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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.The mechanisms of action and resistance of valemetostat, an EZH1–EZH2 dual inhibitor, in patients with adult T cell leukaemia/lymphoma who initially responded but later showed disease progression are explored. [ABSTRACT FROM AUTHOR]

Sediment cores collected at Lake Kogare-ike, a coastal lake on the Pacific coast of central Japan, record the marine inundation history during the last 3000 years. The sediments consist mainly of organic mud, sand, gravel, inorganic mud, and volcanic ash, and inundation events were recognized as 19 event deposits (E1–E19, from top to bottom) interbedded with the organic mud. Visual observation by naked eyes and X-ray computed tomography (CT) images identified 16 event deposits based on quantitative and qualitative changes in sand contents and changes in the textures and colors of the sediment samples (E1–E3, E5, E6, E8, E9, and E11–E19). The other three event deposits (E4, E7, and E10) were identified only on the CT images as layers with higher radiodensity than the underlying and overlying organic mud layers. The sedimentary features, the spatial bias of the event deposits toward seaward areas, the diatom assemblages, and the frequency of inundation events suggest that 13 (E1–E10 and E12–E14) of the 19 event deposits were formed by tsunamis or extraordinary storms. To constrain the depositional ages of the event deposits, Bayesian age–depth models were constructed based on radiocarbon dating of plant macrofossils and concentrated fossil pollen and the 137Cs profile. The depositional ages of the event deposits indicate that five or possibly six event deposits can be correlated with historical tsunamis along the Nankai Trough: E2, either of E3 or E4, E5, E7, and E9 correspond to the 1707 CE Hoei, the 1605 CE Keicho, the 1498 CE Meio, the 1096 CE Eicho, and the 684 CE Hakuho tsunamis, respectively. E1 was possibly formed by the 1944 CE Showa-Tonankai tsunami, the 1854 Ansei–Tokai tsunami, the 1959 Isewan typhoon, or a combination of two or all three events. [ABSTRACT FROM AUTHOR]

Coastal deposits at Tofino, Ucluelet, and Port Alberni in Vancouver Island along the Cascadia subduction zone were re-examined to improve the earthquake history of the southwest coast of Canada. We found sand sheets interbedded within peat and mud, suggesting deposition by strong flows in a low-energy environment. Based on limiting maximum and minimum ages derived from plant macrofossils, the age of one of the sand sheets below the tsunami deposits of the great Cascadia earthquake in 1700 CE was estimated to be 1330–1430 CE. Onshore paleoseismic evidence has been documented in Vancouver Island, northern Washington, and northern Oregon during this period. However, the newly constrained age is between those of coseismic subsidence Y and W events in southern Washington, which have been recognized as the 1700 CE and the penultimate Cascadia earthquakes, respectively. Moreover, the new age partly overlaps with the age of offshore paleoseismic evidence for T2, interpreted to have originated from the penultimate Cascadia earthquake, based on offshore turbidite records. The new chronology prior to the 1700 CE Cascadia tsunami deposit from Vancouver Island contributes to a better understand of the timing of the penultimate Cascadia earthquake. [ABSTRACT FROM AUTHOR]

Geological evidence of recent tsunamis from sediment samples collected from Lake Tokotan, a coastal lagoon in eastern Hokkaido, northern Japan, was detected using computed tomography (CT) and soft X-ray images, grain size, and radionuclide profiles. Initial field observations revealed that sediments had no discernable sedimentary structures at the top of the core. However, results of CT imaging, soft X-ray, and grain size analyses show evidence for three invisible sand layers that are intercalated with mud layers. These sand layers exhibit trends of landward fining and thinning. Furthermore, the distribution of sand layers was limited to the center and seaward parts of the lake. Vertical profiles of cesium and lead concentrations in combination with recent eyewitness accounts indicated that these sand layers are correlated with the 1973 Nemuro-oki, 1960 Chilean, and 1952 Tokachi-oki tsunami events. The deeper part of the sediment cores includes three volcanic ash layers and three prehistoric coarse sand layers. The prehistoric layers are correlated with unusually large tsunamis that were geologically identified in previous studies from eastern Hokkaido. These findings suggest that nondestructive techniques, in combination with radionuclide analysis, allow for detection of frequent but faint tsunami deposits. This technique allows for an improved understanding of the history of tsunami inundation in Lake Tokotan and of other locations for which stratigraphic evidence for faint tsunamis layers is not readily apparent from field assessments. [ABSTRACT FROM AUTHOR]

Hepatic transcriptome and proteome responses against glutathione depletion were investigated by Affymetrix GeneChip Microarray and 2-dimensional gel electrophoresis (2D-DIGE), followed by MALDI-TOF-MS analysis and utilizing a glutathione-depleted rat model treated with diethyl maleate (DEM). Hepatic glutathione content decreased to 1.29 μmol/g liver (25.5% compared to control) after DEM treatment, and there were no apparent hepatotoxic signs estimated by blood chemistry examinations. A total of 247 and 213 annotated gene probe sets exhibited greater than twofold up- and down-regulation compared with controls, respectively. The up-regulated gene list contained a number of glutathione depletion-responsive genes reported previously, such as Trib3, Srxn1, Myc, Asns, Igfbp1, Txnrd1, or Hmox1, suggesting that these genes are robust mRNA biomarkers for evaluating hepatic glutathione depletion. In the 2D-DIGE analysis, proteins for a total of 361 spots were identified by MALDI-TOF-MS analysis. Of the identified proteins, 5 and 14 proteins showed up- and down-regulation, respectively. Some proteins exhibited differential expression in the protein level but not in the mRNA level, including L-FABP, MAWDBP, aldo-keto reductase family 1 member A1, catalase and ATP synthase subunit beta, suggesting that these proteins would be potential protein biomarkers for evaluating glutathione depletion. Moreover, up-regulation of FABP1 protein along with up-regulation of PPARα-regulated gene transcripts (i.e., Acot2 and Acot4) is indicative of PPARα activation, which may contribute to hepatocellular protection against glutathione depletion-induced oxidative stress. The up-regulation of L-FABP1 was detected by proteome data but not by transcriptome data, demonstrating the advantage of utilizing transcriptomics and proteomics combination to investigate glutathione depletion-induced molecular dynamics. [ABSTRACT FROM AUTHOR]

To evaluate the carcinogenicity of troglitazone in rasH2 mice, 7-week-old male and female rasH2 mice were fed a diet containing 0, 3,000 or 6,000 ppm troglitazone for 26 weeks. An increased tendency in the incidence of vascular tumors was observed in females of the 6,000 ppm group. The preliminary analysis using a high-density oligonucleotide microarray on a splenic hemangiosarcoma of a high dose female that could be obtained as a fresh sample showed that several genes related to the ras/MAPK pathway activation, angiogenesis, cell cycle and cell multiplication were up-regulated. In addition, most of the genes up-regulated were confirmed by the reverse transcriptase-polymerase chain reaction (RT-PCR). These results may suggest that the carcinogenic susceptibility of rasH2 mice to troglitazone is relatively low and up-regulations of the ras/MAPK pathway and angiogenesis-related genes are probably involved in the production of splenic hemangiosarcomas in rasH2 mice given troglitazone. [ABSTRACT FROM AUTHOR]

Phenobarbital (PB) increases serum total cholesterol levels in rodents and humans. To investigate the underlying molecular mechanisms, we performed a microarray analysis on liver of rats treated repeatedly with 100 mg/kg PB, and examined the serum blood chemistry. The serum concentration of non-esterified fatty acids was decreased from day 1 to day 14 except for day 7, and that of cholesterol was increased from day 4 to day 14. The serum concentration of total ketone bodies was increased on day 7, and that of triglycerides was decreased on day 14. Transcript content of glycolytic genes was decreased by PB treatments, while that of lipoprotein lipase was continuously increased, suggesting a notion that repetitive PB treatments impaired glycolysis and stimulated lipolysis in the liver. The hypothesis was examined by using a previously reported flux-balance model. The increase in mRNA content of malic enzyme after the PB treatment agreed well with the flux-balance model result, suggesting the validity of our hypothesis. The findings also suggested that there was an abundance of acetyl-CoA and shortage of glycolytic products after the repeated PB treatments. Although ketogenesis would normally occur under such cellular conditions, it was only weakly observed after the repeated PB treatments, presumably owing to a decrease in HMG-CoA synthase mRNA content. On the other hand, the mRNA content of several cholesterogenic genes was slightly induced by PB treatments. Thus, serum chemistry and microarray results suggested that repeated PB treatments induced cholesterogenesis in rat livers, which may have contributed to the elevation of the serum total cholesterol concentration. [ABSTRACT FROM AUTHOR]