Histone deacetylases (Hdacs) remove acetyl groups (CH3CO-) from ε-amino groups in lysine residues within histones and other proteins. This posttranslational (de) modification alters protein ...stability, protein-protein interactions, and chromatin structure. Hdac activity plays important roles in the development of all organs and tissues, including the mineralized skeleton. Bone is a dynamic tissue that forms and regenerates by two processes: endochondral and intramembranous ossification. Chondrocytes and osteoblasts are responsible for producing the extracellular matrices of skeletal tissues. Several Hdacs contribute to the molecular pathways and chromatin changes that regulate tissue-specific gene expression during chondrocyte and osteoblast specification, maturation, and terminal differentiation. In this review, we summarize the roles of class I and class II Hdacs in chondrocytes and osteoblasts. The effects of small molecule Hdac inhibitors on the skeleton are also discussed.
Abstract Introduction We report the long-term results of RTOG 9801, a randomized trial investigating the ability of amifostine, a radioprotector, to reduce chemoradiation-induced esophagitis. Methods ...Patients with stages II and IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m2 intravenously (IV) and carboplatin area under the curve (AUC) 6 both days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m2 ) and carboplatin (AUC 2), with hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy BID). Patients were randomly assigned to amifostine (AM) 500 mg IV four times per week or no-AM during chemoradiotherapy. Stratification factors included age (<70 vs. ≥70 years), stage and performance status. Results 243 patients (pts) were enrolled; 120 received AM, 123 received no-AM. Two pts on each arm were found ineligible. Overall, 85% of patients were ≤70 years; 75% had a KPS ≥90. 34% had squamous histology. With median follow-up of 96.3 months (for patients still alive), overall survival was identical (hazard ratio 1.03 (0.79–1.34), NS): five-year survival 17% in both arms. The incidence of late grade 3–5 toxicities was 16% in the AM arm and 19% in the control arm (hazard ratio 1.24 (0.66–2.32), NS). There was no significant difference between the arms regarding overall survival, disease-free survival or long-term toxicity. Conclusion The chemoradiation regimen of carboplatin and paclitaxel produced long-term results in the multi-institutional setting comparable to other regimens. Amifostine did not appear to compromise survival. As done in RTOG 9801, more consistent reporting of long term toxicity is needed for comparison of different chemoradiation regimens.
The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor ...suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a transgene to create mice that overexpress Mdm2. The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.
The longitudinal relationship between stunting and wasting in children is poorly characterized. Instances of wasting or poor weight gain may precede linear growth retardation. We analyzed ...longitudinal anthropometric data for 1599 children from 8 cohort studies to determine the effect of wasting weight-for-length Z-score (WLZ) < -2 and variability in WLZ in the first 17 mo on length-for-age Z-score (LAZ) at 18-24 mo of age. In addition, we considered the effects of change in WLZ during the previous 6-mo period on length at 18 and 24 mo. Wasting at 6-11 or 12-17 mo was associated with decreased LAZ; however, children who experienced wasting only at 0-5 mo did not suffer any long-term growth deficits compared with children with no wasting during any period. Children with greater WLZ variability (≥0.5 SD) in the first 17 mo of life were shorter LAZ = -0.51 SD (95% CI: -0.67, -0.36 SD) at 18-24 mo of age than children with WLZ variability <0.5. Change in WLZ in the previous 6-mo period was directly associated with greater attained length at 18 mo 0.33 cm (95% CI: 0.11, 0.54 cm) and 24 mo 0.72 cm (95% CI: 0.52, 0.92 cm). Children with wasting, highly variable WLZ, or negative changes in WLZ are at a higher risk for linear growth retardation, although instances of wasting may not be the primary cause of stunting in developing countries.
Demonstrating the validity of a public health simulation model helps to establish confidence in the accuracy and usefulness of a model's results. In this study we evaluated the validity of the ...Prevention Impacts Simulation Model (PRISM), a system dynamics model that simulates health, mortality, and economic outcomes for the US population. PRISM primarily simulates outcomes related to cardiovascular disease but also includes outcomes related to other chronic diseases that share risk factors. PRISM is openly available through a web application.
We applied the model validation framework developed independently by the International Society of Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modeling task force to validate PRISM. This framework included model review by external experts and quantitative data comparison by the study team.
External expert review determined that PRISM is based on up-to-date science. One-way sensitivity analysis showed that no parameter affected results by more than 5%. Comparison with other published models, such as ModelHealth, showed that PRISM produces lower estimates of effects and cost savings. Comparison with surveillance data showed that projected model trends in risk factors and outcomes align closely with secular trends. Four measures did not align with surveillance data, and those were recalibrated.
PRISM is a useful tool to simulate the potential effects and costs of public health interventions. Results of this validation should help assure health policy leaders that PRISM can help support community health program planning and evaluation efforts.
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