CircaDB (http://circadb.org) is a new database of circadian transcriptional profiles from time course expression experiments from mice and humans. Each transcript’s expression was evaluated by three separate algorithms, JTK_Cycle, Lomb Scargle and DeLichtenberg. Users can query the gene annotations using simple and powerful full text search terms, restrict results to specific data sets and provide probability thresholds for each algorithm. Visualizations of the data are intuitive charts that convey profile information more effectively than a table of probabilities. The CircaDB web application is open source and available at http://github.com/itmat/circadb.

Alignment is the first step in most RNA-seq analysis pipelines, and the accuracy of downstream analyses depends heavily on it. Unlike most steps in the pipeline, alignment is particularly amenable to benchmarking with simulated data. We performed a comprehensive benchmarking of 14 common splice-aware aligners for base, read, and exon junction-level accuracy and compared default with optimized parameters. We found that performance varied by genome complexity, and accuracy and popularity were poorly correlated. The most widely cited tool underperforms for most metrics, particularly when using default settings.

Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-offunction screen, we identifi ed that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnifi ed by the induction of CAR T-cell functional impairment. These fi ndings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fi tness. Our fi ndings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction. SIGNIFICANCE:Resistance to CART19 is a signifi cant barrier to effi cacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigenindependent resistance to CAR therapy.