EBioMedicine最新文献

Background: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear.

Methods: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status.

Findings: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood.

Interpretation: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival.

Funding: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).

Background: Current treatment regimens for nontuberculous mycobacteria (NTM) infections, especially Mycobacterium abscessus, have suboptimal clinical outcomes, demanding novel therapeutic options. The aminoglycoside apramycin (APR) has been suggested as a therapeutic alternative to amikacin (AMK). Here, we report experimental data as part of an ongoing preclinical assessment of APR.

Methods: Antimicrobial activity against 828 isolates comprising the clinically most relevant NTM species were determined by broth microdilution. Bactericidal activity and killing kinetics of APR were determined across a variety of assay conditions against rough and smooth M. abscessus isolates in vitro and in vivo.

Findings: Both the MIC₉₀ and tentative epidemiological cutoff (TECOFF) of APR was 4 μg/mL for 358 M. abscessus isolates and thus eight-fold lower than the 32 μg/mL determined for AMK. For 25 Mycobacterium chelonae isolates, the MIC₉₀ and TECOFF of APR was 4 μg/mL and thus four-fold lower than the 16 μg/mL determined for AMK. For 360 Mycobacterium avium complex (MAC) isolates the MIC₉₀ was 32 μg/mL and the TECOFF was 64 μg/mL for both APR and AMK. The MICs of APR and AMK were largely indifferent to mucin, DNA, sputum or standard of care antimicrobials except bedaquiline, which appeared to exert an additive effect. 16 μg/mL of APR resulted in a multi-log CFU reduction of M. abscessus within 12 h, in contrast to AMK, which was bacteriostatic for at least 24 h up to a concentration of 256 μg/mL. This difference in bacterial killing was consistent across pH 6.0-7.4 in 7H9 and CAMHB culture medium, respectively. APR resulted in multi-log CFU reduction in surrogate caseum and, unlike AMK, demonstrated intracellular killing of M. abscessus and M. avium in macrophages. Concentrations of 16 μg/mL of APR or ≥128 μg/mL of AMK suppressed the dose-dependent M. abscessus frequency of spontaneous resistance to near below the detection limit. In a cystic fibrosis surrogate CFTR^-/- mouse infection model, APR demonstrated dose dependent CFU reduction of pulmonary M. abscessus 4530, by up to 2 logs at 64 mg/kg.

Interpretation: For M. abscessus and M. chelonae, the APR MIC₉₀ was four-to eight-fold lower than that of AMK, and demonstrated enhanced bacterial killing. Collectively, our findings suggest APR has potent activity against NTM and warrants consideration for further clinical development.

Funding: This study was supported by the Cystic Fibrosis Foundation (CFF) Therapeutic Development Award JUVABIS22W0 and CFF grant HOBBIE19I0.

Background: Brain age estimated from structural magnetic resonance images is commonly used as a biomarker of biological ageing and brain health. Ideally, as a clinically useful biomarker, brain age should indicate the current state of health and be predictive of future disease onset and detrimental changes in brain biology.

Methods: In this preregistered study, we evaluated and compared the clinical utility, i.e., diagnostic and prognostic performance, of six publicly available brain age prediction packages using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Findings: Baseline brain age differed significantly between groups consisting of individuals with normal cognitive function, mild cognitive impairment, and Alzheimer's disease for all packages, but with comparable performance to estimates of grey matter volume. Further, brain age estimates were not centred around zero for participants with normal cognition and showed considerable variation between packages. Finally, brain age was only weakly correlated with disease onset, memory decline, and grey matter atrophy within four years from baseline in individuals without neurodegenerative disease.

Interpretation: The systematic discrepancy between chronological age and brain age among healthy subjects, combined with the weak associations between brain age and longitudinal changes in memory performance or grey matter volume, suggests that the current brain age estimates have limited clinical utility as a biomarker for biological ageing.

Funding: This work was supported by a Longevity Impetus Grant from the Norn Group, the Karolinska Institutet Loo och Hans Ostermans Stiftelse, Gun och Bertil Stohnes Stiftelse, Stiftelsen Gamla Tjänarinnor, Stiftelsen Söderström - Königska and Åhlén-stiftelsen (243016). PPS was supported by a grant from the Swedish Brain Foundation (PD2024-0444) and the Åke Wibergs Stiftelse (M24-0117).

Background: Human cytomegalovirus (HCMV) is one of the pathogens with the most significant impact on the immune system's composition, including the expansion of virus-specific CD8 T cells. Nevertheless, it remains unclear why individuals with expanded CD8 T cells recognising the pp65-HLA-A^∗02:01-restricted viral epitope NLVPMVATV (NLV-T cells) exhibit weakened immune control of HCMV reactivation.

Methods: Here, we characterised NLV-T cells from 116 healthy HCMV-positive donors, dividing them into two groups: those with low and those with high NLV-T cell frequencies (LF and HF, respectively). We phenotyped the cells using multi-colour spectral flow cytometry and single-cell RNA sequencing coupled with TCR profiling and examined their killing properties against peptide-loaded and virus-infected target cells.

Findings: Our comprehensive multimodal analysis revealed that NLV-T cells from HF donors exhibited a phenotype of advanced differentiation, marked by high levels of granzyme B and perforin expression, and efficiently eliminated peptide-loaded targets and HCMV-infected cells as long as cell surface HLA expression was unaffected. However, NLV-T cells from LF donors, possessing a less differentiated granzyme K-intermediate phenotype, demonstrated enhanced cytokine secretion and the ability to eliminate HCMV-infected cells, even in the presence of virus-induced HLA class-I downregulation.

Interpretation: Overall, these findings suggest that HCMV exploits CD8 T cell differentiation to evade immune protection. These data are crucial for understanding the previously observed decline in HCMV reactivation control in individuals with NLV-T cell accumulation. Moreover, our findings have clinical implications and could guide future research on adoptive T-cell therapy, and the potential use of HCMV as a vaccine vector.

Funding: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Projects number 390874280 and FO334/7-2.

Background: Two crucial needs persist in delivering effective critical care: reliable differentiation of infectious vs non-infectious systemic inflammation and detection of impending sepsis before the occurrence of organ dysfunction. This prospective cohort study evaluates the clinical utility of the polymorphonuclear neutrophil (PMN) biomarker CD177/CD10 ratio to differentiate and monitor infections.

Methods: A total of 219 healthy volunteers and 145 patients were assigned to four clinically defined groups: healthy controls (HC), non-infectious inflammation (NI), non-septic infection (NS-I), and sepsis (S). Serial flow cytometric analysis of CD177 and CD10 expression in PMNs was conducted with longitudinal monitoring. Diagnostic efficacy was standardised against conventional biomarkers and organ dysfunction indices. A dynamic CD177/CD10 ratio-based subtyping system (rising/declining/stable pattern) was established for prognostic stratification.

Findings: The CD177/CD10 ratio exhibited superior diagnostic performance in infection identification. At a cut-off point (CFP) of 6.07, the area under the curve (AUC) value of the ratio to differentiate NS-I from S was 0.92, exceeding those of CRP (0.85) and PCT (0.85). Notably, this biomarker effectively differentiated NI (CFP = 0.67, AUC = 0.79) from NS-I (CFP = 0.98, AUC = 0.71). The dynamic CD177/CD10 ratio-based subtyping system showed robust prognostic efficacy: patients with the rising subtype exhibited a 7-day mortality rate of 62.5%, while those with decreasing and stable subtypes demonstrated survival rates of 85% and 92.59%, respectively.

Interpretation: The CD177/CD10 ratio can facilitate infection-specific differentiation and real-time therapeutic monitoring by quantifying the dynamic equilibrium between the extent of neutrophil activation and maturation. However, the CD177/CD10 ratio still requires validation through a multi-centre trial to confirm the generalisability of the established diagnostic and prognostic thresholds.

Funding: National Natural Science Foundation of China (No. U21A20370), Natural Science Foundation of Jiangsu Province (BK20240382), Science and Technology Innovation Project of Suzhou (SYW2024116).

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).