EBioMedicine最新文献

Background: Heart failure (HF) is a currently incurable disorder that increases the risk for stroke and sudden cardiac death. Shortened telomeres have been linked to the development of cardiomyocyte abnormalities and dysfunction, and telomere reprotection has become a favourable strategy for designing novel heart failure therapies. This study aims to design a pan-HF gene therapy where modified human telomerase expression is driven by cardiac troponin promoter and to evaluate cardiac protection.

Methods: Telomere shortening was determined in cardiomyocytes from Macaca fascicularis (cynomolgus monkey) and patients with HF by quantitative fluorescence in situ hybridisation (Q-FISH) assays. We bioengineered a catalytic inactivation and nuclear retaining modified human TERT (telomerase reverse transcriptase) gene therapy (AAV9-modhTERT^{Y707F, D868A}). In transverse aortic constriction (TAC)-induced WT and myocardial p53 deficient (p53^CKO) mice HF model, as well as Ang II-induced human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we evaluate cardiac protection of modhTERT via echocardiography, RNA-sequence, Western blotting, Proteome Profiler Mouse XL Cytokine Array panel, RT-qPCR, transmission electron microscopy, and immunofluorescence.

Findings: AAV9-modhTERT^{Y707F, D868A} reversed cardiac function decline and prevented onset of cardiac fibrosis in TAC-induced HF murine. At cellular level, modhTERT alleviated contractile dysfunction and aberrant calcium handling in cardiomyocytes isolated from TAC hearts and prevented Ang II-stimulated hiPSC-CMs hypertrophy. Overexpression of modhTERT blocked telomeric DNA damage response (DDR) and p53 ser15-phosphorylation. Myocardial chronic inflammation and reactive oxygen species (ROS) levels were reverted by modhTERT overexpression. Additionally, modhTERT rescued mitochondrial ultrastructure, increased mitochondrial DNA (mtDNA) copy, and restored ATP production through restoration of PGC-1 α and TFAM expression.

Interpretation: We provide evidence that telomere re-protection confers cardiac protection and may serve as a potential gene therapeutic option for treating heart failure.

Funding: This research was supported by the National Natural Science Foundation of China (82070248, 82300282, 82300476), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (0900000024), 2023 Shanghai Action Plan for Promoting Scientific and Technological Innovation and Industrial Development of Gene Therapy (23J11900600).

The pathoanatomy of local cancer spread is approached by the ontogenetic cancer field model, deduced from aspects of evolution, development, immunity, and wound healing/regeneration in multicellular animals, postulating: (1) Cancer cells canonically respond to the disruption of tissue homeostasis caused by their uncontrolled proliferation with progressive de-differentiation, which paradoxically enlarges the cancer wound instead of healing it. (2) The de-differentiating cancer cells adhere in reverse sequence to a principle of topological order laid down during embryonic development by the metazoan cell type differentiation trajectory. The model predicts with high anatomical accuracy ontogenetic stage-dependent permissive tissue territories for local cancer propagation, i.e., cancer fields, as demonstrated for cancers of the alimentary and genital tracts. Assuming the 'export' of the local cancer field into the draining lymph nodes by tissue macrophages and regulatory T cells, the model is also applicable for regional carcinoma spread. The clinical translation into cancer field surgery has led to a marked reduction of locoregional recurrences and to increased cure rates.

Background: Circadian rhythms play a crucial role in human health, including reproductive health. Disruption of circadian rhythm is associated with female infertility. However, how circadian disruption affects ovarian function remains unclear. The main purpose of this study is to verify the impact of long-photoperiod exposure on follicular development and ovarian function.

Methods: In this study, we employed long-photoperiod (LP) conditions (18 h lightness/6 h darkness) in rats to mimic increased light exposure in human lifestyles. Hormone indicators, oestrus cycle, ovary morphology, follicular development and ovulation were used to validate the ovarian function. To investigate the underlying mechanisms, a series of experiments, including RNA sequencing, metabolomics, ChIP/qPCR, transmission electron microscopy, immunofluorescence, and western blotting, were conducted. Additionally, the impact of nicotinamide mononucleotide (NMN) on ovarian function was evaluated using the mentioned methods above.

Findings: LP exposure reduced the number of growing ovarian follicles and retrieved oocytes. Mechanistically, LP exposure led to granulosa cell oxidative stress and mitochondria dysfunction via inhibiting SIRT3 activity and SOD2 deacetylation. Metabolomic analysis showed that LP exposure lowered NAD⁺ levels, a cofactor that determines SIRT3 deacetylase activity. Further study showed that NAMPT, the rate-limiting enzyme in NAD⁺ synthesis, exhibited a circadian rhythmic expression pattern in the ovary, and LP exposure disrupted the ovarian circadian expression of NAMPT through the core clock protein BMAL1. Treatment with the NAD⁺ metabolic precursor nicotinamide mononucleotide could ameliorate mitochondria function and increase the numbers of antral follicles (49.56 ± 0.55 vs. 21.83 ± 1.35, p = 0.001) and retrieved oocytes (18.40 ± 1.91 vs. 3.80 ± 1.16, p < 0.001) in LP-exposed rats.

Interpretation: Our study demonstrates that circadian rhythm disruption by LP exposure affect follicular development and ovulation through impaired NAD⁺ metabolism, and suggests targeting NAD⁺ pathways as a potential therapeutic strategy for ovarian diseases.

Funding: This work was supported by the National Natural Science Foundation of China - Joint Fund for Regional Innovation and Development, the National Natural Science Foundation of China, the National Key Research and Development Program of China.

Background: Pathogenic germline variants in certain genes are associated with somatic tumour mutation signatures. The use of somatic tumour mutation data has the potential to improve the identification of true pathogenic variants but remains underexplored. We investigated the integration of tumour homologous recombination (HR) deficiency status as a predictor of pathogenicity for germline BRCA1 and BRCA2 variants, building on the established link between HR deficiency and germline pathogenic variants in these genes.

Methods: We analysed breast tumour whole-genome sequence and matching germline data from 350 patients across four datasets: Familial Breast Cancer (N = 77), The Cancer Genome Atlas (TCGA-BRCA, N = 96), the MAGIC study (N = 136), and Q-IMPROvE (N = 41). A total of 15,156 germline variants (including structural variations) in BRCA1, BRCA2, and other cancer genes (ATM, BARD1, BRIP1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53) underwent variant curation. Patients were categorised based on germline classification as BRCA1 positive (N = 27), BRCA2 positive (N = 21), and BRCA1/2 negative (N = 232), excluding those with BRCA1/2 variants of uncertain significance (N = 8) and pathogenic or only uncertain variants in other cancer genes (N = 62). Somatic HR status (deficient or proficient) was predicted using three algorithms: HRDetect, CHORD, and HRDsum. HR-deficient and HR-proficient status were significant predictors of germline BRCA1/2 pathogenic variant status (positive and negative directions).

Findings: The CHORD algorithm, which estimates BRCA1 and BRCA2 subtype specifically, added precision contributing evidence towards pathogenicity for the corresponding gene, reaching pathogenic moderate strength for the relevant gene-subtype. Finally, we assessed CHORD HR predictions for variants of uncertain significance in BRCA1 and BRCA2, and reported their tumour HR status for potential use as additional evidence in variant curation.

Interpretation: Analysis across multiple tumour whole-genome sequencing datasets has shown that HR status prediction algorithms can separate profiles for BRCA1 and BRCA2 pathogenic variants and provide further evidence at increased weight to aid in the classification of germline BRCA1 and BRCA2 variants. Tumour sequencing offers a promising strategy for reducing the uncertainty in germline variant interpretation.

Funding: This work was funded by the National Breast Cancer Foundation.

Background: Adiponectin is a circulating adipokine involved in energy metabolism and inflammation, with reported protective effects against cardiometabolic diseases such as type 2 diabetes (T2D) and early kidney disease. However, its regulation remains poorly understood. This study aimed to identify epigenetic loci associated with adiponectin levels.

Methods: DNA methylation was profiled using Illumina 450K and EPIC (850K) arrays in 315 Ghanaians (RODAM-Pros study) and 593 Nigerians (AADM study). Differentially methylated positions (DMPs) were identified using linear regression models adjusted for age, sex, BMI, blood cell proportions, and technical covariates. Analyses were stratified by T2D status and cohort, then meta-analysed to identify DMPs associated with adiponectin across T2D status (combining participants with-and-without diabetes). RNA-seq data on 77 blood, 49 subcutaneous adipose tissue (SAT), and 55 skeletal muscle samples from the AADM study were used to identify eQTMs for identified DMPs.

Findings: We identified three epigenome-wide significant DMPs: cg03546163 (Z-score = 5.76, p ≤ 0.001, 5'UTR of FKBP5), cg02561343 (Z-score = 5.11, p ≤ 0.001, within UST), and cg23969380 (Z-score = 5.13, p ≤ 0.001, ADGRD1 body). cg03546163 was an eQTM for PLA2G12B in SAT (beta = -0.039, FDR = 0.047), cg02561343 for PSMD8 (beta = -11.85, FDR = 0.029) and TECR (beta = -9.48, FDR = 0.029) in SAT, and cg23969380 for HIGD2AP1 (beta = -0.095, FDR = 0.024) in blood. These genes have been reported to be involved in lipid metabolism (PLA2G12B and TECR), proteasomal degradation (PSMD8), and cellular stress-responses (HIGD2AP1).

Interpretation: This epigenome-wide study of adiponectin in sub-Saharan African populations identified DNA methylation loci potentially involved in adiponectin regulation through lipid-metabolism, inflammation, proteostasis, and stress-response pathways. These findings provide a foundation for replication and further investigation to improve understanding of the role of adiponectin in cardiometabolic-health.

Funding: National Institutes of Health and European Research Council.

Background: Environmental stress and iron deficiency are increasingly recognised as prevalent challenges during pregnancy, with significant implications for both maternal and foetal health. Environmental stressors such as chronic maternal anxiety can elevate cortisol levels and trigger inflammatory responses which might subsequently disrupt foetal brain development. Concurrently, iron deficiency during critical windows of gestation can hinder the formation of brain structures and neurotransmitter systems vital for emotional regulation and cognitive function after birth. Iron deficiency and exposure to stress are among the most prevalent nutritional and environmental challenges during pregnancy, and their combined influence may substantially increase the risk of neuropsychiatric disorders in the offspring. Although the individual effects of each factor are relatively well understood, their interaction during gestation remains unexplored.

Methods: In the present study, we employed human placental samples from mildly stressed and non-stressed mothers, a chronic environmental stress mouse model, and advanced in vitro techniques to examine whether gestational environmental stress alters placental iron transport.

Findings: Our findings indicate that stress enhanced placental iron uptake and accumulation, but paradoxically reduced iron transfer to the foetus-an effect observed exclusively in females and reproducible in vitro following both stress exposure and dexamethasone treatment.

Interpretation: These results provide insights into the sex-specific impact of environmental stress on placental and foetal iron availability and highlight a previously unrecognised pathway through which prenatal stress could influence long-term health trajectories in the offspring.

Funding: This study was supported by the Swiss National Science Foundation (SNF grant no. 310030_197408), the Swiss National Science Foundation via the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland (grant no. 51NF40_185544) and the Swiss 3R Competence Centre (3RCC; grant no OC-2019-019). TF was supported by the Hans Sigrist Foundation, Switzerland.

Background: Most gastric cancer (GC) patients receive uniform treatment due to the lack of predictive biomarkers for chemotherapy or radiotherapy. We previously identified epithelial-mesenchymal transition (EMT) and metabolism subgroups in GC cell lines based on kinomic profiles, but their clinical relevance was unknown.

Methods: We developed an ensemble model using 37 kinases that differed between cell line subgroups to classify stage II-IV GC into EMT and metabolism subgroups. Survival differences between those who received chemotherapy or radiotherapy and those who did not were compared within each subgroup to validate the model effectiveness in predicting therapeutic response. An iteration approach was further applied to optimise and validate the feature set via multiple publicly-available datasets.

Findings: An 11-kinase signature stratified 893 patients into two subgroups. The metabolism subgroup showed significantly better survival with chemotherapy (HR_{multivariable} = 0.56) and radiotherapy (HR_{multivariable} = 0.55), whereas no such improvement was observed in the EMT subgroup. Significant interaction between kinomic subgroups and treatments were noted. The chemotherapy benefits between subgroups were greater with 5-fluorouracil-based regimens than cisplatin-based ones. This kinomic taxonomy was distinct from Lauren classification and previous transcriptomic subtypes and also suggested differential therapeutic vulnerabilities between subgroups.

Interpretation: This model holds promise for optimising chemotherapy and radiotherapy decisions for GC.

Funding: Biomedicine Discovery Scholarship and Graduate Research Completion Award, Monash University; National Natural Science Foundation of China (81602165) (C.H.). Australian Research Council Centre of Excellence for the Mathematical Analysis of Cellular Systems (CE230100001) (L.K.N.).

Background: Lung cancer is mainly diagnosed in elderly adults, yet the incidence of early-onset disease in people aged ≤45 years is increasing. Current screening strategies largely target elder populations, leaving younger individuals at risk of delayed diagnosis and adverse outcomes. Phenotypic Age Acceleration (PhenoAgeAccel), which indicates the difference between biological age and chronological age, has been associated with cancer susceptibility, but its role in early-onset lung cancer is unclear.

Methods: We performed a case-control and prognostic cohort study in China, including 222 early-onset lung cancer patients and 222 age- and sex-matched healthy volunteers, and externally validated findings in the UK Biobank. PhenoAgeAccel was calculated from routinely available haematological and biochemical markers. Logistic regression models estimated associations between PhenoAgeAccel and lung cancer risk. Survival analyses assessed the relationship between PhenoAgeAccel and overall survival among early-onset patients.

Findings: Early-onset lung cancer patients had substantially higher PhenoAgeAccel than matched controls (P < 0.001). PhenoAgeAccel was associated with a dose-dependent increase in early-onset lung cancer risk (odds ratio [OR] = 1.18; 95% CI: 1.14-1.23). Subgroup analyses by chronological age demonstrated a stronger association in earlier adulthood, whereas associations among elder adults (≥65 years) were not significant. In early-onset patients, higher PhenoAgeAccel predicted worse overall survival (hazard ratio [HR] = 2.17; 95% CI: 1.20-3.93). Results were corroborated in the UK Biobank cohort.

Interpretation: PhenoAgeAccel is positively associated with both a greater risk of early-onset lung cancer and poorer prognosis, supporting its potential utility for early detection and risk stratification in younger populations.

Funding: National Natural Science Foundation of China (no. 82303969); Beijing Xisike Clinical Oncology Research Foundation (no. Y-2024AZ [EGFR]MS-0079); Beijing Natural Science Foundation (no. 7222144).