Precision off-the-shelf natural killer cell therapies for oncology with logic-gated gene circuits.

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis (5-year survival rate of 30.5% in the United States). Designing cell therapies to target AML is challenging because no single tumor-associated antigen (TAA) is highly expressed on all cancer subpopulations. Furthermore, TAAs are also expressed on healthy cells, leading to toxicity risk. To address these targeting challenges, we engineer natural killer (NK) cells with a multi-input gene circuit consisting of chimeric antigen receptors (CARs) controlled by OR and NOT logic gates. The OR gate kills a range of AML cells from leukemic stem cells to blasts using a bivalent CAR targeting FLT3 and/or CD33. The NOT gate protects healthy hematopoietic stem cells (HSCs) using an inhibitory CAR targeting endomucin, a protective antigen unique to healthy HSCs. NK cells with the combined OR-NOT gene circuit kill multiple AML subtypes and protect primary HSCs, and the circuit also works in vivo.

Differential and interacting effects of age and sleep restriction on daytime sleepiness and vigilance in adolescence: a longitudinal study.

Study Objectives: There is contradictory evidence on whether sleep need decreases across adolescence. We investigated this question longitudinally with a dose-response design to test the effects of varied sleep durations on daytime sleepiness and on vigilance and to test whether these relations change with age across early and mid-adolescence. Methods: Data from 76 participants who completed at least 2 years of the 3-year study are included in this report. Annually, participants ranging in age from 9.8 to 16.2 years completed three different time in bed (TIB) schedules each consisting of four consecutive nights of 7, 8.5, or 10 hours. Daytime sleepiness (multiple sleep latency test [MSLT]) and vigilance (psychomotor vigilance test [PVT]) were measured on the day following the fourth night of each TIB schedule. Results: Electroencephalogram (EEG)-measured sleep durations changed linearly with TIB. MSLT-measured daytime sleepiness decreased with longer TIB and increased with age. The TIB and age effects interacted such that the TIB effect decreased with age. PVT performance improved with longer TIB and improved with age, but the benefit that increased TIB conferred on PVT performance did not change with age. Conclusions: These results seem paradoxical because daytime sleepiness increased but vigilance improved with age. The significant age effect on the relation between TIB and sleepiness compared to the lack of an age effect on the relation between TIB and vigilance performance suggests different rates of maturation in underlying brain systems. We interpret these findings in relation to our model of adolescent brain development driven by synaptic elimination.