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Biomedical subjects

Yan Chen

Publications and source records attributed to Yan Chen.

12 recordsLinked to original sources

PGS-GS: a framework integrating polygenic scores and genomic selection in animal breeding.

Genomic prediction has become a central paradigm in biology, enabling quantitative inference of genetic contributions to complex traits across humans, animals, and plants. Although genomic research in human genetics and animal breeding shares a highly homologous methodological foundation, significant barriers persist in their analytical paradigms and application scenarios. This study aims to promote cross-disciplinary integration by introducing human-derived polygenic scores (PGS) algorithms into animal genomic selection (GS) and proposing a PGS-GS framework with a preliminary weighting-based implementation. We systematically benchmarked the predictive performance and computational efficiency of 20 algorithms, including classical linear models, machine learning, PGS, and PGS-GS using both array and whole-genome sequencing (WGS) data across four major agricultural species: beef cattle, sheep, pigs, and chickens. Our results demonstrate that PGS and PGS-GS algorithms achieve predictive accuracy competitive with genomic best linear unbiased prediction (GBLUP) while offering markedly higher computational efficiency. Moreover, incorporating PGS-derived prior information into weighted linear and non-linear models outperformed conventional weighted GBLUP. The results provide empirical evidence to inform algorithm selection and highlight the potential of integrating human-derived PGS methodologies into animal genomic prediction frameworks.

Animals

Liver Cancer Risk and Incidence Attributable to Human Immunodeficiency Virus: A Meta-Analysis and Population-Attributable Modeling Study of Over 1.2 Million Individuals.

HIV-induced immune suppression and chronic inflammation elevate the risk of cancer progression. We conducted a systematic review and meta-analysis of studies published between January 1, 1984 and October 13, 2023 to assess the association between HIV infection and liver cancer. People living with HIV (PLHIV) had a higher risk (pooled relative risk = 3.36, 95% CI: 2.72-4.15). The global PAF for HIV-attributed liver cancer was 1.43% in 2019, with a three-fold increase over the past 30 years. The Asia-Pacific region recorded the second highest new cases of HIV-attributed liver cancer in 2019, and the highest age-standardized incidence rate (ASIR) in Eastern and Southern Africa. Particularly, the ASIR of HIV-attributed liver cancer increased rapidly in Eastern Europe and Central Asia, with the highest estimated annual percentage change reaching 22.98%. PLHIV have an increased risk and incidence of liver cancer. In regions with high burden of HIV-attributed liver cancer, it is essential to integrate prevention and effective treatment for HIV, viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, and liver cancer.

Humans

Targeting pancreatic cancer progression: The formononetin and salvianolic acid B combination suppresses JAK/STAT signaling via MBOAT2 downregulation.

OBJECTIVE: Formononetin and salvianolic acid B (FcS) are the primary bioactive components of the Astragalus mongholicus-Salvia miltiorrhiza herbal pair, a classic combination for treating pancreatic cancer associated with qi deficiency and blood stasis. This study elucidates the therapeutic potential and mechanisms of FcS in the treatment of pancreatic cancer. METHODS: A zebrafish xenograft model was used to screen bioactive combinations derived from A. mongholicus and S. miltiorrhiza, identifying FcS as a candidate with antitumor activity. Its efficacy was evaluated in vivo using the zebrafish model, orthotopic LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx-1-Cre (KPC) mice, and subcutaneous xenograft models. Cell viability and proliferation were assessed using cell counting kit-8, 5-ethynyl-2'-deoxyuridine and colony formation assays, and migration and invasion were evaluated by wound healing and transwell assays. Membrane-bound O-acyltransferase 2 (MBOAT2) was identified as a potential target through a molecular docking study and the Cancer Genome Atlas (TCGA) analysis. MBOAT2 knockdown cells were used to explore its roles and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in FcS-mediated inhibition. RESULTS: In the zebrafish model, FcS strongly inhibited pancreatic tumor growth. FcS reduced tumor volume, the expression of proliferation marker Ki-67, and proliferating cell nuclear antigen in KPC mice. In vitro, FcS inhibited pancreatic cancer cell viability, proliferation, migration and invasion, which was accompanied by downregulation of MBOAT2 expression. TCGA analysis linked high MBOAT2 expression to aggressive phenotypes. MBOAT2 knockdown reduced the survival, proliferation and invasion of BxPC-3 cells. Rescue experiments revealed that MBOAT2 knockdown attenuated the antitumor effects of FcS, possibly through modulation of the JAK/STAT signaling pathway. FcS also inhibited tumor proliferation in xenograft models, and MBOAT2 expression was elevated in tumor tissues from pancreatic cancer patients. CONCLUSION: FcS suppresses pancreatic cancer progression via MBOAT2 downregulation and JAK/STAT pathway inhibition, which highlights MBOAT2 as a potential therapeutic target. Please cite this article as: Xu Y, Xu CS, Jin HB, Gu WG, Shen HZ, Lu L, Chen Y, Xu DC, Zhang XF, Yang JF, Wang Y. Targeting pancreatic cancer progression: The formononetin and salvianolic acid B combination suppresses JAK/STAT signaling via MBOAT2 downregulation. J Integr Med. 2026; 24(5):725-741.

Animals

Transposable element-driven expansion of enhancer RNA repertoires underlies regulatory innovation and polyploid adaptation in cereal crops.

Cereal genomes have undergone repeated polyploidization and transposable element (TE) proliferation, collectively generating complex regulatory landscapes. However, the evolutionary trajectories and functional implications of these landscapes remain largely unexplored. Using chromatin-bound RNA sequencing across seven cereal species, we systematically mapped 45,952 regulatory element transcripts (RETs), including 32,867 distal RETs corresponding to enhancer RNAs (eRNAs). Our analysis revealed that 56% of lineage-specific eRNAs originated from TE expansions, indicating that TEs serve as major reservoirs of species-specific regulatory innovation in cereals. Notably, we identified remarkable conservation in defense-related functions, root-specific expression, and TE-derived origins of eRNAs across both ancient and recent evolutionary layers of Triticeae, suggesting recurrent recruitment of TE-derived, root-associated regulatory elements throughout Triticeae evolution. Furthermore, we found that young eRNA pairs in hexaploid wheat with high sequence similarity, many originating from RLG_famc8.3 and DTC_famc4.3, exhibited pronounced root specificity and coordinated expression, suggesting targeted amplification and refinement of successful ancestral regulatory strategies established after Triticeae divergence. To facilitate community access, we developed Cereal-eRNAdb (http://bioinfo.cemps.ac.cn/Cereal-eRNAdb/), a comprehensive database integrating 69,426 eRNAs with functional annotations across 296 samples. Our findings suggest that TE-mediated innovation of root-specific eRNAs may contribute to Triticeae adaptation and provide a foundational resource for exploiting regulatory variation in cereal crop breeding.

Enhancer RNAs

Integration of Genome-Wide Association Studies With Single-Cell and Bulk Expression Quantitative Trait Locus to Identify Stroke Susceptibility Genes.

BACKGROUND: Previous studies have integrated genome-wide association studies with expression quantitative trait locus (eQTL) data from bulk tissues to identify stroke susceptibility genes. However, eQTL data exhibit high cell-type specificity, and genetic variants may have distinct effects across stroke subtypes. METHODS: We applied the summary-data-based Mendelian randomization (MR) method to integrate eQTL data from 7 brain cell types with genome-wide association studies data for 5 stroke phenotypes (stroke, ischemic stroke, cardioembolic stroke, large artery stroke, and small vessel stroke). Results were compared with summary-data-based MR using eQTL data from 49 tissues in the Genotype-Tissue Expression project. Robustness of significant single-cell summary-data-based MR associations was assessed via MR and colocalization analyses. Further evaluations included single-cell RNA-seq differential expression, protein-protein interaction, druggability, and phenome-wide association studies. RESULTS: Single-cell summary-data-based MR identified many novel significant genes not detected using bulk tissue eQTL data. Validated associations revealed 2 stroke risk genes (LRCH1, ICA1L), 3 stroke protective genes (AHI1, LYRM9, CENPQ), 2 large artery stroke risk genes (LIPA, ELL), and 1 ischemic stroke protective gene (CENPQ). Single-cell RNA-seq showed significantly increased LIPA expression in mouse stroke samples compared with controls. Protein-protein interaction and druggability analyses, along with phenome-wide association studies, prioritized LIPA and LRCH1 as potential therapeutic targets for stroke while indicating possible adverse effects. CONCLUSIONS: Integrating single-cell eQTL with stroke-subtype genome-wide association studies uncovers novel cell-type-specific causal genes and highlights promising therapeutic targets, advancing understanding of stroke pathogenesis.

Genome-Wide Association Study

Novel serum small extracellular vesicle miRNAs with multi-target RCA-CRISPR sensor for liver cancer detection.

BACKGROUND: Detecting liver cancer (LC) remains a significant challenge in clinical practice. Small extracellular vesicle (sEV) miRNAs show promise as non-invasive biomarkers for LC detection, yet their diagnostic potential remains largely unexplored. This study aimed to identify specific sEV miRNA signatures for LC detection and develop a novel synchronized multi-miRNA detection platform to enhance diagnostic efficiency and sensitivity. METHODS: High-throughput sequencing was conducted across four distinct cohorts: normal controls (NC), hepatitis B virus (HBV) patients, liver cirrhosis patients, and LC patients. This sequencing process identified miRNAs with differential expression, followed by RT-qPCR validation in serum sEV miRNAs from LC patients and NC. An innovative detection method, RCA-CRISPR, was introduced, combining rolling circle amplification (RCA) with CRISPR/Cas12a (RCA-CRISPR) for quick and sensitive miRNAs detection. RESULTS: Sequencing results showed a consistent elevation of hsa-miR-203b-5p, hsa-miR-4661-5p, and hsa-miR-219a-2-3p across all cohorts. RT-qPCR validations confirmed significant upregulation of these miRNAs in serum sEVs from LC patients, and the combined three-miRNA panel exhibited high diagnostic accuracy (p = 0.0003; AUC = 0.81). The RCA-CRISPR method demonstrated a detection limit of 3.12 pM for simultaneous multi-target miRNA detection, highlighting its exceptional sensitivity. CONCLUSIONS: Our study identifies hsa-miR-203b-5p, hsa-miR-4661-5p, and hsa-miR-219a-2-3p as promising sEV miRNA biomarkers for LC detection. The developed RCA-CRISPR sensor provides a robust tool for multi-miRNA analysis, potentially advancing non-invasive LC diagnostics. Future validation in larger, prospectively collected cohorts is essential to establish the clinical utility and performance of this biomarker panel and RCA-CRISPR sensor.

MicroRNAs

Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.

BACKGROUND: Plasma and cerebrospinal fluid (CSF) protein biomarkers in amyotrophic lateral sclerosis (ALS) may provide insight into disease mechanisms and yield clinically useful biomarkers. METHODS: Overall, 363 proteins in plasma and CSF from 198 patients with ALS and 125 matched controls were profiled using Olink assays. Associations with disease status, survival, and functional decline, as well as longitudinal biomarker stability across the disease course were assessed, together with network and enrichment analyses. ALS risk-associated biomarkers were externally validated in the UK Biobank (UKB). RESULTS: Overall, 125 proteins were significantly associated with at least one outcome (i.e., case status, risk, survival, or functional decline), and 21 were associated with three or more outcomes. NEFL was the most robust biomarker in plasma and CSF, alongside TNFRSF12A in plasma and CSF, EDA2R in plasma, and FABP4 in plasma and CSF. Most biomarkers remained stable longitudinally across the disease course. ALS risk-associated biomarkers were replicated in UKB, in which > 3000 plasma proteins were measured in 52,990 participants, including 298 with ALS. Network and enrichment analyses highlighted their roles in immune response and extracellular-matrix remodeling, and their enrichments in the brain and T-cell subsets. Construction of an ALS risk-prediction model achieved an ROC-AUC of 0.72 in the UKB validation cohort. CONCLUSIONS: These findings suggest candidate protein biomarkers for ALS risk stratification, early detection, and clinical therapeutic monitoring.

Humans

A 7-mm Covered TIPS Reduces Hepatic Encephalopathy Without Increasing Rebleeding in Cirrhotic Patients With Small Liver: A Randomized Study.

BACKGROUND/AIMS: International guidelines recommend initiating transjugular intrahepatic portosystemic shunt (TIPS) placement with an 8-mm stent. However, there is an evident lack of randomized controlled trials evaluating TIPS diameters <&#x2009;8&#x2009;mm in cirrhotic patients with a relatively small liver. The aim of this study was to determine whether 7&#x2009;mm-covered TIPS, compared with 8-mm stents, could achieve comparable shunt function with a lower incidence of hepatic encephalopathy (HE). METHODS: In this multicenter randomized controlled trial, patients with cirrhosis and relatively small liver were randomized 1:1 to receive TIPS with a 7-mm (n&#x2009;=&#x2009;92) or 8-mm (n&#x2009;=&#x2009;92) covered stent to prevent variceal rebleeding. The primary endpoint was the incidence of overt HE after randomization. All-cause rebleeding, orthotopic liver transplantation (OLT)-free survival and a composite of these outcomes, were designated as secondary endpoints. RESULTS: Among the 184 enrolled patients, the predominant etiologies of liver cirrhosis were hepatitis B virus infection (56.0%) and alcohol-related liver disease (20.7%). Over a median follow-up of 26.5&#x2009;months, overt HE occurred in 19 patients (20.7%) in the 7-mm group and 33 patients (35.9%) in the 8-mm group. The 2-year cumulative incidence of overt HE was significantly lower in the 7-mm group than in the 8-mm group (21.4% vs. 37.2%, p&#x2009;=&#x2009;0.02). Stent diameter, post-TIPS portosystemic pressure gradient, pre-covert HE and MELD-Na score were identified as independent risk factors for overt HE. The rates of shunt dysfunction were statistically similar between groups (8.7% vs. 8.7%, p&#x2009;=&#x2009;1.0), as were 2-year rebleeding rates (10.9% vs. 9.8%, p&#x2009;=&#x2009;0.81) and OLT-free survival rates (91.3% vs. 88.0%, p&#x2009;=&#x2009;0.82). CONCLUSIONS: A 7-mm covered TIPS demonstrated comparable shunt function to an 8-mm covered stents, with a significantly lower risk of overt HE. These findings support consideration of 7-mm TIPS stents for preventing variceal rebleeding in cirrhotic patients with a small liver who are undergoing TIPS. TRAIL REGISTRATION: ClinicalTrials.gov, NCT02541825.

Humans

Engineering Polyketide Stereocenters with Ketoreductase Domain Exchanges.

Polyketide synthases (PKSs) are versatile biosynthetic megasynthases capable of producing a diverse range of natural products with many applications, including in pharmaceuticals. The stereochemical precision of PKSs makes them a powerful tool for engineering tailored, unnatural polyketides; however, modifying the stereocenters of a PKS product while maintaining production levels remains a significant challenge. In this study, we systematically tested and evaluated strategies for ketoreductase (KR) domain exchanges, the domain responsible for setting stereocenters of polyketide products. After first optimizing the method for KR exchanges, we then performed 44 KR domain exchanges on three different PKSs to obtain high production of all four stereoisomers in vivo. By testing both one- and two-module PKS systems, we investigated how downstream modules process intermediates with altered stereochemistry and found that the configuration of the &#x3b1;-substituents was critical for gatekeeping by the ketosynthase (KS). To overcome this constraint, we investigated two different strategies for altering the KS domain, including introducing targeted mutations in the downstream KS, and exploring boundaries in exchanging the entire functional unit from the donor PKS. Both strategies successfully modified the KS stereocontrol with distinct trade-offs; the functional unit exchange resulted in higher titer improvements, though it was more likely to break the entire PKS. This study demonstrates a comprehensive approach to successfully engineering all four stereochemical configurations in multiple PKS systems, advancing our understanding of and ability to rationally modify polyketide stereochemistry through multiple engineering strategies.

Polyketides

Whole Genome Development of Specific Alien-Chromosome Oligo (SAO) Markers for Wild Peanut Chromosomes Based on Chorus2.

The cultivated peanut (Arachis hypogaea L.) is a globally important oilseed and economic crop, but its narrow genetic base limits breeding progress. Wild Arachis species represent valuable genetic resources for enhancing the resilience of the peanut cultigen. While wild species from section Arachis are widely used in breeding programs, the detection of alien chromosomes in hybrids remains challenging due to limited molecular tools. In this study, a cost-effective and efficient system was established for generating species-specific molecular markers using low-coverage next-generation sequencing data, bypassing the need for whole-genome assembly. Utilizing the Chorus2 software, specific alien-chromosome oligo (SAO) markers were developed for four wild species, A. duranensis (accession A19), A. pusilla (A10), A. appresipilla (A33), and A. glabrata (G2 and G3). A total of 1166 primer pairs were designed, resulting in 220 SAO markers specific to A. duranensis, 77 to A. pusilla, 112 to A. appresipilla, 69 to A. glabrata G2, and 59 to A. glabrata G3, with the highest development efficiency observed in A. duranensis (55.0%). These markers span all chromosomes of the five wild accessions. Genome-wide, chromosome-specific SAO markers enable the efficient detection of introgressed alien chromosomes and provide insight into syntenic relationships among homoeologous chromosomes. These markers offer an effective tool for identifying favorable genes and facilitating targeted introgression for the genetic improvement of the cultivated peanut.

Chorus2

Comprehensive analysis of the expression, prognostic, and immune infiltration for COL4s in stomach adenocarcinoma.

BACKGROUND: Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking. METHODS: The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques. RESULTS: The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8&#x2009;+&#x2009;T cells, dendritic cells, macrophages, neutrophils and CD4&#x2009;+&#x2009;T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines. CONCLUSION: COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD.

Stomach Neoplasms