The validity and reliability of walking as exercise modality during VO2max testing.

BACKGROUND: Although walking is the most common exercise modality in daily life for most humans, running and cycling are the most applied exercise modalities during maximal oxygen uptake (VO2max) testing. The aim of this study was to assess the reliability and validity of walking as exercise modality during VO2max testing. METHODS: Sixteen participants (25±3 years, 172±9 cm, 69±15 kg, and VO2max 50±4 mL/kg/min) performed four incremental running- and walking VO2max tests (two tests in each condition) within 2-3 weeks. During the walking condition, the speed was set to 7 km/h, and the treadmill incline increased by 2.5% each min until exhaustion. Results from these tests were validated against a running protocol with 5.3% treadmill incline where the speed increased by 1 km/h each min until exhaustion. RESULTS: The walking protocol achieved similar reliability values for absolute and relative VO2max when compared to the running condition. No significant differences in VO2max were observed between test session 1 and 2 for any of the tests. Significantly higher absolute VO2max (3.39±0.77 vs. 3.50±0.84 L/min; trivial difference) were observed in the running versus walking condition, while no significant differences in relative VO2max, BLa or Borg were detected. CVs for absolute and relative VO2max between the analyzed exercise modalities were ~5%. CONCLUSIONS: Although the present participants achieved 2-3% lower VO2max when the walking test protocol was applied, walking seems to be a promising exercise-modality alternative during VO2max testing in clinical settings.

A novel synthetic smoothened antagonist transiently inhibits pancreatic adenocarcinoma xenografts in a mouse model.

BACKGROUND: Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials. PRINCIPAL FINDINGS: Using Shh-Light II (Shh-L2) and alkaline phosphatase (AP) based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low µM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo. SIGNIFICANCE: We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists.