Synthesis and characterization of novel phosphonocarboxylate inhibitors of RGGT.

Phosphonocarboxylate (PC) analogs of the anti-osteoporotic drugs, bisphosphonates, represent the first class of selective inhibitors of Rab geranylgeranyl transferase (RabGGTase, RGGT), an enzyme implicated in several diseases including ovarian, breast and skin cancer. Here we present the synthesis and biological characterization of an extended set of this class of compounds, including lipophilic derivatives of the known RGGT inhibitors. From this new panel of PCs, we have identified an inhibitor of RGGT that is of similar potency as the most active published phosphonocarboxylate, but of higher selectivity towards this enzyme compared to prenyl pyrophosphate synthases. New insights into structural requirements are also presented, showing that only PC analogs of the most potent 3rd generation bisphosphonates inhibit RGGT. In addition, the first phosphonocarboxylate-derived GGPPS inhibitor is reported.

Predictive validity of three ActiGraph energy expenditure equations for children.

PURPOSE: This study evaluated the predictive validity of three previously published ActiGraph energy expenditure (EE) prediction equations developed for children and adolescents. METHODS: A total of 45 healthy children and adolescents (mean age: 13.7 +/- 2.6 yr) completed four 5-min activity trials (normal walking, brisk walking, easy running, and fast running) in an indoor exercise facility. During each trial, participants wore an ActiGraph accelerometer on the right hip. EE was monitored breath by breath using the Cosmed K4b portable indirect calorimetry system. Differences and associations between measured and predicted EE were assessed using dependent t-tests and Pearson correlations, respectively. Classification accuracy was assessed using percent agreement, sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve. RESULTS: None of the equations accurately predicted mean energy expenditure during each of the four activity trials. Each equation, however, accurately predicted mean EE in at least one activity trial. The Puyau equation accurately predicted EE during slow walking. The Trost equation accurately predicted EE during slow running. The Freedson equation accurately predicted EE during fast running. None of the three equations accurately predicted EE during brisk walking. The equations exhibited fair to excellent classification accuracy with respect to activity intensity, with the Trost equation exhibiting the highest classification accuracy and the Puyau equation exhibiting the lowest. CONCLUSIONS: These data suggest that the three accelerometer prediction equations do not accurately predict EE on a minute-by-minute basis in children and adolescents during overground walking and running. The equations maybe useful, however, for estimating participation in moderate and vigorous activity.