Background The optimal screening policy for lung cancer is unknown. Objective To identify efficient CT-screening scenarios where relatively more lung cancer deaths are averted for fewer CT screens. Design Comparative modeling study using 5 independent models. Data Sources The National Lung Screening Trial, the Prostate, Lung, Colorectal and Ovarian trial, the Surveillance, Epidemiology, and End Results program, and U.S. Smoking History Generator. Target Population U.S. cohort born in 1950. Time Horizon Cohort followed from ages 45 to 90. Perspective Societal. Intervention 576 scenarios with varying eligibility criteria (age, smoking pack-years, years quit) and screening intervals. Outcome Measures Benefits: lung cancer deaths averted or life-years gained; harms: CT-exams, false positives (including biopsy/surgery), overdiagnosed cases, radiation-related deaths. Results of Best-Case Annual screening from age 55 through 80 for ever-smokers with at least 30 pack-years and ex-smokers with less than 15 years since quitting was the most advantageous strategy. It would lead to 50% (45 to 54%) of cancers being detected at an early stage (I/II); 575 screens per lung cancer death averted; a 14% (8.2 to 23.5%) lung cancer mortality reduction; 497 lung cancer deaths averted; and 5,250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive tests, 910 biopsies or surgeries for benign lesions and 190 overdiagnosed cancers (3.7%; 1.4 to 8.3%). Results of Sensitivity Analysis The number of cancer deaths averted for the scenario varied across models between 177 and 862, and for overdiagnosed cancers between 72 and 426. Limitations Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to life-time follow-up. Conclusion Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-year exposure to smoking.

Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions1–4. Acute regulation of autophagy by nutrient-sensing kinases is well defined3, 5–7, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor FXR8, 9 and the fasting transcriptional activator CREB10, 11 coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver ChIP-seq data12–15, FXR and CREB binding peaks were detected at 178 and 112, respectively, of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted lipophagy, autophagic degradation of lipids16, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1, and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB/CRTC2 complex. This study identifies the novel FXR/CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.