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Identification of potential immune-related mechanisms related to the development of multiple myeloma

Chinese Medical Journal 2024年第13期137卷 1603-1613页

作者： Yaomei Wang Wenli Zhang Tiandong Li Mengmeng Liu Mengya Gao Xinqing Li Yufei Chen Yongping Song Wei Li Chunyan Du Fang Wang Lina Liu Department of Hematology The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhouHenan 450008China The Academy of Medical Science College of MedicalZhengzhou UniversityZhengzhouHenan 450052China College of Public Health Zhengzhou UniversityZhengzhouHenan 450000China Department of Research and Foreign Affairs The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhouHenan 450008China Department of Clinical Medicine Zhengzhou UniversityZhengzhouHenan 450052China Department of Hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Laboratory Animal Center School of Medical SciencesZhengzhou UniversityZhengzhouHenan 450052China

Background:Although significant advances have been made in the treatment of multiple myeloma(MM),leading to unprecedented response and survival rates among patients,the majority eventually relapse,and a cure remains *** situation is closely related to an incomplete understanding of the immune microenvironment,especially monocytes/macrophages in patients with treatment-naïve *** aim of this study was to provide insight into the immune microenvironment,especially monocytes/macrophages,in patients with treatment-naïve ***:This study used the single-cell RNA sequencing(scRNA-seq)data of both patients with MM and heathy donors to identify immune cells,including natural killer(NK)cells,T cells,dendritic cells(DCs),and monocytes/*** data and flow cytometry analysis of monocytes/macrophages were used to further examine the effect of monocytes/macrophages in treatment-naïve MM ***:A significant difference was observed between the bone marrow(BM)immune cells of the healthy controls and treatment-naïve MM patients through *** is noteworthy that,through an scRNA-seq data analysis,this study found that interferon(IFN)-induced NK/T cells,terminally differentiated effector memory(TEMRA)cells,T-helper cells characterized by expression of IFN-stimulated genes(ISG^(+)Th cells),IFN-responding exhausted T cells,mannose receptor C-type 1(mrc1)^(+)DCs,IFN-responding DCs,MHCII^(+)DCs,and immunosuppressive monocytes/macrophages were enriched in patients with treatment-naïve ***,transcriptomic data of monocytes/macrophages demonstrated that"don’t eat me"-related genes and IFN-induced genes increase in treatment-naïve MM ***,scRNA-seq,transcriptomic data,and flow cytometry also showed an increased proportion of CD16^(+)monocytes/macrophages and expression level of ***-cell communication analysis indicated that monocytes/macrophages,whose related important signaling pathways include migration i

关键词： Multiple myeloma Monocytes/macrophages Single-cell RNA sequencing Immune cell Microenvironment Bone marrow Molecular characterization

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Biomarkers in Barrett's esophagus and esophageal adenocarcinoma:Predictors of progression and prognosis

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World Journal of Gastroenterology 2010年第45期16卷 5669-5681页

作者： Chin-Ann J Ong Pierre Lao-Sirieix Rebecca C Fitzgerald mrc cancer cell unit Hutchison-MRC Research CentreCambridgeCB20XZUnited Kingdom

Barrett’s esophagus is a well-known premalignant lesion of the lower esophagus that is characterized by intestinal metaplasia of the squamous epithelium. It is clinically important due to the increased risk (0.5% per annum) of progression to esophageal adenocarcinoma (EA), which has a poor outcome unless diagnosed early. The current clinical management of Barrett’s esophagus is hampered by the lack of accurate predictors of progression. In addition, when patients develop EA, the current staging modalities are limited in stratifying patients into different prognostic groups in order to guide the optimal therapy for an individual patient. Biomarkers have the potential to improve radically the clinical management of patients with Barrett’s esophagus and EA but have not yet entered mainstream clinical practice. This is in contrast to other cancers like breast and prostate for which biomarkers are utilized routinely to inform clinical decisions. This review aims to highlight the most promising predictive and prognostic biomarkers in Barrett’s esophagus and EA and to discuss what is required to move the field forward towards clinical application.

关键词： Barrett’s esophagus Esophageal adenocar cinoma Esophageal dysplasia Prognosis

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The metabolome identity:basis for discovery of biomarkers in neurodegeneration

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Neural Regeneration Research 2019年第3期14卷 387-390页

作者： Julie-Myrtille Bourgognon Joern R.Steinert mrc Toxicology unit University of Leicester

Neurodegenerative disorders are often associated with cellular dysfunction caused by underlying protein-misfolding signalling. Numerous neuropathologies are diagnosed at late stage symptomatic changes which occur in response to these molecular malfunctions and treatment is often too late or restricted only to the slowing of further cell death. Important new strategies to identify early biomarkers with predictive value to intervene with disease progression at stages where cell dysfunction has not progressed irreversibly is of paramount importance. Thus, the identification of these markers presents an essential opportunity to identify and target disease pathways. This review highlights some important metabolic alterations detected in neurodegeneration caused by misfolded prion protein and discusses common toxicity pathways identified across different neurodegenerative diseases. Thus, having established some commonalities between various degenerative conditions, detectable metabolic changes may be of extreme value as an early diagnostic biomarker in disease.

关键词： metabolome neurodegeneration neuroinflammation nitric oxide redox stress biomarker misfolded protein prion disease

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Genetic and molecular changes in ovarian cancer

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cancer Biology & Medicine 2016年第2期13卷 236-247页

作者： Robert L Hollis Charlie Gourley Edinburgh cancer Research UK Centre MRC Institute of Genetics and Molecular Medicine University of Edinburgh

Epithelial ovarian cancer represents the most lethal gynecological malignancy in the developed world, and can be divided into five main histological subtypes: high grade serous, endometrioid, clear cell, mucinous and low grade serous. These subtypes represent distinct disease entities, both clinically and at the molecular level. Molecular analysis has revealed significant genetic heterogeneity in ovarian cancer, particularly within the high grade serous subtype. As such, this subtype has been the focus of much research effort to date, revealing molecular subgroups at both the genomic and transcriptomic level that have clinical ***, stratification of ovarian cancer patients based on the underlying biology of their disease remains in its infancy. Here, we summarize the molecular changes that characterize the five main ovarian cancer subtypes, highlight potential opportunities for targeted therapeutic intervention and outline priorities for future research.

关键词：分子水平遗传异质性卵巢癌基础生物学临床意义浆液性恶性肿瘤发达国家

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Developing a pill to treat sickle cell disease

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四川生理科学杂志 2024年第7期46卷 1420-1420页

作者： Douglas Higgs Laboratory of Gene Regulation MRC Weatherall Institute of Molecular Medicine and Chinese Academy of Medical Sciences Oxford Institute University of Oxford Oxford UK.

A newly identified epigenetic modifier increases fetal hemoglobin in preclinical studies.

关键词： fetal clinical modifier

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Human cancergermlineantigen-specific cytotoxicTcell-what canwelearnfrompatient

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cellular & Molecular Immunology 2020年第7期17卷 684-692页

作者： Megat Abd Hamid Yanchun Peng Tao Dong Nufield Department of Medicine Chinese Academy of Medical Science Oxford Institute(COI)University of OxfordOxfordUK mrc Human Immunology unit MRC Weatherall Institute of Molecular MedicineUniversity of OxfordOxfordUK

In this review,we will highlight the importance of cancer germline antigen-specific cytotoxic CD8^(+) T lymphocytes(CTL)and the factors affecting antitumor CTL *** light of cancer immunotherapy,we will emphasis the need to further understand the features,characteristics,and actions of modulatory receptors of human cancer germline-specific CTLs,in order to determine the optimal conditions for antitumor CTL responses.

关键词： cytotoxic T cell immune check point receptor immune therapy T cell receptor cancer antigen

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mTOR-S6K1 pathway mediates cytoophidium assembly

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Journal of Genetics and Genomics 2019年第2期46卷 65-74页

作者： Zhe Sun Ji-Long Liu School of Life Science and Technology ShanghaiTech University mrc Functional Genomics unit Department of Physiology Anatomy and Genetics University of Oxford

CTP synthase(CTPS), the rate-limiting enzyme in de novo CTP biosynthesis, has been demonstrated to assemble into evolutionarily conserved filamentous structures, termed cytoophidia, in Drosophila, bacteria, yeast and mammalian cells. However, the regulation and function of the cytoophidium remain elusive. Here, we provide evidence that the mechanistic target of rapamycin(mTOR) pathway controls cytoophidium assembly in mammalian and Drosophila cells. In mammalian cells, we find that inhibition of mTOR pathway attenuates cytoophidium formation. Moreover, CTPS cytoophidium assembly appears to be dependent on the mTOR complex 1(mTORC1) mainly. In addition, knockdown of the mTORC1 downstream target S6 K1 can inhibit cytoophidium formation, while overexpression of the constitutively active S6 K1 reverses mTOR knockdown-induced cytoophidium disassembly. Finally, reducing m TOR protein expression results in a decrease of the length of cytoophidium in Drosophila follicle ***, our study connects CTPS cytoophidium formation with the mTOR signaling pathway.

关键词： mTOR Cytoophidium CTP synthase Colorectal cancer cell Drosophila

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Engineering immunosuppressive drug-resistant armored(IDRA)SARS-CoV-2 T cells for cell therapy

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cellular & Molecular Immunology 2023年第11期20卷 1300-1312页

作者： Qi Chen Adeline Chia Shou Kit Hang Amy Lim Wee Kun Koh Yanchun Peng Fei Gao Jili Chen Zack Ho Lu-En Wai Kamini Kunasegaran Anthony Tanoto Tan Nina Le Bert Chiew Yee Loh Yun Shan Goh Laurent Renia Tao Dong Anantharaman Vathsala Antonio Bertoletti Emerging Infectious Disease Program Duke-NUS Medical SchoolSingaporeSingapore National University Centre for Organ Transplantation National University HospitalSingaporeSingapore mrc Human Immunology unit MRC Weatherall Institute of Molecular MedicineRadcliffe Department of MedicineUniversity of OxfordOxfordUK Lion TCR Pte Ltd SingaporeSingapore A*STAR ID labs Agency for ScienceTechnology and ResearchSingaporeSingapore Lee Kong Chian School of Medicine Nanyang Technological UniversitySingaporeSingapore Department of Medicine Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore Singapore Immunology Network A*STARSingaporeSingapore

Solid organ transplant(SOT)recipients receive immunosuppressive drugs(ISDs)and are susceptible to developing severe ***,we analyze the Spike-specific T-cell response after 3 doses of mRNA vaccine in a group of SOT patients(n=136)treated with different *** demonstrate that a combination of a calcineurin inhibitor(CNI),mycophenolate mofetil(MMF),and prednisone(Pred)treatment regimen strongly suppressed the mRNA vaccine-induced Spike-specific cellular *** defects have clinical consequences because the magnitude of vaccine-induced Spike-specific T cells was directly proportional to the ability of SOT patients to rapidly clear SARS-CoV-2 after breakthrough *** then compensate for the T-cell defects induced by immunosuppressive treatment and to develop an alternative therapeutic strategy for SOT patients,we describe production of 6 distinct SARS-CoV-2 epitope-specific ISD-resistant T-cell receptor(TCR)-T cells engineered using the mRNA electroporation method with reactivity minimally affected by mutations occurring in Beta,Delta,Gamma,and Omicron *** strategy with transient expression characteristics marks an improvement in the immunotherapeutic field and provides an attractive and novel therapeutic possibility for immunosuppressed COVID-19 patients.

关键词： T cell therapy Transplantation SARS-CoV-2 Immunosuppressive drug resistant T cells

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A Genome-Wide CRISPR Library for High-Throughput Genetic Screening in Drosophila cells

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Journal of Genetics and Genomics 2015年第6期42卷 301-309页

作者： Andrew R.Bassett Lesheng Kong Ji-Long Liu mrc Functional Genomics unit University of OxfordDepartment of PhysiologyAnatomy and Genetics Genome Engineering Oxford Sir William Dunn School of PathologyUniversity of Oxford

The simplicity of the CRISPR/Cas9 system of genome engineering has opened up the possibility of performing genome-wide targeted mutagenesis in cell lines,enabling screening for cellular phenotypes resulting from genetic *** cells have proven to be highly effective in identifying genes involved in cellular processes through similar screens using partial knockdown by *** is in part due to the lower degree of redundancy between genes in this organism,whilst still maintaining highly conserved gene networks and orthologs of many human disease-causing *** ability of CRISPR to generate genetic loss of function mutations not only increases the magnitude of any effect over currently employed RNAi techniques,but allows analysis over longer periods of time which can be critical for certain *** this study,we have designed and built a genome-wide CRISPR library covering 13,501 genes,among which 8989 genes are targeted by three or more independent single guide RNAs（sg RNAs）.Moreover,we describe strategies to monitor the population of guide RNAs by high throughput sequencing（HTS）.We hope that this library will provide an invaluable resource for the community to screen loss of function mutations for cellular phenotypes,and as a source of guide RNA designs for future studies.

关键词： CRISPR/Cas9 Genome-wide library Drosophila

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Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

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四川生理科学杂志 2024年第7期46卷 1635-1635页

作者： Anissa A Widjaja Cardiovascular and Metabolic Disorders Program Duke–National University of Singapore Medical School Singapore Singapore National Heart Research Institute Singapore National Heart Centre Singapore Singapore Singapore Institute for Big Data and Artificial Intelligence in Medicine School of Science China Pharmaceutical University Nanjing China mrc Laboratory of Medical Sciences London UK Barts Heart Centre Barts Health NHS Trust London UK Cardiovascular and Metabolic Sciences Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany DZHK (German Centre for Cardiovascular Research) Partner Site Berlin Berlin Germany Charité–Universitätsmedizin Berlin Germany Institute of Clinical Sciences Faculty of Medicine Imperial College London UK Bone Biology and Disease unit St Vincent’s Institute of Medical Research Melbourne Victoria Australia Department of Medicine St Vincent’s Hospital The University of Melbourne Melbourne Victoria Australia

For healthspan and lifespan,ERK,AMPK and mTORC1 represent critical pathways and inflammation is a centrally important *** we examined whether IL-11,a pro-inflammatory cytokine of the IL-6 family,has a negative effect on age-associated disease and *** mice age,IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular,tissue-and organismal-level ageing *** of Il11 or Il11ra1 protects against metabolic decline,multi-morbidity and frailty in old age.

关键词： inflammation mTORC1 life

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