No abstract

KRAS is one of the most common oncogenic driver mutations in NSCLC, with prior attempts at direct inhibition being unsuccessful. In recent years, there has been significant advancement in the understanding of the biology of KRAS and its downstream effectors. This has translated into a multitude of important preclinical studies and clinical trials that are currently underway to find effective therapeutic drugs for KRAS mutant lung cancer. Ultimately, better therapeutics need to be engineered to arrive at RAS-driven precision medicine.

Organisations should ensure that nurse leaders have the resources they need to support the positive transition of new graduate nurses including adequate staffing and realistic workloads for both experienced and new nurses. Nurse leaders should work to create unit cultures that foster learning by encouraging new graduate nurses to ask questions and seek feedback without fear of criticism or incivility.

No abstract

Children consume too much sugar and not enough fruit and vegetables, increasing their risk of adverse health outcomes. Inhibitory control training (ICT) reduces children's and adults' intake of energy-dense foods in both laboratory and real-life settings. However, no studies have yet examined whether ICT can increase healthy food choice when energy-dense options are also available. We investigated whether a food-specific Go/No-Go task could influence the food choices of children aged 4-11, as measured by a hypothetical food choice task using healthy and unhealthy food images printed on cards. Participants played either an active game (healthy foods = 100% go, unhealthy foods = 100% no-go; Studies 1 & 2), a food control game (both healthy and unhealthy foods = 50% go, 50% no-go; Studies 1 & 2) or a non-food control game (sports equipment = 100% go, technology = 100% no-go; Study 2 only) followed by the choice task. In Study 2, food card choices were also measured before training to examine change in choices. A post-training real food choice task was added to check that choices made in the card-based task were representative of choices made when faced with real healthy and unhealthy foods. Overall, the active group chose the greatest number of healthy food cards. Study 2 confirmed that this was due to increases in healthy food card choice in this group only. Active group participants chose a greater number of healthy foods in the real food choice task compared to children in the non-food control group only. The results are discussed with reference to methodological issues and the development of future healthy eating interventions.

BackgroundManipulating maternal nutrition during specific periods of gestation can result in re-programming of fetal and post-natal development. In this experiment we investigated how a feed restriction of 85% compared with 140% of total metabolizable energy requirements, fed to cows during mid-to-late gestation, influences phenotypic development of fetuses and mRNA expression of growth (Insulin-Like Growth Factor family and Insulin Receptor (INSR)), myogenic (Myogenic Differentiation 1 (MYOD1), Myogenin (MYOG), Myocyte Enhancer Factor 2A (MEF2A), Serum Response Factor (SRF)) and adipogenic (Peroxisome Proliferator Activated Receptor Gamma (PPARG)) genes in fetal longissimus dorsi (LD) and semitendinosus (ST) muscle. DNA methylation of imprinted genes, Insulin Like Growth Factor 2 (IGF2) and Insulin Like Growth Factor 2 Receptor (IGF2R), and micro RNA (miRNA) expression, were also examined as potential consequences of poor maternal nutrition, but also potential regulators of altered gene expression patterns.ResultsWhile the nutrient restriction impacted dam body weight, no differences were observed in phenotypic fetal measurements (weight, crown-rump length, or thorax circumference). Interestingly, LD and ST muscles responded differently to the differential pre-natal nutrient levels. While LD muscle of restricted fetal calves had greater mRNA abundances for Insulin Like Growth Factor 1 and its receptor (IGF1 and IGF1R), IGF2R, INSR, MYOD1, MYOG, and PPARG, no significant differences were observed for gene expression in ST muscle. Similarly, feed restriction had a greater impact on the methylation level of IGF2 Differentially Methylated Region 2 (DMR2) in LD muscle as compared to ST muscle between treatment groups. A negative correlation existed between IGF2 mRNA expression and IGF2 DMR2 methylation level in both LD and ST muscles. Differential expression of miRNAs 1 and 133a were also detected in LD muscle.ConclusionsOur data suggests that a nutrient restriction of 85% as compared to 140% of total metabolizable energy requirements during the 2nd half of gestation can alter the expression of growth, myogenic and adipogenic genes in fetal muscle without apparent differences in fetal phenotype. It also appears that the impact of feed restriction varies between muscles suggesting a priority for nutrient partitioning depending on muscle function and/or fiber composition. Differences in the methylation level in IGF2, a well-known imprinted gene, as well as differences in miRNA expression, may be functional mechanisms that precede the differences in gene expression observed, and could lead to trans-generational epigenetic programming.

No abstract

HypothesisThe majority of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1/PD-L1 therapy develop either innate or acquired resistance. Across tumor types, the “T cell-inflamed” tumor microenvironment correlates with clinical response to immunotherapy. We hypothesize that clinical characteristics may be predictive of resistance and that “T cell-inflamed” NSCLC tumors can be identified by gene expression profiling.ResultsOf 93 patients, 36 (38.7%) had innate resistance and 57 (61.3%) had initial benefit to immunotherapy. Innate resistance was associated with non-smokers (p = 0.013), more involved disease sites (p = 0.011), more prior therapy (p = 0.001), and a lower albumin level (p = 0.014). Among patients with initial benefit, factors associated with subsequent progression-free survival included higher Karnofsky Performance Status (KPS) (p = 0.004) and lower depth of response to anti-PD-1 therapy (p = 0.003). A “T cell-inflamed” microenvironment was identified in 42% of TCGA adenocarcinoma samples versus 21.0% of squamous cell.DiscussionSpecific clinical characteristics appear to be predictive of either innate or acquired resistance to anti-PD-1/PD-L1 therapy. A “T cell-inflamed” tumor was more common in adenocarcinoma than squamous histology.MethodsA retrospective review of NSCLC patients treated with anti-PD-1/PD-L1 monotherapy. Patients with innate resistance to anti-PD-1/PD-L1 therapy (defined as progression at first CT evaluation) were compared to patients with initial clinical benefit. Among those with initial clinical benefit, we identified prognostic factors for time to progression (acquired resistance) or death. To further corroborate our findings on limited numbers, immune gene expression profiling of all NSCLC samples from the TCGA database was also pursued.