EBioMedicine最新文献

Background: Antibiotic abuse has become a top public health problem worldwide. Ciprofloxacin (CIP) has the highest detection rate in human but its association with unexplained miscarriage (UM) is completely unknown. Senescence is a ubiquitous cellular process but its association with UM is still unclear.

Methods: We combined case-control study using a UM case-control group and in vitro functional assays using mouse model and human trophoblast HTR-8/SVneo cells. The associations between environmental exposure to CIP and cell senescence were explored. Trophoblast cell senescence, the mitochondrial dysfunctions, and the TRIM21-mediated ubiquitination degradation of MFF were investigated.

Findings: Higher urinary CIP levels are associated with villous tissue senescence and woman miscarriage. CIP-exposed mouse model further confirms that CIP exposure causes placental senescence to induce mouse miscarriage. Mechanistically, CIP up-regulates tripartite motif containing 21 (TRIM21) levels, promotes TRIM21-mediated ubiquitination degradation of mitochondrial fission factor (MFF), and thus reduces MFF levels. Subsequently, the reduced MFF causes mitochondrial dysfunctions and cell senescence, further inducing miscarriage.

Interpretation: Collectively, this study discovers new risk of CIP exposure on miscarriage, explores pathogenesis and biological mechanisms of CIP-induced miscarriage, provides targets for treatment against miscarriage, and describes the crosstalk among environmental antibiotics, biological mechanisms, and reproductive health.

Funding: This work was supported by the NSFC (NSFC No. 82373602 and No. 82571347), SMRF (No. B2303002), GBABRF (2023B1515120054 and 2023A1515110497), NSFC Joint Fund Key Support Project (grant no. U24A20748), the JITCBR (202407), HCGP (A2024281), SSTP (No. JCYJ20220530144403008, JCYJ20220818103607015, JCYJ20230807111401002, JCYJ20240813180400002, and JCYJ20241202152800001), CRSFFWJMF 320.6750.2022-06-47, FHRP (No. FTWS011 and FTWS2022002).

Alzheimer's disease-related dementia (ADRD) is a progressive neurodegenerative condition characterised by cognitive decline and overlapping pathological features. Despite advances in diagnostic tools and therapies, challenges persist due to limited efficacy, high costs, and the complexity of ADRD pathophysiology. Evidence suggests that ADRD arises from a lifelong interplay of genetic, lifestyle, and environmental factors, with recent findings indicating potential neurodevelopmental origins. Proteins implicated in neurodegeneration, such as amyloid and tau, may play critical roles in early nervous system development, whereas disruptions during critical periods, such as adolescence, may increase later-life susceptibility to ADRD. The global prevalence of ADRD is projected to reach 153 million by 2050, emphasising the urgent need for prevention strategies in addition to therapeutic interventions. Reframing ADRD as a neurodevelopmental condition with a delayed onset may provide alternative insights into its aetiology, paving the way for alternative innovative therapeutic and preventive approaches.

Background: Pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination is highly refractory to chemotherapy and immunotherapy, leading to poor prognosis. We aimed to develop an innovative therapeutic approach for advanced PDAC.

Methods: We performed comprehensive analyses of 498 bulk and 99 single-cell RNA-sequencing datasets. We established a syngeneic mouse model for subcutaneous and intraperitoneal metastatic tumours using mouse Kras^G12D; Trp53^R172H PDAC cells. A multimodal immunotherapy with mRNA-induced cytokines (MIMIC), that is, oxaliplatin, anti-PD-1 and anti-CTLA-4 antibodies, and intratumoural administration of mRNA therapeutics encoding interferon-α and interleukin-12, was evaluated in this preclinical model.

Findings: The aggressive PDAC subtype exhibited a paucity of dendritic cells (DCs) and T cells, causing an immunosuppressive tumour microenvironment. The syngeneic mouse model recapitulated this immunological phenotype with resistance to conventional systemic therapies. The MIMIC therapy not only significantly reduced the local tumour burden but also elicited a robust abscopal effect, suppressing distant peritoneal metastases and prolonging survival (P < 0.001). The omission of any single agent from the MIMIC regimen substantially abrogated the therapeutic efficacy. Flow cytometry and immunohistochemical analyses revealed that the MIMIC treatment enhanced immunogenic cell death, increased peripheral CD44+ CD62L- effector memory T cells, induced intratumoural infiltration of CD11c+ DCs and CD8+ T cells, and expanded TCR repertoire diversity.

Interpretation: Combining cytokine mRNA immunotherapy with cytotoxic killing and immune checkpoint blockade can reactivate antitumour immunity, offering a promising strategy for treating advanced PDAC.

Funding: This work was supported by Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), Japan Agency for Medical Research and Development (AMED), and the Princess Takamatsu Cancer Research Fund.

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: The oral delivery of native glucagon like peptide-1 (GLP-1) using recombinant probiotics has shown hypoglycaemic effects and glucose tolerance improvement in diabetic mice. However, the pharmacological mechanisms remain incompletely understood. This study aimed to clarify whether GLP-1 analogues cross the intestinal mucosal barrier and exert systemic hypoglycaemic effects.

Methods: The recombinant Lactococcus lactis (L. lactis) was constructed for oral delivery of long-duration GLP-1 (LGLP) or exendin-4 (EX4). The hypoglycemic effects in vivo were investigated in db/db mice. The pancreatic islet structure and DNA replication were studied with BrdU-labelled double immunofluorescence. The peptide absorptions in vitro and in vivo were traced with tetramethylrhodamine (TMR) labelled LGLP or EX4. The Ussing Chamber test with rat intestinal mucosa and the absorption test in the ligated loops of intestinal tube were used to verify the absorption of GLP-1 analogues.

Findings: The supernatant of recombinant L. lactis expressing LGLP or EX4 stimulated proliferation and insulin secretion in rat insulinoma cell INS-1 in vitro. The LGLP-recombinant L. lactis significantly reduced fasting blood glucose, improved oral glucose tolerance, especially increased the number and size of pancreatic islets after oral administration for 4 weeks in diabetic mice. TMR-labelled LGLP or EX4 peptides were internalized by intestinal epithelial cells in vitro. LGLP and EX4 peptides crossed the rat intestinal mucosa and entered the opposite chamber in a receptor-mediated endocytosis manner in the Ussing Chamber test. Following injection into the ligated intestinal loops, a small amount of TMR-labelled LGLP or EX4 was observed in the lamina propria of intestinal villi, pancreas and other tissues through mucosal absorption.

Interpretation: Oral delivery of GLP-1 analogues by recombinant L. lactis restored the structure of pancreatic islets and exerted systemic hypoglycaemic effects through receptor-mediated intestinal mucosa absorption.

Funding: The study was supported by the National Natural Science Foundation of China, the Science and Technology Program Key Projects of Guangdong Province (China), the Science and Technology Planning Project of Guangdong Province (China), and the Biomedical Innovation Foundation of China Pharmaceutical Association &Yiling Pharmaceutical Company.

Background: High-grade serous ovarian carcinoma (HGSOC) presents a significant therapeutic challenge. Late-stage disease is frequently associated with peritoneal carcinomatosis. The peritoneal metastases exhibit a unique tumour microenvironment (TME) distinct from the primary tumours and other metastatic sites. Understanding the critical influence of the extracellular matrix (ECM) in shaping the tumour phenotype is essential for the development of effective new therapies.

Methods: This study introduces a three-dimensional (3D) model of HGSOC peritoneal metastases using a porcine decellularised peritoneal-derived ECM scaffold, referred to as peritoneal matrix (PerMa).

Findings: We show that the decellularisation maintains the structural integrity and composition of ECM molecules. Comparative analysis reveals structural, compositional, and mechanical similarities between porcine and human peritoneal matrices, underscoring the porcine model's translational relevance for modelling human peritoneum physiology. The PerMa supports the 3D growth of HGSOC cell lines. The model enables the assessment of sensitivity to traditional chemotherapy and novel cell-based immunotherapy through confocal imaging and quantification of cell volume.

Interpretation: Our model offers a valuable platform for investigating peritoneal carcinomatosis in HGSOC, with the potential to contribute significantly to developing novel therapeutic approaches.

Funding: Financial support was provided by the University of Bergen, Helse Vest RHF (F-12183-D10616, 779, 911182, 912035, and 912146), Helse Bergen HF (240222), the Norwegian Cancer Society (6833652 and 182735), the Research Council of Norway grants (250317, 326300, 223250, 262652, and 295910), the Novo Nordisk Foundation (NNF21OC0070381), the Kolbjørn Brambani Legat for Kreftforskning, the National Institute of Health (R01CA199646) and the Swedish Cancer Society (21 1888 Pj).

Background: The presence of cystic fibrosis (CF) in diverse groups is known but its incidence is not established in non-European populations. We predict that the number of births with CF in populations with non-European and European ancestry are comparable, and that sampling the general population may inform improved diagnostic and therapeutic strategies.

Methods: We curated pathogenic CFTR variants from the Genome Aggregation Database (gnomAD, versions 2.1 and 4.0) for different groups and estimated the incidence per 100,000 births using Hardy-Weinberg equilibrium. To estimate annual births with CF, we used United Nations population statistics. Additionally, we estimated the percentages of alleles missed by common screening panels and those not approved for treatment using highly effective modulator therapies (HEMT).

Findings: CF affects 44-52, 11-14, 7, 6, 4, and 0.2-1 births per 100,000 in European, African/African American, Admixed American, South Asian, East Asian, and Middle Eastern groups, respectively. Due to higher birth rates, the estimated annual births with CF in India (1426-1582) and Brazil (330-390) are comparable to those in the US (∼1000) and UK (∼300). The expanded Wisconsin screening panel misses the fewest variants in all groups (1-30% pathogenic alleles), while other screening panels miss 25->70% of pathogenic alleles from non-European groups. Of the pathogenic alleles in non-European groups, 25-40% were not approved for treatment using HEMT.

Interpretation: Absolute number of CF births in South America, Asia, and Africa may be comparable to those in the US and Europe. Improved diagnostics, therapeutics, and access to HEMT will benefit thousands of people with CF globally.

Funding: None.

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.