EBioMedicine最新文献

{"title":"Contributions of inherited mtDNA to longevity: evidence from extended pedigrees with 176 million kinship pairs.","authors":"S Alexandra Burt, S Mason Garrison, Xuanyu Lyu, Joseph L Rodgers, Sarah L Carroll, Ken R Smith, Michael D Hunter","doi":"10.1016/j.ebiom.2025.105911","DOIUrl":"10.1016/j.ebiom.2025.105911","url":null,"abstract":"<p><strong>Background: </strong>Mitochondria are bacteria-like organelles with their own DNA (mtDNA) that exist in the cellular cytoplasm of almost every cell in the human body. Because mitochondria are critical for sustaining life, it follows that inherited mtDNA could be a key aetiologic element underlying longevity. Unfortunately, biometric approaches able to quantify heritable contributions of mtDNA have not been available.</p><p><strong>Methods: </strong>We directly leveraged the unique matrilineal inheritance pattern of mtDNA to estimate its effects on longevity (defined as the top 10% oldest survivors within their birth cohort). We employed the Utah Population Database (UPDB) to identify 176,348,110 unique kinship links amongst 1,018,929 individuals born between 1700 and 1925 with information on matrilineal versus patrilineal relatedness.</p><p><strong>Findings: </strong>Across 1st, 2nd, 3rd, 4th, and 5th degree kin, matrilineal relatives were more similar in their longevity outcomes than were non-maternal relatives. Variance component analyses indicated nuclear DNA heritability of 23-26% and mtDNA heritability of at least 5% - despite mtDNA constituting only ∼16.6 k base pairs (versus 2,875,002 k base pairs for nuclear DNA). Moreover, sharing the maternal line of a longevous relative translated to an average of 11.3 months extra years of life.</p><p><strong>Interpretation: </strong>Results collectively suggest that mtDNA may be an important element of unusually long lifespans.</p><p><strong>Funding: </strong>This project was supported by RF1-AG073189 and R01-AG022095 from the National Institute on Aging (NIA). We also acknowledge partial support through grant P30-CA2014 from the National Cancer Institute, University of Utah, and from the University of Utah's program in Personalized Health and Utah Clinical and Translational Science Institute.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105911"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota regulates exercise-induced hormetic modulation of cognitive function.","authors":"Elisa Cintado, Pablo Muela, Lucía Martín-Rodríguez, Ignacio Alcaide, Patricia Tezanos, Klara Vlckova, Benjamín Valderrama, Thomaz F S Bastiaanssen, María Rodríguez-Muñoz, María L de Ceballos, María R Aburto, John F Cryan, José Luis Trejo","doi":"10.1016/j.ebiom.2025.105876","DOIUrl":"10.1016/j.ebiom.2025.105876","url":null,"abstract":"<p><strong>Background: </strong>Lifestyle factors, particularly physical exercise, significantly influence brain structure and cognitive function through a hormetic effect -a phenomenon where low to moderate doses of a stimulus (in this case, exercise) induce beneficial adaptations, while excessive doses could lead to detrimental effects. This effect depends on exercise intensity and duration, though the underlying mechanisms remain largely unexplored. Recently, the gut microbiota has emerged as potent modulator of lifestyle-induced changes in brain and behaviour.</p><p><strong>Methods: </strong>We used a 40-min, 1200 cm/min exercise protocol. We measured cognition through several tests and analysed microbiota composition comparing adult exercised animals to sedentary controls. Finally, we performed fecal microbiota transplantation from exercised to sedentary mice.</p><p><strong>Findings: </strong>Exercise enhances cognitive abilities related to object recognition and object location memory, as well as increases hippocampal neurogenesis. However, these cognitive and neurogenic benefits vanish when the exercise intensity or duration is increased. Furthermore, we identified significant changes in alpha and beta diversity and distinct bacteria composition profiles in the gut microbiota associated with different exercise regimens. Specific bacterial families showed altered relative abundances depending on exercise intensity and duration, with certain families' quantities significantly correlating with cognitive performance (Angelakisella, Acetatifactor, Erysipelatoclostridium, and Coriobacteriaceae UCG-002.). To explore causal mechanisms, we performed fecal microbiota transplantation from exercised to sedentary mice, which replicated the cognitive and neurogenic changes observed in the donor animals.</p><p><strong>Interpretation: </strong>These findings suggest that the hormetic effects of physical exercise on cognitive function and neurogenesis are mediated by corresponding changes in the gut microbiota, highlighting a novel mechanistic link between exercise, brain function, and gut microbiota composition.</p><p><strong>Funding: </strong>E.C. and P.M. were funded by predoctoral fellowship (FPI) grants from the Spanish Ministry of Economy and Competitiveness (BES-2017/080415 E.C.) and the Spanish Ministry of Science and Innovation (PRE2020/093032 P.M.), and P.T. by a predoctoral fellowship (FPU) from the Spanish Ministry of Universities (18/00069). Work was supported by project grants PID2019-110292RB-100 and PID2022-136891NB-I00 (from Spanish Ministry of Science and Innovation), (to J.L.T.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105876"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baseline α-synuclein seeding activity and disease progression in sporadic and genetic Parkinson's disease in the PPMI cohort.","authors":"Jackson G Schumacher, Xinyuan Zhang, Eric A Macklin, Jian Wang, Armin Bayati, Johannes M Dijkstra, Hirohisa Watanabe, Michael A Schwarzschild, Marianna Cortese, Xuehong Zhang, Xiqun Chen","doi":"10.1016/j.ebiom.2025.105866","DOIUrl":"10.1016/j.ebiom.2025.105866","url":null,"abstract":"<p><strong>Background: </strong>α-Synuclein (α-syn) seed amplification assays (SAAs) have shown remarkable potential in diagnosing Parkinson's disease (PD). Using data from the Parkinson's Progression Markers Initiative (PPMI) cohort, we aimed to test whether baseline α-syn seeding activity and α-syn SAA kinetic parameters are associated with disease progression in sporadic PD, LRRK2-associated PD (LRRK2 PD), and GBA-associated PD (GBA PD).</p><p><strong>Methods: </strong>We analysed 7 years of motor, non-motor, and cognitive assessments and 5 years of dopamine transporter imaging along with baseline α-syn SAA results from 564 PPMI participants (n = 332 sporadic PD, 162 LRRK2 PD, and 70 GBA PD) using linear mixed-effects models, adjusted for potential confounders, to test whether baseline α-syn SAA positivity (n = 315 sporadic PD, 111 LRRK2 PD, and 66 GBA PD) and α-syn SAA kinetic parameters are associated with PD progression.</p><p><strong>Findings: </strong>While non-statistically significant, there was a trend towards faster motor decline in participants with α-syn SAA positive LRRK2 PD compared to those with α-syn SAA negative LRRK2 PD (MDS-UPDRS III points per year: 2.39 (95% confidence interval: 1.86-2.92) vs. 1.76 (0.93-2.60); difference = 0.63 (-0.29 to 1.55, p = 0.18). This trend appeared to be driven by R1441C/G + M1646T carriers (3.89 (1.22-6.55) vs. 0.31 (-1.32 to 1.93); difference = 3.58 (0.56-6.60, p = 0.02) and excluding them eliminated any trend (2.33 (1.79-2.86) vs. 2.26 (1.34-3.18); difference = 0.07 (-0.93 to 1.07, p = 0.89). Based on a clinically meaningful difference of 4.63 points we found no statistically significant or clinically meaningful difference in motor decline between α-syn SAA positive and α-syn SAA negative participants with sporadic PD (2.46 (2.20-2.72) vs. 2.39 (1.36-3.42); difference = 0.07 (-0.99 to 1.12), p = 0.90) or GBA PD (2.67 (1.91-3.44) vs. 2.40 (-0.18 to 4.99); difference = 0.27 (-2.42 to 2.96), p = 0.84). No statistically significant or clinically meaningful differences were seen in the progression of non-motor symptoms, cognition, or DAT imaging. Additionally, we found no clinically meaningful association between α-syn SAA kinetic parameters and PD progression.</p><p><strong>Interpretation: </strong>We found no statistically significant associations between baseline α-syn seeding activity, α-syn SAA kinetic parameters, and PD progression among manifest patients in the PPMI cohort. Future studies are needed to further investigate relationships among α-syn seeding activity, disease heterogeneity, disease stage, and PD progression.</p><p><strong>Funding: </strong>This research was funded by Aligning Science Across Parkinson's grant ASAP-237603 through the Michael J. Fox Foundation for Parkinson's Research and by the National Institutes of Health through the National Institute of Neurological Disorders and Stroke grants R01NS102735 and 5R01NS126260.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105866"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights from a Pseudo-Polygyny Cohort unmasking high sperm concentration and low forward motility as potential risk factors for recurrent failure of sperm donation IVF (RFDI), a subset of unexplained male infertility (UMI).","authors":"Tiancheng Zhang, Fan Dong, Xu Zhang, Ping Ping, Jin Qiu, Zhen Lu, Huachun Zou, Qian Xiao, Jianhui Li, Gaoyue Zhang, Huijuan Shi, Xiangfeng Chen","doi":"10.1016/j.ebiom.2025.105871","DOIUrl":"10.1016/j.ebiom.2025.105871","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Unexplained male infertility (UMI) accounts for 15%-30% of cases of male infertility, but it is poorly understood. We investigated potential risk factors for UMI leveraging data from a sperm bank with a \"one male to multiple females\" structure to reduce confounding arising from female factors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Data on sperm donation provided by the Shanghai Human Sperm Bank (SHSB) to 39 qualified reproduction centres across China, along with information on IVF (In Vitro Fertilization) donor insemination cycles (DICs) performed at these centres and their reported outcomes, were retrieved from the Shanghai Human Sperm Bank (SHSB) for the period from 2004 to 2018. The association between semen parameters, demographic factors, and Cumulative Live Birth Rate from Donor Insemination (cLBR -DI) was analysed using linear regression analysis. Recurrent Failure of Sperm Donation IVF (RFDI) was defined as ≤1 pregnancy despite ≥4 DICs (indicating a cLBR -DI of ≤25%). Progressive Motility Rate (PR) refers to the percentage of grade (a + b) sperm among all sperm ((a + b)/(a + b + c + d)%). Forward Motility Rate (FR) refers to the percentage of grade (a + b) sperm among (a + b + c) sperm ((a + b)/(a + b + c)%). Sperm concentration&lt;100 × 10&lt;sup&gt;6&lt;/sup&gt;/mL and FR &gt; 95% was termed as normal group. The group with sperm concentration&gt;200 × 10&lt;sup&gt;6&lt;/sup&gt;/mL or FR &lt; 90% was termed high-risk RFDI (HR-RFDI). Logistic regression was used to assess correlations of RFDI. Propensity score matching (PSM) was used to match the RFDI and non-RFDI populations. Miscarriage conditions were also analysed in this study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;We included 4734 qualifying sperm donors and 17,307 IVF DICs, of which 2447 donors had more than 4 DICs per donor, forming a Pseudo-Polygyny Cohort. 8.05% of the 2447 donors with normal semen parameters and more than 4 DICs met RFDI criteria. RFDI donors exhibited higher sperm concentration (96.00 [75.00, 130.00] vs. 90.00 [72.00, 122.22], p = 0.057) and lower Forward Motility Rate (95.12 [89.02, 97.01] vs. 96.59 [93.33, 97.30], p &lt; 0.001) compared to non-RFDI. Forward Motility Rate, rather than Progressive Motility Rate, correlated with cLBR -DI Compared to the normal group, HR-RFDI had an over three-fold higher risk of RFDI before (RR = 3.48, 95% CI [1.94, 6.25], p &lt; 0.0001) and after (OR = 3.04, 95% CI [1.92, 4.81], p &lt; 0.0001) PSM adjustment. Notably, RFDI donors had higher miscarriage rates (10.80 ± 14.20% vs. 3.90 ± 8.50%, p &lt; 0.0001) compared to non-RFDI donors. High-risk RFDI donors also had higher miscarriage rates (5.40 ± 9.20% vs. 4.20 ± 9.40%, p = 0.011) compared to low-risk RFDI donors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;The negative impact of high sperm concentration on pseudo-polygyny cohort in vitro fertilization (IVF) outcomes strongly supports the hypothesis of a potential \"inverted U-shape\" relationship between sperm concentration and fertility. The superior correl","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105871"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential regulation of FADS2 by EZH2 reveals a metabolic vulnerability in ovarian cancer treatment.","authors":"Zhengyang Guo, Yuqing Wang, Jiagui Song, Ying Song, Yang Bai, Yinjia Li, Jianling Yang, Tong Liu, Lijun Ma, Celina G Kleer, Xiao Huo, Lixiang Xue","doi":"10.1016/j.ebiom.2025.105879","DOIUrl":"10.1016/j.ebiom.2025.105879","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Ovarian cancer (OC) is the most aggressive and lethal gynaecological cancer and is characterised by abnormal lipid metabolism. Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2). It functions as a tumour promoter through both canonical H3K27me3 modification and noncanonical mechanisms. Although EZH2 has been developed as a potential anticancer target, the therapeutic effects of EZH2 inhibitors in solid tumours are still limited.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The levels of fatty acid and tricarboxylic acid (TCA) cycle-related metabolites were measured via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). EZH2-knockout cells, ChIP‒qPCR, qPCR, and western blotting were used to investigate the regulatory effect of EZH2 on FADS2. The expression of FADS2 transcript variants and their correlations with prognosis in clinical OC tissues were analysed via the GEPIA 2 database. Various OC cell lines, patient-derived organoids and tumour-bearing models have been used to test the therapeutic effects of EZH2 and FADS2 inhibitors. 4D-DIA proteomics, the Seahorse assay and flow cytometry-based detection of mitochondrial function and protein synthesis were performed to explore the mechanism of combined therapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;EZH2 knockout increased FADS2 variant 1 (v1) and decreased variant 2/3 (v2/3) at both the mRNA and protein levels. EZH2 occupied the promoters of FADS2 v1 and v2/3, but the enrichment of H3K27me3 at the v2/v3 promoter was significantly lower than that at the v1 promoter. Furthermore, EZH2 inhibitors increased full-length FADS2 v1 expression and polyunsaturated fatty acid abundance in OC cells. A high FADS2 v1/v2 ratio was associated with poor prognosis in patients with OC. Targeting FADS2 with shRNAs or inhibitors reduced EZH2 levels and sensitised cancer cells to EZH2 inhibitors. The combined inhibition of EZH2 and FADS2 induced mitochondrial dysfunction and energy stress and synergised to reduce tumour growth in vitro and in vivo.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;EZH2 inhibition increases the proportion of the full FADS2 isoform through differential regulation, which suggests a poor prognosis in OC patients. Simultaneous inhibition of EZH2 and FADS2 causes mitochondrial dysfunction and energy stress in OC, resulting in a more pronounced antitumour effect. Our study reveals a mechanistic connection between EZH2 and FADS2 and provides a potential therapeutic strategy for OC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This work was supported by the Youth Program of the National Natural Science Foundation of China (No. 82203102, No. 82303801, No. 82203433), the National Key Research and Development Program of China (2022YFA1104001), the General Program of the National Natural Science Foundation of China (No. 82272745, No. 82072870, No. 81972966, No. 82373173, No. 82073057), and the Peking University Third Hospital Clini","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105879"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional and clinical insights into nuclear receptor variants for advancing precision diagnostics in male infertility.","authors":"Avinash S Gaikwad, Margot J Wyrwoll, Sophie A Koser, Jana Emich, Johanna Kuß, Mariya Aravina, Claudia Krallmann, Jörg Gromoll, Sabine Kliesch, Sandra Laurentino, Birgit Stallmeyer, Corinna Friedrich, Frank Tüttelmann","doi":"10.1016/j.ebiom.2025.105899","DOIUrl":"10.1016/j.ebiom.2025.105899","url":null,"abstract":"<p><strong>Background: </strong>Nuclear receptors, including steroidogenic factor 1 (NR5A1/SF1) and the androgen receptor (AR), are transcription factors regulating physiological processes, e.g., reproduction. Pathogenic variants in these receptors are associated with a broad spectrum of phenotypes, ranging from differences in sexual development to isolated male infertility. However, standardised methods to classify variants of uncertain significance (VUS) in these genes are lacking, complicating diagnosis and individualised treatment.</p><p><strong>Methods: </strong>We queried rare NR5A1 and AR variants in exome/genome sequencing data of 2127 infertile men. Pathogenicity assessment included thorough clinical phenotyping, familial segregation, in silico pathogenicity prediction combining traditional and machine-learning tools, and functional evaluation of the variants using in vitro assays.</p><p><strong>Findings: </strong>We identified a total of seven heterozygous NR5A1 variants in 10 infertile men and 22 hemizygous AR variants in 31 infertile men with severe oligo-/azoospermia. Of these, three SF1 and seven AR variants displayed significantly reduced transcriptional activity. This study led to the reclassification of one NR5A1 variant and ten AR variants, including three AR variants that were reclassified from VUS to (likely) pathogenic. Combined phenotype, in silico, and in vitro data led to 60% of all variants (17 out of 29) being classified as (likely) pathogenic per ACMG guidelines, providing insights into the phenotypic features and spermatogenic impairment in affected men.</p><p><strong>Interpretation: </strong>This study highlights the importance of combining clinical and experimental data for the assessment of VUS in nuclear receptors to reliably classify pathogenicity and to improve patient diagnosis and care.</p><p><strong>Funding: </strong>This study was carried out within the frame of the Deutsche Forschungsgemeinschaft (DFG)-sponsored Clinical Research Unit 'Male Germ Cells' (CRU326, project 329621271, to F.T., C.F., S.L., and J.G.) and the German Federal Ministry of Education and Research (BMBF)-sponsored Junior Scientist Research Centre 'ReproTrack.MS' (grant 01GR2303, to F.T. and S.K.), and was supported by the Medical Faculty Münster via an Innovative Medical Research (IMF) grant (GA-122104, to A.S.G.) and the Clinician Scientist programme CareerS (to S.A.K.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105899"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A sensitive and specific non-invasive urine biomarker panel for prostate cancer detection.","authors":"Menglang Yuan, Marcio Covas Moschovas, Kandarp Joshi, Yohei Sanada, Roshane A Perera, Bongyong Lee, Rudramani Pokhrel, Jiri Polivka, Alexandra Miller, Ernest K Amankwah, Ignacio Gonzalez-Gomez, Naren Nimmagadda, Ezra Baraban, Anant Jaiswal, Cuncong Zhong, Inoel Rivera, Guru P Sonpavde, Chetan Bettegowda, Vipul Patel, Christian P Pavlovich, Ranjan J Perera","doi":"10.1016/j.ebiom.2025.105895","DOIUrl":"10.1016/j.ebiom.2025.105895","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) is one of the leading causes of cancer death in men. While prostate-specific antigen (PSA) testing is widely used for screening, its diagnostic accuracy is limited, often failing to distinguish between benign and malignant prostate conditions, underscoring the need for novel biomarkers with improved diagnostic performance. This study aimed to identify and validate a panel of urinary RNA biomarkers with improved diagnostic accuracy for PCa.</p><p><strong>Methods: </strong>RNA-sequencing analysis of exfoliated cells in urine specimens identified 50 candidate RNAs. After initial qPCR testing in pooled urine, three biomarkers (TTC3, H4C5, EPCAM) with optimal specificity and sensitivity were selected as a biomarker panel. Diagnostic performance was evaluated in a case-control study divided into development (n = 243 participants) and validation (n = 646 participants) datasets. Biomarker expression was confirmed in tissue specimens, and the oncogenic function of TTC3 was assessed in vitro and in vivo.</p><p><strong>Findings: </strong>The three-biomarker urine panel robustly identified PCa with an area under the curve (AUC) of 0.96 (95% CI: 0.94-0.98) compared to 0.83 (95% CI: 0.77-0.88) for urinary prostate cancer antigen 3 (PCA3) RNA in the development dataset and 0.92 (95% CI: 0.89-0.94) compared to 0.76 (95% CI: 0.72-0.80) for PCA3 in the validation dataset. Urine biomarkers were nearly eliminated post-prostatectomy and were confirmed to originate from prostate tissue at both the RNA and protein levels. The panel maintained high diagnostic accuracy of PSA-negative PCa cases and distinguished PCa from benign prostate conditions (BPH, prostatitis). Functional studies demonstrated that TTC3 depletion significantly suppressed in vitro and in vivo tumour growth.</p><p><strong>Interpretation: </strong>This urine-based biomarker panel offers a promising sensitive and specific noninvasive diagnostic for PCa with the potential to form the basis for laboratory-developed and in vitro diagnostic assays.</p><p><strong>Funding: </strong>This study was supported by the International Prostate Cancer Foundation, JHU SKCCC (grant number P30CA006973), and Bankhead-Coley Cancer Research Program (grant number 24B16) to R. J. Perera and by the Maryland Innovation Initiative Grant to C. P. Pavlovich and R. J. Perera.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105895"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to 'Post COVID 19 resurgence of diphtheria in Kano, Nigeria: analysis of 18,320 cases' [EBioMedicine 2025 Jul 25:118:105877].","authors":"Muhammad Adamu Abbas, Abubakar Labaran Yusuf, Hassan Adam Murtala, Aisha Adam Abdullahi, Adam Muhammad Murtala, Jordi Bertran Torrelles, Muktar Hassan Aliyu, Hamisu Mohammed Salihu","doi":"10.1016/j.ebiom.2025.105901","DOIUrl":"10.1016/j.ebiom.2025.105901","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105901"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triheptanoin treatment in ataxia-telangiectasia: the significance of innovative clinical trials targeting mitochondrial dysfunction.","authors":"Osamu Onodera","doi":"10.1016/j.ebiom.2025.105882","DOIUrl":"10.1016/j.ebiom.2025.105882","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105882"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating cytotoxic and inflammatory human IL-7 receptor low effector memory CD8⁺ T cells in lupus.","authors":"Sang Jin Lee, Min Sun Shin, Yeon-Joo Lee, Lais Osmani, Won Jae Seong, Helen Cai, Jennefer Par-Young, Jong Gyun Ahn, Hong-Jai Park, Minhyung Kim, Serhan Unlu, Hyoungsu Kim, Man Hoon Han, Xuemei Dong, Sungyong You, Eun Bong Lee, Insoo Kang","doi":"10.1016/j.ebiom.2025.105898","DOIUrl":"10.1016/j.ebiom.2025.105898","url":null,"abstract":"<p><strong>Background: </strong>This study aims to interrogate the implications of CD8⁺ T cells in lupus by examining CD8⁺ T cell heterogeneity and assessing the significance of this heterogeneity in promoting inflammation and tissue damage.</p><p><strong>Methods: </strong>Our own and publicly available RNA-seq and microarray data from the peripheral blood and kidney tissues of patients with lupus were analysed. Imaging Mass Cytometry (IMC) analysis of immune cells was conducted in lupus and normal kidney tissues. The effects of CD8⁺ T cell subsets on neutrophils were evaluated ex vivo.</p><p><strong>Findings: </strong>Our scRNA-seq analysis showed an accumulation of effector memory (EM) CD8⁺ T cell subsets that expressed low levels of the IL7 receptor gene (IL7R^low) but high levels of effector molecule genes, including GZMB, GZMK, PRF1, and GNLY, in the peripheral blood and kidneys of patients with lupus. CD8⁺ T cell infiltrations and cytotoxic molecule expression in lupus kidney tissues were associated with treatment outcomes, as determined by IMC. The gene signatures of IL7R^low CD8⁺ T cell subsets correlated with type I IFN gene signature in the peripheral blood of paediatric and adult patients with lupus. IL7R^low EM CD8⁺ T cells induced neutrophil extracellular trap (NET), a key inflammatory pathway in lupus pathogenesis, dependently of TNF-α and IFN-γ.</p><p><strong>Interpretation: </strong>Our study provides insights into lupus pathogenesis by demonstrating the clinical and biological implications of cytotoxic and inflammatory IL7R^low EM CD8⁺ T cell accumulation in lupus. This raises the prospect of therapeutic targets aimed at such CD8⁺ T cells.</p><p><strong>Funding: </strong>Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00249,430) as well as by the National Institutes of Health (1R01AR082203 and 2RF1AG056728 to IK, 5T32AR007107 to LO and JPY) and the Rheumatology Research Foundation (to IK).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"119 ","pages":"105898"},"PeriodicalIF":10.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946917","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}