrenia using multi-omics data,which are hoped to improve the diagnosis and treatment of this illness in the future.

关键词： schizophrenia antipsychotics adverse drug reaction drug efficacy omics

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3D-bioprinted cholangiocarcinoma-on-a-chip model for evaluating drug responses

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Bio-Design and Manufacturing 2023年第4期6卷 373-389页

作者： Qiong Liu Luis SMille Cesar Villalobos Ingrid Anaya Matthias Vostatek Sili Yi Wanlu Li Junlong Liao Huanghui Wu Yongteng Song Lize Xiong Yu Shrike Zhang Division of Engineering in medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolCambridgeMA 02139USA translational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation Shanghai 200434China Department of Bioengineering Stanford UniversityPalo AltoCA 94305USA Biotechnological Engineering Program Monterrey Institute of Technology and Higher Education64849 MonterreyNuevo LeónMexico Molecular Biotechnology University of Applied Sciences Campus Vienna1100 ViennaAustria Rapid Manufacturing Engineering Center School of Mechatronical Engineering and AutomationShanghai UniversityShanghai 200444China

Cholangiocarcinoma(CCA)is characterized by heterogeneous mutations and a refractory ***,the development of a model for effective drug screening is urgently *** the established therapeutic testing models for CCA are often ineffective,we fabricated an enabling three-dimensional(3D)-bioprinted CCA-on-a-chip model that to a good extent resembled the multicellular microenvironment and the anatomical microstructure of the hepato-vascular-biliary system to perform high-content antitumor drug ***,cholangiocytes,hepatocytes,and vascular endotheliocytes were employed for 3D bioprinting of the models,allowing for a high degree of spatial and tube-like microstructural ***,it was possible to observe CCA cells attached to the surfaces of the gelatin methacryloyl(GelMA)hydrogelembedded microchannels and overgrown in a thickening manner,generating bile duct stenosis,which was expected to be analogous to the in vivo *** 4000 differentially expressed genes were detected in the CCA cells in our 3D coculture model compared to the traditional two-dimensional(2D)*** screening revealed that the CCA cells grown in the 3D traditional model were more sensitive to the antitumoral prodrug than those in the 2D monoculture due to drug biotransformation by the neighboring functional *** study provides proof-of-concept validation of our bioprinted CCA-on-a-chip as a promising drug screening model for CCA treatment and paves the way for potential personalized medicine strategies for CCA patients in the future.

关键词： Tumor-on-a-chip Biliary tumor 3D bioprinting Tumor microenvironment Drug screening

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