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Epigenome-wide analysis in West Africans identifies DNA methylation markers for circulating adiponectin. 西非人的全表观基因组分析鉴定了循环脂联素的DNA甲基化标记。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-06 DOI: 10.1016/j.ebiom.2026.106192
Muhulo Muhau Mungamba, Johanna Wijburg, Eva L van der Linden, Felix P Chilunga, Ayo P Doumatey, Amy R Bentley, Charles F Hayfron-Benjamin, Constance R Sewani-Rusike, Benedicta N Nkeh-Chungag, Rexford S Ahima, Charles Agyemang, Peter Henneman, Adebowale A Adeyemo, Charles N Rotimi, Karlijn A C Meeks

Background: Adiponectin is a circulating adipokine involved in energy metabolism and inflammation, with reported protective effects against cardiometabolic diseases such as type 2 diabetes (T2D) and early kidney disease. However, its regulation remains poorly understood. This study aimed to identify epigenetic loci associated with adiponectin levels.

Methods: DNA methylation was profiled using Illumina 450K and EPIC (850K) arrays in 315 Ghanaians (RODAM-Pros study) and 593 Nigerians (AADM study). Differentially methylated positions (DMPs) were identified using linear regression models adjusted for age, sex, BMI, blood cell proportions, and technical covariates. Analyses were stratified by T2D status and cohort, then meta-analysed to identify DMPs associated with adiponectin across T2D status (combining participants with-and-without diabetes). RNA-seq data on 77 blood, 49 subcutaneous adipose tissue (SAT), and 55 skeletal muscle samples from the AADM study were used to identify eQTMs for identified DMPs.

Findings: We identified three epigenome-wide significant DMPs: cg03546163 (Z-score = 5.76, p ≤ 0.001, 5'UTR of FKBP5), cg02561343 (Z-score = 5.11, p ≤ 0.001, within UST), and cg23969380 (Z-score = 5.13, p ≤ 0.001, ADGRD1 body). cg03546163 was an eQTM for PLA2G12B in SAT (beta = -0.039, FDR = 0.047), cg02561343 for PSMD8 (beta = -11.85, FDR = 0.029) and TECR (beta = -9.48, FDR = 0.029) in SAT, and cg23969380 for HIGD2AP1 (beta = -0.095, FDR = 0.024) in blood. These genes have been reported to be involved in lipid metabolism (PLA2G12B and TECR), proteasomal degradation (PSMD8), and cellular stress-responses (HIGD2AP1).

Interpretation: This epigenome-wide study of adiponectin in sub-Saharan African populations identified DNA methylation loci potentially involved in adiponectin regulation through lipid-metabolism, inflammation, proteostasis, and stress-response pathways. These findings provide a foundation for replication and further investigation to improve understanding of the role of adiponectin in cardiometabolic-health.

Funding: National Institutes of Health and European Research Council.

背景:脂联素是一种参与能量代谢和炎症的循环脂肪因子,对2型糖尿病(T2D)和早期肾脏疾病等心脏代谢疾病具有保护作用。然而,人们对其监管仍知之甚少。本研究旨在确定与脂联素水平相关的表观遗传位点。方法:采用Illumina 450K和EPIC (850K)阵列对315名加纳人(RODAM-Pros研究)和593名尼日利亚人(AADM研究)的DNA甲基化进行分析。使用线性回归模型对年龄、性别、BMI、血细胞比例和技术协变量进行调整,确定差异甲基化位点(dmp)。根据T2D状态和队列对分析进行分层,然后进行荟萃分析,以确定T2D状态下与脂联素相关的dmp(合并有糖尿病和无糖尿病的参与者)。来自AADM研究的77个血液样本、49个皮下脂肪组织(SAT)样本和55个骨骼肌样本的RNA-seq数据用于鉴定鉴定的dmp的eQTMs。结果:我们鉴定了三个表观基因组范围内显著的dmp: cg03546163 (Z-score = 5.76, p≤0.001,FKBP5的5'UTR), cg02561343 (Z-score = 5.11, p≤0.001,在UST内)和cg23969380 (Z-score = 5.13, p≤0.001,ADGRD1体)。cg03546163是SAT中PLA2G12B (β = -0.039, FDR = 0.047)的eQTM, cg02561343是SAT中PSMD8 (β = -11.85, FDR = 0.029)和TECR (β = -9.48, FDR = 0.029)的eQTM, cg23969380是HIGD2AP1 (β = -0.095, FDR = 0.024)的eQTM。据报道,这些基因参与脂质代谢(PLA2G12B和TECR)、蛋白酶体降解(PSMD8)和细胞应激反应(HIGD2AP1)。解释:这项对撒哈拉以南非洲人群脂联素的全表观基因组研究发现了DNA甲基化位点,这些位点可能通过脂质代谢、炎症、蛋白质平衡和应激反应途径参与脂联素调节。这些发现为进一步研究脂联素在心脏代谢健康中的作用提供了基础。资助:美国国立卫生研究院和欧洲研究委员会。
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引用次数: 0
Placental iron transport under maternal stress: a missing link in foetal programming and mental health. 母体应激下的胎盘铁转运:胎儿编程和心理健康的缺失环节。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-13 DOI: 10.1016/j.ebiom.2026.106170
Mariana Schroeder, Nan Yi, Barbara Fuenzalida, Timothee C Furrer, Therina du Toit, Martin Mueller, Edgar Ontsouka, Christiane Albrecht

Background: Environmental stress and iron deficiency are increasingly recognised as prevalent challenges during pregnancy, with significant implications for both maternal and foetal health. Environmental stressors such as chronic maternal anxiety can elevate cortisol levels and trigger inflammatory responses which might subsequently disrupt foetal brain development. Concurrently, iron deficiency during critical windows of gestation can hinder the formation of brain structures and neurotransmitter systems vital for emotional regulation and cognitive function after birth. Iron deficiency and exposure to stress are among the most prevalent nutritional and environmental challenges during pregnancy, and their combined influence may substantially increase the risk of neuropsychiatric disorders in the offspring. Although the individual effects of each factor are relatively well understood, their interaction during gestation remains unexplored.

Methods: In the present study, we employed human placental samples from mildly stressed and non-stressed mothers, a chronic environmental stress mouse model, and advanced in vitro techniques to examine whether gestational environmental stress alters placental iron transport.

Findings: Our findings indicate that stress enhanced placental iron uptake and accumulation, but paradoxically reduced iron transfer to the foetus-an effect observed exclusively in females and reproducible in vitro following both stress exposure and dexamethasone treatment.

Interpretation: These results provide insights into the sex-specific impact of environmental stress on placental and foetal iron availability and highlight a previously unrecognised pathway through which prenatal stress could influence long-term health trajectories in the offspring.

Funding: This study was supported by the Swiss National Science Foundation (SNF grant no. 310030_197408), the Swiss National Science Foundation via the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland (grant no. 51NF40_185544) and the Swiss 3R Competence Centre (3RCC; grant no OC-2019-019). TF was supported by the Hans Sigrist Foundation, Switzerland.

背景:环境压力和缺铁越来越被认为是怀孕期间普遍存在的挑战,对孕产妇和胎儿健康都有重大影响。环境压力因素,如母亲的慢性焦虑,会提高皮质醇水平,引发炎症反应,从而可能破坏胎儿的大脑发育。同时,在妊娠的关键窗口期缺铁会阻碍出生后对情绪调节和认知功能至关重要的大脑结构和神经递质系统的形成。缺铁和压力暴露是怀孕期间最普遍的营养和环境挑战,它们的综合影响可能大大增加后代患神经精神疾病的风险。虽然每个因素的个体影响已经被很好地理解,但它们在妊娠期的相互作用仍未被探索。方法:在本研究中,我们采用来自轻度应激和非应激母亲的人类胎盘样本,慢性环境应激小鼠模型,以及先进的体外技术来研究妊娠期环境应激是否会改变胎盘铁转运。研究结果:我们的研究结果表明,应激增强了胎盘铁的摄取和积累,但矛盾的是减少了铁向胎儿的转移——这一效应仅在女性中观察到,并且在体外应激暴露和地塞米松治疗后均可重复。解释:这些结果提供了环境压力对胎盘和胎儿铁可用性的性别特异性影响的见解,并强调了以前未被认识到的产前压力可能影响后代长期健康轨迹的途径。资助:本研究由瑞士国家科学基金会(SNF)资助。瑞士伯尔尼大学国家研究能力中心(NCCR)(批准号:310030_197408),瑞士国家科学基金。51NF40_185544)和瑞士3R能力中心(3RCC;批准号OC-2019-019)。TF由瑞士汉斯·西格里斯特基金会资助。
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引用次数: 0
Identification and validation of an 11-kinase signature that predicts chemo- and radiosensitivity in gastric cancer. 鉴定和验证11-激酶标记预测胃癌的化疗和放射敏感性。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-11 DOI: 10.1016/j.ebiom.2026.106154
Changyuan Hu, Sung-Young Shin, Yanan Wang, Chenbin Chen, Pei Liu, Rita A Busuttil, Yunjian Wu, Catriona A McLean, Hongying Shi, Terry Kwok, Lan K Nguyen, Jiangning Song, Alex Boussioutas, Xian Shen, Roger J Daly

Background: Most gastric cancer (GC) patients receive uniform treatment due to the lack of predictive biomarkers for chemotherapy or radiotherapy. We previously identified epithelial-mesenchymal transition (EMT) and metabolism subgroups in GC cell lines based on kinomic profiles, but their clinical relevance was unknown.

Methods: We developed an ensemble model using 37 kinases that differed between cell line subgroups to classify stage II-IV GC into EMT and metabolism subgroups. Survival differences between those who received chemotherapy or radiotherapy and those who did not were compared within each subgroup to validate the model effectiveness in predicting therapeutic response. An iteration approach was further applied to optimise and validate the feature set via multiple publicly-available datasets.

Findings: An 11-kinase signature stratified 893 patients into two subgroups. The metabolism subgroup showed significantly better survival with chemotherapy (HRmultivariable = 0.56) and radiotherapy (HRmultivariable = 0.55), whereas no such improvement was observed in the EMT subgroup. Significant interaction between kinomic subgroups and treatments were noted. The chemotherapy benefits between subgroups were greater with 5-fluorouracil-based regimens than cisplatin-based ones. This kinomic taxonomy was distinct from Lauren classification and previous transcriptomic subtypes and also suggested differential therapeutic vulnerabilities between subgroups.

Interpretation: This model holds promise for optimising chemotherapy and radiotherapy decisions for GC.

Funding: Biomedicine Discovery Scholarship and Graduate Research Completion Award, Monash University; National Natural Science Foundation of China (81602165) (C.H.). Australian Research Council Centre of Excellence for the Mathematical Analysis of Cellular Systems (CE230100001) (L.K.N.).

背景:由于缺乏化疗或放疗的预测性生物标志物,大多数胃癌(GC)患者接受统一的治疗。我们之前根据基因组学特征确定了GC细胞系的上皮-间质转化(EMT)和代谢亚群,但其临床相关性尚不清楚。方法:我们利用37种不同细胞系亚组的激酶建立了一个集合模型,将II-IV期GC分为EMT和代谢亚组。在每个亚组中比较接受化疗或放疗的患者和未接受化疗或放疗的患者的生存差异,以验证模型在预测治疗反应方面的有效性。进一步采用迭代方法,通过多个公开可用的数据集来优化和验证特征集。结果:11-激酶标记将893例患者分为两个亚组。代谢亚组化疗(HRmultivariable = 0.56)和放疗(HRmultivariable = 0.55)的生存率明显提高,而EMT亚组没有观察到这种改善。注意到动力学亚组与治疗之间存在显著的相互作用。以5-氟尿嘧啶为基础的化疗方案比以顺铂为基础的化疗方案在亚组间的获益更大。这种基因组分类不同于Lauren分类和以前的转录组亚型,也表明亚组之间的治疗脆弱性存在差异。解释:该模型有望优化胃癌的化疗和放疗决策。资助:蒙纳士大学生物医学发现奖学金和研究生研究完成奖;国家自然科学基金(81602165);澳大利亚研究理事会细胞系统数学分析卓越中心(CE230100001) (L.K.N.)。
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引用次数: 0
Phenotypic age acceleration and early-onset lung cancer: a case-control and prognostic cohort study involving multiple clinical centres with validation in the UK Biobank. 表型年龄加速和早发性肺癌:一项涉及多个临床中心的病例对照和预后队列研究,并在英国生物银行得到验证。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-10 DOI: 10.1016/j.ebiom.2026.106162
Ruolin Gao, Yuxuan Liao, Qiwen Zheng, Zhijian Xu, Xiaowei Zhao, Qinxiang Guo, Zhijie Wang, Jianchun Duan, Rui Wan, Jiachen Xu, Kailun Fei, Boyang Sun, Wei Zhuang, Hua Bai, Yanhui Cheng, Jia Zhong, Jie Wang

Background: Lung cancer is mainly diagnosed in elderly adults, yet the incidence of early-onset disease in people aged ≤45 years is increasing. Current screening strategies largely target elder populations, leaving younger individuals at risk of delayed diagnosis and adverse outcomes. Phenotypic Age Acceleration (PhenoAgeAccel), which indicates the difference between biological age and chronological age, has been associated with cancer susceptibility, but its role in early-onset lung cancer is unclear.

Methods: We performed a case-control and prognostic cohort study in China, including 222 early-onset lung cancer patients and 222 age- and sex-matched healthy volunteers, and externally validated findings in the UK Biobank. PhenoAgeAccel was calculated from routinely available haematological and biochemical markers. Logistic regression models estimated associations between PhenoAgeAccel and lung cancer risk. Survival analyses assessed the relationship between PhenoAgeAccel and overall survival among early-onset patients.

Findings: Early-onset lung cancer patients had substantially higher PhenoAgeAccel than matched controls (P < 0.001). PhenoAgeAccel was associated with a dose-dependent increase in early-onset lung cancer risk (odds ratio [OR] = 1.18; 95% CI: 1.14-1.23). Subgroup analyses by chronological age demonstrated a stronger association in earlier adulthood, whereas associations among elder adults (≥65 years) were not significant. In early-onset patients, higher PhenoAgeAccel predicted worse overall survival (hazard ratio [HR] = 2.17; 95% CI: 1.20-3.93). Results were corroborated in the UK Biobank cohort.

Interpretation: PhenoAgeAccel is positively associated with both a greater risk of early-onset lung cancer and poorer prognosis, supporting its potential utility for early detection and risk stratification in younger populations.

Funding: National Natural Science Foundation of China (no. 82303969); Beijing Xisike Clinical Oncology Research Foundation (no. Y-2024AZ [EGFR]MS-0079); Beijing Natural Science Foundation (no. 7222144).

背景:肺癌主要在老年人中诊断,但早发性疾病在≤45岁人群中的发病率正在增加。目前的筛查策略主要针对老年人群,使年轻人面临延迟诊断和不良后果的风险。表型年龄加速(PhenoAgeAccel)表明生物年龄和实足年龄之间的差异,与癌症易感性有关,但其在早发性肺癌中的作用尚不清楚。方法:我们在中国进行了一项病例对照和预后队列研究,包括222名早发性肺癌患者和222名年龄和性别匹配的健康志愿者,并在英国生物银行进行了外部验证。PhenoAgeAccel是根据常规可用的血液学和生化标志物计算的。Logistic回归模型估计了PhenoAgeAccel与肺癌风险之间的关联。生存分析评估了早发患者中PhenoAgeAccel与总生存率之间的关系。结果:早发性肺癌患者的PhenoAgeAccel显著高于对照组(P < 0.001)。PhenoAgeAccel与早发性肺癌风险的剂量依赖性增加相关(优势比[OR] = 1.18; 95% CI: 1.14-1.23)。按实足年龄进行的亚组分析显示,在成年早期有较强的相关性,而在老年人(≥65岁)中相关性不显著。在早发患者中,较高的PhenoAgeAccel预示着较差的总生存期(风险比[HR] = 2.17; 95% CI: 1.20-3.93)。结果在英国生物银行队列中得到证实。解释:PhenoAgeAccel与早发性肺癌的高风险和较差的预后呈正相关,支持其在年轻人群中早期检测和风险分层的潜在效用。基金资助:国家自然科学基金项目(no.;82303969);北京西思科临床肿瘤研究基金资助项目;y - 2024 -阿兹女士(EGFR) - 0079);北京市自然科学基金资助项目;7222144)。
{"title":"Phenotypic age acceleration and early-onset lung cancer: a case-control and prognostic cohort study involving multiple clinical centres with validation in the UK Biobank.","authors":"Ruolin Gao, Yuxuan Liao, Qiwen Zheng, Zhijian Xu, Xiaowei Zhao, Qinxiang Guo, Zhijie Wang, Jianchun Duan, Rui Wan, Jiachen Xu, Kailun Fei, Boyang Sun, Wei Zhuang, Hua Bai, Yanhui Cheng, Jia Zhong, Jie Wang","doi":"10.1016/j.ebiom.2026.106162","DOIUrl":"10.1016/j.ebiom.2026.106162","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer is mainly diagnosed in elderly adults, yet the incidence of early-onset disease in people aged ≤45 years is increasing. Current screening strategies largely target elder populations, leaving younger individuals at risk of delayed diagnosis and adverse outcomes. Phenotypic Age Acceleration (PhenoAgeAccel), which indicates the difference between biological age and chronological age, has been associated with cancer susceptibility, but its role in early-onset lung cancer is unclear.</p><p><strong>Methods: </strong>We performed a case-control and prognostic cohort study in China, including 222 early-onset lung cancer patients and 222 age- and sex-matched healthy volunteers, and externally validated findings in the UK Biobank. PhenoAgeAccel was calculated from routinely available haematological and biochemical markers. Logistic regression models estimated associations between PhenoAgeAccel and lung cancer risk. Survival analyses assessed the relationship between PhenoAgeAccel and overall survival among early-onset patients.</p><p><strong>Findings: </strong>Early-onset lung cancer patients had substantially higher PhenoAgeAccel than matched controls (P < 0.001). PhenoAgeAccel was associated with a dose-dependent increase in early-onset lung cancer risk (odds ratio [OR] = 1.18; 95% CI: 1.14-1.23). Subgroup analyses by chronological age demonstrated a stronger association in earlier adulthood, whereas associations among elder adults (≥65 years) were not significant. In early-onset patients, higher PhenoAgeAccel predicted worse overall survival (hazard ratio [HR] = 2.17; 95% CI: 1.20-3.93). Results were corroborated in the UK Biobank cohort.</p><p><strong>Interpretation: </strong>PhenoAgeAccel is positively associated with both a greater risk of early-onset lung cancer and poorer prognosis, supporting its potential utility for early detection and risk stratification in younger populations.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (no. 82303969); Beijing Xisike Clinical Oncology Research Foundation (no. Y-2024AZ [EGFR]MS-0079); Beijing Natural Science Foundation (no. 7222144).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"125 ","pages":"106162"},"PeriodicalIF":10.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12914819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164601","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
High-dimensional single-cell analyses reveal neutrophil heterogeneity in guttate psoriasis. 高维单细胞分析揭示了点滴状银屑病中性粒细胞的异质性。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-19 DOI: 10.1016/j.ebiom.2026.106172
Avinash Padhi, Anoop T Ambikan, Panagiotis Andriopoulos, Indranil Sinha, Mira Akber, Wenning Zheng, Rokeya Sultana Rekha, Laura Palma Medina, Jan-Inge Henter, Mattias Svensson, Liv Eidsmo, Anna Norrby-Teglund, Ujjwal Neogi, Peter Bergman, Josefin Lysell, Magda Lourda

Background: Guttate psoriasis (GP) is associated with streptococcal throat infection. Neutrophils are the first immune cells to respond to Group A Streptococcal (GAS) infection, but detailed analysis of their contribution to GP pathogenesis is lacking. The study primarily focuses on phenotyping the neutrophils located at the site of inflammation in GP skin and understanding their specific contribution to the pathogenesis of the disease.

Methods: Here, we performed a comprehensive immunophenotypic and transcriptomic analysis of neutrophils from blood and inflamed GP skin using high-dimensional single-cell protein and RNA analyses. Ex vivo stimulation of neutrophils and co-culture with CD4+ T cells was performed to validate the function of neutrophil subsets upon GAS stimulation.

Findings: We uncovered high diversity of human neutrophils in GP, with enrichment of an immature subset in GP skin that exhibited antigen processing and presentation signature. A similar subset in healthy controls was observed only upon ex vivo stimulation of neutrophils with GAS bacteria. Additionally, the GAS-induced neutrophil subset was found to induce CD4+ T cell proliferation mediated by HLA-DR. Other neutrophil subsets that expanded in GP were characterised by enrichment of genes related to neutrophil migration, formation of neutrophil extracellular traps and phagocytosis.

Interpretation: Our study depicts the landscape of neutrophils in GP skin and highlights HLA-DR+ neutrophils with possible role in disease pathogenesis.

Funding: This work was supported by HudFonden, Psoriasisfonden, Gösta A Karlssons 60-års fond, Magnus Bergvall stiftelse, Åke Wibergs stiftelse, and Karolinska Institute. AP was supported by HudFonden. PA was partially supported by Karolinska Institute's doctoral funding (KID). LPM was supported by grants from Svenska Sällskapet för Medicinsk Forskning (SSMF) and European Society of Clinical Microbiology and Infectious Diseases (ESCMID). UN was supported by grants from the Swedish Research Council. JL was supported by Region Stockholm (clinical postdoctoral appointment). ML was supported by the Swedish Childhood Cancer research fund and the Karolinska Institute. Part of the data handling was enabled by resources at project number SNIC-2021/22-49 provided by the Swedish National Infrastructure for Computing (SNIC), partially funded by the Swedish Research Council through grant agreement no. 2018-05973.

背景:点滴型牛皮癣(GP)与链球菌性咽喉感染有关。中性粒细胞是第一个对A群链球菌(GAS)感染作出反应的免疫细胞,但缺乏对其在GP发病机制中的作用的详细分析。该研究主要关注GP皮肤炎症部位的中性粒细胞的表型,并了解它们对疾病发病机制的特殊贡献。方法:在这里,我们使用高维单细胞蛋白和RNA分析对血液和炎症GP皮肤中的中性粒细胞进行了全面的免疫表型和转录组学分析。通过体外刺激中性粒细胞和与CD4+ T细胞共培养来验证中性粒细胞亚群在GAS刺激下的功能。研究结果:我们发现GP中人类中性粒细胞的高度多样性,在GP皮肤中富集了一个未成熟的亚群,表现出抗原加工和递呈特征。在健康对照中,只有在体外用GAS细菌刺激中性粒细胞时才观察到类似的亚群。此外,gas诱导的中性粒细胞亚群可诱导HLA-DR介导的CD4+ T细胞增殖。其他在GP中扩增的中性粒细胞亚群的特征是与中性粒细胞迁移、中性粒细胞胞外陷阱形成和吞噬有关的基因富集。解释:我们的研究描绘了GP皮肤中中性粒细胞的景观,并强调了HLA-DR+中性粒细胞在疾病发病机制中的可能作用。资助:这项工作得到了HudFonden, Psoriasisfonden, Gösta A Karlssons 60- rs fond, Magnus Bergvall stifelse, Åke Wibergs stifelse和卡罗林斯卡研究所的支持。美联社得到了HudFonden的支持。PA部分由卡罗林斯卡学院的博士基金(KID)支持。LPM得到了Svenska Sällskapet för Medicinsk Forskning (SSMF)和欧洲临床微生物学和传染病学会(ESCMID)的资助。联合国得到了瑞典研究委员会的资助。JL由斯德哥尔摩地区(临床博士后聘任)支持。ML得到了瑞典儿童癌症研究基金和卡罗林斯卡研究所的支持。部分数据处理由瑞典国家计算基础设施(SNIC)提供的SNIC-2021/22-49项目资源实现,部分资金由瑞典研究委员会通过赠款协议提供。2018 - 05973。
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引用次数: 0
Reconsidering serological strategies for HPV-driven oropharyngeal cancer screening. 重新考虑hpv驱动口咽癌筛查的血清学策略。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-10 DOI: 10.1016/j.ebiom.2026.106164
Nitya Krishnasamy, Hema Shree, Sameep Shetty, Saravanan Sekaran
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引用次数: 0
Fusing data from CT deep learning, CT radiomics and peripheral blood immune profiles to diagnose lung cancer in a cohort of patients experiencing symptoms. 融合来自CT深度学习、CT放射组学和外周血免疫谱的数据,在有症状的患者队列中诊断肺癌。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-19 DOI: 10.1016/j.ebiom.2026.106173
Rami Mustapha, Balaji Ganeshan, Sam Ellis, Luigi Dolcetti, Mukunthan Tharmakulasingam, Karen DeSouza, Xiaolan Jiang, Courtney Savage, Sheena Lim, Emily Chan, Andrew Thornton, Luke Hoy, Raymond Endozo, Rob Shortman, Darren Walls, Shih-Hsin Chen, Mark Rowley, Anthony C C Coolen, Ashley M Groves, Julia A Schnabel, Thida Win, Paul R Barber, Tony Ng

Background: Lung cancer is the leading cause of cancer-related deaths. Diagnosis at late stages is common due to the largely non-specific nature of presenting symptoms contributing to high mortality. There is a lack of specific, minimally invasive low-cost tests to screen patients ahead of the diagnostic biopsy.

Methods: 344 patients experiencing symptoms from the lung clinic of Lister hospital suspected of lung cancer were recruited. Predictive covariates were successfully generated on 170 patients from Computed Tomography (CT) scans using CT Texture Analysis (CTTA) and Deep Learning Autoencoders (DLA) as well as from peripheral blood data for immunity using high depth flow-cytometry and for exosome protein components. Predictive signatures were formed by combining covariates using Bayesian regression on a randomly chosen 128-patient training set and validated on a 42-patient held-out set. Final signatures were generated by fusing the data sources at different levels.

Findings: Immune, CTTA and DLA single modality signatures had overall AUCs of 0.69, 0.70 and 0.73 respectively. The final combined signature had a ROC AUC of 0.81. The overall sensitivity and specificity were 0.72 and 0.77 respectively.

Interpretation: Combining immune monitoring with CT scan data is an effective approach to improving sensitivity and specificity of Lung cancer screening even in patients experiencing symptoms.

Funding: CRUK [C1519/A27375], Wellcome Trust/EPSRC Centre for Medical Engineering [WT203148/Z/16/Z], NIHR Clinical Research Facility at Guy's and St Thomas' NHS Foundation Trust, NIHR Biomedical Research Centre.

背景:肺癌是癌症相关死亡的主要原因。由于出现的症状在很大程度上是非特异性,导致高死亡率,因此晚期诊断很常见。在诊断性活组织检查之前,缺乏专门的、微创的低成本检查来筛查患者。方法:选取李斯特医院肺内科有症状的疑似肺癌患者344例。使用CT纹理分析(CTTA)和深度学习自动编码器(DLA),以及使用高深度流式细胞术和外泌体蛋白质成分的外周血免疫数据,成功地对170名患者的计算机断层扫描(CT)生成了预测协变量。预测特征是通过在随机选择的128例患者训练集上使用贝叶斯回归组合协变量形成的,并在42例患者保留集上进行验证。通过融合不同级别的数据源生成最终签名。结果:免疫、CTTA和DLA单模态特征的总auc分别为0.69、0.70和0.73。最终联合特征的ROC AUC为0.81。总敏感性和特异性分别为0.72和0.77。解释:将免疫监测与CT扫描数据相结合是提高肺癌筛查敏感性和特异性的有效方法,即使在有症状的患者中也是如此。资助:CRUK [C1519/A27375], Wellcome Trust/EPSRC医学工程中心[WT203148/Z/16/Z],英国国立卫生研究院Guy's and St Thomas NHS基金会信托临床研究设施,英国国立卫生研究院生物医学研究中心。
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引用次数: 0
Platelets as immune sensors: monitoring immune dynamics and diagnosing disease states across multiple disorders. 血小板作为免疫传感器:监测免疫动力学和诊断多种疾病的疾病状态。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-19 DOI: 10.1016/j.ebiom.2026.106174
Lin Zheng, Dan Feng, Yuting Wu, Wei Liang, Juan Chen, Shijun Ni, Yezi Ma, Pei Su, Cuicui Liu, Sizhou Feng, Wen Zhou, Cha Han, Fei Wang, Erlie Jiang, Jiaxi Zhou, Hongtao Wang

Background: Beyond their classical roles in haemostasis and thrombosis, platelets have been recognised as active regulators of immune responses. However, whether platelets can function as immune sensors capable of monitoring immune status remains largely unexplored.

Methods: We first analysed platelet transcriptomes from patients at different stages following haematopoietic stem cell transplantation (HSCT) to assess their ability to capture immune reconstitution dynamics. We then employed immune cell-platelet co-incubation experiments to elucidate the mechanistic role of RNA transfer in reshaping platelet immune molecular profiles. Subsequently, platelet transcriptomes were examined in immune-related conditions, including HSCT-associated acute graft-versus-host disease (aGVHD), cytomegalovirus (CMV) DNAemia, and immune-inflammatory diseases such as systemic lupus erythematosus (SLE) and ulcerative colitis (UC), to evaluate their capacity to identify disease-specific immune dysregulation. Finally, machine learning models were developed based on platelet immune gene signatures to assess diagnostic performance.

Findings: Platelet transcriptomes accurately reflected the dynamics of immune reconstitution following HSCT. Mechanistically, immune cells directly reprogrammed platelet immune-related molecular features through RNA transfer. Moreover, platelets sensitively detected immune alterations associated with transplant complications, including aGVHD and CMV DNAemia, and effectively monitored immune activity and inflammatory states in SLE and UC. Machine learning models based on platelet immune gene profiles further improved diagnostic accuracy across disease settings.

Interpretation: This study establishes platelets as precise, readily accessible, and noninvasive immune sensors, extending their functional repertoire from immune regulation to immune surveillance and diagnosis in immune-related diseases.

Funding: National Natural Science Foundation of China; CAMS Innovation Fund for Medical Sciences; Science and Technology Projects of Xizang Autonomous Region, China; National Key Research and Development Program of China; Tianjin Municipal Science and Technology Commission Grant; and Natural Science Foundation of Tianjin.

背景:血小板除了在止血和血栓形成中的经典作用外,还被认为是免疫反应的积极调节因子。然而,血小板是否可以作为监测免疫状态的免疫传感器,在很大程度上仍未被探索。方法:我们首先分析了造血干细胞移植(HSCT)后不同阶段患者的血小板转录组,以评估其捕获免疫重建动力学的能力。然后,我们采用免疫细胞-血小板共孵育实验来阐明RNA转移在重塑血小板免疫分子谱中的机制作用。随后,在免疫相关疾病中检测血小板转录组,包括hsct相关的急性移植物抗宿主病(aGVHD)、巨细胞病毒(CMV) dna血症和免疫炎性疾病(如系统性红斑狼疮(SLE)和溃疡性结肠炎(UC)),以评估其识别疾病特异性免疫失调的能力。最后,基于血小板免疫基因特征开发了机器学习模型来评估诊断性能。结果:血小板转录组准确反映了造血干细胞移植后免疫重建的动态。在机制上,免疫细胞通过RNA转移直接重编程血小板免疫相关分子特征。此外,血小板可以灵敏地检测与移植并发症相关的免疫改变,包括aGVHD和CMV dna血症,并有效监测SLE和UC的免疫活性和炎症状态。基于血小板免疫基因谱的机器学习模型进一步提高了疾病诊断的准确性。解释:这项研究确立了血小板作为精确的、容易获得的、无创的免疫传感器,将其功能从免疫调节扩展到免疫监测和免疫相关疾病的诊断。资助:国家自然科学基金;医学科学创新基金;西藏自治区科技项目;国家重点研究发展计划;天津市科委资助项目;天津市自然科学基金。
{"title":"Platelets as immune sensors: monitoring immune dynamics and diagnosing disease states across multiple disorders.","authors":"Lin Zheng, Dan Feng, Yuting Wu, Wei Liang, Juan Chen, Shijun Ni, Yezi Ma, Pei Su, Cuicui Liu, Sizhou Feng, Wen Zhou, Cha Han, Fei Wang, Erlie Jiang, Jiaxi Zhou, Hongtao Wang","doi":"10.1016/j.ebiom.2026.106174","DOIUrl":"10.1016/j.ebiom.2026.106174","url":null,"abstract":"<p><strong>Background: </strong>Beyond their classical roles in haemostasis and thrombosis, platelets have been recognised as active regulators of immune responses. However, whether platelets can function as immune sensors capable of monitoring immune status remains largely unexplored.</p><p><strong>Methods: </strong>We first analysed platelet transcriptomes from patients at different stages following haematopoietic stem cell transplantation (HSCT) to assess their ability to capture immune reconstitution dynamics. We then employed immune cell-platelet co-incubation experiments to elucidate the mechanistic role of RNA transfer in reshaping platelet immune molecular profiles. Subsequently, platelet transcriptomes were examined in immune-related conditions, including HSCT-associated acute graft-versus-host disease (aGVHD), cytomegalovirus (CMV) DNAemia, and immune-inflammatory diseases such as systemic lupus erythematosus (SLE) and ulcerative colitis (UC), to evaluate their capacity to identify disease-specific immune dysregulation. Finally, machine learning models were developed based on platelet immune gene signatures to assess diagnostic performance.</p><p><strong>Findings: </strong>Platelet transcriptomes accurately reflected the dynamics of immune reconstitution following HSCT. Mechanistically, immune cells directly reprogrammed platelet immune-related molecular features through RNA transfer. Moreover, platelets sensitively detected immune alterations associated with transplant complications, including aGVHD and CMV DNAemia, and effectively monitored immune activity and inflammatory states in SLE and UC. Machine learning models based on platelet immune gene profiles further improved diagnostic accuracy across disease settings.</p><p><strong>Interpretation: </strong>This study establishes platelets as precise, readily accessible, and noninvasive immune sensors, extending their functional repertoire from immune regulation to immune surveillance and diagnosis in immune-related diseases.</p><p><strong>Funding: </strong>National Natural Science Foundation of China; CAMS Innovation Fund for Medical Sciences; Science and Technology Projects of Xizang Autonomous Region, China; National Key Research and Development Program of China; Tianjin Municipal Science and Technology Commission Grant; and Natural Science Foundation of Tianjin.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"125 ","pages":"106174"},"PeriodicalIF":10.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12936757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257451","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
Region-specific brain structural modulation and amyloid-β pathology associated with dietary biotin: insights into dementia neuropathology. 与饮食生物素相关的特定区域脑结构调节和淀粉样蛋白-β病理:对痴呆神经病理学的见解。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-11 DOI: 10.1016/j.ebiom.2026.106155
Junhan Zhang, Celi Yang, Yuefeng Tan, Muzi Na, Evaniya Shakya, Da Zhang, Xiaojin Shi, Xiaona Na, Zhihui Li, John S Ji, Yucheng Yang, Ai Zhao

Background: The association and mechanisms between biotin and dementia remain unclear.

Methods: We investigated the association through a population and animal study. UK Biobank data were used to evaluate the association of biotin with incident dementia and brain structural alteration. To validate our findings, we established a biotin-deficient mouse model, and performed behavioural tests, immunofluorescence, RT-qPCR, Western blotting, and molecular docking.

Findings: In humans, higher biotin intake was significantly associated with reduced risks of all-cause dementia (moderate: 0.83 [0.74-0.94]; high: 0.78 [0.68-0.89]), Alzheimer's disease (AD, moderate: 0.74 [0.61-0.89]; high: 0.79 [0.64-0.98]), and delayed-onset dementia (DOD, moderate: 0.810 [0.715-0.918]; high: 0.776 [0.672-0.896]), but not vascular dementia (VD) and early-onset dementia (EOD). Neuroimaging results revealed a "pseudo-atrophy" pattern-reduced cortical volume with increased tissue intensity-resembling structural remodelling rather than neurodegeneration. In mice, biotin deficiency triggered region-specific alteration of APP, PSEN1, and APOE in the hippocampus and prefrontal cortex. It was accompanied by elevated Aβ42 levels and an increased Aβ42/40 ratio. Molecular docking suggested that biotin physically interacts with the catalytic pocket of PSEN1 and the receptor-binding domain of APOE.

Interpretation: Dietary biotin is associated with a lower risk of dementia, especially AD, potentially by inhibiting amyloidogenic processing and modulating APOE-mediated clearance. The observed neuroimaging and molecular patterns suggest that maintaining adequate biotin intake is a viable strategy for dementia prevention.

Funding: This work was supported by the National Natural Science Foundation of China (No. 82273619).

背景:生物素与痴呆之间的关系和机制尚不清楚。方法:我们通过人群和动物研究来调查两者之间的关系。英国生物银行的数据被用来评估生物素与痴呆和脑结构改变的关系。为了验证我们的发现,我们建立了生物素缺乏小鼠模型,并进行了行为测试、免疫荧光、RT-qPCR、Western blotting和分子对接。研究结果:在人类中,较高的生物素摄入量与全因痴呆(中度:0.83[0.74-0.94];高:0.78[0.68-0.89])、阿尔茨海默病(AD,中度:0.74[0.61-0.89];高:0.79[0.64-0.98])和迟发性痴呆(DOD,中度:0.810[0.715-0.918];高:0.776[0.672-0.896])的风险降低显著相关,但与血管性痴呆(VD)和早发性痴呆(EOD)无关。神经影像学结果显示“假性萎缩”模式-皮质体积减少,组织强度增加-类似于结构重塑而不是神经变性。在小鼠中,生物素缺乏引发海马和前额皮质中APP、PSEN1和APOE的区域特异性改变。a - β42水平升高,a - β42/40比值升高。分子对接表明,生物素与PSEN1的催化口袋和APOE的受体结合域发生物理相互作用。解释:饮食生物素可能通过抑制淀粉样蛋白生成过程和调节apoe介导的清除与痴呆,特别是AD的低风险相关。观察到的神经影像学和分子模式表明,维持足够的生物素摄入是预防痴呆的可行策略。基金资助:国家自然科学基金(82273619)资助。
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引用次数: 0
Parvimonas micra exacerbates periodontitis by infiltrating host cells through TmpC and circumventing lysosomal elimination via AppA. 微细小单胞菌通过TmpC浸润宿主细胞,并通过AppA绕过溶酶体消除,从而加重牙周炎。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-01 Epub Date: 2026-02-24 DOI: 10.1016/j.ebiom.2026.106187
Zixuan Li, Pingping Wang, Haiting Gao, Mengfan Zhi, Xiufeng Gu, Tianyong Sun, Yushang Wang, Song Shen, Xiaomei Ma, Xiaoli Ji, Xiumei Zhang, Dongxu Liu, Qiang Feng

Background: Periodontitis poses a significant threat to human oral health, and microorganisms serving as the initiating factor in its pathogenesis. Parvimonas micra (P. micra), a Gram-positive anaerobic bacterium prevalent within the oral cavities of patients with periodontitis, remains underexplored in terms of its full contribution to periodontitis pathogenesis.

Methods: 16S rRNA sequencing was performed on human gingival crevicular fluid samples, whilst micro-CT was used in experimental rat models to assess the impact of P. micra on periodontitis progression. Single-cell RNA sequencing was employed to examine dynamic alterations in rat periodontal cell composition and the enrichment of gene pathways during P. micra infection. Finally, His pull-down assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to identify key virulence factors of P. micra and host cell receptors.

Findings: In this study, we examined the abundance of P. micra in gingival crevicular fluid and validated its pathogenic potential in vivo. Single-cell RNA sequencing revealed that P. micra disrupted the periodontal immune and mineralisation microenvironment. Further investigation showed that P. micra manipulated its surface adhesins to bind receptors on periodontal ligament stem cells, activating the intracellular NF-κB and ERK1/2 signalling pathways and impairing osteogenic activity. Finally, we identified a mechanism by which P. micra employed a surface protein to evade autophagic clearance, thereby facilitating immune escape.

Interpretation: This study identifies P. micra as a pivotal periodontal pathogen, and the elucidation of its molecular mechanisms provides potential therapeutic targets for periodontitis and related systemic conditions.

Funding: This work was supported by the National Natural Science Foundation of China (No. 82270980, 82071122), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501400), Taishan TePin Scientist Project of Shandong Province (tstp20250546), the Natural Science Foundation of Jiangsu Province (No. BK20240268), High-Level Hospital Construction Project of Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University (No. 0024C035), Shandong Provincial Key Research and Development Program (Competitive Innovation Platform, 2025CXPT042), the Major Innovation Projects in Shandong Province (No. 2021SFGC0502), and the Shandong Province Key Research and Development Program (No. 2021ZDSYS18).

背景:牙周炎对人类口腔健康构成严重威胁,而微生物是其发病的起始因素。微微小单胞菌(P. micra)是一种普遍存在于牙周炎患者口腔内的革兰氏阳性厌氧菌,在其对牙周炎发病机制的全部贡献方面仍未得到充分的研究。方法:对人龈沟液样本进行16S rRNA测序,并在实验大鼠模型中应用micro-CT评估微假单胞菌对牙周炎进展的影响。采用单细胞RNA测序技术检测微假单胞菌感染过程中大鼠牙周细胞组成的动态变化和基因通路的富集。最后,采用His下拉法联合液相色谱-串联质谱法(LC-MS/MS)鉴定微假单胞菌和宿主细胞受体的关键毒力因子。结果:在本研究中,我们检测了牙龈沟液中微假单胞菌的丰度,并验证了其在体内的致病潜力。单细胞RNA测序显示微假单胞菌破坏牙周免疫和矿化微环境。进一步的研究表明,微假单胞菌操纵其表面粘附素与牙周韧带干细胞上的受体结合,激活细胞内NF-κB和ERK1/2信号通路,并损害成骨活性。最后,我们确定了微假单胞菌利用表面蛋白逃避自噬清除的机制,从而促进免疫逃逸。本研究确定微假单胞菌是一种关键的牙周病原体,其分子机制的阐明为牙周炎和相关全身疾病的治疗提供了潜在的靶点。基金资助:国家自然科学基金项目(No. 82270980, 82071122)、非传染性慢性病国家科技重大专项(No. 2023ZD0501400)、山东省泰山TePin科学家项目(No. tstp20250546)、江苏省自然科学基金项目(No. 82270980, 82071122)资助;南京大学医学院附属医院口腔研究所高水平医院建设项目(0024C035),山东省重点研发计划(竞争创新平台,2025CXPT042),山东省重大创新项目(No. 2021SFGC0502),山东省重点研发计划(No. 2021ZDSYS18)。
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引用次数: 0
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