Description: Atmospheric black carbon (BC) absorbs solar radiation, and exacerbates global warming through exerting positive radiative forcing (RF). However, the contribution of BC to ongoing changes in global climate is under debate. Anthropogenic BC emissions, and 5 the resulting distribution of BC concentration, are highly uncertain. In particular, long range transport and processes affecting BC atmospheric lifetime are poorly understood. Here we discuss whether recent assessments may have overestimated present day BC radiative forcing in remote regions. We compare vertical profiles of BC concentration from four recent aircraft measurement campaigns to simulations by 13 aerosol 10 models participating in the AeroCom Phase II intercomparision. An atmospheric lifetime of BC of less than 5 days is shown to be essential for reproducing observations in remote ocean regions, in line with other recent studies. Adjusting model results to measurements in remote regions, and at high altitudes, leads to a 25% reduction in AeroCom Phase II median direct BC forcing, from fossil fuel and biofuel burning, over 15 the industrial era. The sensitivity of modeled forcing to BC vertical profile and lifetime highlights an urgent need for further flight campaigns, close to sources and in remote regions, to provide improved quantification of BC effects for use in climate policy.

Description: Purpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAF V600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy- D -glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose–response relationship. Experimental Design: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data. Results: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (〉80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAF V600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAF V600 mutation–positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma. Conclusion: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose–response relationship. A maximum tolerated dose for dabrafenib was not determined. Clin Cancer Res; 20(17); 4449–58. ©2014 AACR .