EBioMedicine最新文献

Background: The number and type of genetic alterations required to initiate breast and ovarian cancer remain unclear. While germline BRCA1/2 carriers show markedly elevated cancer risk, it is uncertain whether point mutations or copy number alterations constitute the rate-limiting events of tumourigenesis.

Methods: We developed a statistical framework extending prior incidence-mutation models to estimate the minimal number and type of driver events required for cancer initiation. Somatic mutation and copy-number data from >3000 breast and ovarian cancers in TCGA and METABRIC were compared between germline BRCA1/2 carriers and non-carriers matched on subtypes. Results were validated through analyses of evolutionary timing data, as well as single-cell whole genome sequencing (scWGS) data of genetically-engineered and patient-derived cancer/pre-cancerous cells.

Findings: Deletions, rather than single-nucleotide variants (SNVs), emerged as the likely rate-limiting events. Modeling indicated that 1-3 deletions are sufficient to initiate tumourigenesis, whereas SNVs alone could not explain observed incidence ratios. BRCA1/2-driven and sporadic tumours converged on similar deletion profiles, including early recurrent deletions of chromosomes 13q and 17, though carriers accumulated them more rapidly.

Interpretation: Deletion-associated chromosomal instability likely represents the central trigger for breast and ovarian cancer initiation. These results explain why certain somatic driver mutations detected in normal tissues may not predict malignant progression, and that early detection strategies should instead prioritize testing deletions as potential biomarkers.

Funding: NIH/NCI (P30CA016042; 1U01CA214194-01), NIH NIGMS (R35GM138113, 2R35GM138113), ACS (RSG-22-115-01-DMC), CIHR Vanier Fellowship, and the Francis Crick Institute with core funding from Cancer Research UK, UK Medical Research Council, and Wellcome Trust.

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: 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).

Background: Both low-grade systemic inflammation and acute inflammatory events may contribute to Alzheimer Disease (AD) progression. However, studies examining the prognostic utility of systemic inflammatory biomarkers in AD, and how systemic inflammatory events may contribute to clinical trajectories in AD, have yielded conflicting results.

Methods: We quantified plasma cytokines/chemokines in 333 individuals with mild-moderate AD at baseline, 12 and 18 months alongside baseline neurodegenerative biomarkers. AD severity was assessed using the Alzheimer Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating Scale (CDR-Sb) and Disability Assessment for Dementia (DAD).

Findings: Systemic inflammatory biomarkers were primarily associated with age/socio-demographic characteristics, remained strikingly stable over time, and were not associated with AD progression. Rather, higher baseline plasma p-tau217 was associated with greater yearly progression on both the ADAS-Cog (β: 2.82; 95% CI: 1.12, 4.52; nominal p = 0.001) and DAD (β: -2.34; 95% CI: -3.86, -0.82; nominal p = 0.003). Higher baseline GFAP was also associated with subsequent decline on both the CDR-Sb (β: 1.02; 95% CI: 0.38, 1.67; nominal p = 0.002) and DAD (β: 1.91; 95% CI: -3.45, -0.37; nominal p = 0.02). Experiencing one or more episodes of delirium was associated with accelerated decline on the CDR-Sb at 18-months (β: 2.63; 95% CI: 1.55, 3.71; adjusted p < 0.001).

Interpretation: Biomarkers of neuroinflammation (GFAP), neurodegeneration (p-tau217) and incident delirium, rather than systemic inflammatory biomarkers, were associated with clinically-significant decline in mild-moderate AD.

Funding: European Commission (FP7 grant; 279093); Meath Foundation (MFRG 121/2021); Wellcome Trust (227946/Z/23/Z & 203930/B/16/Z); Health Research Board (203930/B/16/Z; ECSA-2024-003).

Background: Physical activity helps maintain a healthy stable body weight. One mechanism underlying this beneficial effect could be the improved coupling between energy intake and expenditure, since hunger and satiety are better regulated in active individuals. Whether this enhancement of appetite control by exercise is reflected in overall adaptations in the gut and gut-brain communication remains poorly defined.

Methods: We investigated how increased physical activity alters gut morphology, intestinal endocrine function, and central appetite signalling in C57BL/6NRJ male mice fed ad-libitum chow diet. We assessed intestinal growth, L-cell density, and glucose-stimulated endocrine secretion, as well as circulating levels and gene expression of gut derived peptide hormones. Additionally, we quantified neuronal activity in the brainstem dorsal vagal complex following a fasting-refeeding intervention and examined the effects of PYY, CCK, ghrelin, and GLP-1 administration on food intake in sedentary and physically active mice. Depending on the dataset, unpaired or paired Student's t-tests, two-way ANOVA followed by Bonferroni's post hoc test, simple linear regression or a linear mixed-effects model were applied. Statistical significance was set at P < 0.05.

Findings: Physical activity induced a slight growth of the small intestine, increased L-cell density, and enhanced glucose-stimulated GLP-1 secretion. It altered the circulating levels of PYY and ghrelin and increased the dynamic regulation of neuronal activity in the area postrema and nucleus tractus solitarius. Active mice displayed greater sensitivity to gut-derived hormones PYY, CCK, and ghrelin exerting amplified and prolonged effects on food intake, whereas native GLP-1 showed no effect, likely due to its short half-life. Physical activity prevented post-fasting hyperphagia, thereby promoting sustained maintenance of fasting-induced weight loss.

Interpretation: The findings demonstrate that physical activity promotes adaptations in the gut and gut-to-brain communication possibly enhancing the responsiveness to appetite-regulating signals. Such adaptations may strengthen the alignment between energy intake and expenditure to support body weight maintenance.

Funding: This study was supported by Novo Nordisk Foundation (0059436) and Trygfonden Centre for Physical Activity Research (101390, 20045, 125132, and 177225). P.S. is supported by Lundbeck Foundation (R380-2021-1300).

Background: Upper tract urothelial carcinoma (UTUC) is an uncommon but aggressive malignancy. Muscle invasion is strongly associated with poor prognosis and limited treatment options. Revealing the molecular basis of muscle invasiveness in UTUC is crucial.

Methods: We characterised somatic structural variants (SSVs) from 162 patients with UTUC and integrated these data with bulk RNA-seq, single cell RNA-seq and spatial transcriptomics, with selected SSVs validated by single-molecule sequencing. Furthermore, functional validation experiments, including dual-luciferase reporter assays, wound healing, and invasion/migration assays, were conducted on both the SSV region upstream of TPX2 and the TPX2 gene itself in the 5637 cell line.

Findings: We found that SSVs were enriched in muscle-invasive (MI) -UTUC compared with non-muscle-invasive (NMI)-UTUC, and were associated with gene expression changes independent of copy-number variation. TPX2 emerged as a representative target, with TPX2-associated SSVs linked to TPX2 over expression and patient poorer progression-free and overall survival. Functional study indicated that a TPX2-upstream SSV region enhances TPX2 expression through promoter regulation, leading to increased invasiveness of 5637 cells. Single cell analyses revealed that TPX2-positive cycling epithelial cells exhibited heightened proliferative signalling and distinct ligand-receptor interactions, particularly involving EGFR- and EPHA2-related pathways. Spatial transcriptomics further localised TPX2-positive spots to epithelial mesenchymal transition (EMT) -enriched neighbourhoods with elevated EGFR/EPHA2 associated ligands, and showed markedly higher abundance in MI-UTUC.

Interpretation: SSVs drive transcriptional reprogramming, disease aggressiveness and microenvironmental remodelling in UTUC. The signatures of SSVs could classify UTUC into classes with different prognosis. Furthermore, SSVs of TPX2 might be a potential biomarker and candidate therapeutic vulnerability.

Funding: Stated in acknowledgements section of manuscript.

Sleep disorders, cardiovascular diseases (CVDs), and hormonal imbalances, particularly with respect to testosterone levels, are closely interconnected and significantly impact public health. This review examines the complex interactions between these 3 factors. Poor sleep quality and conditions like obstructive sleep apnea (OSA) are prevalent among individuals with CVDs and contribute to cardiovascular pathology through several mechanisms, including sympathetic activation, oxidative stress, and systemic inflammation. Testosterone plays a critical role in metabolic regulation, muscle and bone health, and mood. Low testosterone levels are associated with increased CVD risk factors like insulin resistance and arterial stiffness. Substantial evidence suggests that sleep disorders may impair testosterone levels, partially improved after specific treatments (for instance: positive airway pressure for OSA). On the other hand, appropriate indications for testosterone replacement therapy (TRT) can alleviate hypogonadism symptoms and cardiometabolic dysfunction, but may increase the risk of OSA, requiring careful management. This narrative review highlights the importance of a holistic approach in managing sleep disorders, CVDs, and hormonal imbalances and emphasises the need for further research to improve patient outcomes.