EBioMedicine最新文献

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: Pallidal deep brain stimulation (DBS) has remarkable effects in patients with cervical dystonia. Yet, its neurophysiological mechanisms are not fully resolved to date. Converging evidence suggests that pallidal DBS modulates sensorimotor and cerebellar network activity in dystonia, possibly by disrupting pathologically enhanced low-frequency oscillations in the basal ganglia. Still, anatomical and electrophysiological findings have rarely been linked, and it is unclear whether oscillatory changes occur in the same network identified in neuroimaging studies.

Methods: In this cross-sectional study, we investigate the effects of pallidal DBS in patients with cervical dystonia using magnetoencephalography recordings on and off stimulation. We correlated DBS outcomes to the whole-cortex pattern of DBS-induced power changes in each cortical vertex.

Findings: This analysis revealed a distinct low-frequency electrophysiological signature that accounted for significant amounts of variance in DBS improvements across the cohort. The signature was characterised by negative peaks within the supplementary motor area and the motor cortex as well as positive peaks in prefrontal and cerebellar areas.

Interpretation: Our study sheds light on the cortical and cerebellar effects of pallidal DBS on a whole-cortex level and puts emphasis on low-frequency power modulation as a mechanism of effective stimulation beyond the basal ganglia in patients with cervical dystonia. Our findings might inform DBS programming and targeting as well as non-invasive stimulation strategies in the future.

Funding: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Project-ID 424778381-TRR 295.

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.

Background: Tumour associated macrophages (TAMs) and exhausted T cells are dominant in the immuno-suppressive tumour microenvironment (TME) and pose a challenge to effective cancer immunotherapy in solid tumours.

Methods: In this study, we immunised llamas and generated monovalent and biparatopic nanobodies (Nbs) against colony stimulating factor 1 receptor (CSF-1R) and programmed death receptor 1 (PD-1) to re-educate TAMs and overcome T cell exhaustion, respectively, in the TME. To circumvent short systemic half-life and low peak concentrations of Nbs in the TME, we developed a platform of allogenic off-the-shelf stem cells (SC) releasing biparatopic PD-1 and CSF-1R Nbs and tested its efficacy in different mouse models.

Findings: Nbs targeting CSF-1R and PD-1 inhibited the CSF1/CSF-1R and PD-1/PD-L1 pathways, respectively, with biparatopic Nbs demonstrating superior efficacy and functionality compared with their monovalent counterparts. Locoregional SC mediated release of biparatopic CSF-1R and PD-1 Nbs, reduced tumour growth by increasing T cell numbers, enhancing T cell activation, and by shifting the macrophage polarisation towards a pro-inflammatory phenotype. Moreover, the presence of both Nbs improved dendritic cells (DCs) activation within the TME. Finally, we show that biocompatible gel encapsulated SC releasing Nbs against PD-1 and CSF-1R have therapeutic efficacy in a highly immunosuppressive glioblastoma model post-tumour resection.

Interpretation: Taken together, our findings establish a cell-based Nb platform targeting both innate and adaptive immune axis within the TME, which has the potential to facilitate treatment of solid cancers that are otherwise refractory to conventional immunotherapies.

Funding: This study was mainly supported by Institutional Funds (K.S). A part of in vivo Nb characterisation was supported by NIH grant R01-CA285519 (K.S.) and the Nb dye conjugation and modelling was supported by NIH grant R01-AI165666 (M.R).

Background: Benign adrenal tumours, found in 1-7% of adults, can be non-functioning (NFAT) or show mild autonomous cortisol secretion (MACS), i.e., biochemical cortisol excess without manifestations of Cushing's syndrome (CS). MACS occurs in 20-50% of cases and is linked to increased cardiometabolic burden.

Methods: In a cross-sectional study, we analysed the 24-h urinary steroid metabolome of 1305 prospectively recruited patients (649 NFAT, 591 MACS, 65 adrenal CS) by tandem mass spectrometry. A sub-group (104 NFAT, 140 MACS, 47 adrenal CS) underwent untargeted serum metabolome analysis by mass spectrometry. Data were analysed using linear regression and supervised machine learning.

Findings: Alongside the expected increase in glucocorticoid excretion from NFAT over MACS to adrenal CS, steroid analysis revealed decreased classic androgen metabolite excretion. By contrast, adrenal-derived 11-oxygenated androgen metabolites remained unchanged. Both glucocorticoid metabolites and the major 11-oxygenated androgen metabolite 11β-hydroxyandrosterone correlated with a higher risk of hypertension and type 2 diabetes. Untargeted metabolome analysis revealed gradual changes towards a lipotoxic phenotype from NFAT over MACS to adrenal CS, with perturbations in glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines.

Interpretation: MACS represents a metabolic continuum between NFAT and adrenal CS. Increased activity of the adrenal enzyme 11β-hydroxylase (CYP11B1), which catalyses key steps in cortisol and 11-oxygenated androgen biosynthesis, may contribute to steroid excess and cardiometabolic morbidity in MACS. These findings suggest that CYP11B1 may be a potential therapeutic target to ameliorate metabolic dysfunction in MACS.

Funding: NIHR Birmingham Biomedical Research Centre; Diabetes UK; Wellcome Trust; European Commission; Medical Research Council.