Background:Mucus hypersecretion and obesity are two prevalent comorbidities that independently worsen childhood asthma outcomes. However, the metabolic mechanisms by which obesity-related factors interact with type 2 (T2) inflammatory signals to exacerbate airway epithelial mucus phenotype remain poorly understood. This study aimed to investigate whether palmitic acid (PA), a representative obesity-related saturated fatty acid, amplifies interleukin-13 (IL-13)-induced mucus phenotype in human bronchial epithelial cells and to determine whether the AMP-activated protein kinase (AMPK) axis mediates this interaction. Methods:We stimulated 16HBE human bronchial epithelial cells with IL-13 (10 ng/mL, 72 h), PA (100 µM, 48 h), or combined IL-13 and PA exposure, in which PA was added during the final 48 h of IL-13 treatment. We activated AMPK pharmacologically with AICAR (1 mM) and suppressed AMPK genetically through small interfering RNA (siRNA)-mediated PRKAA1 knockdown. We quantified MUC5AC, MUC5B, CLCA1, and PRKAA1 messenger RNA (mRNA) transcripts by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), measured IL-8 secretion by enzyme-linked immunosorbent assay (ELISA), assessed AMPKα, phosphorylated acetyl-CoA carboxylase (p-ACC), and acetyl-CoA carboxylase (ACC) by Western blot, and evaluated MUC5AC and zonula occludens-1 (ZO-1) localization by immunofluorescence. Results:Combined IL-13 and PA stimulation markedly elevated MUC5AC and CLCA1 mRNA and protein expression beyond IL-13 alone (P<0.001). In addition, combined stimulation further increased IL-8 secretion (P<0.001), indicating a stronger pro-inflammatory epithelial response after combining inflammatory and metabolic stimuli. In parallel, the p-ACC/ACC ratio, an indicator of AMPK activity, was lowest after combined IL-13 and PA exposure (P<0.001). AMPK activation with AICAR partially reversed MUC5AC, CLCA1, and IL-8 upregulation and restored ZO-1 continuity (P<0.001), whereas PRKAA1 knockdown further aggravated MUC5AC expression (P<0.01) and reduced p-ACC levels (P<0.05). Conclusions:PA amplifies IL-13-induced airway epithelial mucus phenotype through suppression of the AMPK axis. AMPK may represent a potential therapeutic target for mucus hypersecretion in obesity-related childhood asthma.
Background:Genetic causes of early-onset obesity remain undercharacterized in East Asian children. This study evaluated a whole-exome sequencing (WES)-centered diagnostic workflow in Chinese children with obesity onset before 5 years. Methods:Consecutive children with body mass index above the 95th percentile and obesity onset before 5 years who completed structured inpatient assessment at a single center between February 2022 and December 2023 were retrospectively analyzed. Phenotyping included clinical, biochemical, oral glucose tolerance, cortisol rhythm, and liver assessments. Genetic testing combined WES, mitochondrial DNA analysis, multiplex ligation-dependent probe amplification (MLPA) for obesity-related imprinting loci, WES-based copy-number variant and runs-of-homozygosity analyses, and Sanger validation. Variants were interpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. Results:Among 23 children, clinically relevant genetic findings were identified in 6 (26.1%): melanocortin-4 receptor (MC4R) c.831T>A (p.C277*), maternal uniparental disomy of 15q11-13, and four phenotype-correlated variants of uncertain significance in UCP3, BBS1, NCOA1, and SH2B1. The definitive/likely diagnostic yield, restricted to pathogenic or confirmed imprinting findings, was 8.7% (2/23). Findings involved leptin-MC4R signaling, BBSome function, fatty-acid oxidation, and chromosomal imprinting. Genetically positive children showed numerically higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but differences were not statistically significant. BBS1 p.T374S was relatively enriched in East Asian reference data. Conclusions:A WES-centered integrated workflow detected heterogeneous genetic mechanisms in Chinese children with early-onset obesity, but variant of uncertain significance (VUS)-associated findings should be distinguished from confirmed diagnoses. Orthogonal methylation/MLPA and runs of homozygosity (ROH) analyses were necessary for imprinting diagnosis. Larger multicenter studies and functional validation are needed.
Background:Taurine metabolism-related transcriptional programs have not been systematically characterized in neuroblastoma. We aimed to investigate the clinical relevance and biological features of a taurine metabolism-related gene program in neuroblastoma and to determine whether this candidate space could yield a prognostically informative gene signature. Methods:A taurine-related gene program was quantified using single-sample gene set enrichment analysis in the discovery cohort. Its associations with clinicopathologic variables, survival, and hallmark pathways were evaluated, followed by gene-level prognostic screening and construction of a compressed candidate prognostic model. Model performance was assessed in the discovery cohort and externally evaluated in independent validation datasets. Integrative prioritization was then performed to identify core candidate genes, which were further examined using Jansky-based tumor-cell pseudobulk and patient-aware phase analyses. Results:Taurine single-sample gene set enrichment analysis (ssGSEA) score was significantly associated with Children's Oncology Group (COG) risk group, MYCN status, International Neuroblastoma Staging System (INSS) stage, and overall survival in neuroblastoma. Higher taurine ssGSEA scores were generally observed in clinically more favorable subgroups and were associated with better overall survival in the discovery cohort. At the gene-set level, taurine score showed a strong positive correlation with hypoxia, but negative correlations with E2F targets, G2M checkpoint, MYC targets, and DNA repair, indicating a hypoxia/stress-associated biological context. Gene-level screening identified representative prognostic taurine-related candidates, from which an 8-gene candidate prognostic model was derived. In the discovery cohort, this model showed strong survival stratification and time-dependent discrimination, with 1-, 3-, and 5-year area under the receiver operating characteristic curve (AUC) values of 0.917, 0.906, and 0.913, respectively, and improved concordance when combined with clinical variables. External evaluation showed the strongest support in GSE181559, where Kaplan-Meier stratification was significant and AUCs were 0.701, 0.769, and 0.761 at 1, 3, and 5 years, respectively, whereas additional cohorts suggested inter-cohort heterogeneity and limited fixed-cutoff transferability. Biologically, the 8-gene score was positively associated with proliferative and metabolically active programs, including E2F, G2M, MYC, DNA repair, and glycolysis, but negatively associated with hypoxia and stromal/inflammatory programs. Integrative prioritization and patient-aware analyses further highlighted ADO, AURKA, GCLC, and MMP9 as four core candidate genes linked to a tumor-intrinsic proliferative component. Conclusions:A taurine metabolism-related transcriptional program is clinically relevant in neuroblastoma and, at the gene-set level, is associated with a hypoxia/stress-oriented biological background. In the discovery cohort, higher taurine ssGSEA scores tended to occur in clinically more favorable subgroups and were associated with better overall survival. From this candidate space, we derived an 8-gene candidate model that preferentially captures a proliferative and metabolically active risk component and receives partial external support. Further integrative prioritization and patient-aware analyses identified ADO, AURKA, GCLC, and MMP9 as core candidate genes for future functional validation.
Background:Kasabach-Merritt phenomenon (KMP), a potentially fatal complication of hemangiomas, necessitates effective therapeutic interventions. This study aimed to evaluate the efficacy of radiofrequency ablation (RFA) in managing severe hemangiomas with KMP, characterized by thrombocytopenia and coagulation abnormalities. While RFA emerges as a promising therapeutic option, its efficacy in pediatric KMP patients warrants further investigation. Methods:This retrospective analysis included 35 pediatric patients diagnosed with KMP who were treated at the Department of Hemangioma Surgery, The Third Affiliated Hospital of Zhengzhou University between March 2018 and September 2024. All patients underwent RFA under general anesthesia, with color Doppler ultrasound continuously monitoring the precise, multi-layer, multi-point ablation procedure. Results:In all 35 patients (15 males, 20 females; age range: 1 day-6 months; median age: 8 days), postoperative normalization of platelet counts was observed. Lesions exhibited initial hardening within 7 days but subsequently returned to normal after 2 weeks of dressing changes. During the follow-up period ranging from 6 to 24 months, complete ablation of all lesions was achieved, tumors resolved entirely, no recurrence was detected, and local function, anatomy, and aesthetics were well preserved. Conclusions:RFA demonstrates as a minimally invasive, safe, and effective therapeutic approach for KMP, associated with a low complication rate. It significantly improves survival rates and quality of life in pediatric patients, positioning itself as a highly promising therapeutic option for broader clinical application.
Background:Down syndrome (DS), the most prevalent chromosomal disorder caused by trisomy 21, manifests intellectual disability and cognitive dysfunction. Cumulative studies confirm epigenetic pathways including DNA methylation and non-coding RNAs drive DS pathological progression. Histone post-translational modifications (PTMs) are core epigenetic regulators of fetal brain development. However, genome-wide PTM alterations and their downstream functions in fetal DS brains remain poorly characterized, leaving a key gap in revealing epigenetic mechanisms underlying DS neurodevelopmental defects. To address this, we aimed to establish the first comprehensive landscape of histone PTMs in fetal DS cortex and investigate whether specific PTM changes contribute to aberrant neurodevelopmental gene expression. Methods:Fetal cortexs from control and DS groups were subjected to global histone modification profiling via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). We detected mono-, di-, and tri-methylation, acetylation, homocysteinylation and malonylation on all four core histones (H2A, H2B, H3, H4). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to map genomic binding profiles of H3 lysine 79 acetylation (H3K79ac). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to quantify mRNA levels of candidate neurodevelopmental genes. Results:HPLC-MS/MS analysis identified 172 distinct histone PTMs in control fetal cortices and 168 PTMs in DS fetal cortical samples. Quantitative comparison of 22 quantifiable histone PTMs revealed that H3K79ac showed the most prominent reduction in DS samples, with a 34% decrease (P<0.05). Chromatin immunoprecipitation (ChIP)-seq verified specific H3K79ac occupancy at the genomic loci of three vital neurodevelopmental genes: TNFSF13B, NXPH1 and CAMK4. Correspondingly, qRT-PCR revealed aberrant transcription levels of these three genes in DS fetal cortices. Conclusions:This study establishes the first quantitative landscape of histone PTMs in in DS fetal cortical tissues. We demonstrate that depleted H3K79ac acts as a candidate epigenetic driver of DS neuropathology by disrupting the transcription of critical neurodevelopmental genes. This work reveals a novel epigenetic mechanism and a promising therapeutic target for DS-related neurodevelopmental disorders.
