EBioMedicine最新文献

Background: Cholesterol is a main contributor to coronary artery disease (CAD). Although the genetic basis of blood cholesterol concentration is well studied, there is currently a lack of studies investigating the genetics of its precursors from de novo biosynthesis.

Methods: We conducted a genome-wide association meta-analysis, combining data from KORA, LIFE-Heart, LIFE-Adult, LURIC, the Sorbs study, and YFS, resulting in up to 10,519 individuals. We investigated 14 traits related to serum concentrations of lanosterol, desmosterol, and cholesterol. Direct and indirect effects of lanosterol on CAD were investigated with a Mendelian randomisation mediation analysis.

Findings: Our analysis revealed four genome-wide significant (p < 5 × 10^-8) associations not previously reported in the GWAS catalogue. These include two loci without prior connection to cholesterol, associated with lanosterol (7q21.2, CYP51A1) and free cholesterol (11q14.1), and two associations with lanosterol at loci previously reported for cholesterol (5q13.3, HMGCR; 11q23.3, APO cluster). We also replicated eight loci previously reported for associations with cholesterol-related traits. Lanosterol exhibited significant total and indirect effects on CAD, but its direct effect was not significant.

Interpretation: We demonstrate that the investigation of intermediate phenotypes can help to functionally fine map previously reported associations for cholesterol, improving our understanding of genetic regulation of cholesterol concentrations. Further, the effect of lanosterol on CAD is probably fully mediated by total cholesterol.

Funding: This investigation was primarily funded by the ministry for science and health of the Rhineland-Palatinate through the CoAGE graduate programme. A complete list of funding organisations is provided in the acknowledgements.

Background: Fibroblast behaviour is a key determinant of outcomes in interstitial lung diseases (ILDs), yet mechanisms governing the switch between reversible repair and progressive fibrosis remain unclear. How disease-specific cellular niches shape fibroblast fate across ILD phenotypes has not been compared in situ.

Methods: We profiled peripheral lung tissues from controls, organising pneumonia (OP), connective tissue disease-associated ILD (CTD-ILD), and idiopathic pulmonary fibrosis (IPF) using High-Definition Visium spatial transcriptomics. A matched single-cell RNA-seq atlas was integrated via robust cell-type deconvolution to map cellular neighbourhoods. Differential expression and pathway activity were validated by immunofluorescence. Predicted ligand-receptor mechanisms and fibroblast responses were tested in vitro under glucocorticoid (GC), TGF-β1, and B-cell/MIF perturbations with receptor blockade.

Findings: Disease-specific niches were tightly coupled to fibroblast states. OP exhibited B-cell-AT2-myofibroblast-enriched niches with high GC responsiveness and apoptosis. IPF was dominated by bronchiolised epithelium, alongside myofibroblasts exhibiting glucocorticoid resistance and strong matrix programmes. CTD-ILD exhibited macrophage-rich niches with multinucleated giant cells. In vitro, GC induced NR3C1-mediated apoptosis in fibroblasts, whereas TGF-β1 drove a senescent, GC-resistant phenotype. IgD + B-cell-derived MIF enhanced fibroblast migration via CD74, an effect blunted by TGF-β1. Thus, niche composition dictates fibroblast fate, distinguishing GC-sensitive resolution from apoptosis-resistant fibrosis.

Interpretation: A GC-sensitive, apoptosis-prone myofibroblast niche in OP may underpin reversibility, whereas CTD-ILD and IPF follow distinct trajectories driven by immune dysregulation and epithelial-stromal maladaptation. These spatial microenvironmental signatures nominate therapeutic targets and may inform precision therapy for fibrotic lung disease.

Funding: The National Natural Science Foundation of China (82172109 to L.X., 82570001 to H.C.), the Ministry of Science and Technology of the People's Republic of China (2023YFC3502605, 2024YFA1108906) (H.C.), the Natural Science Foundation of Tianjin, China (25JCZDJC01260) (H.C.); the Key Laboratory of Medical Rescue Key Technology and Equipment, Ministry of Emergency Management (Open Fund Project No. YJBKFKT202410).

Background: Neuroblastoma and Wilms tumour (WT) are common childhood embryonal malignancies. Germline 2p24 duplication has been reported in several cases of neuroblastoma and WT, either as part of a larger 2p duplication or as a microduplication involving just 2p24.3. Although the larger duplications involve many genes, including ALK, the microduplications have been localised to a region including MYCN and DDX1.

Methods: We analysed Whole Genome Sequence data from adults and children sequenced for various indications. We utilised a workflow to extract structural and copy number variants, filtered to include duplications or gains of 2 kb-20 Mb, including these loci, followed by manual inspection in IGV. Associations were assessed using Fisher's exact test. Penetrance was estimated by Bayesian calculation of the conditional probability of disease.

Findings: Among 113,431 genomes, there were 6 participants with a microduplication that included the MYCN locus. Of these, two had a diagnosis of WT and one of neuroblastoma. The 2p24.3 microduplication was therefore identified in 3/197 with a definite history of WT/neuroblastoma and 3/113,234 without such a history (p < 0.0001). Penetrance is estimated to be 13%. Twelve participants were identified with a 2p24.3 microduplication that included the DDX1 locus but not MYCN, none of whom received a diagnosis of a childhood embryonal tumour.

Interpretation: We have shown that 2p24.3 microduplications that include MYCN predispose to childhood embryonal tumours and should be routinely assessed when WT or neuroblastoma predisposition is suspected. We have also shown that there does not appear to be any increased incidence of childhood tumours when DDX1 alone is duplicated.

Funding: UCL Great Ormond Street Institute of Child Health Child Health Research CIO PhD Studentship, Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK and the National Institute for Health Research.

Background: Metabolomics is a valuable tool for characterising biological mechanisms involved in cancer development, but produces complex datasets with intricate interdependencies. While linear dimension reduction techniques such as principal component analysis (PCA), have proven useful to summarise informative hidden patterns, biological evidence suggests metabolic relationships extend beyond linearity. Non-linear dimension reduction techniques, such as autoencoders (AEs), may identify more meaningful components.

Methods: We applied AEs and PCA to metabolomic data available for 5828 matched case-control pairs from 8 cancer-specific case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, and compared their performance. We evaluated the association between components identified by AEs and PCA with cancer risk, and explored the biological interpretation of components through their association with genetic factors and selected biomarkers.

Findings: PCA and AEs showed similar reconstruction performance. PCA's first component (PCA.1) captured phosphatidylcholines (PCs) as the primary source of variability and was associated with cancer risk. Conversely, AEs decomposed PC metabolism into two components, one of which exhibited a stronger association with cancer risk than PCA.1. Unlike PCA.1, this component was strongly associated with genetic variants mapping to the TMEM258 and FADS genes, key in polyunsaturated fatty acids (PUFA) biosynthesis and regulation. Consistently, the AE component demonstrated stronger associations with circulating omega-3 and omega-6 PUFA levels than PCA.1.

Interpretation: Linear methods remain adequate for general dimension reduction. However, AEs better captured specific pathways, identifying a component reflecting perturbations in PUFA metabolism associated with cancer risk.

Funding: World Cancer Research Fund (IIG_FULL_2022_013).

Background: Proteins have an integral role in cancer aetiology and inform cancer detection, treatment, and prognosis. While published data from prospective proteomic studies identifying early detection cancer risk markers have rapidly increased in the past five years, the landscape of evidence remains unclear. We aim to synthesise the evidence on circulating proteins and cancer risk.

Methods: We conducted a systematic review and meta-analysis. We searched Embase and Medline up to December 2023 with reference-list screening and hand-searching up to August 2025. Prospective cohort studies were eligible if they used multiplex panels, included adults without cancer diagnosis at baseline, and reported associations between baseline circulating proteins and risk of incident cancer. Based on highest global incidence, we included oesophageal, stomach, colorectal, liver, lung, breast, cervical, prostate, bladder, thyroid cancer. We conducted exome-protein-score and Mendelian-randomisation analyses and integrated exome-gene-burden results for protein associations that passed false-discovery-rate correction to assess protein roles in cancer aetiology.

Findings: Of 4949 articles, we included 26 unique studies comprising 84,129 participants and 14,326 cases. The studies profiled 2434 unique proteins and reported 19,130 total protein-cancer-associations. We conducted 3448 meta-analyses and detected 216 associations (131 significant only in the meta-analyses) that passed false-discovery-rate correction for stomach (n = 2), colorectal (n = 27), lung (n = 172), breast (n = 14), and prostate (n = 1) cancer. No significant associations were observed for bladder cancer. Meta-analyses were not possible for oesophageal, liver, cervical, or thyroid cancer, due to limited data. Supporting genetic evidence was found for 39 protein-cancer-associations.

Interpretation: We identified 131 protein-cancer-associations that reached statistical significance in the meta-analysis, of which some may be cancer markers and others may have aetiological roles, indicated by supporting genetic analyses, including ITGA11 and lung cancer. Our findings highlight the need for large, diverse, and mature prospective proteomic cohort studies of cancer risk to ensure the equity and generalisability of insights into cancer risk.

Funding: AD is funded by the University of Oxford. KSB is funded by Cancer Research UK and UK Research Institute. RCT is funded by Cancer Research UK. The funders had no role in study design, data collection, analysis, decision to publish, or manuscript preparation.

Background: This systematic review examined the duration of measles virus airborne transmissibility after a source case is no longer present to identify evidence gaps in measles contact tracing exposure window guidelines.

Methods: A systematic literature review following PRISMA guidelines was conducted using PubMed, EMBASE, Web of Science, and SCOPUS databases for publications from January 1988 to July 2024. Additional sources were identified through reference list reviews and Google Scholar searches. Studies examining how long the measles virus survives in the air or remains transmissible after an infectious case leaves a public space were included, while editorials, opinion pieces, non-evidence-based recommendations, mathematical models, and publications unrelated to airborne transmission of measles in public environments or not available in English were excluded. Researchers extracted summary data.

Findings: Initial database searches identified 1054 studies, with none meeting initial inclusion criteria after screening. Supplemental searches identified five relevant articles (1964-1987). Two experimental studies and three real-world studies demonstrated measles virus survival between 29 and 120 min, with increasing survival time for lower humidity levels.

Interpretation: Current guidelines for measles contact tracing exposure windows rely on limited research from 1964 to 1987. Additional studies are urgently needed to understand how long the virus is transmissible in real-world settings, particularly given the implications for contact tracing efficiency and resource allocation during outbreak responses.

Funding: U.S. Centers for Disease Control & Prevention (Cooperative Agreement #NU38FT000004).

Background: The COVID-19 pandemic underscored how hospital-acquired co-infections with antimicrobial resistance (AMR) bacteria and respiratory viruses can drive high mortality in critically ill patients. Despite antimicrobial stewardship and vaccines, effective prophylactic solutions remain lacking, highlighting the need for safe, antigen-independent strategies that provide rapid, broad-spectrum protection.

Methods: We tested whether a single intraperitoneal pretreatment with n-dodecyl-β-D-maltoside (DDM) could provide broad prophylaxis. Mice were challenged with clinical isolates of carbapenem-resistant Escherichia coli (CREC) and Pseudomonas aeruginosa (CRPA), methicillin-resistant Staphylococcus aureus (MRSA), or pandemic H1N1 influenza. Mechanistic studies assessed intracellular bacterial killing, immune cell dynamics (flow cytometry, histopathology), and neutrophil depletion, transcriptome, and cytokine profiling.

Findings: A single prophylactic administration of DDM conferred complete protection against lethal CREC, CRPA, and MRSA, while reducing viral titres and mortality in influenza-infected mice. DDM primed innate immunity through rapid neutrophil recruitment and activation, enhancing phagocytosis, bacterial clearance, and expression of effector genes linked to chemotaxis, ROS, and NET formation, predominantly mediated by Gi-dependent signalling pathway. Unlike pathogen-associated molecular pattern (PAMP)-based agents, DDM did not induce systemic inflammation or long-term immune reprogramming. Neutrophil depletion abolished protection, confirming their central role. Furthermore, DDM upregulated interferon-stimulated genes in lung tissue only upon viral infection, conferring selective antiviral immunity while attenuating cytokine-driven pathology.

Interpretation: DDM is a first-in-class, non-PAMP immune primer that rapidly and safely induces neutrophil-driven protection against AMR bacterial sepsis and viral infection, offering a host-directed strategy for cross-pathogen prophylaxis in high-risk settings.

Funding: National Research Foundation of Korea (RS-2023-00219213); Korea Environmental Industry and Technology Institute (2022002980009; 1485018881); Korea Research Institute of Bioscience and Biotechnology Research Initiative Program.