EBioMedicine最新文献

{"title":"Predictive gene expression signature diagnoses neonatal sepsis before clinical presentation.","authors":"Andy Y An, Erica Acton, Olubukola T Idoko, Casey P Shannon, Travis M Blimkie, Reza Falsafi, Oghenebrume Wariri, Abdulazeez Imam, Tida Dibbasey, Tue Bjerg Bennike, Kinga K Smolen, Joann Diray-Arce, Rym Ben-Othman, Sebastiano Montante, Asimenia Angelidou, Oludare A Odumade, David Martino, Scott J Tebbutt, Ofer Levy, Hanno Steen, Tobias R Kollmann, Beate Kampmann, Robert E W Hancock, Amy H Lee","doi":"10.1016/j.ebiom.2024.105411","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105411","url":null,"abstract":"<p><strong>Background: </strong>Neonatal sepsis is a deadly disease with non-specific clinical signs, delaying diagnosis and treatment. There remains a need for early biomarkers to facilitate timely intervention. Our objective was to identify neonatal sepsis gene expression biomarkers that could predict sepsis at birth, prior to clinical presentation.</p><p><strong>Methods: </strong>Among 720 initially healthy full-term neonates in two hospitals (The Gambia, West Africa), we identified 21 newborns who were later hospitalized for sepsis in the first 28 days of life, split into early-onset sepsis (EOS, onset ≤7 days of life) and late-onset sepsis (LOS, onset 8-28 days of life), 12 neonates later hospitalized for localized infection without evidence of systemic involvement, and 33 matched control neonates who remained healthy. RNA-seq was performed on peripheral blood collected at birth when all neonates were healthy and also within the first week of life to identify differentially expressed genes (DEGs). Machine learning methods (sPLS-DA, LASSO) identified genes expressed at birth that predicted onset of neonatal sepsis at a later time.</p><p><strong>Findings: </strong>Neonates who later developed EOS already had ∼1000 DEGs at birth when compared to control neonates or those who later developed a localized infection or LOS. Based on these DEGs, a 4-gene signature (HSPH1, BORA, NCAPG2, PRIM1) for predicting EOS at birth was developed (training AUC = 0.94, sensitivity = 0.93, specificity = 0.92) and validated in an external cohort (validation AUC = 0.72, sensitivity = 0.83, and specificity = 0.83). Additionally, during the first week of life, EOS disrupted expression of >1800 genes including those influencing immune and metabolic transitions observed in healthy controls.</p><p><strong>Interpretation: </strong>Despite appearing healthy at birth, neonates who later developed EOS already had distinct whole blood gene expression changes at birth, which enabled the development of a 4-gene predictive signature for EOS. This could facilitate early recognition and treatment of neonatal sepsis, potentially mitigating its long-term sequelae.</p><p><strong>Funding: </strong>CIHR and NIH/NIAID.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105411"},"PeriodicalIF":9.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544390","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}

{"title":"Circulating inflammatory and immune response proteins and endometrial cancer risk: a nested case-control study and Mendelian randomization analyses.","authors":"Sabrina E Wang, Vivian Viallon, Matthew Lee, Niki Dimou, Fergus Hamilton, Carine Biessy, Tracy O'Mara, Maria Kyrgiou, Emma J Crosbie, Therese Truong, Gianluca Severi, Rudolf Kaaks, Renée Turzanski Fortner, Matthias B Schulze, Benedetta Bendinelli, Sieri Sabina, Rosario Tumino, Carlotta Sacerdote, Salvatore Panico, Marta Crous-Bou, Maria-Jose Sánchez, Amaia Aizpurua, Daniel Rodriguez Palacios, Marcela Guevara, Ruth C Travis, Konstantinos K Tsilidis, Alicia Heath, James Yarmolinsky, Sabina Rinaldi, Marc J Gunter, Laure Dossus","doi":"10.1016/j.ebiom.2024.105341","DOIUrl":"10.1016/j.ebiom.2024.105341","url":null,"abstract":"<p><strong>Background: </strong>Inflammation and immune dysregulation are hypothesized contributors to endometrial carcinogenesis; however, the precise underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>We measured pre-diagnostically 152 plasma protein biomarkers in 624 endometrial cancer case-control pairs nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Odds ratios (ORs) were estimated using conditional logistic regression, accounting for confounding and multiple comparisons. Proteins considered as associated with endometrial cancer risk were further tested in a two-sample Mendelian randomization (MR) analysis using summary data from the UK Biobank (n = 52,363) and the Endometrial Cancer Association Consortium (12,270 cases and 46,126 controls).</p><p><strong>Findings: </strong>In the EPIC nested case-control study, IL-6 [OR per NPX (doubling of concentration) = 1.28 (95% confidence interval (CI) 1.03-1.57)], HGF [1.48 (1.06-2.07)], PIK3AP1 [1.22 (1.00-1.50)] and CLEC4G [1.52 (1.00-2.32)] were positively associated; HSD11B1 [0.67 (0.49-0.91)], SCF [0.68 (0.49-0.94)], and CCL25 [0.80 (0.65-0.99)] were inversely associated with endometrial cancer risk; all estimates had multiple comparisons adjusted P-value > 0.05. In complementary MR analysis, IL-6 [OR per inverse-rank normalized NPX = 1.19 (95% CI 1.04-1.36)] and HSD11B1 [0.91 (0.84-0.99)] were associated with endometrial cancer risk.</p><p><strong>Interpretation: </strong>Altered IL-6 signalling and reduced glucocorticoid activity via HSD11B1 might play important roles in endometrial carcinogenesis.</p><p><strong>Funding: </strong>Funding for IIG_FULL_2021_008 was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme; Funding for INCA_15849 was obtained from Institut National du Cancer (INCa).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105341"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282129","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}

{"title":"Customised design of antisense oligonucleotides targeting EGFR driver mutants for personalised treatment of non-small cell lung cancer.","authors":"Trinh T T Tran, Cao Dai Phung, Brendon Z J Yeo, Rebecca C Prajogo, Migara K Jayasinghe, Ju Yuan, Daniel S W Tan, Eric Y M Yeo, Boon Cher Goh, Wai Leong Tam, Minh T N Le","doi":"10.1016/j.ebiom.2024.105356","DOIUrl":"10.1016/j.ebiom.2024.105356","url":null,"abstract":"<p><strong>Background: </strong>Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC.</p><p><strong>Methods: </strong>In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells.</p><p><strong>Findings: </strong>Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour.</p><p><strong>Interpretation: </strong>Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment.</p><p><strong>Funding: </strong>This study was funded by Singapore's Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105356"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282133","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}

{"title":"High mortality of Acinetobacter baumannii infection is attributed to macrophage-mediated induction of cytokine storm but preventable by naproxen.","authors":"Han Wang, Qi Xu, Heng Heng, Wenxing Zhao, Hongyuhang Ni, Kaichao Chen, Bill Kwan Wai Chan, Yang Tang, Miaomiao Xie, Mingxiu Peng, Edward Wai Chi Chan, Guan Yang, Sheng Chen","doi":"10.1016/j.ebiom.2024.105340","DOIUrl":"10.1016/j.ebiom.2024.105340","url":null,"abstract":"<p><strong>Background: </strong>The continuous emergence of multidrug-resistant (MDR) Acinetobacter baumannii (Ab) strains poses further challenges in its control and clinical management. It is necessary to decipher the mechanisms underlying the high mortality of Ab infections to explore unconventional strategies for controlling outbreaks of drug-resistant infections.</p><p><strong>Methods: </strong>The immune responses of Ab sepsis infection were investigated using flow cytometry, RNA-seq, qRT-PCR, and ELISA and scRNA-seq. The detailed pathways mediating Ab immune responses were also depicted and a specific therapy was developed based on the understanding of the mechanisms underlying Ab-induced cytokine storms.</p><p><strong>Findings: </strong>The results highlighted the critical role of alveolar and interstitial macrophages as targets of Ab during the infection process. These cells were found to undergo polarization towards the M1 phenotype, triggering a cytokine storm that eventually caused the death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-κB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen (NPXS) was shown to confer full protection of mice from lethal infections.</p><p><strong>Interpretation: </strong>The findings in this work depict the major mechanisms underlying the high mortality rate of Ab infections and highlight the clinical potential application of anti-inflammatory drugs or immunosuppressants in reducing the mortality of such infections, including those caused by MDR strains.</p><p><strong>Funding: </strong>Funding sources are described in the acknowledgments section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105340"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282134","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}

{"title":"Association of residential air pollution and green space with all-cause and cause-specific mortality in individuals with diabetes: an 11-year prospective cohort study.","authors":"Chunfeng Wu, Jiangdong Liu, Yanyun Li, Luxin Qin, Ruilong Gu, Jiachen Feng, Lulu Xu, Xia Meng, Jiaxin Chen, Renjie Chen, Yan Shi, Haidong Kan","doi":"10.1016/j.ebiom.2024.105376","DOIUrl":"10.1016/j.ebiom.2024.105376","url":null,"abstract":"<p><strong>Background: </strong>To assess the long-term impact of residential air pollution and green space exposure on cause-specific mortality in individuals with type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>This study includes 174,063 participants newly diagnosed with T2DM from a prospective cohort in Shanghai, China, enrolled between 2011 and 2013. Residential annual levels of air pollutants, including fine (PM_2.5) and coarse (PM_2.5-10) particulate matter, nitrogen dioxide (NO₂), along with the normalized difference vegetation index (NDVI), were derived from satellite-based exposure models.</p><p><strong>Findings: </strong>During a median follow-up of 7.9 years (equivalent to 1,333,343 person-years), this study recorded 22,205 deaths. Higher exposure to PM_2.5 was significantly associated with increased risks for all mortality outcomes, whilst PM_2.5-10 showed no significant impacts. The strongest associations of PM_2.5 were observed for diabetes with peripheral vascular diseases [hazard ratio (HR): 2.70; per 10 μg/m³ increase] and gastrointestinal cancer (2.44). Effects of NO₂ became significant at concentrations exceeding approximately 45 μg/m³, with the highest associations for lung cancer (1.20) and gastrointestinal cancer (1.19). Conversely, each interquartile range increase in NDVI (0.10) was linked to reduced mortality risks across different causes, with HRs ranging from 0.76 to 1.00. The association between greenness and mortality was partly and significantly mediated by reduced PM_2.5 (23.80%) and NO₂ (26.60%). There was a significant and negative interaction between NO₂ and greenness, but no interaction was found between PM_2.5 and greenness.</p><p><strong>Interpretation: </strong>Our findings highlight the vulnerability of individuals with T2DM to the adverse health effects of air pollution and emphasise the potential protective effects of greenness infrastructure.</p><p><strong>Funding: </strong>The 6th Three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWVI-11.1-22), the National Key Research and Development Program (2022YFC3702701), and the National Natural Science Foundation of China (82030103, 82373532).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105376"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364798","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}

{"title":"Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis.","authors":"Laura Seldeslachts, Frederik Staels, Marina Gkountzinopoulou, Cato Jacobs, Birger Tielemans, Eliane Vanhoffelen, Agustin Reséndiz-Sharpe, Lander De Herdt, Jeason Haughton, Teresa Prezzemolo, Oliver Burton, Simon Feys, Frank L van de Veerdonk, Agostinho Carvalho, Lieve Naesens, Patrick Matthys, Katrien Lagrou, Erik Verbeken, Georgios Chamilos, Joost Wauters, Stephanie Humblet-Baron, Greetje Vande Velde","doi":"10.1016/j.ebiom.2024.105347","DOIUrl":"10.1016/j.ebiom.2024.105347","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We used a murine model of IAPA to investigate how influenza predisposes to the development of invasive pulmonary aspergillosis. Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (μCT) and fungal burden with bioluminescence imaging (BLI). At endpoint, high parameter immunophenotyping, spatial transcriptomics, histopathology, dynamic phagosome biogenesis assays with live imaging, immunofluorescence staining, specialized functional phagocytosis and killing assays were performed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;We uncovered an early exuberant influenza-induced interferon-gamma (IFN-γ) production as the major driver of immunopathology in IAPA and delineated the molecular mechanisms. Specifically, excessive IFN-γ production resulted in a defective Th17-immune response, depletion of macrophages, and impaired killing of Aspergillus conidia by macrophages due to the inhibition of NADPH oxidase-dependent activation of LC3-associated phagocytosis (LAP). Markedly, mice with partial or complete genetic ablation of IFN-γ had a restored Th17-immune response, LAP-dependent mechanism of killing and were fully protected from invasive fungal infection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;Together, these results identify exuberant viral induced IFN-γ production as a major driver of immune dysfunction in IAPA, paving the way to explore the use of excessive viral-induced IFN-γ as a biomarker and new immunotherapeutic target in IAPA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This research was funded by the Research Foundation Flanders (FWO), project funding under Grant G053121N to JW, SHB and GVV; G057721N, G0G4820N to GVV; 1506114 N to KL and GVV; KU Leuven internal funds (C24/17/061) to GVV, clinical research funding to JW, Research Foundation Flanders (FWO) aspirant mandate under Grant 1186121N/1186123 N to LS, 11B5520N to FS, 1SF2222N to EV and 11M6922N/11M6924N to SF, travel grants V428023N, K103723N, K217722N to LS. FLvdV was supported by a Vidi grant of the Netherlands Association for Scientific Research. FLvdV, JW, AC and GC were supported by the Europeans Union's Horizon 2020 research and innovation program under grant agreement no 847507 HDM-FUN. AC was also supported by the Fundação para a Ciência e a Tecnologia (FCT), with the references UIDB/50026/2020, UIDP/50026/2020, PTDC/MED-OUT/1112/2021 (https://do","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105347"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364800","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}

{"title":"Identification and analysis of microplastics in para-tumor and tumor of human prostate.","authors":"Chenyao Deng, Jun Zhu, Zishui Fang, Yuzhuo Yang, Qiancheng Zhao, Zhe Zhang, Zirun Jin, Hui Jiang","doi":"10.1016/j.ebiom.2024.105360","DOIUrl":"10.1016/j.ebiom.2024.105360","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;While microplastics are widely found in various human organs and tissues, the relationship between microplastics and human health, especially prostate health, remains unclear. This study aims to identify and quantify the properties, types, and abundance of microplastics in paired para-tumor and tumor tissues of human prostate. Additionally, the potential correlation between microplastics abundance and prostate cancer are investigated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Paired para-tumor and tumor samples of the prostate were collected from 22 patients who underwent robot-assisted radical prostatectomy. A combination of laser direct infrared spectroscopy, scanning electron microscopy and pyrolysis-gas chromatography-mass spectrometry was utilized to analyse the properties, type and abundance of microplastics. Correlations between microplastics abundance, demographic characteristics and clinical features of patients were also examined.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Laser direct infrared analysis revealed the presence of microplastics, including polyamide, polyethylene terephthalate, and polyvinyl chloride, in both para-tumor and tumor tissues of human prostate. However, polystyrene was exclusively detected in tumor tissues. The particle size distribution in the prostate tissue mainly ranged from 20 to 100 μm. Approximately 31.58% of para-tumor samples exhibited sizes between 20 and 30 μm, while 35.21% of tumor samples displayed sizes between 50 and 100 μm. The shapes of these microplastics varied considerably with irregular forms being predominant. Additionally, microplastics were detected by pyrolysis-gas chromatography-mass spectrometry in 20 paired prostate tissues. The mean abundance of microplastics was found to be 181.0 μg/g and 290.3 μg/g in para-tumor and tumor of human prostate samples, respectively. Among the 11 target types microplastics polymers, only polystyrene, polypropylene, polyethylene, and polyvinyl chloride were detected. Notably, polystyrene, polyethylene, and polyvinyl chloride, except for polypropylene, demonstrated significantly higher abundance in tumor tissues compared to their respective paired para-tumor. Furthermore, a positive correlation was observed between polystyrene abundance in the tumor samples of human prostate and frequency of take-out food consumption.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;This research provides both qualitative and quantitative evidence of the microplastics presence as well as their properties, types, and abundance in paired para-tumor and tumor samples of human prostate. Correlations between microplastics abundance, demographics, and clinical characteristics of patients need to be further validated in future studies with a larger sample size.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This work was supported by the National Key Research and Development Program of China (2022YFC2702600) and the National Natural Science Foundation of China (Grant No. 82071698, No. 821016","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105360"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343698","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}

{"title":"Bridging gaps: a neural network approach for cross-species scRNA-seq analysis in COVID-19.","authors":"Peng Luo, Zi-Wei Ye, Shuofeng Yuan","doi":"10.1016/j.ebiom.2024.105324","DOIUrl":"10.1016/j.ebiom.2024.105324","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105324"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139629","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}

{"title":"Cis-interaction between CD52 and T cell receptor complex interferes with CD4⁺ T cell activation in acute decompensation of cirrhosis.","authors":"Tong Liu, Gang Wu, Cathrin L C Gudd, Francesca M Trovato, Thomas Barbera, Yan Liu, Evangelos Triantafyllou, Mark J W McPhail, Mark R Thursz, Wafa Khamri","doi":"10.1016/j.ebiom.2024.105336","DOIUrl":"10.1016/j.ebiom.2024.105336","url":null,"abstract":"<p><strong>Background: </strong>Immune dysfunction contributes to a high rate of infection in patients with acute decompensation of cirrhosis. CD52 is a glycoprotein prominently expressed in lymphocytes. Immune regulation by CD52 may be involved in adaptive immune dysfunction in cirrhosis. This study aimed to investigate the function of CD52 on CD4⁺ T cells on the blood of patients with acute decompensation of cirrhosis.</p><p><strong>Methods: </strong>The expression of CD52 in the peripheral blood lymphocytes of 49 patients with cirrhosis was investigated using flow cytometry and transcriptomics. Potential cis-membrane ligands of CD52 were discovered via proximity labelling followed by proteomics. The function of CD52 on antigen-specific activation of CD4⁺ T cells was examined using flow cytometry in CD52 CRISPR-Cas9 knockout primary T cells.</p><p><strong>Findings: </strong>CD52 expression was elevated in CD4⁺ T cells in acute decompensation of cirrhosis, and this elevation was correlated with increased disease severity and mortality. Components of the T cell receptor complex including TCRβ, CD3γ and CD3ε were identified and validated as cis-membrane ligands of CD52. Knockout of CD52 promoted antigen-specific activation, proliferation, and pro-inflammatory cytokine secretion.</p><p><strong>Interpretation: </strong>Membrane bound CD52 demonstrated cis-interaction with the T cell receptor and served as a dynamic regulator of antigen-specific activation of CD4⁺ T cells. The upregulation of CD52 in the periphery of acute decompensation of cirrhosis hinders the recognition of the T cell receptor by MHC, contributing to impaired T cell function. The development of an alternative anti-CD52 antibody is required to restore T cell function and prevent infections in cirrhosis.</p><p><strong>Funding: </strong>This study was supported by the NIHR Imperial Biomedical Research Centre, Institute for Translational Medicine and Therapeutics (P74713), Wellcome Trust (218304/Z/19/Z), and Medical Research Council (MR/X009904/1 and MR/R014019/1).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105336"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282130","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}

{"title":"The inactivated herpes zoster vaccine HZ/su induces a varicella zoster virus specific cellular and humoral immune response in patients on dialysis.","authors":"Franziska Hielscher, Tina Schmidt, Martin Enders, Sarah Leyking, Markus Gerhart, Kai van Bentum, Janine Mihm, David Schub, Urban Sester, Martina Sester","doi":"10.1016/j.ebiom.2024.105335","DOIUrl":"10.1016/j.ebiom.2024.105335","url":null,"abstract":"<p><strong>Background: </strong>To evaluate the immunogenicity of the inactivated herpes-zoster vaccine HZ/su in patients at increased risk for VZV-reactivation, we analysed the quantity and quality of the vaccine-induced cellular and humoral immunity in patients on dialysis with uremic immunodeficiency.</p><p><strong>Methods: </strong>In this observational study, 29 patients and 39 immunocompetent controls underwent standard dual-dose vaccination. Blood samples were analysed before and two weeks after each vaccination, and after one year. Specific T-cells were characterized after stimulation with VZV-gE-peptides based on induction of cytokines and CTLA-4-expression using flow-cytometry. Antibodies were analysed using ELISA.</p><p><strong>Findings: </strong>Both groups showed an increase in VZV-gE-specific CD4 T-cell levels over time (p < 0.0001), although median levels reached after second vaccination were lower in patients (0.17% (IQR 0.21%)) than in controls (0.24% (IQR 0.3%), p = 0.042). VZV-gE specific CD8 T-cells were only poorly induced. CTLA-4 expression on VZV-gE-specific CD4 T-cells was strongest after second dose with no differences between the groups (p = 0.45). Multifunctional cells co-expressing IFNγ, IL-2, and TNF were higher in patients after first vaccination (p = 0.028). Median VZV-specific IgG-levels reached a maximum after second vaccination with significantly lower levels in patients (10796 (IQR 12482) IU/l) than in controls (16899 (IQR 14019) IU/l, p = 0.009). Despite similar CD4 T-cell levels after one year (p = 0.415), antibody levels remained significantly lower in patients (p = 0.0008).</p><p><strong>Interpretation: </strong>VZV-gE vaccination induced specific antibodies and CD4 T-cells in both patients and controls, whereas CD8 T-cell-induction was poor. Quantitative and qualitative differences in immunity may indicate reduced duration of protection which may necessitate booster vaccinations in patients on dialysis.</p><p><strong>Funding: </strong>HOMFORexzellent (to D.S.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105335"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11416227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282143","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}