EBioMedicine最新文献

Xenotransplantation addresses global organ shortages but faces species-specific glycan antigen barriers. Dominant xenoantigens (α-Gal, Neu5Gc, Sda) trigger hyperacute rejection via antibody-mediated immune cascades, complement activation, and thromboinflammation. Advances in precision genome editing, particularly CRISPR-Cas9 now facilitate the generation of multi-gene-edited pigs lacking GGTA1/CMAH/B4GALNT2 to eliminate these epitopes, co-expressing human complement/coagulation regulators to prolong graft survival. The systematic discovery of novel xenoantigens and validation of their immunogenicity, however, are still hampered by limited access to well-defined glycans and reliable functional assays. Emerging technologies, including advanced glycomics, glycoproteomics, and AI-driven prediction, are now accelerating the mapping and prioritisation of immunogenic glycan epitopes. This review synthesises three advances: glycan xenoantigens' immunodominant roles, multi-gene porcine models, and glycomics-driven epitope decoding. These discoveries directly inform next-generation genetic edits and clinical immune monitoring. Convergence of glycobiology, genome engineering, and multi-omics accelerates clinical translation, offering a roadmap for developing rejection-free organs.

Background: Treatment decisions in patients with unresectable colorectal liver metastases (CRLM) are largely guided by radiological response to induction systemic therapy. However, radiological assessment alone provides an imprecise estimate of underlying tumour biology or treatment response. Circulating tumour DNA (ctDNA) is an emerging biomarker that can support clinical decision-making. This study evaluated the independent prognostic value of radiological tumour burden and DELFI-TF, a tumour tissue- and mutation-independent cell-free DNA (cfDNA) fragmentome-based ctDNA assay.

Methods: We analysed 202 plasma samples and CT scans collected at baseline and following induction systemic therapy from 101 patients with unresectable, liver-limited CRC enrolled in the phase-III CAIRO5 trial (NCT02162563), treated with FOLFOX/FOLFIRI plus bevacizumab. Total tumour volume (TTV) was centrally quantified via semi-automated segmentation of liver metastases. ctDNA was measured using the DELFI-TF score. Associations with overall survival (OS) and early recurrence were evaluated using multivariable Cox regression models.

Findings: At baseline, TTV (median = 139 mL, IQR = 23-497 mL) strongly correlated with DELFI-TF (median = 0.29, IQR = 0.13-0.41; Spearman's ρ = 0.70). DELFI-TF showed a more pronounced reduction than TTV on-treatment (-97.6% vs -49.9%). Baseline levels and on-treatment changes of DELFI-TF (P = 0.001; P = 0.012) and TTV (P = 0.002; P = 0.002) were independently associated with OS in the multivariable model; their combination improved prognostic performance (Uno's C-statistic 0.78 vs 0.73; P = 0.036). Baseline (P = 0.016) and on-treatment DELFI-TF (P = 0.001) also predicted early recurrence after local therapy.

Interpretation: Following further validation, integrating cfDNA fragmentome-based testing with radiological tumour volume may provide complementary and clinically meaningful insights for prognostication and treatment response in patients with unresectable CRLM. This exploratory study supports a multimodal biomarker approach to guide personalised treatment strategies.

Funding: German Research Foundation (DFG, 513004649), Heidelberg Medical Faculty, Dutch Cancer Society/KWF Kankerbestrijding (10438), PPP Allowance via Health ∼ Holland (LSHM22027), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up To Cancer (SU2C)in-Time Lung Cancer Interception Dream Team Grant, SU2C-Dutch Cancer Society International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415), Gray Foundation, Commonwealth Foundation, Cole Foundation, Delfi Diagnostics (research grant), US National Institutes of Health (CA121113, CA233259, CA271896).

Background: Chemotherapy remains the first-line treatment for triple-negative breast cancer (TNBC). Anthracycline chemotherapeutics, such as epirubicin (EPI), not only kill tumor cells but also induce immunogenic cell death (ICD). However, accumulated extracellular adenosine triphosphate (eATP) during ICD is converted to adenosine, triggering immunosuppression via adenosine receptor signalling. To address this issue, co-administration of EPI with adenosine receptor antagonists could remodel the immunosuppressive tumor microenvironment and potentiate antitumor immunity.

Methods: The effect of the expression level of adenosine receptors on the immune microenvironment of TNBC was assessed by integrating bioinformatic analysis of public databases with immunofluorescence staining of TNBC clinical samples. Four polymeric prodrugs of EPI were synthesised, and their delivery performances were assessed. A nanomedicine with pH/cathepsin B (CTSB)-responsiveness for co-delivery of EPI and AB928 (an adenosine receptor antagonist) was constructed. The cellular experiments and 4T1 tumor-bearing mice model were employed to evaluate antitumor efficacy.

Findings: Bioinformatic analyses and immunofluorescence staining of TNBC clinical samples supported the rationale for combining ICD-inducing chemotherapeutic agents with adenosine receptor antagonists. The polymeric prodrug of EPI with an optimal delivery efficiency was selected to encapsulate AB928. The constructed nanomedicine for EPI/AB928 co-delivery enhanced antitumor immune responses by effectively inhibiting adenosine-A2A receptor/A2B receptor (A2AR/A2BR) signalling pathways and reversing adenosine-mediated immunosuppression.

Interpretation: Co-delivery of an ICD inducer (EPI) and an adenosine receptor antagonist (AB928) is realised in a stimuli-responsive nanomedicine to address immunosuppression induced by adenosine, thereby enhancing ICD effects and synergistically reprogramming the immunosuppressive tumor microenvironment.

Funding: See Acknowledgements.

Background: Climate change is increasing health risks worldwide, but how extreme temperature events affect Alzheimer's disease and other dementias (ADD) remains poorly understood. We aimed to project future extreme temperature event-attributable ADD deaths in China, accounting for the combined effects of climate change, population ageing, and adaptation methods.

Methods: We analysed 399,036 ADD deaths among adults aged ≥60 years in China during 2013-2020, using a time-stratified case-crossover design to estimate ADD mortality risks associated with extreme temperature events. We subsequently developed an integrated climate-ageing-adaptation framework that combined exposure-response functions, high-resolution climate projections, and demographic forecasts. Using this framework, we projected county-level ADD deaths attributable to heatwaves and cold spells among individuals aged ≥60 years across China under multiple SSP-RCP and adaptation scenarios for the 2030s, 2050s, and 2080s FINDINGS: Without adaptation, ADD heatwave-attributable deaths are projected to rise sharply, especially under rapid socioeconomic development with high greenhouse gas emissions scenario (SSP5-RCP8.5) in the 2080s, which reach 59,088-an 11-fold (+1003%) increase comparing to 2010s levels. Cold spell-attributable deaths generally decline but reductions are insufficient to offset the sharp rise in heatwave mortality, leading to a net increase in total attributable deaths. Adaptation strategies could avert up to 76.4% of heatwave-attributable deaths compared to no-adaptation scenario.

Interpretation: The convergence of climate change and population ageing is projected to substantially magnify dementia-related mortality in China. Under SSP5-RCP8.5, deaths attributable to extreme temperature events are projected to reach unprecedented levels by the end of the 21st century, especially without adaptation measures. These findings underscore the urgent need for massive greenhouse gases emission reductions alongside balanced, region-specific adaptation measures, and highlight dementia care as an essential component of climate resilience planning. Our study provides guidance for designing climate-resilient public health policies, particularly for ageing populations in climate-vulnerable counties and regions.

Funding: This work was supported by the Science and Technology Fundamental Resources Investigation Program of China [2017FY101201, 2017FY101206], and the National Foundation for Australia-China Relations of Australia [6016294].

Background: Sex-based differences in morbidity and mortality in pulmonary hypertension (PH) are underexplored, yet understanding these differences is vital for improving clinical management. This study investigates the influence of sex on survival of patients with PH in dependency of various disease conditions.

Methods: The PVRI GoDeep meta-registry integrates data from international PH registries, of which we analysed 21,123 incident hemodynamically fully characterised patients with PH. Survival analyses employed Kaplan-Meier and Cox proportional hazards models, adjusted for confounders and subjected to sensitivity analyses.

Findings: Male patients consistently showed significantly higher mortality than females across the overall PH population (hazard ratio 1.36 [1.23, 1.50] after adjustment) and within PAH and non-PAH groups. These sex differences in survival persisted regardless of P(A)H severities, age and obesity, cardiovascular diseases, and PAH-specific therapies. The male survival disadvantage was noted across low-, intermediate-, and high-risk groups of the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores, but not the REVEAL 2.0 risk score, which incorporates male sex as non-modifiable factor. Stratification by race revealed that male sex was associated with worse survival in White patients, but not in Black or Asian patients with PH.

Interpretation: Male patients with PH exhibit significantly higher mortality risks than females across both PAH and non-PAH PH groups. This disparity persists regardless of PH severity, underlying cause, age, obesity, comorbidities, or treatment status, though race might modify the observed risk difference. These insights provide new avenues for investigating underlying mechanisms and suggest including male sex as an independent factor in clinical risk assessment tools.

Funding: This work is funded by the Pulmonary Vascular Research Institute (PVRI) and the Cardiovascular Medical Research and Education Fund (CMREF), NIH.

Background: Sjögren's Disease (SjD) is a systemic autoimmune disorder characterised by exocrine gland dysfunction and immune infiltration. However, the spatial cellular architecture and metabolic-immune crosstalk underlying glandular pathology in SjD remain unclear.

Methods: We performed spatial transcriptomics on SjD salivary glands (SGs) and conducted integrative analyses with single-cell RNA sequencing to delineate disease-specific transcriptomic alterations, followed by validation in an independent cohort. Key findings were verified via immunofluorescence, immunohistochemistry, and function assays on cells.

Findings: Spatial clustering revealed distinct perturbations in SjD. We identified a pathogenic CCL2^high fibroblast-ACKR1^high endothelial cell axis that co-localised in lymphoid foci and correlated with immune infiltration and disease activity. Chemokine-receptor axes were associated with immune infiltration, with endothelial ACKR1 facilitating inflammatory niche organisation. Compartmentalised immune-stroma niches exhibited upregulated phospholipid, glycerophospholipid and phosphatidylinositol metabolism in lymphoid foci, correlating with B/T-cell activation and interferon responses. Key metabolic regulators (PIK3CD, PIK3CG, PIKFYVE, and PLCG2) were elevated in SjD, associated with CD45⁺ cell abundance in SGs, and exhibited diagnostic potential. Conversely, epithelial cells showed suppressed glycerolipid metabolism and decreased MGLL expression, linked to enhanced antigen presentation. Inhibiting monoacylglycerol lipase (encoded by MGLL) upregulates MHC in A253 cells, while interferon-γ suppresses MGLL expression.

Interpretation: Our study elucidates spatially organised metabolic-immune networks in SjD, implicating lipid metabolism in immune activation and epithelial metabolic reprogramming in secretory dysfunction, nominating promising therapeutic targets.

Funding: National Natural Science Foundation of China (82104484,32301084), Joint funding from schools (colleges) and enterprises in Guangzhou (2025A03J3203, 2024A03J0987), Natural Science Foundation of Guangdong Province (2023A1515012790), Guangdong Provincial Enterprise Joint Fund (2022A1515220003), and Sun Yat-sen University (P02523).

Breastfeeding is crucial for infant survival, growth, and health, and it enhances maternal-infant bonding and well-being. However, breastfeeding rates typically fall below international targets, partly due to a high prevalence of latching difficulties, intermittent sucking, refusing the breast, or poor milk supply. Here, we propose that such uniquely human difficulties might be ameliorated by recognising, understanding, and facilitating the olfactory mechanisms that, in other mammals, regulate breastfeeding initiation and maternal-infant relationships in the first weeks of life. We briefly review evidence that odour mediates nipple-searching and suckling behaviour in other species, summarise the comparable evidence in humans, and outline pathways that could potentially reap hitherto unrealised benefits of olfactory communication between human mothers and neonates. We argue that enhanced awareness of such odour exchange could inform and enable changes in both policy and practice that might improve breastfeeding success and maternal-infant bonding, ultimately contributing to reduced infant mortality worldwide.