Citations

Evidence is provided that the fibroproliferative actions of TGF‐β are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF‐β signaling is shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for the de novo synthesis of fatty acids. With the use of pharmacologic and genetic approaches, we show that TGF‐β‐stimulated FASN expression is independent of Smad2/ 3 and is mediated via mammalian target of rapamycin complex 1. In the absence of FASN activity or protein, TGF‐β ‐driven fibrogenic processes are reduced with no apparent toxicity. Furthermore, as increased FASN expression was also observed to correlate with the degree of lung fibrosis in bleomycin‐treated mice, inhibition of FASN was examined in a murine‐treatment model of pulmonary fibrosis. Remarkably, inhibition of FASN not only decreased expression of profibrotic targets, but lung function was also stabilized/improved, as assessed by peripheral blood oxygenation.—Jung, M.‐Y., Kang, J.‐H., Hernandez, D. M., Yin, X., Andrianifahanana, M., Wang, Y., Gonzalez‐Guerrico, A., Limper, A. H., Lupu, R., Leof, E. B. Fatty acid synthase is required for profibrotic TGF‐β signaling. FASEB J. 32, 3803–3815 (2018). www.fasebj.org

Abstract Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid–binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b+F4/80+MHCII−Ly6C− phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFκB/miR-29b pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM. Significance: These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy. Cancer Res; 78(9); 2343–55. ©2018 AACR.

PurposeThe aim of this work was to develop an efficient daily quality assurance (QA) program with strict tolerance levels for pencil beam scanning (PBS) proton radiotherapy featuring simultaneous dosimetric testing on a single, nonuniform field.MethodsA nonuniform field measuring beam output, proton range, and spot position was designed for delivery onto a Sun Nuclear Daily‐QA 3 device. A custom acrylic block permitted simultaneous measurement of low‐ and high‐energy proton ranges in addition to beam output. Sensitivities to output, range, and spot position were evaluated to quantitate the device's response. Reproducibility tests were used to identify and control sources of measurement error as well as to assess the QA procedure's robustness. This procedure was implemented in each of our four treatment rooms independently; 4–6 months of daily QA measurements were collected.ResultsThe 1% output, 0.5 mm range, and 1.5 mm spot position tolerances derived from preliminary tests were tighter overall than tolerances found in the literature and equivalent to the limits used for proton system commissioning. The simplicity and automation of the procedure reduced the time required for daily QA to 10 min per treatment room, and competition for beam between multiple treatment rooms was minimized.ConclusionsAn efficient daily PBS QA procedure can be performed using a single, nonuniform field on a nondedicated QA device. A thorough quantitation of the device's response and careful control of measurement uncertainties allowed daily tolerances to match commissioning standards.