Takumi Takizawa

Summary: We conducted a multiomics analysis of paediatric acute promyelocytic leukaemia (APL) in 36 patients enrolled in the Japanese AML‐P05 study. Targeted deep sequencing identified EP300 mutations ( n = 2) and MYC ‐internal tandem duplication (ITD) ( n = 1), which have not been previously reported in APLs. DNA methylation analysis classified 34 paediatric APLs into two groups: hypermethylation and hypomethylation. Patients in the hypermethylation group had significantly worse outcomes compared to those in the hypomethylation group (3‐year overall survival: 80% vs. 100%, p = 0.043; 3‐year event‐free survival: 73% vs. 95%, p = 0.049). Remarkably, the EBF1‐binding motif was enriched in 82.3% of the CpG sites that were differentially methylated between the hyper‐ and hypomethylation groups, and these sites were predominantly located in enhancer regions. Among the 1427 genes that were significantly differentially expressed between the two groups, EP300 was significantly downregulated in the hypermethylation group. Pathway analyses revealed global transcriptional downregulation in the hypermethylation group; however, MYC , a known EP300 ‐repressed gene, was upregulated within the G2M checkpoint. Our findings suggest a potential link among enhancer‐based epigenetic dysregulation involving DNA methylation at EBF1‐binding sites, EP300 dysfunction and MYC activation. These alterations may contribute to disease heterogeneity and prognosis in paediatric APL.

Interleukin-1β (IL-1β) is a key proinflammatory cytokine with critical roles in infections and inflammatory diseases, yet the mechanisms regulating its release from human monocytes remain unclear. Here we used a suite of single-cell approaches, including integrated live-cell imaging of secretion and cell fate, flow cytometry and high-content imaging, to investigate IL-1β secretion dynamics in lipopolysaccharide-stimulated primary human peripheral blood CD14⁺ monocytes. We found marked heterogeneity: a large fraction of cells remained viable and contributed negligibly to IL-1β secretion, challenging established models. Instead, a small subset (5–10%) undergoing canonical NLRP3 inflammasome activation and GSDMD-dependent pyroptosis produced the majority of secreted IL-1β, with a smaller contribution from apoptotic cells transitioning to secondary necrosis. Single-cell profiling of CD14⁺ monocytes from patients with cryopyrin-associated periodic syndrome confirmed lytic cell death as the driver of pathological IL-1β release. These findings redefine IL-1β as a damage-associated molecular pattern, secreted predominantly by dying monocytes.

Background: Pediatric asthma remains a critical public health problem, particularly in Japan, where adherence to new treatment guidelines and effective medication use are inconsistent. Therefore, we aimed to evaluate the current management practices for pediatric asthma to identify areas for improvement and enhance future treatment approaches. Methods: We conducted a web-based cross-sectional survey involving caregivers of children and adolescents aged 0–19 years diagnosed with asthma at various medical institutions in Japan. The survey focused primarily on evaluating the control status of asthma in these patients and examining factors such as treatment adherence, environmental exposure, and the presence of allergic diseases. Results: The data showed that 65.9% of the patients received some form of asthma treatment; however, a significant proportion (26.2%) still experienced poor symptom control (n=2000). The most affected group were children aged 0–3 years. The analysis showed that environmental factors and coexisting allergic diseases notably influenced poor asthma control, although direct correlations with treatment adherence were not statistically significant. Conclusion: These findings highlight the substantial gap in the effective management of pediatric asthma, particularly in very young children. Notably, pharmacotherapy is essential; however, there is an urgent need to develop comprehensive treatment plans that address environmental and lifestyle factors. Future strategies should focus on personalized care tailored to each child’s specific need, incorporating medical and non-medical interventions to optimize asthma control and improve overall health outcomes.

Oxidative stress increases the production of the predominant mucin MUC5AC in airway epithelial cells and is implicated in the pathogenesis of bronchial asthma and chronic obstructive pulmonary disease. Oxidative stress impairs mitochondria, releasing mitochondrial DNA into the cytoplasm and inducing inflammation through the intracytoplasmic DNA sensor STING (stimulator of interferon genes). However, the role of innate immunity in mucin production remains unknown. We aimed to elucidate the role of innate immunity in mucin production in airway epithelial cells under oxidative stress. Human airway epithelial cell line (NCI‐H292) and normal human bronchial epithelial cells were used to confirm MUC5AC expression levels by real‐time PCR when stimulated with hydrogen peroxide (H₂O₂). MUC5AC transcriptional activity was increased and mitochondrial DNA was released into the cytosol by H₂O₂. Mitochondrial antioxidants were used to confirm the effects of mitochondrial oxidative stress where antioxidants inhibited the increase in MUC5AC transcriptional activity. Cyclic GMP‐AMP synthase (cGAS) or STING knockout (KO) cells were generated to investigate their involvement. H₂O₂‐induced MUC5AC expression was suppressed in STING KO cells, but not in cGAS KO cells. The epidermal growth factor receptor was comparably expressed in STING KO and wild‐type cells. Thus, mitochondria and STING play important roles in mucin production in response to oxidative stress in airway epithelial cells.