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Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

Arable land use is generally assumed to be the largest contributor to agricultural diffuse pollution. This study adds to the growing evidence that conventional temperate intensively managed lowland grasslands contribute significantly to soil erosion and diffuse pollution rates. This is the first grassland study to monitor hydrological characteristics and multiple pollutant fluxes (suspended sediment [SS] and the macronutrients: total oxidized nitrogen‐N [TONN], total phosphorus [TP], and total carbon [TC]) at high temporal resolution (monitoring up to every 15 min) over 1 yr. Monitoring was conducted across three fields (6.5–7.5 ha) on the North Wyke Farm Platform, UK. The estimated annual erosion rates (up to 527.4 kg ha−1), TP losses (up to 0.9 kg ha−1), and TC losses (up to 179 kg ha−1) were similar to or exceeded the losses reported for other grassland, mixed land‐use, and arable sites. Annual yields of TONN(up to 3 kg ha−1) were less than arable land‐use fluxes and earlier grassland N studies, an important result as the study site is situated within a Nitrate Vulnerable Zone. The high‐resolution monitoring allowed detailed “system's functioning” understanding of hydrological processes, mobilization‐ transport pathways of individual pollutants, and the changes of the relative importance of diffuse pollutants through flow conditions and time. Suspended sediment and TP concentrations frequently exceeded water quality guidelines recommended by the European Freshwater Fisheries Directive (25 mg L−1) and the European Water Framework Directive (0.04 mg soluble reactive P L−1), suggesting that intensively managed grasslands pose a significant threat to receiving surface waters. Such sediment and nutrient losses from intensively managed grasslands should be acknowledged in land management guidelines and advice for future compliance with surface water quality standards.

Heparin binds and activates the receptor tyrosine kinase ALK, which has no known ligand.