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PubMed2024

Identification of cuproptosis-realated key genes and pathways in Parkinson's disease via bioinformatics analysis.

INTRODUCTION: Parkinson's disease (PD) is the second most common worldwide age-related neurodegenerative disorder without effective treatments. Cuproptosis is a newly proposed conception of cell death extensively studied in oncological diseases. Currently, whether cuproptosis contributes to PD remains largely unclear. METHODS: The dataset GSE22491 was studied as the training dataset, and GSE100054 was the validation dataset. According to the expression levels of cuproptosis-related genes (CRGs) and differentially expressed genes (DEGs) between PD patients and normal samples, we obtained the differentially expressed CRGs. The protein-protein interaction (PPI) network was achieved through the Search Tool for the Retrieval of Interacting Genes. Meanwhile, the disease-associated module genes were screened from the weighted gene co-expression network analysis (WGCNA). Afterward, the intersection genes of WGCNA and PPI were obtained and enriched using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, the key genes were identified from the datasets. The receiver operating characteristic curves were plotted and a PPI network was constructed, and the PD-related miRNAs and key genes-related miRNAs were intersected and enriched. Finally, the 2 hub genes were verified via qRT-PCR in the cell model of the PD and the control group. RESULTS: 525 DEGs in the dataset GSE22491 were identified, including 128 upregulated genes and 397 downregulated genes. Based on the PPI network, 41 genes were obtained. Additionally, the dataset was integrated into 34 modules by WGCNA. 36 intersection genes found from WGCNA and PPI were significantly abundant in 7 pathways. The expression levels of the genes were validated, and 2 key genes were obtained, namely peptidase inhibitor 3 (PI3) and neuroserpin family I member 1 (SERPINI1). PD-related miRNAs and key genes-related miRNAs were intersected into 29 miRNAs including hsa-miR-30c-2-3p. At last, the qRT-PCR results of 2 hub genes showed that the expressions of mRNA were up-regulated in PD. CONCLUSION: Taken together, this study demonstrates the coordination of cuproptosis in PD. The key genes and miRNAs offer novel perspectives in the pathogenesis and molecular targeting treatment for PD.

Humans↗

PubMed2005

Transcriptional regulation of connective tissue growth factor by sphingosine 1-phosphate in rat cultured mesangial cells.

Connective tissue growth factor (CTGF) is induced by transforming growth factor-beta (TGF-beta) via Smad activation in mesangial cells. We recently reported that sphingosine 1-phosphate (S1P) induces CTGF expression in rat cultured mesangial cells. However, the mechanism by which S1P induces CTGF expression is unknown. The present study revealed that S1P-induced CTGF expression is mediated via pertussis toxin-insensitive pathways, which are involved in the activation of small GTPases of the Rho family and protein kinase C. We also showed by luciferase reporter assays and chromatin immunoprecipitation that S1P induces CTGF expression via Smad activation as TGF-beta does.

Animals↗

PubMed2005

12th annual congress of the European Society of Gene Therapy.

The 2004 European Society of Gene Therapy (ESGT) meeting took place at Tampere Hall in Finland and highlighted advances in a variety of topics, including cancer, zinc-fingers, stem cells, small interfering RNA (siRNA), microRNA, and recent developments of non-viral and viral vectors. This meeting was attended by 513 participants from 32 countries, and included 106 oral and 224 poster presentations. One of the aims of this meeting was to take a critical look at gene therapy and the prospects for the future. Se-veral presentations reported on RNA-based technologies, such as siRNA, as potential new classes of therapeutics against a wide range of diseases and for use in expression libraries to identify functional genes involved in biological phenotypes. Critical assessments were made of other aspects of gene therapy, such as genome editing and the use of protein transduction domains (PTDs) in gene- and protein-based therapies, where many researchers have failed to reproduce initial findings reported in the literature. Safety issues related to viral vectors were also important areas of discussion, especially following details released by the UK Gene Therapy Advisory Committee of perhaps the first known case of lentiviral vector-associated oncogenesis. Finally, updates were presented on the clinical development of viral vectors in anticancer therapies with evidence of significant improvements in the mean survival of patients.

Clinical Trials as Topic↗

PubMed2006

Non-coding RNAs in the nervous system.

Increasing evidence suggests that the development and function of the nervous system is heavily dependent on RNA editing and the intricate spatiotemporal expression of a wide repertoire of non-coding RNAs, including micro RNAs, small nucleolar RNAs and longer non-coding RNAs. Non-coding RNAs may provide the key to understanding the multi-tiered links between neural development, nervous system function, and neurological diseases.

Animals↗

PubMed2004

Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma.

The amplification at 13q31-q32 has been reported in not only hematopoietic malignancies but also in other solid tumors. We identified previously frequent amplification of chromosomal band 13q31-q32 in 70 cases of diffuse large B-cell lymphoma patients by conventional comparative genomic hybridization analysis. In an attempt to identify a candidate gene within this region, we used array comparative genomic hybridization and fluorescent in situ hybridization to map the 13q31-q32 amplicon. We then screened the 65 expressed sequence tags and Glypican 5 (GPC5) by reverse transcription-PCR and Northern blotting. As a result, we identified a novel gene, designated Chromosome 13 open reading frame 25 (C13orf25), which was overexpressed in B-cell lymphoma cell lines and diffuse large B-cell lymphoma patients with 13q31-q32 amplifications. However, GPC5, which has been reported to be a target gene for 13q31-q32 amplification, was truncated in one cell line, Rec1, possessing the amplification, and its expression in various cell lines with amplification at 13q31-q32 was not significantly different from that in other cell lines without amplification, suggesting that GPC5 is not likely to be the candidate gene. Additional analysis identified two major transcripts in the C13orf25 gene. The two transcripts A and B predicted open reading frames of 32 and 70-amino acid polypeptides, respectively. The former has been reported as bA121J7.2, which is conserved among species. Transcript-B also contained seven mature microRNAs in its untranslated region. These results suggest that the C13orf25 gene is the most likely candidate gene for the 13q31-q32 amplicon found in hematopoietic malignancies.

Amino Acid Sequence↗

PubMed2026

MiR-26a-5p/EZH2 Mediates Wnt2 Promoter Methylation to Regulate Trophoblast Dysfunction.

INTRODUCTION: Preeclampsia (PE) is a common complication of pregnancy, with a concomitant incidence rate of up to 10% among pregnant women worldwide. METHODS: In the current research, we explored the role and mechanism of miR-26a-5p in trophoblast function using CCK-8, colony formation assay, and flow cytometry. The interaction between miR-26a-5p and EZH2 was analyzed using a luciferase reporter assay. Methylationspecific PCR was performed to detect the methylation level of Wnt2 in HTR8 cells. RESULTS: Wnt2 and miR-26a-5p promoted the proliferation and inhibited the apoptosis in trophoblasts (P<0.05). The secretion of inflammatory cytokines was suppressed by Wnt2 and miR-26a-5p (P<0.05). EZH2 was identified as a regulatory target of miR-26a-5p using HTR8 cells and bioinformatic tools. miR-26a-5p inhibited expression through direct binding to EZH2. Importantly, miR- 26a-5p mediated DNA methylation of Wnt2 to regulate Wnt2 expression in HTR8 cells. DISCUSSION: This study elucidates a novel regulatory axis that alleviates trophoblast dysfunction by promoting proliferation and suppressing inflammation and apoptosis. The findings reveal that the miR-26a-5p/EZH2/Wnt2 pathway, potentially involving promoter methylation, is crucial for maintaining trophoblast function. This work identifies a promising therapeutic target for PE, although further in vivo validation is required to confirm its clinical potential. CONCLUSION: It was found that miR-26a-5p increased the expression of Wnt2 by downregulating EZH2. Moreover, miR-26a-5p/EZH2/Wnt2 promoted the proliferation and inhibited the inflammation and apoptosis in trophoblasts. This research provides insight into the role of miR-26a- 5p/EZH2/Wnt2 as a novel indicator for the prevention and treatment of PE.

MicroRNAs↗

PubMed2005

Regulation of human immunodeficiency virus 1 transcription by nef microRNA.

MicroRNAs (miRNAs) are approximately 21-25 nt long and interact with mRNAs to lead to either translational repression or RNA cleavage through RNA interference. A previous study showed that human immunodeficiency virus 1 (HIV-1) nef dsRNA from AIDS patients who are long-term non-progressors inhibited HIV-1 transcription. In the study reported here, nef-derived miRNAs in HIV-1-infected and nef transduced cells were identified, and showed that HIV-1 transcription was suppressed by nef-expressing miRNA, miR-N367, in human T cells. The miR-N367 could reduce HIV-1 LTR promoter activity through the negative responsive element of the U3 region in the 5'-LTR. Therefore, nef miRNA produced in HIV-1-infected cells may downregulate HIV-1 transcription through both a post-transcriptional pathway and a transcriptional neo-pathway.

Cell Line↗

PubMed2025

Expression of long noncoding RNAs in peripheral blood mononuclear cells of patients with type 1 diabetes mellitus: potential biomarkers for disease onset.

OBJECTIVE: Long non-coding RNAs (lncRNAs) do not encode proteins and are transcripts longer than 200 nucleotides. The precise involvement of lncRNAs in type 1 diabetes mellitus (T1DM) pathogenesis remains unclear. Therefore, this study aimed to analyze the expressions of five lncRNAs in peripheral blood mononuclear cells of individuals with T1DM and without DM. MATERIALS AND METHODS: This study comprised 27 patients with T1DM (cases) and 13 individuals without DM (controls). The case group was divided into two subgroups based on T1DM duration: < 5 years of diagnosis group and long-term diabetes group (≥5 years). LncRNA expression was evaluated by qPCR. RESULTS: MALAT1 and TUG1 were upregulated in patients within the first five years of diagnosis of T1DM compared to the other groups. MEG3 was upregulated in the case group of < 5 years of diagnosis compared to controls. TUG1 and MALAT1 levels were negatively correlated with the duration of T1DM, while TUG1 and MEG3 were positively correlated with glycated hemoglobin levels. Bioinformatics analysis revealed that MALAT1, MEG3, and TUG1 regulate and interact with protein-codifying genes and microRNAs involved in T1DM-related pathways. CONCLUSION: Our study revealed MALAT1, MEG3, and TUG1 upregulation in patients within the first five years of diagnosis of T1DM.

Humans↗

PubMed2025

Mechanism of histone demethylase KDM5A in osteoporotic fracture healing through epigenetic regulation of the miR-495/SKP2/Runx2 axis.

BACKGROUND: Osteoporosis represents a salient metabolic bone disorder. Histone demethylase plays a vital role in bone development and homeostasis. This study explored the mechanism of histone demethylase KDM5A affecting osteoporotic fracture healing via the miR-495/SKP2/Runx2 axis. METHODS: The murine model of osteoporotic fracture was established. The bone mineral density, maximum elastic stress, and maximum load were tested. The relative trabecular bone volume, bone trabecular thickness, and trabecular number at the proximal end of tibia were detected. The histopathological changes of femur tissues and bone microstructure were observed. Expressions of KDM5A and osteogenic factors were detected. The cell proliferation, alkaline phosphatase activity, and calcified nodules were measured. The binding relationships between KDM5A and miR-495 promoter, and miR-495 and SKP2 were verified. The interaction between SKP2 and Runx2 was detected. The ubiquitination level of Runx2 and the stability of Runx2 protein were detected. RESULTS: KDM5A was highly expressed in the murine model of osteoporotic fracture. Interference of KDM5A expression facilitated fracture healing in osteoporotic mice. KDM5A downregulated miR-495 expression by promoting the H3K4me3 methylation of the miR-495 promoter. Inhibition of miR-495 reversed the effect of KDM5A silencing on osteoblast proliferation, differentiation, and mineralization. miR-495 facilitated osteoblast proliferation, differentiation, and mineralization by targeting SKP2. SKP2 suppressed Runx2 expression through ubiquitination degradation. Inhibition of Runx2 reversed the promoting effect of SKP2 silencing on osteogenic differentiation. CONCLUSION: KDM5A attenuated the inhibition of miR-495 on SKP2 and promoted the ubiquitination degradation of Runx2 protein by SKP2, thereby repressing osteoblast differentiation and retarding osteoporotic fracture healing.

Animals↗

PubMed2003

Computational identification of Drosophila microRNA genes.

BACKGROUND: MicroRNAs (miRNAs) are a large family of 21-22 nucleotide non-coding RNAs with presumed post-transcriptional regulatory activity. Most miRNAs were identified by direct cloning of small RNAs, an approach that favors detection of abundant miRNAs. Three observations suggested that miRNA genes might be identified using a computational approach. First, miRNAs generally derive from precursor transcripts of 70-100 nucleotides with extended stem-loop structure. Second, miRNAs are usually highly conserved between the genomes of related species. Third, miRNAs display a characteristic pattern of evolutionary divergence. RESULTS: We developed an informatic procedure called 'miRseeker', which analyzed the completed euchromatic sequences of Drosophila melanogaster and D. pseudoobscura for conserved sequences that adopt an extended stem-loop structure and display a pattern of nucleotide divergence characteristic of known miRNAs. The sensitivity of this computational procedure was demonstrated by the presence of 75% (18/24) of previously identified Drosophila miRNAs within the top 124 candidates. In total, we identified 48 novel miRNA candidates that were strongly conserved in more distant insect, nematode, or vertebrate genomes. We verified expression for a total of 24 novel miRNA genes, including 20 of 27 candidates conserved in a third species and 4 of 11 high-scoring, Drosophila-specific candidates. Our analyses lead us to estimate that drosophilid genomes contain around 110 miRNA genes. CONCLUSIONS: Our computational strategy succeeded in identifying bona fide miRNA genes and suggests that miRNAs constitute nearly 1% of predicted protein-coding genes in Drosophila, a percentage similar to the percentage of miRNAs recently attributed to other metazoan genomes.

Animals↗

PubMed2006

Specification of leaf polarity in Arabidopsis via the trans-acting siRNA pathway.

Plants leaves develop proximodistal, dorsoventral (adaxial-abaxial), and mediolateral patterns following initiation. The Myb domain gene PHANTASTICA (PHAN) is required for adaxial fate in many plants , but the Arabidopsis ortholog ASYMMETRIC LEAVES1 (AS1) has milder effects, suggesting that alternate or redundant pathways exist . We describe enhancers of as1 with more elongate and dissected leaves. As well as RDR6, an RNA-dependent RNA polymerase previously proposed to influence as1 through microRNA , these enhancers disrupt ARGONAUTE7 (AGO7)/ZIPPY, SUPPRESSOR OF GENE SILENCING3 (SGS3), and DICER-LIKE4 (DCL4), which instead regulate trans-acting small interfering RNA (ta-siRNA) . Microarray analysis revealed that the AUXIN RESPONSE FACTOR genes ETTIN (ETT)/ARF3 and ARF4 were upregulated in ago7, whereas FILAMENTOUS FLOWER (FIL) was upregulated only in as1 ago7 double mutants. RDR6 and SGS3 likewise repress these genes, which specify abaxial fate . We show that the trans-acting siRNA gene TAS3, which targets ETT and ARF4, is expressed in the adaxial domain, and ett as1 ago7 triple mutants resemble as1. Thus FIL is downregulated redundantly by AS1 and by TAS3, acting through ETT, revealing a role for ta-siRNA in leaf polarity. RDR6 and DCL4 are required for systemic silencing, perhaps implicating ta-siRNA as a mobile signal.

Arabidopsis↗

PubMed2005

RNAdb--a comprehensive mammalian noncoding RNA database.

In recent years, there have been increasing numbers of transcripts identified that do not encode proteins, many of which are developmentally regulated and appear to have regulatory functions. Here, we describe the construction of a comprehensive mammalian noncoding RNA database (RNAdb) which contains over 800 unique experimentally studied non-coding RNAs (ncRNAs), including many associated with diseases and/or developmental processes. The database is available at http://research.imb.uq.edu.au/RNAdb and is searchable by many criteria. It includes microRNAs and snoRNAs, but not infrastructural RNAs, such as rRNAs and tRNAs, which are catalogued elsewhere. The database also includes over 1100 putative antisense ncRNAs and almost 20,000 putative ncRNAs identified in high-quality murine and human cDNA libraries, with more to be added in the near future. Many of these RNAs are large, and many are spliced, some alternatively. The database will be useful as a foundation for the emerging field of RNomics and the characterization of the roles of ncRNAs in mammalian gene expression and regulation.

Animals↗

PubMed2024

Genetic variants reduced POPs-related colorectal cancer risk via altering miRNA binding affinity and m6A modification.

Exposure to persistent organic pollutants (POPs) may contribute to colorectal cancer risk, but the underlying mechanisms of crucial POPs exposure remain unclear. Hence, we systematically investigated the associations among POPs exposure, genetics and epigenetics and their effects on colorectal cancer. A case-control study was conducted in the Chinese population for detecting POPs levels. We measured the concentrations of 24 POPs in the plasma using gas chromatography-tandem mass spectrometry (GC-MS/MS) and evaluated the clinical significance of POPs by calculating the area under the receiver operating characteristic curve (AUC). To assess the associations between candidate genetic variants and colorectal cancer risk, unconditional logistic regression was used. Compared with healthy control individuals, individuals with colorectal cancer exhibited higher concentrations of the majority of POPs. Exposure to PCB153 was positively associated with colorectal cancer risk, and PCB153 demonstrated superior accuracy (AUC=0.72) for predicting colorectal cancer compared to other analytes. On PCB153-related genes, the rs67734009 C allele was significantly associated with reduced colorectal cancer risk and lower plasma levels of PCB153. Moreover, rs67734009 exhibited an expression quantitative trait locus (eQTL) effect on ESR1, of which the expression level was negatively related to PCB153 concentration. Mechanistically, the risk allele of rs67734009 increased ESR1 expression via miR-3492 binding and m6A modification. Collectively, this study sheds light on potential genetic and epigenetic mechanisms linking PCB153 exposure and colorectal cancer risk, thereby providing insight into the accurate protection against POPs exposure.

Humans↗

PubMed2006

Comprehensive identification of Drosophila dorsal-ventral patterning genes using a whole-genome tiling array.

Dorsal-ventral (DV) patterning of the Drosophila embryo is initiated by Dorsal, a sequence-specific transcription factor distributed in a broad nuclear gradient in the precellular embryo. Previous studies have identified as many as 70 protein-coding genes and one microRNA (miRNA) gene that are directly or indirectly regulated by this gradient. A gene regulation network, or circuit diagram, including the functional interconnections among 40 Dorsal target genes and 20 associated tissue-specific enhancers, has been determined for the initial stages of gastrulation. Here, we attempt to extend this analysis by identifying additional DV patterning genes using a recently developed whole-genome tiling array. This analysis led to the identification of another 30 protein-coding genes, including the Drosophila homolog of Idax, an inhibitor of Wnt signaling. In addition, remote 5' exons were identified for at least 10 of the approximately 100 protein-coding genes that were missed in earlier annotations. As many as nine intergenic uncharacterized transcription units were identified, including two that contain known microRNAs, miR-1 and -9a. We discuss the potential functions of these recently identified genes and suggest that intronic enhancers are a common feature of the DV gene network.

Animals↗

PubMed2006

miRNA and Dicer in the mammalian lens: expression of brain-specific miRNAs in the lens.

Micro RNAs (miRNAs) are approximately 22 nucleotide molecules that regulate gene expression post-transcriptionally and govern a wide range of physiological and developmental processes. Evidence now indicates that miRNAs can also coordinately down-regulate transcript levels for very large groups of genes in a tissue-specific manner, in addition to their ability to suppress protein translation. Here, we examine expression of specific miRNAs and Dicer ribonuclease that is required for miRNA biogenesis in mouse and rat lenses. Northern blot analysis demonstrated lens expression of brain-specific miR-124 and miR-7 in lenses, as well as miR-125b and let-7a. In addition, we provide evidence that muscle specific miR-1 is not present in lens. We detected Dicer transcripts in 21 day, 6 week, and 1 year mouse lenses and 15 day rat lens, and detected Dicer protein in adult lens protein samples. Immunohistochemical examination of late embryonic, post-natal, and adult rat lens sections identified expression of Dicer in differentiating fiber cells that undergo pronounced cell elongation in the lens interior and anterior epithelial cells. The present study provides evidence that miRNAs, which include brain-specific forms, and Dicer are expressed in mammalian lenses, indicating that fundamental aspects of miRNA biology are utilized by the lens during late embryonic and post-natal development and in adult lenses.

Aging↗

PubMed2005

Lactational traits of importance in dairy cows and applications for emerging biotechnologies.

New molecular and quantitative genetic technologies are the latest in a long list of technologies that have been introduced to dairy industries over many decades to improve the performance of cows. The catalysts for future advances will be sequencing of the bovine genome and development of high-throughput technologies to identify and exploit relevant variation in DNA sequences. The new technologies will allow the selection of animals based on specific genotypes that suit specific applications such as once-daily (OAD) milking or extended lactation. These technologies will also allow exploitation of between-cow variation in milk composition, which is currently hidden by bulking of milk on and between farms. Thus, there are opportunities to produce milk from herds of cows selected for specific milk composition that might be, for example, more suitable for cheese-making or have milkfat with specific properties to enhance human health. Identification of genes and gene polymorphisms associated with improved resistance to specific diseases in cows and other farm species also represents a real opportunity to improve animal health over the coming decade. New levels of genetic regulation have been identified, e.g. microRNA and epigenetics, the impacts of which on the performance of cows and humans are only just beginning to be understood. There is a potential role for veterinarians to provide or be the interface for provision of genetic advice to farmers in much the same way that nutritional advice is currently given.

Animals↗

PubMed2026

A modular class-aware workflow for small RNA sequencing analysis using mouse sperm as a case study.

BACKGROUND: Small RNA sequencing analysis is challenging because RNA classes differ in biogenesis, sequence redundancy, genomic organization, and annotation reliability. Integrated workflows accommodating these constraints remain limited, particularly for fragment-level and cluster-level analysis. METHODS: We present a reproducible, containerized, class-aware workflow for small RNA sequencing analysis, using mouse sperm as a case study. The workflow combines standardized preprocessing with complementary annotation and quantification strategies for microRNAs (miRNAs), transfer RNA-derived small RNAs (tsRNAs), ribosomal RNA-derived small RNAs (rsRNAs), and PIWI-interacting RNA (piRNA)-enriched genomic clusters. Using sperm small RNA data from offspring of lipopolysaccharide (LPS)-exposed male mice, we compared integrated-reference mapping, multi-class annotation, fragment-level tsRNA profiling, and genome-based piRNA cluster analysis, with custom modules for locus-aware harmonization and condition-specific cluster analysis. RESULTS: Integrated-reference mapping aligned 88.17% of reads and retained 690 features after filtering. It identified 11 differentially expressed miRNAs between LPS and controls, while other classes showed limited signal. Fragment-level profiling improved tsRNA resolution. piRNA cluster analysis identified 958 control and 940 LPS clusters, with 18 control-specific and no LPS-specific clusters. CONCLUSION: This workflow supports transparent, reproducible, class-aware interpretation of small RNA sequencing data while emphasizing cautious interpretation of piRNA-enriched signals from total small RNA sequencing.

Small non-coding RNA analysis↗

PubMed2026

An Exosomal Signature for Preoperative Detection of Occult Liver Metastasis in Pancreatic Cancer.

IMPORTANCE: Early liver metastasis (early-LiM) after pancreatectomy represents an aggressive biological phenotype of pancreatic ductal adenocarcinoma (PDAC) and is associated with markedly poor survival. Reliable preoperative biomarkers to identify occult hepatic micrometastasis remain lacking. OBJECTIVE: To develop and externally validate a circulating exosomal microRNA (exo-miRNA)-based machine learning model for preoperative detection of occult early-LiM in PDAC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective case-control study included 3 phases: genome-wide discovery using exo-miRNA sequencing (discovery cohort), model development (training cohort), and independent external validation (2 validation cohorts). The study took place at 4 medical centers in China, Japan, and South Korea. A total of 372 patients were enrolled between 2011 and 2024. Data were analyzed from July 2024 to November 2025. EXPOSURES: Circulating plasma-derived exosomal miRNA expression profiles. MAIN OUTCOMES AND MEASURES: The primary outcome was early-LiM, defined as liver recurrence within 6 months after curative-intent resection. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and survival outcomes were assessed using Kaplan-Meier analysis. RESULTS: Among 372 patients with PDAC (median [IQR] age, 67 [59-73] years; 229 [61.6%] male and 143 [38.4%] female; median follow-up among survivors, 969 days),early-LiM was associated with significantly worse overall survival compared with other recurrence patterns (median OS, 9.1 months vs 26.6-31.8 months; log-rank P < .001). A 7-exo-miRNA extreme gradient boosting model demonstrated discrimination in the training cohort (AUC, 0.899; 95% CI, 0.822-0.976) and maintained performance in external testing cohorts (AUC, 0.876; 95% CI, 0.846-0.951 and AUC, 0.862; 95% CI, 0.744-0.981). The exo-miRNA panel score remained an independent identifier of early-LiM in multivariable analysis (odds ratio, 26.49; 95% CI, 18.45-55.28; P < .001) and stratified overall survival (log-rank P < .001). Decision curve analysis suggested improved net clinical benefit compared with conventional clinicopathologic variables. CONCLUSION AND RELEVANCE: In this multicenter study, a circulating exo-miRNA-based machine learning model enabled preoperative detection of occult early liver metastasis risk in PDAC. These findings support the potential of exosomal biomarkers to inform biology-guided treatment sequencing and warrant prospective validation.

Journal Article↗