Mechanisms of action and resistance in histone methylation-targeted therapy.

Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1-7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2-compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.

Double-Layered Perovskite Oxyfluoride Cathodes with High Capacity Involving O-O Bond Formation for Fluoride-Ion Batteries.

Developing electrochemical high-energy storage systems is of crucial importance toward a green and sustainable energy supply. A promising candidate is fluoride-ion batteries (FIBs), which can deliver a much higher volumetric energy density than lithium-ion batteries. However, typical metal fluoride cathodes with conversion-type reactions cause a low-rate capability. Recently, layered perovskite oxides and oxyfluorides, such as LaSrMnO4 and Sr3Fe2O5F2, have been reported to exhibit relatively high rate performance and cycle stability compared to typical metal fluoride cathodes with conversion-type reactions, but their discharge capacities (∼118 mA h/g) are lower than those of typical cathodes used in lithium-ion batteries. Here, we show that double-layered perovskite oxyfluoride La1.2Sr1.8Mn2O7-δF2 exhibits (de) intercalation of two fluoride ions to rock-salt slabs and further (de) intercalation of excess fluoride ions to the perovskite layer, leading to a reversible capacity of 200 mA h/g. The additional fluoride-ion intercalation leads to the formation of O-O bond in the structure for charge compensation (i.e., anion redox). These results highlight the layered perovskite oxyfluorides as a new class of active materials for the construction of high-performance FIBs.

Effective management of lung spindle cell carcinoma with ipilimumab, nivolumab, carboplatin, and paclitaxel, demonstrating efficacy in brain metastases treatment.

A 76-year-old woman with cT1bN2M1b stage IVA spindle cell carcinoma of the right lower lobe of the lung, no driver gene mutation, and programmed death ligand 1 < 1%, was started on ipilimumab+nivolumab+carboplatin+paclitaxel. After two courses, the patient initiated maintenance therapy with ipilimumab+nivolumab. New multiple brain metastases were observed during treatment but resolved with continued treatment. We report a unique case of spindle cell carcinoma treated with ipilimumab+nivolumab+carboplatin+paclitaxel that resulted in long-term response and resolution of new brain metastasis.

Electrical resistivity tomography combined with seismic data estimates heterogeneous distribution of near-seafloor concentrated gas hydrates within gas chimneys.

Near-seafloor concentrated gas hydrates (GHs) containing large amounts of methane have been identified at various gas chimney sites. Although understanding the spatial distribution of GHs is fundamental for assessing their dissociation impact on aggravating global warming and resource potential, the spatial distribution of GHs within gas chimneys remains unclear. Here, we estimate the subseafloor distribution of GHs at a gas chimney site in the Japan Sea using marine electrical resistivity tomography data. The resulting two-dimensional subseafloor resistivity structure shows high anomalies (10-100 Ωm) within seismically inferred gas chimneys. As the resistivity anomalies are aligned with high amplitude seismic reflections and core positions recovering GHs, we interpret the resistivity anomalies are near-seafloor concentrated GH deposits. We also detect various distribution patterns of the high resistivity anomalies including 100-m wide and 40-m thick anomaly near the seafloor and 500-m wide anomaly buried 50 m below the seafloor, suggesting that GHs are heterogeneously distributed. Therefore, considering such heterogeneous GH distribution within gas chimneys is critical for in-depth assessments of GH environmental impacts and energy resources.

Validity of the Cost-Effectiveness of Middle Meningeal Artery Embolization Following Hematoma Evacuation for Initial Chronic Subdural Hematoma.

BACKGROUND: Despite numerous articles about middle meningeal artery embolization (MMAE) highlighting its efficacy and safety for recurrent chronic subdural hematoma (CSDH), the appropriateness of adjunctive MMAE after hematoma evacuation for initial CSDH remains unclear from a cost-effectiveness perspective. METHODS: Patients with CSDH were enrolled in this study and were prospectively divided into 2 groups: the "conventional treatment" group, which was treated with hematoma evacuation alone, and the "MMAE" group, which was treated with adjunctive MMAE after hematoma evacuation. The proportion of patients requiring retreatment, length of hospital stay, economic costs, and modified Rankin Score were compared between the 2 groups. RESULTS: In this study, 53 cases were included, with 30 classified into the conventional treatment group and 23 classified into the MMAE group. In the conventional treatment group, the proportion of patients who required surgical retreatment was higher than that in the MMAE group (16.7% vs. 8.7%). The relative risk was 0.522 (95% confidence interval, 0.111-2.45). Although the addition of MMAE increased the cost per hospitalization by 26%, the increase in cost per patient was limited to 12%, owing to the reduction in patients who relapsed and required a second hospitalization. The increase in cost was not statistically significant. The MMAE group had a significantly higher proportion of patients with favorable outcomes (modified Rankin Score 0-2) (56.7% vs. 87.0%, P = 0.0328). CONCLUSIONS: By minimizing the increase in hospitalization days and procedure costs, MMAE following hematoma evacuation for initial CSDH could decrease the retreatment rate and balance the total medical costs associated with MMAE.