Biomedical subjects

Chen Yu

Publications and source records attributed to Chen Yu.

4 recordsLinked to original sources

PubMed2026

Alternative tandem transcription initiation links noncoding variants to human disease through translational control.

Alternative tandem transcription initiation is a pervasive mechanism of gene regulation, yet its genetic impact on human disease remains largely unknown. Here, we systematically quantify the genetic regulation of alternative tandem transcription initiation across 25,859 samples from 49 normal human tissues and 33 tumor tissues. We identify approximately 0.4 million genetic variants associated with alternative transcription initiation in 5295 genes, with 32% operating independently of gene expression. Moreover, we discover 2238 multi-tissue alternative tandem transcription initiation outliers enriched for rare deleterious promoter and 5' UTR variants, demonstrating that both common and rare variants modulate transcription initiation. Strikingly, 74% of disease variants that colocalize with genetic variants regulating alternative transcription initiation cannot be identified through expression quantitative trait loci. Transcriptome-wide association studies identify 614 disease susceptibility genes associated with alternative transcription initiation, including known cancer drivers such as MAFF and MLLT10. Functional validation uncovers OSGEP as a breast cancer risk gene, where the alternative allele lengthens the 5' UTR and reduces protein abundance through upstream open reading frame-mediated translation repression, and suppresses breast cancer cell proliferation. Our findings establish alternative transcription initiation as a major, underappreciated mechanism associating noncoding variation with disease, providing a critical resource for interpreting disease risk loci.

Humans↗

PubMed2026

A Phase I Study Assessing the Safety, Tolerability, and Pharmacokinetics of Yinfenidone: A Novel, Potent Drug for Idiopathic Pulmonary Fibrosis Treatment in Healthy Chinese Subjects.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a median survival of only 2-3 years after diagnosis. Yinfenidone (HEC585) possesses the potential to inhibit the proliferation of pulmonary fibroblasts, making it a promising candidate for the treatment of IPF. This study assessed the safety, tolerability, pharmacokinetics, and metabolic profile of Yinfenidone hydrochloride capsule in healthy Chinese subjects. METHODS: This single-center, randomized, double-blind, placebo-controlled, single ascending-dose trial included seven dose groups(20, 50, 100, 200, 400, 600, and 800 mg). Each group enrolled8 healthy subjects: 6 received Yinfenidone hydrochloride capsules and 2 received matching placebo under fasting conditions. Serial pharmacokinetic (PK) blood samples were collected pre-dose and post-dose, liquid chromatography-tandem mass spectrometry was used to analyze the plasma concentrations of Yinfenidone. Additionally, metabolic biotransformation of Yinfenidone in plasma were conducted in the 100 mg dose group. Safety and tolerability endpoints were monitored via physical examinations, vital signs measurements, clinical laboratory tests, 12-lead electrocardiography (ECG), and adverse events (AEs) documentation throughout the trial. FINDINGS: Yinfenidone was rapidly absorbed, with a median maximum plasma concentration (Tmax) of 1.8-3.0 hours, and had a mean half-life (t1/2) ranging from 31.9 to 62.0 hours. Within the 20-100 mg dose range, systemic drug exposure generally increased with ascending dose, above 100 mg, exposure increased less than proportionally to dose. Metabolite profiling in the 100 mg group revealed that the parentcompound predominated in plasma, with metabolic pathways including mono-oxygenation and N-dealkylation. All reported AEswere mild, classified as Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1. No serious AEs observed; no subject discontinued the trial due to AEs. Single oral doses of 20-800 mg Yinfenidone hydrochloride capsules administered under fasting conditions demonstrated favorable safety and tolerability profiles in healthy Chinese subjects. IMPLICATIONS: Yinfenidone exhibited rapid absorption (median Tmax, 1.8-3.0 hours) and a long terminal t1/2 ranging from 31.9 to 62.0 hours in this single ascending-dose study, indicating that Yinfenidone can be taken once a day in subsequent clinical studies. Yinfenidone mainly exists in human plasma as the original drug and is metabolized through a variety of metabolic pathways. The AEs observed with Yinfenidone in this study, such as diarrhea, nausea, and dizziness, were similar to those reported with pirfenidone. Overall, Yinfenidone demonstrated a favorable safety and tolerability profile in this cohort of healthy subjects.

Adult↗

PubMed2025

Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis.

BACKGROUND: Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. METHODS: This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). RESULTS: Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10- 5). Additionally, the inhibition of FGFR1, FLT1, and MAP2K2 exhibited suggestive association with corresponding cardiovascular disease outcomes. Nevertheless, only VEGFA expression and stroke shared a causal variant (93.6%), whereas FGFR1, MAP2K2, and FLT1 did not share causal variants with corresponding cardiovascular diseases in the colocalization analysis. CONCLUSIONS: This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy.

Humans↗

PubMed2024

A novel Alteromonas phage with tail fiber containing six potential iron-binding domains.

Viruses play a vital role in regulating microbial communities, contributing to biogeochemical cycles of carbon, nitrogen, and essential metals. Alteromonas is widespread and plays an essential role in marine microbial ecology. However, there is limited knowledge about the interactions of Alteromonas and its viruses (alterophages). This study isolated a novel podovirus, vB_AmeP-R22Y (R22Y), which infects Alteromonas marina SW-47 (T). Phylogenetic analysis suggested that R22Y represented a novel viral genus within the Schitoviridae family. R22Y exhibited a broad host range and a relatively large burst size, exerting an important impact on the adaptability and dynamics of host populations. Two auxiliary metabolic genes, encoding Acyl carrier protein and AAA domain-containing protein, were predicted in R22Y, which may potentially assist in host fatty acid metabolism and VB12 biosynthesis, respectively. Remarkably, the prediction of the R22Y tail fiber structure revealed six conserved histidine residues (HxH motifs) that could potentially bind iron ions, suggesting that alterophages may function as organic iron-binding ligands in the marine environment. Our isolation and characterization of R22Y complements the Trojan Horse hypothesis, proposes the possible role of alterophages for marine iron biogeochemical cycling, and provides new insights into phage-host interactions in the iron-limited ocean.IMPORTANCEIron (Fe), as an essential micronutrient, is often a limiting factor for microbial growth in marine ecosystems. The Trojan Horse hypothesis suggests that iron in the phage tail fibers is recognized by the host's siderophore-bound iron receptor, enabling the phage to attach and initiate infection. The potential role of phages as iron-binding ligands has significant implications for oceanic trace metal biogeochemistry. In this study, we isolated a new phage R22Y with the potential to bind iron ions, using Alteromonas, a major siderophore producer, as the host. The tail fiber structure of R22Y exhibits six conserved HxH motifs, suggesting that each phage could potentially bind up to 36 iron ions. R22Y may contribute to colloidal organically complexed dissolved iron in the marine environment. This finding provides further insights into the Trojan Horse hypothesis, suggesting that alterophages may act as natural iron-binding ligands in the marine environment.

Bacteriophages↗