EMBO Molecular Medicine最新文献

Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. 沙门氏菌癌症疗法以 T 细胞免疫的附带代价破坏肿瘤的代谢。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-18 DOI: 10.1038/s44321-024-00159-2

Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski

{"title":"Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.","authors":"Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski","doi":"10.1038/s44321-024-00159-2","DOIUrl":"10.1038/s44321-024-00159-2","url":null,"abstract":"Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (TCM) formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diagnosis and prognosis prediction of gastric cancer by high-performance serum lipidome fingerprints. 利用高效血清脂质体指纹图谱诊断和预测胃癌预后

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-14 DOI: 10.1038/s44321-024-00169-0

Ze-Rong Cai, Wen Wang, Di Chen, Hao-Jie Chen, Yan Hu, Xiao-Jing Luo, Yi-Ting Wang, Yi-Qian Pan, Hai-Yu Mo, Shu-Yu Luo, Kun Liao, Zhao-Lei Zeng, Shan-Shan Li, Xin-Yuan Guan, Xin-Juan Fan, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju

{"title":"Diagnosis and prognosis prediction of gastric cancer by high-performance serum lipidome fingerprints.","authors":"Ze-Rong Cai, Wen Wang, Di Chen, Hao-Jie Chen, Yan Hu, Xiao-Jing Luo, Yi-Ting Wang, Yi-Qian Pan, Hai-Yu Mo, Shu-Yu Luo, Kun Liao, Zhao-Lei Zeng, Shan-Shan Li, Xin-Yuan Guan, Xin-Juan Fan, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju","doi":"10.1038/s44321-024-00169-0","DOIUrl":"10.1038/s44321-024-00169-0","url":null,"abstract":"Early detection is warranted to improve prognosis of gastric cancer (GC) but remains challenging. Liquid biopsy combined with machine learning will provide new insights into diagnostic strategies of GC. Lipid metabolism reprogramming plays a crucial role in the initiation and development of tumors. Here, we integrated the lipidomics data of three cohorts (n = 944) to develop the lipid metabolic landscape of GC. We further constructed the serum lipid metabolic signature (SLMS) by machine learning, which showed great performance in distinguishing GC patients from healthy donors. Notably, the SLMS also held high efficacy in the diagnosis of early-stage GC. Besides, by performing unsupervised consensus clustering analysis on the lipid metabolic matrix of patients with GC, we generated the gastric cancer prognostic subtypes (GCPSs) with significantly different overall survival. Furthermore, the lipid metabolic disturbance in GC tissues was demonstrated by multi-omics analysis, which showed partially consistent with that in GC serums. Collectively, this study revealed an innovative strategy of liquid biopsy for the diagnosis of GC on the basis of the serum lipid metabolic fingerprints.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia. 来自星形胶质细胞的 APOE 可恢复阿尔茨海默氏症 Aβ 病理学和 APOE 缺乏症小胶质细胞的 DAM 样反应。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-11 DOI: 10.1038/s44321-024-00162-7

Pranav Preman, Daan Moechars, Emre Fertan, Leen Wolfs, Lutgarde Serneels, Disha Shah, Jochen Lamote, Suresh Poovathingal, An Snellinx, Renzo Mancuso, Sriram Balusu, David Klenerman, Amaia M Arranz, Mark Fiers, Bart De Strooper

引用次数: 0

JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia. 将 JAK-STAT1 作为表皮生长因子受体缺乏症相关炎症和瘢痕性脱发的治疗靶点。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-09 DOI: 10.1038/s44321-024-00166-3

Karoline Strobl, Jörg Klufa, Regina Jin, Lena Artner-Gent, Dana Krauß, Philipp Novoszel, Johanna Strobl, Georg Stary, Igor Vujic, Johannes Griss, Martin Holcmann, Matthias Farlik, Bernhard Homey, Maria Sibilia, Thomas Bauer

{"title":"JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia.","authors":"Karoline Strobl, Jörg Klufa, Regina Jin, Lena Artner-Gent, Dana Krauß, Philipp Novoszel, Johanna Strobl, Georg Stary, Igor Vujic, Johannes Griss, Martin Holcmann, Matthias Farlik, Bernhard Homey, Maria Sibilia, Thomas Bauer","doi":"10.1038/s44321-024-00166-3","DOIUrl":"https://doi.org/10.1038/s44321-024-00166-3","url":null,"abstract":"The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hair follicle stem cells and the collapse of self-tolerance in alopecia: the interplay of barrier function, the microbiome, and immunity. 毛囊干细胞与脱发症自我耐受的崩溃：屏障功能、微生物组和免疫的相互作用。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-09 DOI: 10.1038/s44321-024-00170-7

Joseph S Durgin, Sunny Y Wong

引用次数: 0

Author Correction: Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases. 作者更正：通过假定的小分子抑制剂破坏 TSLP-TSLP 受体的相互作用，可为特应性疾病提供一种新颖高效的治疗方案。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-07 DOI: 10.1038/s44321-024-00165-4

Partho Protim Adhikary, Temilolu Idowu, Zheng Tan, Christopher Hoang, Selina Shanta, Malti Dumbani, Leah Mappalakayil, Bhuwan Awasthi, Marcel Bermudez, January Weiner, Dieter Beule, Gerhard Wolber, Brent D G Page, Sarah Hedtrich

引用次数: 0

Rett syndrome: interferon-γ to the rescue? 雷特综合征：干扰素-γ能救命吗？

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-04 DOI: 10.1038/s44321-024-00154-7

Richard R Meehan, Sari Pennings

引用次数: 0

Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches. 败血症诱发的丙酮酸代谢变化：见解和潜在的治疗方法。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-01 Epub Date: 2024-10-28 DOI: 10.1038/s44321-024-00155-6

Louise Nuyttens, Jolien Vandewalle, Claude Libert

引用次数: 0

Liver DE(HP)toxification: luteolin as "phthalates-cleaner" to protect from environmental pollution. 肝脏 DE(HP)中毒：叶黄素作为 "邻苯二甲酸盐清洁剂"，可防止环境污染。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-01 Epub Date: 2024-10-29 DOI: 10.1038/s44321-024-00158-3

Federica Cappelli, Alessandro Mengozzi

引用次数: 0

Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47. 针对遗传性痉挛性截瘫 47 型的 AP4B1 基因替代疗法的临床前开发。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-11-01 Epub Date: 2024-10-02 DOI: 10.1038/s44321-024-00148-5

Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz

{"title":"Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.","authors":"Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz","doi":"10.1038/s44321-024-00148-5","DOIUrl":"10.1038/s44321-024-00148-5","url":null,"abstract":"Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2882-2917"},"PeriodicalIF":9.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0