Effects of Low-Dose Dairy Protein Plus Micronutrient Supplementation during Resistance Exercise on Muscle Mass and Physical Performance in Older Adults: A Randomized, Controlled Trial.

OBJECTIVES: To investigate whether supplementation with low-dose dairy protein plus micronutrients augments the effects of resistance exercise (RE) on muscle mass and physical performance compared with RE alone among older adults. DESIGN: Randomized controlled trial. SETTING: Tokyo, Japan. PARTICIPANTS: Eighty-two community-dwelling older adults (mean age, 73.5 years) were randomly allocated to an RE plus dairy protein and micronutrient supplementation group or an RE only group (n = 41 each). INTERVENTION: The RE plus supplementation group participants ingested supplements with dairy protein (10.5 g/day) and micronutrients (8.0 mg zinc, 12 µg vitamin B12, 200 µg folic acid, 200 IU vitamin D, and others/day). Both groups performed the same twice-weekly RE program for 12 weeks. MEASUREMENTS: Whole-body, appendicular, and leg lean soft-tissue mass (WBLM, ALM, and LLM, respectively) with dual-energy X-ray absorptiometry, physical performance, biochemical characteristics, nutritional intake, and physical activity were measured before and after the intervention. Data were analyzed by using linear mixed-effects models. RESULTS: The groups exhibited similar significant improvements in maximum gait speed, Timed Up-and-Go, and 5-repetition and 30-s chair stand tests. As compared with RE only, RE plus supplementation significantly increased WBLM (0.63 kg, 95% confidence interval [CI]: 0.31-0.95), ALM (0.37 kg, 95% CI: 0.16-0.58), LLM (0.27 kg, 95% CI: 0.10-0.46), and serum concentrations of 25-hydroxyvitamin D (4.7 ng/mL, 95% CI: 1.6-7.9), vitamin B12 (72.4 pg/mL, 95% CI: 12.9-131.9), and folic acid (12.9 ng/mL, 95% CI: 10.3-15.5) (all P < 0.05 for group-by-time interactions). Changes over time in physical activity and nutritional intake excluding the supplemented nutrients were similar between groups. CONCLUSION: Low-dose dairy protein plus micronutrient supplementation during RE significantly increased muscle mass in older adults but did not further improve physical performance.

Sensitivity of breast cancer cell lines to recombinant thiaminase I.

PURPOSE: We have previously shown that the expression of the thiamine transporter THTR2 is decreased sevenfold in breast cancer, which may leave breast cancer cells vulnerable to acute thiamine starvation. This concept was supported by the observation that MDA231 breast cancer xenografts demonstrated growth inhibition in mice fed a thiamine-free diet. METHODS: We purified recombinant Bacillus thiaminolyticus thiaminase I enzyme, which digests thiamine, to study acute thiamine starvation in breast cancer. RESULTS: Thiaminase I enzyme was cytotoxic in six breast cancer cell lines with IC(50)s ranging from 0.012 to 0.022 U/ml. The growth inhibitory effects of the combination of thiaminase I with either doxorubicin or paclitaxel were also examined. Over a wide range of drug concentrations, thiaminase 1 was consistently synergistic or additive with doxorubicin and paclitaxel in MCF-7, ZR75, HS578T and T47D cell lines, with most combinations having a calculated combination index (CI) of less than 0.8, indicating synergy. Although thiaminase I exposure did not stimulate the energy-sensing signaling kinases AKT, AMPK and GSK-3beta in MCF-7, ZR75, HS578T and T47D cell lines, thiaminase I exposure did stimulate expression of the ER stress response protein GRP78. In summary, thiaminase I is cytotoxic in breast cancer cell lines and triggers the unfolded protein response. CONCLUSION: These findings suggest that THTR2 down-regulation in breast tumors may present a nutritional vulnerability that could be exploited by thiaminase I enzyme therapy.

Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase.

Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs.