Relationship between intra-individual variability in nutrition-related lifestyle behaviors and blood glucose outcomes under free-living conditions in adults without type 2 diabetes.

AIMS: This study determined the relationship between intra-individual variability in day-to-day nutrition-related lifestyle behaviors (meal timing, eating window, food intake, movement behaviors, sleep conditions, and body weight) and glycemic outcomes under free-living conditions in adults without type 2 diabetes. METHODS: We analyzed 104 adults without type 2 diabetes. During the 7-day measurement period, dietary intake, movement behaviors, sleep conditions, and glucose outcomes were assessed. Daily food intake was assessed using a mobile-based health application. Movement behaviors and sleep conditions were assessed using a tri-axial accelerometer. Meal timing was assessed from the participant's daily life record. Blood glucose levels were measured continuously using a glucose monitor. Statistical analyses were conducted using a linear mixed-effects model, with mealtime, food intake, body weight, movement behaviors, and sleep conditions as fixed effects and participants as a random effect. RESULTS: Dinner time and eating window were positively significantly correlated with mean (dinner time, p = 0.003; eating window, p = 0.001), standard deviation (SD; both at p < 0.001), and maximum (both at p < 0.001) blood glucose levels. Breakfast time was negatively associated with glucose outcomes (p < 0.01). Sedentary time was positively significantly associated with blood glucose SD (p = 0.040). Total sleep time was negatively significantly correlated with SD (p = 0.035) and maximum (p = 0.032) blood glucose levels. Total daily energy intake (p = 0.001), carbohydrate intake (p < 0.001), and body weight (p < 0.05) were positively associated with mean blood glucose levels. CONCLUSION: Intra-individual variations in nutrition-related lifestyle behaviors, especially morning and evening body weight, and food intake, were associated with mean blood glucose levels, and a long sedentary time and total sleep time were associated with glucose variability. Earlier dinner times and shorter eating windows per day resulted in better glucose control.

Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma.

Patients with melanoma with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner. In both in vitro and in vivo settings, potent inhibition of MEK by DS03090629 or its combination with the BRAF inhibitor dabrafenib was demonstrated in a mutant BRAF-overexpressing melanoma cell line model that exhibited a higher MEK phosphorylation level than the parental cell line and then became resistant to dabrafenib and the MEK inhibitor trametinib. DS03090629 also exhibited superior efficacy against a melanoma cell line-expressing mutant MEK1 protein compared with dabrafenib and trametinib. Biophysical analysis revealed that DS03090629 retained its affinity for the MEK protein regardless of its phosphorylation status, whereas the affinity of trametinib declined when the MEK protein was phosphorylated. These results suggest that DS03090629 may be a novel therapeutic option for patients who acquire resistance to the current BRAF- and MEK-targeting therapies.

An Earlier First Meal Timing Associates with Weight Loss Effectiveness in A 12-Week Weight Loss Support Program.

Recent studies have reported that meal timing may play an important role in weight regulation, however it is unknown whether the timing of meals is related to the amount of weight loss. This study aimed to examine the relationship between indices of meal timing and weight loss during weight loss intervention in adults. A 12-week weight loss support program was conducted for 97 adults (age: 47.6 ± 8.3 years, BMI: 25.4 ± 3.7 kg/m2). After the program, body weight decreased by -3.0 ± 2.7%. Only the start of the eating window was positively correlated with the weight change rate in both sexes (men: r = 0.321, p = 0.022; women: r = 0.360, p = 0.014). The participants were divided into two groups based on the start of the eating window as follows: the early group (6:48 ± 0:21 AM) and the late group (8:11 ± 1:05 AM). The weight loss rate in the early group was significantly higher (-3.8 ± 2.7%) than that in the late group (-2.2 ± 2.5%). The present results showed that the start of the early eating window was associated with weight loss and suggested paying attention to meal timing when doing weight loss.

Impact of walking aids on estimating physical activity using a tri-axial accelerometer in frail older adults.

OBJECTIVES: This study aimed to compare the estimation error of physical activity level (PAL) estimated using a tri-axial accelerometer between an independent walking group and an assisted walking group with walking aids. METHODS: Subjects were 6 older adults who could walk independently and 10 older adults requiring walking assistance during gait. Total energy expenditure (TEE) was measured using the doubly labelled water (DLW) method over 2 weeks and PAL was calculated as the measured TEE divided by the basal metabolic rate measured using indirect calorimetry (PALDLW). The participants wore a tri-axial accelerometer (Active style Pro HJA-750C) on the waist simultaneously as the DLW period, and the estimated PAL was derived from it (PALACC). RESULTS: The median PAL estimation error in the assisted walking group was -0.30 kcal/day (range: -0.77 to -0.01 kcal/day) and more underestimated than that in the independent walking group (p=0.02). The estimation error of PALACC was significantly correlated with PALDLW (r=-0.80, p<0.01). CONCLUSIONS: Using the accelerometer, PAL was underestimated for older adults who used walking aids but not for those who walked independently under free-living conditions.

DS-1205b, a novel selective inhibitor of AXL kinase, blocks resistance to EGFR-tyrosine kinase inhibitors in a non-small cell lung cancer xenograft model.

The AXL receptor tyrosine kinase is involved in signal transduction in malignant cells. Recent studies have shown that the AXL upregulation underlies epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant non-small cell lung cancer (NSCLC). In this study, we investigated the effect of DS-1205b, a novel and selective inhibitor of AXL, on tumor growth and resistance to EGFR TKIs. In AXL-overexpressing NIH3T3 cells, DS-1205b potently inhibited hGAS6 ligand-induced migration in vitro and exerted significant antitumor activity in vivo. AXL was upregulated by long-term erlotinib or osimertinib treatment in HCC827 EGFR-mutant NSCLC cells, and DS-1205b treatment in combination with osimertinib or erlotinib effectively inhibited signaling downstream of EGFR in a cell-based assay. In an HCC827 EGFR-mutant NSCLC xenograft mouse model, combination treatment with DS-1205b and erlotinib significantly delayed the onset of tumor resistance compared to erlotinib monotherapy, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors. DS-1205b also delayed the onset of resistance when used in combination with osimertinib in the model. These findings strongly suggest that DS-1205b can prolong the therapeutic benefit of EGFR TKIs in nonclinical as well as clinical settings.