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The development of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar as an oral antidiabetic was recently discontinued. Here we present tumor data from a 2-year carcinogenicity study in rats given 0.3, 1, 3, and 10 micromol/kg tesaglitazar is presented with focus on the findings of subcutaneous fibrosarcomas. To investigate the mechanism for induction of fibrosarcomas, replicative DNA synthesis (immunohistochemical detection of BrdU-labeled cells) and expression of PPARgamma (immunohistochemistry and reverse transcription-polymerase chain reaction) in subcutaneous adipose tissues was assessed in rats administered 1 or 10 micromol/kg for 2 weeks or 3 months. Poorly differentiated subcutaneous mesenchymal sarcomas with a predominant spindle cell appearance occurred at the highest dose level of 10 micromol/kg in both sexes, and these tumors were diagnosed as fibrosarcomas. The 10-micromol/kg dose was at or above the maximum tolerated dose and caused considerable cardiovascular mortality. Tesaglitazar stimulated DNA synthesis mainly in subcutaneous interstitial mesenchymal cells. The percentage of BrdU-labeled interstitial cells was increased at 1 and 10 micromol/kg after 2 weeks. The increase in DNA synthesis was still significant at the end of the 12-week treatment at 10 mumol/kg, the dose producing fibrosarcoma. However, at 1 micromol/kg, a dose below the no-observed-effect level for fibrosarcoma, the level of DNA synthesis was similar to control levels at 12 weeks. Immunohistochemical analyses showed no detectable PPARgamma protein in the majority of BrdU-labeled interstitial mesenchymal cells in white and brown fat. This indicates that stimulation of DNA synthesis is not mediated via direct activation of PPARgamma in these cells. The results suggest that the induction of rat fibrosarcoma by tesaglitazar, at exposures 100-fold above the human therapeutic exposure, may involve proliferation of undifferentiated mesenchymal cells in subcutaneous tissues.

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The National Oceanic and Atmospheric Administration's (NOAA) Sensing Hazards with Operational Unmanned Technology (SHOUT) project evaluated the ability of observations from high-altitude unmanned aircraft to improve forecasts of high-impact weather events like tropical cyclones or mitigate potential degradation of forecasts in the event of a future gap in satellite coverage. During three field campaigns conducted in 2015 and 2016, the National Aeronautics and Space Administration (NASA) Global Hawk, instrumented with GPS dropwindsondes and remote sensors, flew 15 missions sampling 6 tropical cyclones and 3 winter storms. Missions were designed using novel techniques to target sampling regions where high model forecast uncertainty and a high sensitivity to additional observations existed. Data from the flights were examined in real time by operational forecasters, assimilated in operational weather forecast models, and applied postmission to a broad suite of data impact studies. Results from the analyses spanning different models and assimilation schemes, though limited in number, consistently demonstrate the potential for a positive forecast impact from the observations, both with and without a gap in satellite coverage. The analyses with the then-operational modeling system demonstrated large forecast improvements near 15% for tropical cyclone track at a 72-h lead time when the observations were added to the otherwise complete observing system. While future decisions regarding use of the Global Hawk platform will include budgetary considerations, and more observations are required to enhance statistical significance, the scientific results support the potential merit of the observations. This article provides an overview of the missions flown, observational approach, and highlights from the completed and ongoing data impact studies.