Effects of selective breeding for increased wheel-running behavior on circadian timing of substrate oxidation and ingestive behavior

Fluctuations in substrate preference and utilization across the circadian cycle may be influenced by the degree of physical activity and nutritional status. In the present study, we assessed these relationships in control mice and in mice from a line selectively bred for high voluntary wheel-running behavior, either when feeding a carbohydrate-rich/low-fat (LF) or a high-fat (HF) diet. Housed without wheels, selected mice, and in particular the females, exhibited higher cage activity than their non-selected controls during the dark phase and at the onset of the light phase, irrespective of diet. This was associated with increases in energy expenditure in both sexes of the selection line. In selected males, carbohydrate oxidation appeared to be increased compared to controls. In contrast, selected females had profound increases in fat oxidation above the levels in control females to cover the increased energy expenditure during the dark phase. This is remarkable in light of the finding that the selected mice, and in particular the females showed higher preference for the LF diet relative to controls. It is likely that hormonal and/or metabolic signals increase carbohydrate preference in the selected females, which may serve optimal maintenance of cellular metabolism in the presence of augmented fat oxidation. (C) 2010 Elsevier Inc. All rights reserved

Behavioral Traits are Affected by Selective Breeding for Increased Wheel-Running Behavior in Mice

Voluntary physical activity may be related to personality traits. Here, we investigated these relations in two mouse lines selectively bred for high voluntary wheel-running behavior and in one non-selected control line. Selection lines were more explorative and “information gathering” in the open-field test, either with increased upright positions or horizontal locomotion toward the middle ring. Furthermore, one of the selection lines had an increased risk-taking behavior relative to the control line in approaching a novel object placed in the center of the open field. However, anxiety behavior was increased in selection lines during the plus-maze test. Maze learning was not statistically different among lines, but routine behavior was increased in both selection lines when the maze exit after 2 days of testing was displaced. Specifically, in the displaced maze, selected mice traveled more frequently to the old, habituated exit, bypassing the new exit attached to their home cage. Although the generality of the results would need to be confirmed in future studies including all eight lines in the selection experiment, the increased routine and exploratory behavior (at least in the lines used in the present study) may be adaptive to sustain high activity levels

An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system

Background: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population. Patients and methods: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397). Results: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib. Conclusions: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work. © 2018 Elsevier Lt

Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

Background: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. Methods: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m−2 q3w, paclitaxel 80 mg m−2 every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m−2 q3w. The primary endpoint was safety/tolerability. Results: A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade 3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; 225 mg, 33%), and grade 3 neutropenia occurred more commonly at doses 225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w. Conclusion:  Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials