Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. Here, we show that in BRAF V600E -melanoma, autophagy is induced by BRAF inhibitor (BRAFi), as part of a transcriptional program coordinating lysosome biogenesis/function, mediated by the TFEB transcription factor. TFEB is phosphorylated and thus inactivated by BRAF V600E via its downstream ERK independently of mTORC1. BRAFi disrupts TFEB phosphorylation, allowing its nuclear translocation, which is synergized by increased phosphorylation/inactivation of the ZKSCAN3 transcriptional repressor by JNK2/p38-MAPK. Blockade of BRAFi-induced transcriptional activation of autophagy-lysosomal function in melanoma xenografts causes enhanced tumor progression, EMT-transdifferentiation, metastatic dissemination, and chemoresistance, which is associated with elevated TGF-β levels and enhanced TGF-β signaling. Inhibition of TGF-β signaling restores tumor differentiation and drug responsiveness in melanoma cells. Thus, the “BRAF-TFEB-autophagy-lysosome” axis represents an intrinsic regulatory pathway in BRAF-mutant melanoma, coupling BRAF signaling with TGF-β signaling to drive tumor progression and chemoresistance.

Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAGFS. To investigate the role of UVRAGFS in vivo, we generated mutant mice that inducibly express UVRAGFS (iUVRAGFS). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAGFS mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAGFS mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.

Background Widespread vaccination is an essential component of the public health response to the COVID‐19 pandemic, yet vaccine hesitancy remains pervasive. This prospective survey investigation aimed to measure the prevalence of vaccine hesitancy in a patient cohort at two urban Emergency Departments (EDs) and characterize underlying factors contributing to hesitancy. Methods Adult ED patients with stable clinical status (Emergency Severity Index 3‐5) and without active COVID‐19 disease or altered mental status were considered for participation. Demographic elements were collected, as well as reported barriers/concerns related to vaccination and trusted sources of health information. Data were collected in‐person via a survey instrument proctored by trained research assistants. Results 1,555 patients were approached, and 1,068 patients completed surveys (completion rate 68.7%). Mean age was 44.1 y (SD 15.5, range 18‐93), 61% were female, and 70% were Black. 31.6% of ED patients reported vaccine hesitancy. Of note, 19.7% of the hesitant cohort were healthcare workers. In multivariable regression analysis, Black race (OR 4.24, 95%CI 2.62‐6.85) and younger age (age 18‐24 y, OR 4.57, 95%CI 2.66‐7.86; age 25‐35 y, OR 5.71, 95% CI 3.71‐8.81) were independently associated with hesitancy, to a greater degree than level of education (high school education or less, OR 2.27, 95%CI 1.23‐4.19). Hesitant patients were significantly less likely to trust governmental sources of vaccine information than non‐hesitant patients (39.6% vs 78.9%, p<0.001); less difference was noted in the domain of trust towards friends/family (51.1% vs. 61.0%, p=0.004). Hesitant patients also reported perceived vaccine safety concerns and perceived insufficient research. Conclusions Vaccine hesitancy is common among ED patients, and more common among Black and younger patients, independent of education level. Hesitant patients report perceived safety concerns and low trust in government information sources, but less so friends or family. This suggests strategies to combat hesitancy may need tailoring to specific populations.

Program synthesis tasks are commonly specified via inputoutput examples. Existing enumerative techniques for such tasks are primarily guided by program syntax and only make indirect use of the examples. We identify a class of synthesis algorithms for programming-by-examples, which we call Example-Guided Synthesis (EGS), that exploits latent structure in the provided examples while generating candidate programs. We present an instance of EGS for the synthesis of relational queries and evaluate it on 86 tasks from three application domains: knowledge discovery, program analysis, and database querying. Our evaluation shows that EGS outperforms state-of-the-art synthesizers based on enumerative search, constraint solving, and hybrid techniques in terms of synthesis time, quality of synthesized programs, and ability to prove unrealizability. CCS Concepts:• Information systems → Relational database query languages; • Software and its engineering → Automatic programming; Programming by example; • Theory of computation → Constraint and logic programming.