Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-02-27DOI: 10.1016/j.xcrm.2025.101984
Suying Wu, Zhouliang Wu, Zefang Lu, Feilong Qi, Jin Cheng, Tianjiao Chu, Bozhao Li, Yuliang Zhao, Guangjun Nie, Suping Li
{"title":"Selective apoptosis of tumor-associated platelets boosts the anti-metastatic potency of PD-1 blockade therapy.","authors":"Suying Wu, Zhouliang Wu, Zefang Lu, Feilong Qi, Jin Cheng, Tianjiao Chu, Bozhao Li, Yuliang Zhao, Guangjun Nie, Suping Li","doi":"10.1016/j.xcrm.2025.101984","DOIUrl":"10.1016/j.xcrm.2025.101984","url":null,"abstract":"<p><p>Despite the transformative impact of programmed cell death protein-1 (PD-1) blockade therapy on metastatic/advanced solid tumor treatment, its efficacy is hindered by a limited response rate. Platelets play a pivotal role in tumor metastasis by shielding circulating tumor cells and secreting immunosuppressive factors. We here demonstrate that selectively inducing apoptosis in tumor-associated platelets (TAPs) using ABT-737-loaded nanoparticles (cyclic arginine-glycine-aspartate containing peptide-modified ABT-737-loaded nanoparticles [cRGD-NP@A]) enhances the anti-metastatic efficacy of the anti-PD-1 antibody (aPD-1). cRGD-NP@A specifically binds to TAPs, disrupting platelet-tumor cell interactions and exposing tumor cells to immune surveillance in vivo. Combined with aPD-1, cRGD-NP@A substantially augments immune activation and reduces TAP-derived immunosuppressive factors, notably transforming growth factor β1 (TGF-β1), consequently improving anti-metastatic outcomes across multiple metastasis-bearing animal models without observable adverse effects. Our study underscores the importance of depleting TAPs to enhance PD-1 blockade therapy, presenting a promising strategy to improve response rates and clinical outcomes for patients with metastatic cancer.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101984"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531349","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-03-06DOI: 10.1016/j.xcrm.2025.101997
Chen Wang, Wangjian Sheng, Yu Zhou, Xudong Hang, Jiayi Zhao, Yuanyuan Gu, Xiangfeng Meng, Yuefan Bai, Weili Li, Yujing Zhang, Linlin Zhang, Jing Yu, Zhen Zhou, Xiaona Li, Haorui Sun, Yanhong Xue, Tao Xu, Ke Zen, Hong Ling, Chen-Yu Zhang, Hongkai Bi, Huan Wang
{"title":"siRNA-AGO2 complex inhibits bacterial gene translation: A promising therapeutic strategy for superbug infection.","authors":"Chen Wang, Wangjian Sheng, Yu Zhou, Xudong Hang, Jiayi Zhao, Yuanyuan Gu, Xiangfeng Meng, Yuefan Bai, Weili Li, Yujing Zhang, Linlin Zhang, Jing Yu, Zhen Zhou, Xiaona Li, Haorui Sun, Yanhong Xue, Tao Xu, Ke Zen, Hong Ling, Chen-Yu Zhang, Hongkai Bi, Huan Wang","doi":"10.1016/j.xcrm.2025.101997","DOIUrl":"10.1016/j.xcrm.2025.101997","url":null,"abstract":"<p><p>Silencing resistance genes of pathogenic bacteria by RNA interference (RNAi) is a potential strategy to fight antibiotic-resistant bacterial infections. Currently, RNAi cannot be achieved in bacteria due to the lack of RNA-induced silencing complex machinery and the difficulty of small interfering RNA (siRNA) delivery. Here, we show that exosomal siRNAs can be efficiently delivered into bacterial cells and can silence target genes primarily through translational repression without mRNA degradation. The exosomal Argonaute 2 (AGO2) protein forms a complex with siRNAs, which is essential for bacterial gene silencing. Both in vitro and in vivo-generated exosome-packaged siRNAs resensitize methicillin-resistant Staphylococcus aureus (MRSA) to methicillin treatment by silencing the mecA gene, which is the primary beta-lactam resistance determinant of MRSA. This approach significantly enhances the therapeutic effect in a mouse model of MRSA infection. In summary, our study provides a method for siRNA delivery to bacteria that may facilitate the treatment of antibiotic-resistant bacterial infection.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101997"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583718","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-03-06DOI: 10.1016/j.xcrm.2025.101991
Michael K Simoni, Seble G Negatu, Ju Young Park, Sneha Mani, Montserrat C Arreguin, Kevin R Amses, Dan Dongeun Huh, Monica Mainigi, Kellie A Jurado
{"title":"Type I interferon exposure of an implantation-on-a-chip device alters invasive extravillous trophoblast function.","authors":"Michael K Simoni, Seble G Negatu, Ju Young Park, Sneha Mani, Montserrat C Arreguin, Kevin R Amses, Dan Dongeun Huh, Monica Mainigi, Kellie A Jurado","doi":"10.1016/j.xcrm.2025.101991","DOIUrl":"10.1016/j.xcrm.2025.101991","url":null,"abstract":"<p><p>Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluate the consequence of elevated type I IFN exposure on implantation using a human implantation in an organ-on-a-chip device. We reveal that type I IFN reduces extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes, we uncover that IFN truncates invasive EVT emergence in the implantation-on-a-chip device by stunting EVT epithelial-to-mesenchymal transition. Disruptions to the epithelial-to-mesenchymal transition are associated with the pathogenesis of preeclampsia, a life-threatening disorder of pregnancy. Strikingly, IFN stimulation induces genes associated with increased preeclampsia risk in EVTs. These dysregulated EVT phenotypes ultimately reduce EVT-mediated endothelial cell vascular remodeling in the implantation-on-a-chip device. Overall, our work implicates unwarranted type I IFN as a maternal disturbance that can result in abnormal EVT function that could trigger preeclampsia.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101991"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584204","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}
Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-03-07DOI: 10.1016/j.xcrm.2025.101999
Shijun Yan, Wenjing Zhang, Xinying Li, Suman Dutta, Andrew R Castle, Yiming Liu, Anis Sahoo, Chor Lai Lam, Nicholas J F Gatford, Michele T Hu, Chen-Zhong Li, Cheng Jiang, Bowen Shu, George K Tofaris
{"title":"Single extracellular vesicle detection assay identifies membrane-associated α-synuclein as an early-stage biomarker in Parkinson's disease.","authors":"Shijun Yan, Wenjing Zhang, Xinying Li, Suman Dutta, Andrew R Castle, Yiming Liu, Anis Sahoo, Chor Lai Lam, Nicholas J F Gatford, Michele T Hu, Chen-Zhong Li, Cheng Jiang, Bowen Shu, George K Tofaris","doi":"10.1016/j.xcrm.2025.101999","DOIUrl":"10.1016/j.xcrm.2025.101999","url":null,"abstract":"<p><p>Accurate diagnosis of early Parkinson's disease requires platforms suitable for detecting minute amounts of neuronally derived biomarkers in the massive protein excess of easily accessible biofluids such as blood. Here, we describe an on-chip droplet-confined fluorescence reporting assay that identified α-synuclein on the membrane of L1CAM+ extracellular vesicles (EVs) immunocaptured from human serum and corroborate this finding by super-resolution direct stochastic optical reconstruction microscopy (dSTORM) microscopy. Using conditioned media from neuroblastoma cells expressing α-synuclein mutants or patient-derived induced pluripotent stem cell (iPSC) neurons with α-synuclein gene triplication, we found that association of α-synuclein with the L1CAM+ EV surface is increased under pathological conditions. Accordingly, this readout, as measured by the droplet-based assay, is an improved predictive biomarker in the prodromal phase (area under the receiver operating characteristic curve [AUC] = 0.93) or diagnostic biomarker in the clinical phase (AUC = 0.95) of Parkinson's disease. More broadly, our platform will simplify the assessment of EV membrane proteins and facilitate their application as diagnostic biomarkers across diverse clinical indications.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101999"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584939","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}
Lele Zhang, Chen Qiu, Ruonan Li, Yucan Shen, Linzhu Tian, Hong Chang, Qian Liang, Hong Pan, Zhen Gao, Weiwang Li, Jingyu Zhao, Liwei Fang, Xiao Yu, Jing Xu, Zhexiang Kuang, Weiping Yuan, Yajing Chu, Jun Shi
{"title":"KLRG1 re-defines a leukemic clone of CD8 effector T cells sensitive to PI3K inhibitor in T cell large granular lymphocytic leukemia.","authors":"Lele Zhang, Chen Qiu, Ruonan Li, Yucan Shen, Linzhu Tian, Hong Chang, Qian Liang, Hong Pan, Zhen Gao, Weiwang Li, Jingyu Zhao, Liwei Fang, Xiao Yu, Jing Xu, Zhexiang Kuang, Weiping Yuan, Yajing Chu, Jun Shi","doi":"10.1016/j.xcrm.2025.102036","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102036","url":null,"abstract":"<p><p>T cell large granular lymphocytic leukemia (T-LGLL) is a clonal lymphoproliferative disorder, originated from mature effector memory CD8<sup>+</sup> T cells. It is a challenge to define the leukemic T cell clones due to the lack of definite markers. Here, we decipher the heterogeneity of CD8<sup>+</sup> T cells using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and T cell receptor (TCR) profiling in T-LGLL patients. A CD8<sup>+</sup> terminal effector subset is identified, marked by reduced KLRG1 expression. Remarkably, high fidelity of leukemic clonality was specially limited in KLRG1<sup>-</sup> large granular lymphocytes (LGLs), not seen in KLRG1<sup>+</sup> LGLs in T-LGLL patients or in KLRG1<sup>-</sup> LGLs in healthy controls. KLRG1<sup>-</sup> leukemic LGLs show upregulated PI3K signaling with enhanced cytotoxicity and exhaustion, persisting after conventional treatment. In a pilot trial of linperlisib (a PI3Kδ inhibitor) for refractory cases, 7 of 8 participants quickly respond with satisfactory safety. This study is registered at ClinicalTrials.gov (NCT05676710).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102036"},"PeriodicalIF":11.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728727","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}
Maria Balaguer-Montero, Adrià Marcos Morales, Marta Ligero, Christina Zatse, David Leiva, Luz M Atlagich, Nikolaos Staikoglou, Cristina Viaplana, Camilo Monreal, Joaquin Mateo, Jorge Hernando, Alejandro García-Álvarez, Francesc Salvà, Jaume Capdevila, Elena Elez, Rodrigo Dienstmann, Elena Garralda, Raquel Perez-Lopez
{"title":"A CT-based deep learning-driven tool for automatic liver tumor detection and delineation in patients with cancer.","authors":"Maria Balaguer-Montero, Adrià Marcos Morales, Marta Ligero, Christina Zatse, David Leiva, Luz M Atlagich, Nikolaos Staikoglou, Cristina Viaplana, Camilo Monreal, Joaquin Mateo, Jorge Hernando, Alejandro García-Álvarez, Francesc Salvà, Jaume Capdevila, Elena Elez, Rodrigo Dienstmann, Elena Garralda, Raquel Perez-Lopez","doi":"10.1016/j.xcrm.2025.102032","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102032","url":null,"abstract":"<p><p>Liver tumors, whether primary or metastatic, significantly impact the outcomes of patients with cancer. Accurate identification and quantification are crucial for effective patient management, including precise diagnosis, prognosis, and therapy evaluation. We present SALSA (system for automatic liver tumor segmentation and detection), a fully automated tool for liver tumor detection and delineation. Developed on 1,598 computed tomography (CT) scans and 4,908 liver tumors, SALSA demonstrates superior accuracy in tumor identification and volume quantification, outperforming state-of-the-art models and inter-reader agreement among expert radiologists. SALSA achieves a patient-wise detection precision of 99.65%, and 81.72% at lesion level, in the external validation cohorts. Additionally, it exhibits good overlap, achieving a dice similarity coefficient (DSC) of 0.760, outperforming both state-of-the-art and the inter-radiologist assessment. SALSA's automatic quantification of tumor volume proves to have prognostic value across various solid tumors (p = 0.028). SALSA's robust capabilities position it as a potential medical device for automatic cancer detection, staging, and response evaluation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102032"},"PeriodicalIF":11.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673343","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}
Nicholas J Tursi, Sachchidanand Tiwari, Nicole Bedanova, Toshitha Kannan, Elizabeth Parzych, Nisreen Okba, Kevin Liaw, András Sárközy, Cory Livingston, Maria Ibanez Trullen, Ebony N Gary, Máté Vadovics, Niklas Laenger, Jennifer Londregan, Mohammad Suhail Khan, Serena Omo-Lamai, Hiromi Muramatsu, Kerry Blatney, Casey Hojecki, Viviane Machado, Igor Maricic, Trevor R F Smith, Laurent M Humeau, Ami Patel, Andrew Kossenkov, Jacob S Brenner, David Allman, Florian Krammer, Norbert Pardi, David B Weiner
{"title":"Modulation of lipid nanoparticle-formulated plasmid DNA drives innate immune activation promoting adaptive immunity.","authors":"Nicholas J Tursi, Sachchidanand Tiwari, Nicole Bedanova, Toshitha Kannan, Elizabeth Parzych, Nisreen Okba, Kevin Liaw, András Sárközy, Cory Livingston, Maria Ibanez Trullen, Ebony N Gary, Máté Vadovics, Niklas Laenger, Jennifer Londregan, Mohammad Suhail Khan, Serena Omo-Lamai, Hiromi Muramatsu, Kerry Blatney, Casey Hojecki, Viviane Machado, Igor Maricic, Trevor R F Smith, Laurent M Humeau, Ami Patel, Andrew Kossenkov, Jacob S Brenner, David Allman, Florian Krammer, Norbert Pardi, David B Weiner","doi":"10.1016/j.xcrm.2025.102035","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102035","url":null,"abstract":"<p><p>Nucleic acid vaccines have grown in importance over the past several years, with the development of new approaches remaining a focus. We describe a lipid nanoparticle-formulated DNA (DNA-LNP) formulation which induces robust innate and adaptive immunity with similar serological potency to mRNA-LNPs and adjuvanted protein. Using an influenza hemagglutinin (HA)-encoding construct, we show that priming with our HA DNA-LNP demonstrated stimulator of interferon genes (STING)-dependent upregulation and activation of migratory dendritic cell (DC) subpopulations. HA DNA-LNP induced superior antigen-specific CD8<sup>+</sup> T cell responses relative to mRNA-LNPs or adjuvanted protein, with memory responses persisting beyond one year. In rabbits immunized with HA DNA-LNP, we observed immune responses comparable or superior to mRNA-LNPs at the same dose. In an additional model, a SARS-CoV-2 spike-encoding DNA-LNP elicited protective efficacy comparable to spike mRNA-LNPs. Our study identifies a platform-specific priming mechanism for DNA-LNPs divergent from mRNA-LNPs or adjuvanted protein, suggesting avenues for this approach in prophylactic and therapeutic vaccine development.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102035"},"PeriodicalIF":11.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691133","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}
Yu-Qing Wang, Shuo Wang, Hong-Mei Yi, Ying Qian, Yue Wang, Hai-Min Xu, Zijun Y Xu-Monette, Kelly Au, Shuang Tian, Yan Dong, Jing Zhao, Di Fu, Rong-Ji Mu, Shu-Ye Wang, Li Wang, Ken H Young, Peng-Peng Xu, Wei-Li Zhao
{"title":"Practical microenvironment classification in diffuse large B cell lymphoma using digital pathology.","authors":"Yu-Qing Wang, Shuo Wang, Hong-Mei Yi, Ying Qian, Yue Wang, Hai-Min Xu, Zijun Y Xu-Monette, Kelly Au, Shuang Tian, Yan Dong, Jing Zhao, Di Fu, Rong-Ji Mu, Shu-Ye Wang, Li Wang, Ken H Young, Peng-Peng Xu, Wei-Li Zhao","doi":"10.1016/j.xcrm.2025.102030","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102030","url":null,"abstract":"<p><p>Diffuse large B cell lymphoma (DLBCL) is a heterogeneous B cell neoplasm with variable clinical outcomes influenced by both tumor-derived and lymphoma microenvironment (LME) alterations. A recent transcriptomic study identifies four DLBCL subtypes based on LME characteristics: germinal center (GC)-like, mesenchymal (MS), inflammatory (IN), and depleted (DP). However, integrating this classification into clinical practice remains challenging. Here, we utilize deconvolution methods to assess microenvironment component abundance, establishing an LME classification of DLBCL using immunohistochemistry markers and digital pathology based on CD3, CD8, CD68, PD-L1, and collagen. This staining-based algorithm demonstrates over 80% concordance with transcriptome-based classification. Single-cell sequencing confirms that the immune microenvironments distinguished by this algorithm align with transcriptomic profiles. Significant disparities in overall and progression-free survival are observed among LME subtypes following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP with targeted agents (R-CHOP-X) immunochemotherapy. LME subtypes differed from distinct immune escape mechanisms, highlighting specific immunotherapeutic targets and supporting application of this classification in future precision medicine trials.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102030"},"PeriodicalIF":11.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669108","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}
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