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Modified hTERT treatment ameliorates pressure overload-induced heart failure. 改良hTERT治疗可改善压力超载引起的心力衰竭。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-09 DOI: 10.1016/j.ebiom.2026.106203
Yinlong Zhao, Xiaolu Bao, Weiyao Xiong, Xin Wan, Qingying Yu, Teng Wang, Andrew C H Chang, Yangyang Liu, Yanqiu Wang, Ching Shang, Min Wu, Euan A Ashley, Ming Lei, Junfeng Zhang, Yueheng Wu, Wei Han, Alex C Y Chang

Background: Heart failure (HF) is a currently incurable disorder that increases the risk for stroke and sudden cardiac death. Shortened telomeres have been linked to the development of cardiomyocyte abnormalities and dysfunction, and telomere reprotection has become a favourable strategy for designing novel heart failure therapies. This study aims to design a pan-HF gene therapy where modified human telomerase expression is driven by cardiac troponin promoter and to evaluate cardiac protection.

Methods: Telomere shortening was determined in cardiomyocytes from Macaca fascicularis (cynomolgus monkey) and patients with HF by quantitative fluorescence in situ hybridisation (Q-FISH) assays. We bioengineered a catalytic inactivation and nuclear retaining modified human TERT (telomerase reverse transcriptase) gene therapy (AAV9-modhTERTY707F, D868A). In transverse aortic constriction (TAC)-induced WT and myocardial p53 deficient (p53CKO) mice HF model, as well as Ang II-induced human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we evaluate cardiac protection of modhTERT via echocardiography, RNA-sequence, Western blotting, Proteome Profiler Mouse XL Cytokine Array panel, RT-qPCR, transmission electron microscopy, and immunofluorescence.

Findings: AAV9-modhTERTY707F, D868A reversed cardiac function decline and prevented onset of cardiac fibrosis in TAC-induced HF murine. At cellular level, modhTERT alleviated contractile dysfunction and aberrant calcium handling in cardiomyocytes isolated from TAC hearts and prevented Ang II-stimulated hiPSC-CMs hypertrophy. Overexpression of modhTERT blocked telomeric DNA damage response (DDR) and p53 ser15-phosphorylation. Myocardial chronic inflammation and reactive oxygen species (ROS) levels were reverted by modhTERT overexpression. Additionally, modhTERT rescued mitochondrial ultrastructure, increased mitochondrial DNA (mtDNA) copy, and restored ATP production through restoration of PGC-1 α and TFAM expression.

Interpretation: We provide evidence that telomere re-protection confers cardiac protection and may serve as a potential gene therapeutic option for treating heart failure.

Funding: This research was supported by the National Natural Science Foundation of China (82070248, 82300282, 82300476), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (0900000024), 2023 Shanghai Action Plan for Promoting Scientific and Technological Innovation and Industrial Development of Gene Therapy (23J11900600).

背景:心力衰竭(HF)是一种目前无法治愈的疾病,可增加中风和心源性猝死的风险。缩短的端粒与心肌细胞异常和功能障碍的发展有关,端粒再保护已成为设计新型心力衰竭治疗的有利策略。本研究旨在设计一种泛hf基因疗法,通过心肌肌钙蛋白启动子驱动修饰的人类端粒酶表达,并评估心脏保护作用。方法:采用定量荧光原位杂交法(Q-FISH)测定掌状猕猴和心衰患者心肌细胞端粒缩短情况。我们生物工程的催化失活和核保留修饰的人TERT(端粒酶逆转录酶)基因治疗(AAV9-modhTERTY707F, D868A)。在横断主动脉收缩(TAC)诱导的WT和心肌p53缺陷(p533cko)小鼠HF模型以及Ang ii诱导的人诱导多能干细胞来源的心肌细胞(hiPSC-CMs)中,我们通过超声心动图、rna序列、Western blotting、Proteome Profiler小鼠XL细胞因子阵列面板、RT-qPCR、透射电镜和免疫荧光来评估modhTERT对心脏的保护作用。研究结果:AAV9-modhTERTY707F、D868A可逆转tac诱导的HF小鼠心功能下降,防止心脏纤维化的发生。在细胞水平上,modtert减轻了TAC心脏分离心肌细胞的收缩功能障碍和异常钙处理,并阻止Ang ii刺激的hiPSC-CMs肥大。过表达modtert阻断了端粒DNA损伤反应(DDR)和p53 ser15磷酸化。心肌慢性炎症和活性氧(ROS)水平通过modtert过表达得到恢复。此外,modtert修复线粒体超微结构,增加线粒体DNA (mtDNA)拷贝,并通过恢复PGC-1 α和TFAM的表达恢复ATP的产生。解释:我们提供的证据表明,端粒再保护可以保护心脏,并可能作为治疗心力衰竭的潜在基因治疗选择。基金资助:国家自然科学基金项目(82070248,82300282,82300476)、上海高等学校特聘教授(东方学者)项目(0900000024)、2023上海市促进基因治疗科技创新与产业发展行动计划(23J11900600)资助。
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引用次数: 0
From dysbiosis to cellular invasion: reassessing the pathogenic role of parvimonas micra in periodontitis as an understudied pathobiont. 从生态失调到细胞侵袭:重新评估微细小单胞菌在牙周炎中的致病作用,作为一种尚未充分研究的病原体。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-09 DOI: 10.1016/j.ebiom.2026.106202
Gaetano Isola
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引用次数: 0
The pathoanatomy of cancer: order in paradox. 癌症的病理解剖学:悖论中的秩序。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-09 DOI: 10.1016/j.ebiom.2026.106161
Michael Höckel

The pathoanatomy of local cancer spread is approached by the ontogenetic cancer field model, deduced from aspects of evolution, development, immunity, and wound healing/regeneration in multicellular animals, postulating: (1) Cancer cells canonically respond to the disruption of tissue homeostasis caused by their uncontrolled proliferation with progressive de-differentiation, which paradoxically enlarges the cancer wound instead of healing it. (2) The de-differentiating cancer cells adhere in reverse sequence to a principle of topological order laid down during embryonic development by the metazoan cell type differentiation trajectory. The model predicts with high anatomical accuracy ontogenetic stage-dependent permissive tissue territories for local cancer propagation, i.e., cancer fields, as demonstrated for cancers of the alimentary and genital tracts. Assuming the 'export' of the local cancer field into the draining lymph nodes by tissue macrophages and regulatory T cells, the model is also applicable for regional carcinoma spread. The clinical translation into cancer field surgery has led to a marked reduction of locoregional recurrences and to increased cure rates.

从多细胞动物的进化、发育、免疫和伤口愈合/再生等方面推导出的个体发生癌症场模型探讨了局部癌症扩散的病理解剖学,假设:(1)癌细胞通常会对组织稳态的破坏做出反应,这种破坏是由癌细胞不受控制的增殖引起的,并伴有渐进的去分化,这矛盾地扩大了癌症伤口,而不是愈合伤口。(2)去分化癌细胞以相反的顺序遵循胚胎发育过程中由后生细胞类型分化轨迹确定的拓扑顺序原则。该模型以较高的解剖学精度预测了局部癌症传播的个体发育阶段相关的允许组织区域,即癌症场,如消化道和生殖道的癌症。假设局部癌野通过组织巨噬细胞和调节性T细胞“出口”到引流淋巴结,该模型也适用于局部癌扩散。临床转化为癌症领域的手术导致了局部复发的显著减少和治愈率的提高。
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引用次数: 0
Circadian rhythm disruption impairs ovarian follicular development via NAD+ metabolic reprogramming. 昼夜节律紊乱通过NAD+代谢重编程损害卵巢卵泡发育。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-07 DOI: 10.1016/j.ebiom.2026.106200
Yan-Yun Ying, Xin Chen, Sen-Yi Yao, Rui-Xue Chen, Yue Ying, Hong Qiu, Qi-Qi Xu, Zheng-Yi Li, Cun-Qi Ye, Yu-Li Qian, Hong-Qing Liang, Xiao Sun, Dan Zhang

Background: Circadian rhythms play a crucial role in human health, including reproductive health. Disruption of circadian rhythm is associated with female infertility. However, how circadian disruption affects ovarian function remains unclear. The main purpose of this study is to verify the impact of long-photoperiod exposure on follicular development and ovarian function.

Methods: In this study, we employed long-photoperiod (LP) conditions (18 h lightness/6 h darkness) in rats to mimic increased light exposure in human lifestyles. Hormone indicators, oestrus cycle, ovary morphology, follicular development and ovulation were used to validate the ovarian function. To investigate the underlying mechanisms, a series of experiments, including RNA sequencing, metabolomics, ChIP/qPCR, transmission electron microscopy, immunofluorescence, and western blotting, were conducted. Additionally, the impact of nicotinamide mononucleotide (NMN) on ovarian function was evaluated using the mentioned methods above.

Findings: LP exposure reduced the number of growing ovarian follicles and retrieved oocytes. Mechanistically, LP exposure led to granulosa cell oxidative stress and mitochondria dysfunction via inhibiting SIRT3 activity and SOD2 deacetylation. Metabolomic analysis showed that LP exposure lowered NAD+ levels, a cofactor that determines SIRT3 deacetylase activity. Further study showed that NAMPT, the rate-limiting enzyme in NAD+ synthesis, exhibited a circadian rhythmic expression pattern in the ovary, and LP exposure disrupted the ovarian circadian expression of NAMPT through the core clock protein BMAL1. Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide could ameliorate mitochondria function and increase the numbers of antral follicles (49.56 ± 0.55 vs. 21.83 ± 1.35, p = 0.001) and retrieved oocytes (18.40 ± 1.91 vs. 3.80 ± 1.16, p < 0.001) in LP-exposed rats.

Interpretation: Our study demonstrates that circadian rhythm disruption by LP exposure affect follicular development and ovulation through impaired NAD+ metabolism, and suggests targeting NAD+ pathways as a potential therapeutic strategy for ovarian diseases.

Funding: This work was supported by the National Natural Science Foundation of China - Joint Fund for Regional Innovation and Development, the National Natural Science Foundation of China, the National Key Research and Development Program of China.

背景:昼夜节律在人类健康,包括生殖健康中起着至关重要的作用。昼夜节律紊乱与女性不孕症有关。然而,昼夜节律紊乱如何影响卵巢功能仍不清楚。本研究的主要目的是验证长时间光周期照射对卵泡发育和卵巢功能的影响。方法:在本研究中,我们采用长光周期(LP)条件(18小时亮/6小时暗)的大鼠来模拟人类生活方式中增加的光暴露。通过激素指标、发情周期、卵巢形态、卵泡发育及排卵情况验证卵巢功能。为了研究其潜在机制,我们进行了一系列实验,包括RNA测序、代谢组学、ChIP/qPCR、透射电镜、免疫荧光和western blotting。此外,采用上述方法评估烟酰胺单核苷酸(NMN)对卵巢功能的影响。结果:LP暴露减少了卵巢卵泡生长和卵母细胞回收的数量。从机制上讲,LP暴露通过抑制SIRT3活性和SOD2去乙酰化导致颗粒细胞氧化应激和线粒体功能障碍。代谢组学分析显示,LP暴露降低了NAD+水平,NAD+是决定SIRT3去乙酰化酶活性的辅助因子。进一步研究表明,NAD+合成的限速酶NAMPT在卵巢中表现出昼夜节律表达模式,LP暴露通过核心时钟蛋白BMAL1破坏了NAMPT在卵巢的昼夜节律表达。NAD+代谢前体烟酰胺单核苷酸治疗可改善大鼠线粒体功能,增加窦卵泡数量(49.56±0.55比21.83±1.35,p = 0.001)和卵母细胞数量(18.40±1.91比3.80±1.16,p < 0.001)。解释:我们的研究表明,LP暴露导致的昼夜节律紊乱通过NAD+代谢受损影响卵泡发育和排卵,并建议靶向NAD+通路作为卵巢疾病的潜在治疗策略。基金资助:国家自然科学基金-区域创新与发展联合基金、国家自然科学基金、国家重点研发计划资助。
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引用次数: 0
Integrating breast tumour homologous recombination deficiency status to aid germline BRCA1 and BRCA2 variant classification. 整合乳腺肿瘤同源重组缺陷状态以帮助种系BRCA1和BRCA2变异分类。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-07 DOI: 10.1016/j.ebiom.2026.106199
Cristina Fortuno, Jia Zhang, Lambros T Koufariotis, Georgina Hollway, Scott Wood, John V Pearson, Peter T Simpson, Sunil R Lakhani, Amy E McCart Reed, Heather Thorne, G Bruce Mann, Anita R Skandarajah, Lisa Devereux, Qihong Zhao, Dilanka L De Silva, Geoffrey J Lindeman, Paul Waring, Paul A James, Ian Campbell, Amanda B Spurdle, Nicola Waddell

Background: Pathogenic germline variants in certain genes are associated with somatic tumour mutation signatures. The use of somatic tumour mutation data has the potential to improve the identification of true pathogenic variants but remains underexplored. We investigated the integration of tumour homologous recombination (HR) deficiency status as a predictor of pathogenicity for germline BRCA1 and BRCA2 variants, building on the established link between HR deficiency and germline pathogenic variants in these genes.

Methods: We analysed breast tumour whole-genome sequence and matching germline data from 350 patients across four datasets: Familial Breast Cancer (N = 77), The Cancer Genome Atlas (TCGA-BRCA, N = 96), the MAGIC study (N = 136), and Q-IMPROvE (N = 41). A total of 15,156 germline variants (including structural variations) in BRCA1, BRCA2, and other cancer genes (ATM, BARD1, BRIP1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53) underwent variant curation. Patients were categorised based on germline classification as BRCA1 positive (N = 27), BRCA2 positive (N = 21), and BRCA1/2 negative (N = 232), excluding those with BRCA1/2 variants of uncertain significance (N = 8) and pathogenic or only uncertain variants in other cancer genes (N = 62). Somatic HR status (deficient or proficient) was predicted using three algorithms: HRDetect, CHORD, and HRDsum. HR-deficient and HR-proficient status were significant predictors of germline BRCA1/2 pathogenic variant status (positive and negative directions).

Findings: The CHORD algorithm, which estimates BRCA1 and BRCA2 subtype specifically, added precision contributing evidence towards pathogenicity for the corresponding gene, reaching pathogenic moderate strength for the relevant gene-subtype. Finally, we assessed CHORD HR predictions for variants of uncertain significance in BRCA1 and BRCA2, and reported their tumour HR status for potential use as additional evidence in variant curation.

Interpretation: Analysis across multiple tumour whole-genome sequencing datasets has shown that HR status prediction algorithms can separate profiles for BRCA1 and BRCA2 pathogenic variants and provide further evidence at increased weight to aid in the classification of germline BRCA1 and BRCA2 variants. Tumour sequencing offers a promising strategy for reducing the uncertainty in germline variant interpretation.

Funding: This work was funded by the National Breast Cancer Foundation.

背景:某些基因的致病种系变异与体细胞肿瘤突变特征相关。体细胞肿瘤突变数据的使用有可能改善真正致病变异的识别,但仍未得到充分探索。我们研究了肿瘤同源重组(HR)缺陷状态作为种系BRCA1和BRCA2变异致病性的预测因子的整合,建立了HR缺陷与这些基因的种系致病变异之间的联系。方法:我们分析了来自350名患者的乳腺肿瘤全基因组序列和匹配的生殖系数据,这些数据来自四个数据集:家族性乳腺癌(N = 77)、癌症基因组图谱(TCGA-BRCA, N = 96)、MAGIC研究(N = 136)和Q-IMPROvE (N = 41)。BRCA1、BRCA2和其他癌症基因(ATM、BARD1、BRIP1、CHEK2、PALB2、PTEN、RAD51C、RAD51D、TP53)共有15,156种系变异(包括结构变异)进行了变异培养。根据种系分类将患者分为BRCA1阳性(N = 27)、BRCA2阳性(N = 21)和BRCA1/2阴性(N = 232),不包括具有不确定意义的BRCA1/2变异(N = 8)和其他癌症基因致病性或仅不确定变异(N = 62)的患者。躯体HR状态(缺乏或熟练)预测使用三种算法:HRDetect, CHORD和HRDsum。hr缺陷和hr精通状态是种系BRCA1/2致病变异状态的显著预测因子(阳性和阴性方向)。结果:CHORD算法对BRCA1和BRCA2亚型进行了特异性估计,增加了对相应基因致病性证据的准确性,达到了相关基因亚型的致病性中等强度。最后,我们评估了BRCA1和BRCA2中意义不确定的变异的CHORD HR预测,并报告了它们的肿瘤HR状态,作为变异管理的潜在额外证据。解释:对多个肿瘤全基因组测序数据集的分析表明,HR状态预测算法可以分离BRCA1和BRCA2致病变异的谱,并在增加权重时提供进一步的证据,以帮助对种系BRCA1和BRCA2变异进行分类。肿瘤测序为减少种系变异解释的不确定性提供了一种有前途的策略。资助:本研究由国家乳腺癌基金会资助。
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引用次数: 0
Serological and faecal markers of irritable bowel syndrome: a systematic review and meta-analysis. 肠易激综合征的血清学和粪便标志物:系统回顾和荟萃分析。
IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2026-03-06 DOI: 10.1016/j.ebiom.2026.106198
Grace L Burns, Freya Roberts, Jasmine A Wark, Sophie Fowler, Michael P Jones, Kerith Duncanson, Nicholas J Talley, Simon Keely
<p><strong>Background: </strong>The irritable bowel syndrome (IBS) has long been considered a functional disorder, but recent work has demonstrated clear biological signatures in immune, microbiome and enteric nervous systems of patients with IBS. Despite this new knowledge, there is still no clear biological marker of IBS, with patient symptom reporting and exclusion of organic disease the main criteria for diagnosis. We aimed to perform a systematic review and meta-analysis to identify consistent biomarkers for IBS in serum and stool samples.</p><p><strong>Methods: </strong>We searched Medline, EMBASE, Cochrane Library, Web of Science and Scopus to obtain all relevant publications published between 1992 and January 2026. Original, peer-reviewed research articles including adults with IBS and healthy or outpatient controls, and/or patients with organic gastrointestinal conditions (e.g. IBD) were included. All articles had quantification of blood and faecal markers between IBS and controls. Descriptive data presented as median and range or median (interquartile range) was converted to mean ± SD. To account for methodological assay differences between studies, standardised mean difference (SMD) with 95% confidence interval was used as the primary outcome measure for the meta-analyses, with a random effects model fitted to the data.</p><p><strong>Findings: </strong>The search strategy identified 55,444 citations across all databases. 124 studies were included encompassing 14,930 patients with IBS, 7544 healthy/asymptomatic controls and 4317 patients with organic diseases. The top serum discriminators between IBS and healthy controls were TNF-⍺ (13 studies, 1025 controls and 1244 IBS, SMD = 2.74, 95% CI = 0.70, 4.70, p = 0.006), IL-6 (13 studies, 736 controls and 1022 IBS, SMD = 1.87, 95% CI = 0.13, 3.61, p = 0.035) and IFN-ɣ (4 studies, n = 195 controls, n = 372 IBS, SMD = 2.79, 95% CI = 1.07, 4.51, p = 0.002). For faecal markers calprotectin was significantly higher in patients with IBS over controls (11 studies, 1624 controls and 1383 IBS, SMD = 0.75, 95% CI = 0.30, 1.21, p = 0.001), while faecal valerate levels were lower in IBS versus controls (4 studies, 290 controls and 488 IBS, SMD = -0.79, 95% CI = -1.48, -0.11, p = 0.02). For discriminating IBS overall from organic diseases, serum albumin (4 studies, 282 IBS and 312 organic, SMD = 2.15, 95% CI = 0.20, 4.11, p = 0.031) and faecal calprotectin (16 studies, 1591 IBS and 1685 organic, SMD = -1.13, 95% CI = -1.51, -0.75, p < 0.0001) were significantly different. In discriminating IBS subtypes from controls, only diarrhoeal IBS (IBS-D) could be distinguished by albumin (3 studies, 248 controls and 219 IBS-D, SMD = -0.39, 95% CI = -0.68, -0.11, p = 0.007) and IL-6 (4 studies, 153 IBS-D and 169 controls, SMD = 2.53, 95% CI = 0.86, 4.21, p = 0.003). Heterogeneity across the studies ranged from moderate to high, but few overly influential studies were identified between comparisons.</p><p><strong>In
背景:肠易激综合征(IBS)长期以来被认为是一种功能性疾病,但最近的研究表明,IBS患者的免疫、微生物组和肠神经系统具有明确的生物学特征。尽管有了这些新知识,IBS仍然没有明确的生物学标志物,患者症状报告和排除器质性疾病是诊断的主要标准。我们的目的是进行系统回顾和荟萃分析,以确定血清和粪便样本中肠易激综合征的一致生物标志物。方法:检索Medline、EMBASE、Cochrane Library、Web of Science和Scopus,获取1992年至2026年1月间发表的所有相关文献。原始的,同行评审的研究文章包括成人肠易激综合征和健康或门诊对照,和/或有机胃肠道疾病(如肠易激综合征)患者。所有文章都有IBS和对照组之间的血液和粪便标记物的定量。描述性数据以中位数和极差或中位数(四分位间距)表示,转换为平均值±SD。为了解释研究之间的方法学分析差异,采用95%置信区间的标准化平均差(SMD)作为meta分析的主要结果测量,并对数据进行随机效应模型拟合。研究结果:该搜索策略在所有数据库中确定了55,444条引用。124项研究纳入了14930例肠易激综合征患者,7544例健康/无症状对照和4317例器质性疾病患者。IBS与健康对照之间的主要血清鉴别因子为TNF-(13项研究,1025例对照和1244例IBS, SMD = 2.74, 95% CI = 0.70, 4.70, p = 0.006)、IL-6(13项研究,736例对照和1022例IBS, SMD = 1.87, 95% CI = 0.13, 3.61, p = 0.035)和IFN-(4项研究,195例对照,372例IBS, SMD = 2.79, 95% CI = 1.07, 4.51, p = 0.002)。肠易激综合征患者的粪便标记物钙保护蛋白明显高于对照组(11项研究,1624例对照组和1383例肠易激综合征,SMD = 0.75, 95% CI = 0.30, 1.21, p = 0.001),而肠易激综合征患者的粪便中缬氨酸水平低于对照组(4项研究,290例对照组和488例肠易激综合征,SMD = -0.79, 95% CI = -1.48, -0.11, p = 0.02)。在区分肠易激综合征与器质性疾病时,血清白蛋白(4项研究,282例肠易激综合征和312例器质性疾病,SMD = 2.15, 95% CI = 0.20, 4.11, p = 0.031)和粪便钙保护蛋白(16项研究,1591例肠易激综合征和1685例器质性疾病,SMD = -1.13, 95% CI = -1.51, -0.75, p < 0.0001)存在显著差异。在区分IBS亚型和对照组时,只有腹泻IBS (IBS- d)可以通过白蛋白(3项研究,248例对照和219例IBS- d, SMD = -0.39, 95% CI = -0.68, -0.11, p = 0.007)和IL-6(4项研究,153例IBS- d和169例对照,SMD = 2.53, 95% CI = 0.86, 4.21, p = 0.003)来区分。研究的异质性从中等到高度不等,但在比较之间发现的影响过大的研究很少。解释:IBS患者表现出外周细胞因子水平升高,这与报道的上皮通透性增加一致,这可能是区分IBS患者亚组的重要因素。肠易激综合征患者的粪便钙保护蛋白水平也高于健康个体,尽管这些水平仍显著低于器质性疾病患者。同样,与健康对照相比,IBS- d患者的血清白蛋白水平较低,而器质性疾病患者的血清白蛋白水平低于IBS患者,无论其亚型如何。在肠易激综合征患者中,有明确的生物学特征在发挥作用,这可能对建立肠易激综合征的临床诊断有用,并可能表明疾病症状的机制。资助:国家卫生和医学研究委员会消化健康卓越研究中心(NJT, SK) G180219。
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引用次数: 0
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。
{"title":"Epigenome-wide analysis in West Africans identifies DNA methylation markers for circulating adiponectin.","authors":"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","doi":"10.1016/j.ebiom.2026.106192","DOIUrl":"10.1016/j.ebiom.2026.106192","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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).</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>National Institutes of Health and European Research Council.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"126 ","pages":"106192"},"PeriodicalIF":10.8,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12993010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371951","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
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)。
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EBioMedicine
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