Kindai University

Long-term treatment with eicosapentaenoic acid (EPA) has been reported to reduce the risk of atrial fibrillation (AF) in mice fed a high-fat diet (HFD); however, the appropriate dose required to attenuate atrial vulnerability to AF remains unclear. The present study aimed to determine whether different amounts of daily intake of EPA exert preventive effects against AF. We conducted a series of experiments in HFD-fed mice treated with either low-dose EPA (30 mg/kg) or high-dose EPA (300 mg/kg). Both EPA doses similarly shortened AF duration and improved atrial conduction, as assessed by P-wave duration on surface electrocardiography. Notably, neither low- nor high-dose EPA significantly improved HFD-induced dyslipidemia, and no difference in cholesterol-lowering effects was observed between the two EPA treatment groups. These findings suggest that physiologically relevant dietary intake of EPA is sufficient to prevent atrial arrhythmias and to ameliorate impaired atrial conduction associated with AF, independent of systemic lipid-lowering effects.

BACKGROUNDImmune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 axis have revolutionized metastatic non–small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood.METHODSIn this biomarker study involving 103 patients with mNSCLC, including 81 patients who received ICI treatment, we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex IHC platform built for in-depth dissection of the TME.RESULTSAmong various types of intratumoral lymphocytes, including Th1, Treg, and NK cells, only CD8+ T cells (tumor-infiltrating lymphocytes [TILs]) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.CONCLUSIONOur study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies.FUNDINGOsaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.

A free mobile application called ForestScanner (FS) was recently developed to enable LiDAR-based forest inventories using LiDAR-equipped iPhones or iPads. Although FS has been shown to reduce the cost, labor, and time required to measure the diameter at breast height ( D ) of trees within forests, its applicability to trees in urban green spaces (UGS) has not been evaluated. Here, we conducted two experiments to evaluate the performance of FS in the UGS. The first experiment involved the measurement of 70 trees at various distances and directions. The results revealed that FS tended to underestimate D compared to the traditional diameter tape (DT), with greater bias and variability at longer distances. These results suggest that measurements should be taken as close to the tree as possible to improve the accuracy and precision. In the second experiment, 39 trees were measured repeatedly by multiple observers. The results demonstrated that FS produced slightly greater variability between and within observers than did DT, although the overall agreement remained high. The underestimation was more pronounced for larger trees across both experiments, and for broad-leaved trees than for conifers in the second experiment. Overall, these findings highlight the potential of FS for citizen science-based assessments of carbon stocks in UGS, while also emphasizing the need for careful application when measuring larger and broad-leaved trees.

Abstract We have performed 1–12 keV spectral analyses of the recombining plasma associated with the supernova remnant (SNR) W49B using the Suzaku archive data. The analysis results for the whole SNR spectrum indicate that the recombination timescale varies within (5–7) × 10 11 cm −3 s among elements from Mg to Fe and Ni of the RP or that the initial ionization temperatures of the elements vary between 1.6 and 2.7 keV. This paper reports on the results of a more detailed investigation using the latter approach, the multicomponent ionization temperature model. In the overall spectrum, the initial ionization temperatures is estimated to be 2 keV for the lighter elements (Mg, Si) and 5 keV for the heavier elements (Ar and Fe group). For electron cooling scenarios, plasma ionization must proceed at once during a period of high density within about 500 yr after the explosion. The initial ionization temperatures tend to be higher in the east, which would be due to difference of density in circumstellar medium in the early period. On the other hand, current ionization temperatures are found to be spatially uniform, which would be explained by the ionization enhancement scenario by low-energy cosmic rays.

Minimal residual disease (MRD) detection using liquid biopsy is an emerging tool for risk stratification and monitoring for recurrence in resected early stage NSCLC. There is increasing need for clear guidance on its optimal clinical implementation. The Asian Thoracic Oncology Research Group (ATORG) convened a multidisciplinary panel of 27 experts to develop a consensus statement on the clinical application of circulating tumor DNA-based MRD testing in early stage resected NSCLC, using a structured Delphi methodology. Statements were organized into the following broad thematic domains: assay validity and standardization; harmonization in research and trials; clinical application; challenges in implementation; consensus recommendations; infrastructure for regional MRD adoption; and roadmap for pragmatic trials. A total of 23 position statements were developed, of which all except one achieved strong consensus. The consensus highlighted the need to define minimum analytical performance thresholds for MRD assays, improve standardization of reporting metrics, and clear guidelines for pre-analytical handling. Harmonization of blood sampling time points and terminology across clinical trials is also essential to confirm the prognostic value of MRD assays. Although current MRD assays demonstrate high specificity and positive predictive value, variable sensitivity precludes routine use for adjuvant therapy de-escalation outside clinical trials. Broader access, sustainable funding, ongoing consensus building, and collaborative real-world data generation are also critical to support clinical implementation and adoption. Future clinical trials must account for the distinct biology and changing standards of care associated with different driver genes. These consensus recommendations provide a pragmatic framework to guide the responsible integration of MRD testing into clinical research and practice.

Abstract Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by proliferation of immature myeloblasts 1 . It shows profound molecular heterogeneity, which has been primarily studied through genetic abnormalities, providing the basis for disease classification, prognostication, and therapeutic choice 2–8 . However, genetic factors alone may not fully explain AML pathogenesis and diversity, while leaving the role of abnormal epigenome, particularly chromatin state, largely unexplored in a large cohort of patients. Here we show that AML is classified into 16 subgroups with distinct chromatin accessibility profiles based on ATAC-seq in 1,563 AML cases, derived from the encyclopedia of chromatin in AML (eCHROMA AML) dataset, including novel AML subgroups not previously recognized in conventional genomic classifications. By integrating multi-omics analyses of genome, transcriptome, and major histone marks, we show that these epigenetic subgroups exhibit unique features in clinical presentation, gene mutations, differentiation states, gene expression, and super-enhancer profiles, which are validated across independent cohorts. Single-cell sequencing demonstrates the presence of subgroup-specific ATAC signatures that are shared by all leukemic cells, confirming the key role of the epigenome in the ATAC-based classification. Mechanistically, each subgroup is associated with a distinct gene regulatory network centered on key transcription factors, where subgroup-specific super-enhancers play a pivotal role. These ATAC subgroups also have prognostic significance independent of genomic classification, and help reveal unexpected drug sensitivities. In summary, ATAC-based chromatin profiling in this large sample set, combined with multi-omics data, provides new insights into AML pathogenesis beyond genomic profiling and also serves as an invaluable resource for AML research.

Avelumab, pembrolizumab, and enfortumab vedotin (EV) demonstrated efficacy in mUC following platinum-based chemotherapy. However, real-world data in patients with urothelial carcinoma with squamous differentiation (UCSD) are limited. The aim of this study is to assess the real-world clinical outcomes of avelumab, pembrolizumab, or EV in mUCSD patients. The ARON-2EV study is a retrospective, international, multicenter analysis in patients with mUC treated with avelumab, pembrolizumab, or EV across 79 centers in 21 countries. Patients were divided into three cohorts: 1 (avelumab), 2 (pembrolizumab), and 3 (EV). Primary endpoints were overall survival (OS) and time on treatment (ToT). Secondary objectives included evaluating clinical factors associated with outcomes and exploring the impact of UCSD histology on response to therapy. Statistical methods included Kaplan-Meier estimates, log-rank tests, Fisher's exact and chi-square tests, and Pearson's correlation coefficients. A total of 1918 patients, 1696 with advanced pure UC (pUC) and 222 with mUCSD (36 in cohort 1, 111 in cohort 2, and 75 in cohort 3), were included. Median OS was shorter in patients with UCSD compared to patients with pUC histology in the three cohorts (1: 13.0 vs 26.8months, HR 2.66,p = 0.003; 2: 10.2 vs 18.5months, HR 1.52,p = 0.008; and 3: 7.6 vs 13.1months, HR 1.68,p = 0.011). Median ToT was shorter in patients with UCSD compared to patients with pUC histology in cohort 1 (3.5 vs 5.6months, HR 1.57,p = 0.044) and 3 (7.6 vs 13.6months, HR 1.83,p = 0.005) but not in cohort 2 (3.7 vs 4.7months, HR 1.19,p = 0.177). Response to therapy was negatively correlated with UCSD histology in cohorts 2 (correlation coefficient 0.094,p = 0.008) and 3 (correlation coefficient 0.107,p = 0.021), while response to avelumab was not correlated with UCSD (correlation coefficient 0.072,p = 0.263). UCSD is a histology with a poor prognosis and response to treatments compared to pUC. Treatments activity and effectiveness in divergent differentiations should be addressed in dedicated prospective studies. NCT05290038.