Bisphosphonates (BPs) are widely used in the treatment of osteolytic bone disease associated with multiple myeloma, and have been demonstrated to exert antitumor effects both in vitro and in vivo. However, the precise molecular mechanisms involved in the direct antitumor effects of BPs in vitro are not known. Nitrogen-containing BPs, such as risedronate (RIS), act by inhibiting protein prenylation. A phosphonocarboxylate analogue of RIS, 3-PEHPC, has previously been shown in osteoclasts and macrophages to specifically inhibit prenylation of Rab GTPases. The aim of this study was to identify the molecular targets of RIS and 3-PEHPC in human myeloma cells and to determine the cellular effects of selective inhibition of Rab prenylation by 3-PEHPC as compared to nonspecific inhibition of protein prenylation by RIS in human myeloma cells. RIS dose-dependently inhibited prenylation of both Rap1A and Rab6, whereas 3-PEHPC only inhibited Rab6 prenylation. Both RIS and 3-PEHPC dose-dependently increased apoptosis in human myeloma cells. RIS induced an accumulation of cells in the S-phase of the cell cycle, associated with inhibition of DNA replication. In contrast, 3-PEHPC did not cause cell-cycle arrest. Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell-cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3-PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3-PEHPC. In conclusion, our studies demonstrate that selective inhibition of Rab prenylation induces apoptosis, but not S-phase arrest, thus identifying distinct molecular pathways that mediate the antimyeloma effect of nitrogen-containing BPs. © 2006 Wiley-Liss, Inc.
PURPOSE OF REVIEW:The Scored Patient-Generated Subjective Global Assessment (PG-SGA) is used internationally as the reference method for proactive risk assessment (screening), assessment, monitoring and triaging for interventions in patients with cancer. This review aims to explain the rationale behind and data supporting the PG-SGA, and to provide an overview of recent developments in the utilization of the PG-SGA and the PG-SGA Short Form.RECENT FINDINGS:The PG-SGA was designed in the context of a paradigm known as 'anabolic competence'. Uniquely, the PG -SGA evaluates the patient's status as a dynamic rather than static process. The PG-SGA has received new attention, particularly as a screening instrument for nutritional risk or deficit, identifying treatable impediments and guiding patients and professionals in triaging for interdisciplinary interventions. The international use of the PG-SGA indicates a critical need for high-quality and linguistically validated translations of the PG-SGA.SUMMARY:As a 4-in-1 instrument, the PG-SGA can streamline clinic work flow and improve the quality of interaction between the clinician and the patient. The availability of multiple high-quality language versions of the PG-SGA enables the inclusion of the PG-SGA in international multicenter studies, facilitating meta-analysis and benchmarking across countries.
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OBJECTIVE: To further test the validity and clinical usefulness of the steep ramp test (SRT) in estimating exercise tolerance in cancer survivors by external validation and extension of previously published prediction models for peak oxygen consumption (Vo2peak) and peak power output (Wpeak).DESIGN: Cross-sectional study.SETTING: Multicenter.PARTICIPANTS: Cancer survivors (N=283) in 2 randomized controlled exercise trials.INTERVENTIONS: Not applicable.MAIN OUTCOME MEASURES: Prediction model accuracy was assessed by intraclass correlation coefficients (ICCs) and limits of agreement (LOA). Multiple linear regression was used for model extension. Clinical performance was judged by the percentage of accurate endurance exercise prescriptions.RESULTS: ICCs of SRT-predicted Vo2peak and Wpeak with these values as obtained by the cardiopulmonary exercise test were .61 and .73, respectively, using the previously published prediction models. 95% LOA were ±705mL/min with a bias of 190mL/min for Vo2peak and ±59W with a bias of 5W for Wpeak. Modest improvements were obtained by adding body weight and sex to the regression equation for the prediction of Vo2peak (ICC, .73; 95% LOA, ±608mL/min) and by adding age, height, and sex for the prediction of Wpeak (ICC, .81; 95% LOA, ±48W). Accuracy of endurance exercise prescription improved from 57% accurate prescriptions to 68% accurate prescriptions with the new prediction model for Wpeak.CONCLUSIONS: Predictions of Vo2peak and Wpeak based on the SRT are adequate at the group level, but insufficiently accurate in individual patients. The multivariable prediction model for Wpeak can be used cautiously (eg, supplemented with a Borg score) to aid endurance exercise prescription.
