首页 > 最新文献

EBioMedicine最新文献

英文 中文
Bifidobacterium longum and microbiome maturation modify a nutrient intervention for stunting in Zimbabwean infants. 长双歧杆菌和微生物组的成熟改变了对津巴布韦婴儿发育迟缓的营养干预。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-27 DOI: 10.1016/j.ebiom.2024.105362
Ethan K Gough, Thaddeus J Edens, Lynnea Carr, Ruairi C Robertson, Kuda Mutasa, Robert Ntozini, Bernard Chasekwa, Hyun Min Geum, Iman Baharmand, Sandeep K Gill, Batsirai Mutasa, Mduduzi N N Mbuya, Florence D Majo, Naume Tavengwa, Freddy Francis, Joice Tome, Ceri Evans, Margaret Kosek, Andrew J Prendergast, Amee R Manges

Background: Small-quantity lipid-based nutrient supplements (SQ-LNS), which has been widely tested to reduce child stunting, has largely modest effects to date, but the mechanisms underlying these modest effects are unclear. Child stunting is a longstanding indicator of chronic undernutrition and it remains a prevalent public health problem. The infant gut microbiome may be a key contributor to stunting; and mother and infant fucosyltransferase (FUT) phenotypes are important determinants of infant microbiome composition.

Methods: We investigated whether mother-infant FUT status (n = 792) and infant gut microbiome composition (n = 354 fecal specimens from 172 infants) modified the impact of an infant and young child feeding (IYCF) intervention, that included SQ-LNS, on stunting at age 18 months in secondary analysis of a randomized trial in rural Zimbabwe.

Findings: We found that the impact of the IYCF intervention on stunting was modified by: (i) mother-infant FUT2+/FUT3- phenotype (difference-in-differences -32.6% [95% CI: -55.3%, -9.9%]); (ii) changes in species composition that reflected microbiome maturation (difference-in-differences -68.1% [95% CI: -99.0%, -28.5%); and (iii) greater relative abundance of B. longum (differences-in-differences 49.1% [95% CI: 26.6%, 73.6%]). The dominant strains of B. longum when the intervention started were most similar to the proficient milk oligosaccharide utilizer subspecies infantis, which decreased with infant age and differed by mother-infant FUT2+/FUT3- phenotypes.

Interpretation: These findings indicate that a persistently "younger" microbiome at initiation of the intervention reduced its benefits on stunting in areas with a high prevalence of growth restriction.

Funding: Bill and Melinda Gates Foundation, UK DFID/Aid, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, UNICEF, and Nutricia Research Foundation.

背景:小量脂质营养补充剂(SQ-LNS)已被广泛测试用于减少儿童发育迟缓,但迄今为止,这种补充剂的效果并不明显,而产生这种微弱效果的机制尚不清楚。儿童发育迟缓是慢性营养不良的一个长期指标,也是一个普遍存在的公共卫生问题。婴儿肠道微生物组可能是导致发育迟缓的一个关键因素;而母亲和婴儿的岩藻糖基转移酶(FUT)表型是婴儿微生物组组成的重要决定因素:我们调查了母婴岩藻糖基转移酶状态(n = 792)和婴儿肠道微生物组组成(n = 来自 172 名婴儿的 354 份粪便标本)是否会改变包括 SQ-LNS 在内的婴幼儿喂养(IYCF)干预措施对 18 个月大婴儿发育迟缓的影响:我们发现,"养育子女干预措施 "对发育迟缓的影响受以下因素影响(i) 母婴 FUT2+/FUT3- 表型(差异-32.6% [95% CI: -55.3%, -9.9%]);(ii) 反映微生物组成熟的物种组成变化(差异-68.1% [95% CI: -99.0%, -28.5%]);(iii) B. longum 的相对丰度增加(差异 49.1% [95% CI: 26.6%, 73.6%])。干预开始时,长鼻杆菌的优势菌株与精通牛奶寡糖利用的婴儿亚种最为相似,随着婴儿年龄的增长,优势菌株减少,母婴FUT2+/FUT3-表型也有所不同:这些研究结果表明,在生长受限高发地区,干预开始时持续 "年轻化 "的微生物群降低了干预对发育迟缓的益处:比尔及梅林达-盖茨基金会、英国国际发展部/援助署、惠康基金会、瑞士发展与合作署、美国国立卫生研究院、联合国儿童基金会和Nutricia研究基金会。
{"title":"Bifidobacterium longum and microbiome maturation modify a nutrient intervention for stunting in Zimbabwean infants.","authors":"Ethan K Gough, Thaddeus J Edens, Lynnea Carr, Ruairi C Robertson, Kuda Mutasa, Robert Ntozini, Bernard Chasekwa, Hyun Min Geum, Iman Baharmand, Sandeep K Gill, Batsirai Mutasa, Mduduzi N N Mbuya, Florence D Majo, Naume Tavengwa, Freddy Francis, Joice Tome, Ceri Evans, Margaret Kosek, Andrew J Prendergast, Amee R Manges","doi":"10.1016/j.ebiom.2024.105362","DOIUrl":"10.1016/j.ebiom.2024.105362","url":null,"abstract":"<p><strong>Background: </strong>Small-quantity lipid-based nutrient supplements (SQ-LNS), which has been widely tested to reduce child stunting, has largely modest effects to date, but the mechanisms underlying these modest effects are unclear. Child stunting is a longstanding indicator of chronic undernutrition and it remains a prevalent public health problem. The infant gut microbiome may be a key contributor to stunting; and mother and infant fucosyltransferase (FUT) phenotypes are important determinants of infant microbiome composition.</p><p><strong>Methods: </strong>We investigated whether mother-infant FUT status (n = 792) and infant gut microbiome composition (n = 354 fecal specimens from 172 infants) modified the impact of an infant and young child feeding (IYCF) intervention, that included SQ-LNS, on stunting at age 18 months in secondary analysis of a randomized trial in rural Zimbabwe.</p><p><strong>Findings: </strong>We found that the impact of the IYCF intervention on stunting was modified by: (i) mother-infant FUT2+/FUT3- phenotype (difference-in-differences -32.6% [95% CI: -55.3%, -9.9%]); (ii) changes in species composition that reflected microbiome maturation (difference-in-differences -68.1% [95% CI: -99.0%, -28.5%); and (iii) greater relative abundance of B. longum (differences-in-differences 49.1% [95% CI: 26.6%, 73.6%]). The dominant strains of B. longum when the intervention started were most similar to the proficient milk oligosaccharide utilizer subspecies infantis, which decreased with infant age and differed by mother-infant FUT2+/FUT3- phenotypes.</p><p><strong>Interpretation: </strong>These findings indicate that a persistently \"younger\" microbiome at initiation of the intervention reduced its benefits on stunting in areas with a high prevalence of growth restriction.</p><p><strong>Funding: </strong>Bill and Melinda Gates Foundation, UK DFID/Aid, Wellcome Trust, Swiss Agency for Development and Cooperation, US National Institutes of Health, UNICEF, and Nutricia Research Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105362"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343770","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
Hypervirulent Klebsiella pneumoniae: an old enemy with a more powerful weapon. 高病毒性肺炎克雷伯氏菌:拥有更强大武器的老对手。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1016/j.ebiom.2024.105402
eBioMedicine
{"title":"Hypervirulent Klebsiella pneumoniae: an old enemy with a more powerful weapon.","authors":"eBioMedicine","doi":"10.1016/j.ebiom.2024.105402","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105402","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105402"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406235","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
Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic. 血浆 pTau181 对预测记忆诊所大型实际队列中阿尔茨海默病病理变化的临床价值。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-18 DOI: 10.1016/j.ebiom.2024.105345
Amanda Cano, María Capdevila, Raquel Puerta, Javier Arranz, Laura Montrreal, Itziar de Rojas, Pablo García-González, Claudia Olivé, Fernando García-Gutiérrez, Oscar Sotolongo-Grau, Adelina Orellana, Nuria Aguilera, Maribel Ramis, Maitee Rosende-Roca, Alberto Lleó, Juan Fortea, Juan Pablo Tartari, Asunción Lafuente, Liliana Vargas, Alba Pérez-Cordón, Nathalia Muñoz, Ángela Sanabria, Montserrat Alegret, Xavier Morató, Lluís Tárraga, Victoria Fernández, Marta Marquié, Sergi Valero, Daniel Alcolea, Mercè Boada, Agustín Ruiz

Background: The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic.

Methods: Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181.

Findings: CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value.

Interpretation: Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable.

Funding: This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.

背景:如何识别阿尔茨海默病(AD)痴呆症高风险患者并在早期阶段对其进行疾病改变治疗(DMTs)是临床实践中面临的最大挑战之一。血浆生物标志物具有预测这些问题的潜力,但要将其转化为临床实践仍需进一步研究。在这里,我们评估了血浆 pTau181 作为记忆诊所大型真实世界队列中 AD 病理学预测标志物的临床适用性:方法: 纳入了三个独立队列(建模[n = 991,59.7%为女性]、测试[n = 642,56.2%为女性]和验证[n = 441,55.1%为女性]),对象是现实世界中患有主观认知能力下降(SCD)、轻度认知障碍(MCI)、AD痴呆和其他痴呆症的患者。采用配对的脑脊液(CSF)和血浆样本测量 AT(N) CSF 生物标记物和血浆 pTau181:除SCD和其他痴呆症外,脑脊液和血浆pTau181在所有表型中均显示出相关性。年龄对生物标志物的性能有明显影响。一般Aβ(+)与Aβ(-)的ROC曲线显示AUC = 0.77 [0.74-0.80],而AD导致的MCI与非AD导致的MCI的特定ROC曲线显示AUC = 0.89 [0.85-0.93]。血浆 pTau181 的临界值为 1.30 pg/ml 时,检测队列中 MCI 受试者的灵敏度为 93.57% [88.72-96.52],特异度为 72.38% [62.51-79.01],VPP 为 77.85% [70.61-83.54],假阴性率为 8.30%。Cox回归的HR显示,与截断值以下的MCI患者相比,截断值以上的MCI患者转化为AD痴呆的风险HR=1.84 [1.05-3.22]:血浆pTau181有可能在记忆门诊中用作MCI患者的AD病理学筛选生物标志物,在预测MCI转为AD痴呆方面具有重要的预后作用。在现实世界人群中,采用黄金标准程序进行确证测试仍然是可取的:本研究主要由巴塞罗那阿尔茨海默中心(Ace Alzheimer Center Barcelona)、卡洛斯三世健康研究所(ISCIII)、神经退行性疾病生物医学研究网络中心(CIBERNED)、西班牙科学与创新部、ADEY基金会、Echevarne基金会和Grífols S.A.共同资助。
{"title":"Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic.","authors":"Amanda Cano, María Capdevila, Raquel Puerta, Javier Arranz, Laura Montrreal, Itziar de Rojas, Pablo García-González, Claudia Olivé, Fernando García-Gutiérrez, Oscar Sotolongo-Grau, Adelina Orellana, Nuria Aguilera, Maribel Ramis, Maitee Rosende-Roca, Alberto Lleó, Juan Fortea, Juan Pablo Tartari, Asunción Lafuente, Liliana Vargas, Alba Pérez-Cordón, Nathalia Muñoz, Ángela Sanabria, Montserrat Alegret, Xavier Morató, Lluís Tárraga, Victoria Fernández, Marta Marquié, Sergi Valero, Daniel Alcolea, Mercè Boada, Agustín Ruiz","doi":"10.1016/j.ebiom.2024.105345","DOIUrl":"10.1016/j.ebiom.2024.105345","url":null,"abstract":"<p><strong>Background: </strong>The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic.</p><p><strong>Methods: </strong>Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181.</p><p><strong>Findings: </strong>CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(-) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value.</p><p><strong>Interpretation: </strong>Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable.</p><p><strong>Funding: </strong>This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105345"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282132","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
Crowd-sourced machine learning prediction of long COVID using data from the National COVID Cohort Collaborative. 利用国家 COVID 队列协作组织的数据,通过众包机器学习预测长 COVID。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-24 DOI: 10.1016/j.ebiom.2024.105333
Timothy Bergquist, Johanna Loomba, Emily Pfaff, Fangfang Xia, Zixuan Zhao, Yitan Zhu, Elliot Mitchell, Biplab Bhattacharya, Gaurav Shetty, Tamanna Munia, Grant Delong, Adbul Tariq, Zachary Butzin-Dozier, Yunwen Ji, Haodong Li, Jeremy Coyle, Seraphina Shi, Rachael V Philips, Andrew Mertens, Romain Pirracchio, Mark van der Laan, John M Colford, Alan Hubbard, Jifan Gao, Guanhua Chen, Neelay Velingker, Ziyang Li, Yinjun Wu, Adam Stein, Jiani Huang, Zongyu Dai, Qi Long, Mayur Naik, John Holmes, Danielle Mowery, Eric Wong, Ravi Parekh, Emily Getzen, Jake Hightower, Jennifer Blase

Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID.

Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.).

Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events.

Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions.

Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.

背景:虽然许多患者似乎都能从 SARS-CoV-2 感染中康复,但许多患者报告说,他们在急性 COVID-19 结束后的数周或数月内都会出现 SARS-CoV-2 症状,甚至在感染数周后出现新的症状。这些长期影响被称为 SARS-CoV-2 急性后遗症 (PASC),或更常见的 Long COVID。Long COVID 的总体发病率目前尚不清楚,需要一些工具来帮助识别有可能患上 Long COVID 的病人:由美国国立卫生研究院(NIH)各研究所和中心的人员组成的快速加速诊断-激进(RADx-rad)项目工作组与 "研究COVID,促进康复"(RECOVER)合作,开发并组织了 "长COVID计算挑战赛"(L3C),这是一项社区挑战赛,旨在激励更广泛的科学界开发可解释的准确方法,以识别有罹患长COVID风险的患者。从 2022 年 8 月到 2022 年 12 月,参赛者利用全美 COVID 队列协作组织 (N3C) 的数据飞地(来自全美超过 75 家医疗保健机构的统一数据存储库)开发了 Long COVID 风险预测算法:在挑战赛期间,74 个团队利用 N3C 数据飞地设计并构建了 35 个长 COVID 预测模型。前 10 个团队的得分均超过了 0.80 的接收器运算曲线下面积 (AUROC),得分最高的模型平均 AUROC 为 0.895。最高分提交的报告中包括一个可视化仪表板,该仪表板可为每位患者建立时间轴,并根据临床事件更新患者发生长COVID的风险:通过 L3C,联邦评审员发现了多种机器学习模型,可用于识别有罹患 Long COVID 风险的患者。许多团队在提交的报告中使用了可应用于未来临床预测问题的方法:本 RADx® Rad 出版物中报道的研究得到了美国国立卫生研究院的支持。Timothy Bergquist、Johanna Loomba和Emily Pfaff得到了Axle分包合同:NCATS-STSS-P00438的支持。
{"title":"Crowd-sourced machine learning prediction of long COVID using data from the National COVID Cohort Collaborative.","authors":"Timothy Bergquist, Johanna Loomba, Emily Pfaff, Fangfang Xia, Zixuan Zhao, Yitan Zhu, Elliot Mitchell, Biplab Bhattacharya, Gaurav Shetty, Tamanna Munia, Grant Delong, Adbul Tariq, Zachary Butzin-Dozier, Yunwen Ji, Haodong Li, Jeremy Coyle, Seraphina Shi, Rachael V Philips, Andrew Mertens, Romain Pirracchio, Mark van der Laan, John M Colford, Alan Hubbard, Jifan Gao, Guanhua Chen, Neelay Velingker, Ziyang Li, Yinjun Wu, Adam Stein, Jiani Huang, Zongyu Dai, Qi Long, Mayur Naik, John Holmes, Danielle Mowery, Eric Wong, Ravi Parekh, Emily Getzen, Jake Hightower, Jennifer Blase","doi":"10.1016/j.ebiom.2024.105333","DOIUrl":"10.1016/j.ebiom.2024.105333","url":null,"abstract":"<p><strong>Background: </strong>While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID.</p><p><strong>Methods: </strong>A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.).</p><p><strong>Findings: </strong>Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events.</p><p><strong>Interpretation: </strong>As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions.</p><p><strong>Funding: </strong>Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105333"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343695","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
Empirical application of a multidimensional approach to capture a broader assessment of clinical benefits in a heterogenous spine population - author's reply. 多维方法的经验应用,在异质脊柱人群中更广泛地评估临床效益--作者回复。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-26 DOI: 10.1016/j.ebiom.2024.105365
Karlo M Pedro, Mohammed Ali Alvi, Michael G Fehlings
{"title":"Empirical application of a multidimensional approach to capture a broader assessment of clinical benefits in a heterogenous spine population - author's reply.","authors":"Karlo M Pedro, Mohammed Ali Alvi, Michael G Fehlings","doi":"10.1016/j.ebiom.2024.105365","DOIUrl":"10.1016/j.ebiom.2024.105365","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105365"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343696","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
Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model. 从全局和单细胞蛋白质组学视角观察神经祖细胞和乳腺癌细胞在共培养模型中的共同演化。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-04 DOI: 10.1016/j.ebiom.2024.105325
Ole Vidhammer Bjørnstad, Manuel Carrasco, Kenneth Finne, Vandana Ardawatia, Ingeborg Winge, Cecilie Askeland, Jarle B Arnes, Gøril Knutsvik, Dimitrios Kleftogiannis, Joao A Paulo, Lars A Akslen, Heidrun Vethe

Background: Presence of nerves in tumours, by axonogenesis and neurogenesis, is gaining increased attention for its impact on cancer initiation and development, and the new field of cancer neuroscience is emerging. A recent study in prostate cancer suggested that the tumour microenvironment may influence cancer progression by recruitment of Doublecortin (DCX)-expressing neural progenitor cells (NPCs). However, the presence of such cells in human breast tumours has not been comprehensively explored.

Methods: Here, we investigate the presence of DCX-expressing cells in breast cancer stromal tissue from patients using Imaging Mass Cytometry. Single-cell analysis of 372,468 cells across histopathological images of 107 breast cancers enabled spatial resolution of neural elements in the stromal compartment in correlation with clinicopathological features of these tumours. In parallel, we established a 3D in vitro model mimicking breast cancer neural progenitor-innervation and examined the two cell types as they co-evolved in co-culture by using mass spectrometry-based global proteomics.

Findings: Stromal presence of DCX + cells is associated with tumours of higher histological grade, a basal-like phenotype, and shorter patient survival in tumour tissue from patients with breast cancer. Global proteomics analysis revealed significant changes in the proteomic landscape of both breast cancer cells and neural progenitors in co-culture.

Interpretation: These results support that neural involvement plays an active role in breast cancer and warrants further studies on the relevance of nerve elements for tumour progression.

Funding: This work was supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 223250 (to L.A.A), the Norwegian Cancer Society (to L.A.A. and H.V.), the Regional Health Trust Western Norway (Helse Vest) (to L.A.A.), the Meltzer Research Fund (to H.V.) and the National Institutes of Health (NIH)/NIGMS grant R01 GM132129 (to J.A.P.).

背景:肿瘤中神经的轴突生成和神经发生对癌症的发生和发展的影响日益受到关注,癌症神经科学这一新领域正在兴起。最近一项关于前列腺癌的研究表明,肿瘤微环境可能会通过招募表达双皮质素(DCX)的神经祖细胞(NPCs)来影响癌症的进展。方法:在此,我们使用成像质谱细胞计数法研究了患者乳腺癌基质组织中是否存在表达 DCX 的细胞。我们对 107 例乳腺癌组织病理图像中的 372,468 个细胞进行了单细胞分析,从而获得了基质区神经元的空间分辨率以及这些肿瘤的临床病理特征。与此同时,我们建立了一个模拟乳腺癌神经祖细胞神经支配的三维体外模型,并利用基于质谱的全蛋白质组学研究了两种细胞类型在共培养过程中的共同进化:研究结果:在乳腺癌患者的肿瘤组织中,DCX +细胞基质的存在与组织学级别较高的肿瘤、基底样表型和较短的患者生存期有关。全局蛋白质组学分析表明,乳腺癌细胞和神经祖细胞在共培养过程中的蛋白质组结构发生了显著变化:这些结果支持神经参与在乳腺癌中发挥了积极作用,因此有必要进一步研究神经元素与肿瘤进展的相关性:这项工作得到了挪威研究理事会(Research Council of Norway)卓越中心资助计划(项目编号:223250,资助人:L.A.A.)、挪威癌症协会(资助人:L.A.A.和H.V.)、挪威西部地区健康信托基金(Helse Vest)(资助人:L.A.A.)、梅尔泽研究基金(资助人:H.V.)和美国国立卫生研究院(NIH)/美国国立卫生研究院(NIGMS)R01 GM132129基金(资助人:J.A.P.)的支持。
{"title":"Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model.","authors":"Ole Vidhammer Bjørnstad, Manuel Carrasco, Kenneth Finne, Vandana Ardawatia, Ingeborg Winge, Cecilie Askeland, Jarle B Arnes, Gøril Knutsvik, Dimitrios Kleftogiannis, Joao A Paulo, Lars A Akslen, Heidrun Vethe","doi":"10.1016/j.ebiom.2024.105325","DOIUrl":"10.1016/j.ebiom.2024.105325","url":null,"abstract":"<p><strong>Background: </strong>Presence of nerves in tumours, by axonogenesis and neurogenesis, is gaining increased attention for its impact on cancer initiation and development, and the new field of cancer neuroscience is emerging. A recent study in prostate cancer suggested that the tumour microenvironment may influence cancer progression by recruitment of Doublecortin (DCX)-expressing neural progenitor cells (NPCs). However, the presence of such cells in human breast tumours has not been comprehensively explored.</p><p><strong>Methods: </strong>Here, we investigate the presence of DCX-expressing cells in breast cancer stromal tissue from patients using Imaging Mass Cytometry. Single-cell analysis of 372,468 cells across histopathological images of 107 breast cancers enabled spatial resolution of neural elements in the stromal compartment in correlation with clinicopathological features of these tumours. In parallel, we established a 3D in vitro model mimicking breast cancer neural progenitor-innervation and examined the two cell types as they co-evolved in co-culture by using mass spectrometry-based global proteomics.</p><p><strong>Findings: </strong>Stromal presence of DCX + cells is associated with tumours of higher histological grade, a basal-like phenotype, and shorter patient survival in tumour tissue from patients with breast cancer. Global proteomics analysis revealed significant changes in the proteomic landscape of both breast cancer cells and neural progenitors in co-culture.</p><p><strong>Interpretation: </strong>These results support that neural involvement plays an active role in breast cancer and warrants further studies on the relevance of nerve elements for tumour progression.</p><p><strong>Funding: </strong>This work was supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 223250 (to L.A.A), the Norwegian Cancer Society (to L.A.A. and H.V.), the Regional Health Trust Western Norway (Helse Vest) (to L.A.A.), the Meltzer Research Fund (to H.V.) and the National Institutes of Health (NIH)/NIGMS grant R01 GM132129 (to J.A.P.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105325"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132156","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
Transcriptomic signatures during normothermic liver machine perfusion correspond with graft quality and predict the early graft function. 常温肝机灌注过程中的转录组特征与移植物质量相对应,并能预测移植物的早期功能。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-18 DOI: 10.1016/j.ebiom.2024.105330
Theresa Hautz, Hubert Hackl, Hendrik Gottschling, Raphael Gronauer, Julia Hofmann, Stefan Salcher, Bettina Zelger, Rupert Oberhuber, Benno Cardini, Annemarie Weissenbacher, Thomas Resch, Jakob Troppmair, Stefan Schneeberger

Background: A better understanding of the molecular events during liver normothermic machine perfusion (NMP) is warranted to develop a data-based approach for the identification of biomarkers representative of graft quality and posttransplant outcome. We analysed the dynamic transcriptional changes during NMP and linked them to clinical and biochemical parameters.

Methods: 50 livers subjected to NMP for up to 24 h were enrolled. Bulk RNA sequencing was performed in serial biopsies collected pre and during NMP, and after reperfusion. Perfusate was sampled to monitor liver function. qPCR and immunohistochemistry were performed to validate findings. Molecular profiles were compared between transplanted and non-transplanted livers, and livers with and without early allograft dysfunction.

Findings: Pathways related to immune and cell stress responses, cell trafficking and cell regulation were activated during NMP, while cellular metabolism was downregulated over time. Anti-inflammatory responses and genes involved in tissue remodelling were induced at later time-points, suggesting a counter-response to the immediate damage. NMP strongly induced a gene signature associated with ischemia-reperfusion injury. A 7-gene signature corresponds with the benchmarking criteria for transplantation or discard at 6 h NMP (area under curve 0.99). CD274 gene expression (encoding programmed cell-death ligand-1) showed the highest predictive value. LEAP2 gene expression at 6 h NMP correlated with impaired graft function.

Interpretation: Assessment of gene expression markers could serve as a reliable tool to evaluate liver quality during NMP and predicts early graft function after transplantation.

Funding: The research was supported by "In Memoriam Dr. Gabriel Salzner Stiftung", Tiroler Wissenschaftsfond, Jubiläumsfonds-Österreichische Nationalbank and MUI Start grant.

背景:我们需要更好地了解肝脏常温机器灌注(NMP)过程中的分子事件,以开发一种基于数据的方法来鉴定代表移植物质量和移植后预后的生物标志物。我们分析了 NMP 期间的动态转录变化,并将其与临床和生化参数联系起来。在 NMP 前、NMP 期间和再灌注后收集的连续活检组织中进行了大量 RNA 测序。对灌注液进行采样以监测肝功能。对移植肝脏和非移植肝脏、早期同种异体移植功能障碍肝脏和非早期同种异体移植功能障碍肝脏的分子特征进行了比较:研究结果:与免疫和细胞应激反应、细胞贩运和细胞调控有关的通路在 NMP 期间被激活,而细胞代谢则随着时间的推移而下调。抗炎反应和参与组织重塑的基因在较晚的时间点被诱导,这表明了对直接损伤的反作用。NMP 能强烈诱导与缺血再灌注损伤相关的基因特征。7 个基因的特征与 6 h NMP 时移植或丢弃的基准标准一致(曲线下面积为 0.99)。CD274 基因表达(编码程序性细胞死亡配体-1)的预测价值最高。6 h NMP时的LEAP2基因表达与移植物功能受损相关:基因表达标记物的评估可作为评估 NMP 期间肝脏质量的可靠工具,并可预测移植后的早期移植物功能:该研究得到了 "纪念 Gabriel Salzner 博士基金会"、Tiroler Wissenschaftsfond、Jubiläumsfonds-Österreichhe Nationalbank 和 MUI Start 基金的支持。
{"title":"Transcriptomic signatures during normothermic liver machine perfusion correspond with graft quality and predict the early graft function.","authors":"Theresa Hautz, Hubert Hackl, Hendrik Gottschling, Raphael Gronauer, Julia Hofmann, Stefan Salcher, Bettina Zelger, Rupert Oberhuber, Benno Cardini, Annemarie Weissenbacher, Thomas Resch, Jakob Troppmair, Stefan Schneeberger","doi":"10.1016/j.ebiom.2024.105330","DOIUrl":"10.1016/j.ebiom.2024.105330","url":null,"abstract":"<p><strong>Background: </strong>A better understanding of the molecular events during liver normothermic machine perfusion (NMP) is warranted to develop a data-based approach for the identification of biomarkers representative of graft quality and posttransplant outcome. We analysed the dynamic transcriptional changes during NMP and linked them to clinical and biochemical parameters.</p><p><strong>Methods: </strong>50 livers subjected to NMP for up to 24 h were enrolled. Bulk RNA sequencing was performed in serial biopsies collected pre and during NMP, and after reperfusion. Perfusate was sampled to monitor liver function. qPCR and immunohistochemistry were performed to validate findings. Molecular profiles were compared between transplanted and non-transplanted livers, and livers with and without early allograft dysfunction.</p><p><strong>Findings: </strong>Pathways related to immune and cell stress responses, cell trafficking and cell regulation were activated during NMP, while cellular metabolism was downregulated over time. Anti-inflammatory responses and genes involved in tissue remodelling were induced at later time-points, suggesting a counter-response to the immediate damage. NMP strongly induced a gene signature associated with ischemia-reperfusion injury. A 7-gene signature corresponds with the benchmarking criteria for transplantation or discard at 6 h NMP (area under curve 0.99). CD274 gene expression (encoding programmed cell-death ligand-1) showed the highest predictive value. LEAP2 gene expression at 6 h NMP correlated with impaired graft function.</p><p><strong>Interpretation: </strong>Assessment of gene expression markers could serve as a reliable tool to evaluate liver quality during NMP and predicts early graft function after transplantation.</p><p><strong>Funding: </strong>The research was supported by \"In Memoriam Dr. Gabriel Salzner Stiftung\", Tiroler Wissenschaftsfond, Jubiläumsfonds-Österreichische Nationalbank and MUI Start grant.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105330"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282147","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
Higher small pulmonary artery and vein volume on computed tomography is associated with mortality in current and former smokers. 计算机断层扫描显示的肺小动脉和小静脉容量较高与当前和过去吸烟者的死亡率有关。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-30 DOI: 10.1016/j.ebiom.2024.105366
Anastasia K A L Kwee, Eleni-Rosalina Andrinopoulou, Tjeerd van der Veer, Leticia Gallardo-Estrella, Jean-Paul Charbonnier, Stephen M Humphries, David A Lynch, Harm A W M Tiddens, Pim A de Jong, Esther Pompe

Background: In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear.

Methods: We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95th percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume.

Findings: Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m2 increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium.

Interpretation: In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers.

Funding: Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

背景:在慢性阻塞性肺病(COPD)中,血管改变已被证明是导致缺氧和肺动脉高压的原因之一,但小血管异常对死亡率的独立影响仍不清楚:我们对计算机断层扫描(CT)上的动脉和静脉尺寸进行了量化,最小可达 0.2 毫米。374名从不吸烟者的小血管体积(小动脉和小静脉的百分位数)分为两组:正常组和高小动脉或小静脉体积组。我们描述了小动脉和小静脉容量大的受试者的临床、生理和成像特征:研究结果:小动脉和小静脉容量高与死亡率有独立关联,调整后的危险比分别为每 mL/m2 增加 1.07 [1.01, 1.14] 和 1.34 [1.21, 1.49]。在 COPDGene 中,447 例(5.7%)受试者的小动脉容积偏高,519 例(9.1%)受试者的小静脉容积偏高,两者都有更多的肺气肿、更多的空气潴留和更严重的冠状动脉钙化:解释:在吸烟者中,小动脉和小静脉的异常高容量都与死亡率有关,因此需要对吸烟者肺部小血管和心脏功能的病因进行研究:获奖编号:U01-HL089897 和 U01-HL089856,由美国国家健康与生物研究所(NHLBI)颁发。COPD 基金会,阿斯利康、勃林格殷格翰、基因泰克、葛兰素史克、诺华、辉瑞、西门子和 Sunovion 提供捐款。
{"title":"Higher small pulmonary artery and vein volume on computed tomography is associated with mortality in current and former smokers.","authors":"Anastasia K A L Kwee, Eleni-Rosalina Andrinopoulou, Tjeerd van der Veer, Leticia Gallardo-Estrella, Jean-Paul Charbonnier, Stephen M Humphries, David A Lynch, Harm A W M Tiddens, Pim A de Jong, Esther Pompe","doi":"10.1016/j.ebiom.2024.105366","DOIUrl":"10.1016/j.ebiom.2024.105366","url":null,"abstract":"<p><strong>Background: </strong>In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear.</p><p><strong>Methods: </strong>We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95<sup>th</sup> percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume.</p><p><strong>Findings: </strong>Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m<sup>2</sup> increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium.</p><p><strong>Interpretation: </strong>In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers.</p><p><strong>Funding: </strong>Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105366"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364801","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
Chronic lung inflammation and CK14+ basal cell proliferation induce persistent alveolar-bronchiolization in SARS-CoV-2-infected hamsters. 慢性肺部炎症和CK14+基底细胞增殖诱导SARS-CoV-2感染仓鼠肺泡支气管持续扩张
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-25 DOI: 10.1016/j.ebiom.2024.105363
Can Li, Na Xiao, Wenchen Song, Alvin Hiu-Chung Lam, Feifei Liu, Xinrui Cui, Zhanhong Ye, Yanxia Chen, Peidi Ren, Jianpiao Cai, Andrew Chak-Yiu Lee, Honglin Chen, Zhihua Ou, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Hin Chu, Anna Jin-Xia Zhang

Background: Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive.

Methods: We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection.

Findings: We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion.

Interpretation: Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC.

Funding: Funding is listed in the Acknowledgements section.

背景:COVID-19急性后遗症是指在感染SARS-CoV-2后很长一段时间内持续出现的一系列症状和病症,包括呼吸系统疾病。肺部组织病理学变化及其内在机制仍难以捉摸:我们研究了感染 SARS-CoV-2 的雄性仓鼠在 7、14、42、84 和 120dpi 的肺组织病理学和转录变化,并与甲型 H1N1 pdm09 感染进行了比较:我们发现,SARS-CoV-2 而非 H1N1 感染后,肺部出现病毒残留、炎症和纤维化变化。从 42dpi 到 120dpi 期间,每只感染了 SARS-CoV-2 的仓鼠(31/31)都出现了最显著的组织病理学病变,即多灶肺泡支气管化。增殖的(Ki67+)CK14+基底细胞在7dpi时聚集在支气管附近的肺泡中,它们在那里增殖并分化成SCGB1A+俱乐部细胞或Tubulin+纤毛细胞,形成肺泡-支气管化病灶。分子上,Notch通路在42和120dpi时明显上调,在肺泡-支气管化病灶中Notch3和Hes1蛋白密集表达,表明Notch信号转导参与了肺泡-支气管化的持续。空间转录组分析进一步证明了这一点。耐人寻味的是,一些促进细胞生长的通路和基因(如 Tubb4b、Stxbp4、Grb14 和 Mlf1)的显著上调与支气管化病变在空间上重叠:解读:肺部 SARS-CoV-2 感染未完全清除,病毒残留、慢性炎症和纤维化损伤以及肺泡支气管化损害了呼吸功能。在组织再生过程中,CK14+基底细胞的异常激活导致持续的 Notch 信号传导导致肺泡支气管化。这项研究加深了我们对呼吸道PASC的理解,为疾病管理提供了启示,并强调了监测呼吸道PASC患者疾病进展的必要性:经费来源见致谢部分。
{"title":"Chronic lung inflammation and CK14+ basal cell proliferation induce persistent alveolar-bronchiolization in SARS-CoV-2-infected hamsters.","authors":"Can Li, Na Xiao, Wenchen Song, Alvin Hiu-Chung Lam, Feifei Liu, Xinrui Cui, Zhanhong Ye, Yanxia Chen, Peidi Ren, Jianpiao Cai, Andrew Chak-Yiu Lee, Honglin Chen, Zhihua Ou, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Hin Chu, Anna Jin-Xia Zhang","doi":"10.1016/j.ebiom.2024.105363","DOIUrl":"10.1016/j.ebiom.2024.105363","url":null,"abstract":"<p><strong>Background: </strong>Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive.</p><p><strong>Methods: </strong>We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection.</p><p><strong>Findings: </strong>We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion.</p><p><strong>Interpretation: </strong>Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC.</p><p><strong>Funding: </strong>Funding is listed in the Acknowledgements section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105363"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343692","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
Cellular and molecular determinants of bacterial burden in leprosy granulomas revealed by single-cell multimodal omics. 单细胞多模态全息研究揭示麻风肉芽肿中细菌负担的细胞和分子决定因素。
IF 9.7 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 Epub Date: 2024-09-24 DOI: 10.1016/j.ebiom.2024.105342
Zihao Mi, Zhenzhen Wang, Yi Wang, Xiaotong Xue, Xiaojie Liao, Chuan Wang, Lele Sun, Yingjie Lin, Jianwen Wang, Dianhao Guo, Tingting Liu, Jianjun Liu, Robert L Modlin, Hong Liu, Furen Zhang

Background: Which cell populations that determine the fate of bacteria in infectious granulomas remain unclear. Leprosy, a granulomatous disease with a strong genetic predisposition, caused by Mycobacterium leprae infection, exhibits distinct sub-types with varying bacterial load and is considered an outstanding disease model for studying host-pathogen interactions.

Methods: We performed single-cell RNA and immune repertoire sequencing on 11 healthy controls and 20 patients with leprosy, and integrated single-cell data with genome-wide genetic data on leprosy. Multiplex immunohistochemistry, and in vitro and in vivo infection experiments were conducted to confirm the multimodal omics findings.

Findings: Lepromatous leprosy (L-LEP) granulomas with high bacterial burden were characterised by exhausted CD8+ T cells, and high RGS1 expression in CD8+ T cells was associated with L-LEP. By contrast, tuberculoid leprosy (T-LEP) granulomas with low bacterial burden displayed enrichment in resident memory IFNG+ CD8+ T cells (CD8+ Trm) with high GNLY expression. This enrichment was potentially attributable to the communication between IL1B macrophages and CD8+ Trm via CXCL10-CXCR3 signalling. Additionally, IL1B macrophages in L-LEP exhibited anti-inflammatory phenotype, with high APOE expression contributing to high bacterial burden. Conversely, IL1B macrophages in T-LEP were distinguished by interferon-γ induced GBP family genes.

Interpretation: The state of IL1B macrophages and functional CD8+ T cells, as well as the relationship between them, is crucial for controlling bacterial persistence within granulomas. These insights may indicate potential targets for host-directed immunotherapy in granulomatous diseases caused by mycobacteria and other intracellular bacteria.

Funding: The Key research and development program of Shandong Province (2021LCZX07), Natural Science Foundation of Shandong Province (ZR2023MH046), Youth Science Foundation Cultivation Funding Plan of Shandong First Medical University (Shandong Academy of Medical Sciences) (202201-123), National Natural Science Foundation of China (82471800, 82230107, 82273545, 82304039), the China Postdoctoral Science Foundation (2023M742162), Shandong Province Taishan Scholar Project (tspd20230608), Joint Innovation Team for Clinical & Basic Research (202410), Central guidance for local scientific and technological development projects of Shandong Province (YDZX2023058).

背景:目前尚不清楚哪些细胞群决定着感染性肉芽肿中细菌的命运。麻风病是一种由麻风分枝杆菌感染引起的肉芽肿性疾病,具有很强的遗传倾向,表现出细菌负荷不同的独特亚型,被认为是研究宿主-病原体相互作用的杰出疾病模型:我们对 11 名健康对照组和 20 名麻风病患者进行了单细胞 RNA 和免疫复合物测序,并将单细胞数据与麻风病全基因组遗传数据进行了整合。我们还进行了多重免疫组化、体外和体内感染实验,以证实多模态全息研究结果:结果:具有高细菌负荷的麻风肉芽肿(L-LEP)的特点是CD8+ T细胞衰竭,CD8+ T细胞中RGS1的高表达与L-LEP有关。与此相反,细菌负荷低的结核性麻风(T-LEP)肉芽肿则富集了具有高 GNLY 表达的常驻记忆 IFNG+ CD8+ T 细胞(CD8+ Trm)。这种富集可能归因于 IL1B 巨噬细胞和 CD8+ Trm 之间通过 CXCL10-CXCR3 信号的交流。此外,L-LEP 中的 IL1B 巨噬细胞表现出抗炎表型,高 APOE 表达导致高细菌负荷。相反,T-LEP 中的 IL1B 巨噬细胞则因干扰素-γ 诱导的 GBP 家族基因而与众不同:IL1B巨噬细胞和功能性CD8+ T细胞的状态以及它们之间的关系对于控制肉芽肿内细菌的持续存在至关重要。这些发现可能为分枝杆菌和其他细胞内细菌引起的肉芽肿疾病的宿主定向免疫疗法指明了潜在的靶点:山东省重点研发计划(2021LCZX07)、山东省自然科学基金(ZR2023MH046)、山东第一医科大学(山东省医学科学院)青年科学基金项目(202201-123)、国家自然科学基金(82471800、82230107、82273545、82304039)、中国博士后科学基金(2023M742162)、山东省泰山学者项目(tspd20230608)、山东省临床与基础研究联合创新团队(202410)、中央引导地方科技发展项目(YDZX2023058)。
{"title":"Cellular and molecular determinants of bacterial burden in leprosy granulomas revealed by single-cell multimodal omics.","authors":"Zihao Mi, Zhenzhen Wang, Yi Wang, Xiaotong Xue, Xiaojie Liao, Chuan Wang, Lele Sun, Yingjie Lin, Jianwen Wang, Dianhao Guo, Tingting Liu, Jianjun Liu, Robert L Modlin, Hong Liu, Furen Zhang","doi":"10.1016/j.ebiom.2024.105342","DOIUrl":"10.1016/j.ebiom.2024.105342","url":null,"abstract":"<p><strong>Background: </strong>Which cell populations that determine the fate of bacteria in infectious granulomas remain unclear. Leprosy, a granulomatous disease with a strong genetic predisposition, caused by Mycobacterium leprae infection, exhibits distinct sub-types with varying bacterial load and is considered an outstanding disease model for studying host-pathogen interactions.</p><p><strong>Methods: </strong>We performed single-cell RNA and immune repertoire sequencing on 11 healthy controls and 20 patients with leprosy, and integrated single-cell data with genome-wide genetic data on leprosy. Multiplex immunohistochemistry, and in vitro and in vivo infection experiments were conducted to confirm the multimodal omics findings.</p><p><strong>Findings: </strong>Lepromatous leprosy (L-LEP) granulomas with high bacterial burden were characterised by exhausted CD8<sup>+</sup> T cells, and high RGS1 expression in CD8<sup>+</sup> T cells was associated with L-LEP. By contrast, tuberculoid leprosy (T-LEP) granulomas with low bacterial burden displayed enrichment in resident memory IFNG<sup>+</sup> CD8<sup>+</sup> T cells (CD8<sup>+</sup> Trm) with high GNLY expression. This enrichment was potentially attributable to the communication between IL1B macrophages and CD8<sup>+</sup> Trm via CXCL10-CXCR3 signalling. Additionally, IL1B macrophages in L-LEP exhibited anti-inflammatory phenotype, with high APOE expression contributing to high bacterial burden. Conversely, IL1B macrophages in T-LEP were distinguished by interferon-γ induced GBP family genes.</p><p><strong>Interpretation: </strong>The state of IL1B macrophages and functional CD8<sup>+</sup> T cells, as well as the relationship between them, is crucial for controlling bacterial persistence within granulomas. These insights may indicate potential targets for host-directed immunotherapy in granulomatous diseases caused by mycobacteria and other intracellular bacteria.</p><p><strong>Funding: </strong>The Key research and development program of Shandong Province (2021LCZX07), Natural Science Foundation of Shandong Province (ZR2023MH046), Youth Science Foundation Cultivation Funding Plan of Shandong First Medical University (Shandong Academy of Medical Sciences) (202201-123), National Natural Science Foundation of China (82471800, 82230107, 82273545, 82304039), the China Postdoctoral Science Foundation (2023M742162), Shandong Province Taishan Scholar Project (tspd20230608), Joint Innovation Team for Clinical & Basic Research (202410), Central guidance for local scientific and technological development projects of Shandong Province (YDZX2023058).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"108 ","pages":"105342"},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343771","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
期刊
EBioMedicine
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1