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The genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic. To address this, rapid and genetically tractable animal models are needed that recapitulate the heterogeneity of RAS-driven cancers in vivo. Here, we generate a Drosophila melanogaster model of Ras/Lkb1 mutant carcinoma. We show that low-level expression of oncogenic Ras (RasLow) promotes the survival of Lkb1 mutant tissue, but results in autonomous cell cycle arrest and non-autonomous overgrowth of wild-type tissue. In contrast, high-level expression of oncogenic Ras (RasHigh) transforms Lkb1 mutant tissue resulting in lethal malignant tumors. Using simultaneous multiview light-sheet microcopy, we have characterized invasion phenotypes of Ras/Lkb1 tumors in living larvae. Our molecular analysis reveals sustained activation of the AMPK pathway in malignant Ras/Lkb1 tumors, and demonstrate the genetic and pharmacologic dependence of these tumors on CaMK-activated Ampk. We further show that LKB1 mutant human lung adenocarcinoma patients with high levels of oncogenic KRAS exhibit worse overall survival and increased AMPK activation. Our results suggest that high levels of oncogenic KRAS is a driving event in the malignant transformation of LKB1 mutant tissue, and uncovers a vulnerability that may be used to target this aggressive genetic subset of RAS-driven tumors. Rackley, Seong et al use a Drosophila model of Ras/Lkb1 mutant carcinoma to show that high levels of the KRAS oncogene drive the malignant transformation of LKB1 mutant tissue. This pathway could be used as a target for future therapies that aim to treat RAS-driven tumours. [ABSTRACT FROM AUTHOR]

Treatment with fludarabine phosphate (9-β-D-arabinofuranosyl-2-F-adenine 5'-phosphate, F-araAMP) leads to regressions and cures of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (EcPNP). This occurs despite the fact that fludarabine (F-araA) is a relatively poor substrate for EcPNP, and is cleaved to liberate 2-fluoroadenine at a rate only 0.3% that of the natural E. coli PNP substrate, adenosine. In this study, we investigated a panel of naturally occurring PNPs to identify more efficient enzymes that may be suitable for metabolizing F-araA as part of experimental cancer therapy. We show that Trichomonas vaginalis PNP (TvPNP) cleaves F-araA with a catalytic efficiency 25-fold greater than the prototypic E. coli enzyme. Cellular extracts from human glioma cells (D54) transduced with lentivirus stably expressing TvPNP (D54/TvPNP) were found to cleave F-araA at a rate similar to extracts from D54 cells expressing EcPNP, although much less enzyme was expressed per cell in the TvPNP transduced condition. As a test of safety and efficacy using TvPNP, human head and neck squamous cell carcinoma (FaDu) xenografts expressing TvPNP were studied in nude mice and shown to exhibit robust tumor regressions, albeit with partial weight loss that resolved post-therapy. F-araAMP was also a very effective treatment for mice bearing D54/TvPNP xenografts in which approximately 10% of tumor cells expressed the enzyme, indicating pronounced ability to kill non-transduced tumor cells (high bystander activity). Moreover, F-araAMP demonstrated activity against D54 tumors injected with an E1, E3 deleted adenoviral vector encoding TvPNP. In that setting, despite higher F-araA cleavage activity using TvPNP, tumor responses were similar to those obtained with EcPNP, indicating factors other than F-Ade production may limit regressions of the D54 murine xenograft model. Our results establish that TvPNP is a favorable enzyme for activating F-araA, and support further studies in combination with F-araAMP for difficult-to-treat human cancers. [ABSTRACT FROM AUTHOR]

Objectives: This study examined the prevalence and correlates of maternal and infant sleep problems among low-income families receiving home visiting services. Methods: The study sample includes 1142 mother–infant dyads in Wisconsin, United States. Women completed a survey when their infants were between two weeks and one year old. Outcome data were collected using the PROMIS® sleep disturbance short form-4a and the Brief Infant Sleep Questionnaire. Correlates of sleep problems were assessed in two domains: maternal health and home environment quality. Descriptive analyses produced prevalence estimates, and multivariate regressions were performed to test hypothesized correlates of maternal and infant sleep problems. Subgroup analyses were conducted to examine the prevalence and correlates of sleep problems across different infant age groups. Results: Approximately 24.5% of women reported poor or very poor sleep in the past week; 13% reported an infant sleep problem and 11% reported more than three infant wakings per night. Reported night wakings were more prevalent among younger infants but maternal and infant sleep problems were not. Multivariate results showed that poor maternal physical and mental health and low social support were associated with maternal sleep disturbance but not infant sleep problems. Bed sharing and smoking were associated with infant sleep outcomes but not maternal sleep. There was limited evidence that the correlates of maternal and infant sleep varied by infant age. Conclusions for Practice: The findings point to alterable factors that home visiting programs and other interventions may target to enhance maternal and infant sleep. [ABSTRACT FROM AUTHOR]