Omar M. Ibrahim

. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

BACKGROUND: Antimicrobial stewardship programs are advised to measure and risk-adjust antimicrobial use to facilitate interhospital comparisons, a process called benchmarking. The purpose of this investigation was to evaluate a new benchmarking strategy for antibacterials. METHODS: Hospital-wide adult antibacterial drug use in 2009 was measured as days of therapy (DOT) and length of therapy (LOT) from billing records in 70 US academic medical centers (AMCs). Patients were assigned to 1 of 35 clinical service lines (CSL) based on their Medicare Severity Diagnosis Related Group. Expected (E) use was determined by indirect standardization and compared with observed (O) use. RESULTS: Of 1,791 ,180 discharged adults, 63.7% received antibacterial drugs; the range by CSL was 14.3% (psychiatry) to 99.7% (lung transplant). Mean ± SD hospital-wide use was 839 ± 106 DOTs (range, 594-1109) and 536 ± 53.0 LOT (range, 427-684) per 1000 patient-days. The ventilator support CSL had the most DOT per discharge, 39.4 ± 9.4 days; the LOT was 21.5 ± 4.5 days. The hospital-wide O/E ratio range was 0.7-1.45; in 5 AMCs the ratio exceeded the 90% confidence interval (CI) and was below the 90% CI in 6. Variability in use was explained by the proportion of treated patients within each CSL and mean LOT and DOT per discharge. CONCLUSIONS: Adult antibacterial drug use was benchmarked to expected use adjusted for patient mix, and outlier hospitals were identified. Differences between expected and observed use reflect usage patterns that were benchmarked and are targets for evaluation and intervention.