Small molecule receptor tyrosine kinase inhibitor of platelet-derived growth factor signaling (SU9518) modifies radiation response in fibroblasts and endothelial cells

BACKGROUND: Several small receptor tyrosine kinase inhibitors (RTKI) have entered clinical cancer trials alone and in combination with radiotherapy or chemotherapy. The inhibitory spectrum of these compounds is often not restricted to a single target. For example Imatinib/Gleevec (primarily a bcr/abl kinase inhibitor) or SU11248 (mainly a VEGFR inhibitor) are also potent inhibitors of PDGFR and other kinases. We showed previously that PDGF signaling inhibition attenuates radiation-induced lung fibrosis in a mouse model. Here we investigate effects of SU9518, a PDGFR inhibitor combined with ionizing radiation in human primary fibroblasts and endothelial cells in vitro, with a view on utilizing RTKI for antifibrotic therapy. METHODS: Protein levels of PDGFR-α/-β and phosphorylated PDGFR in fibroblasts were analyzed using western and immunocytochemistry assays. Functional proliferation and clonogenic assays were performed (i) to assess PDGFR-mediated survival and proliferation in fibroblasts and endothelial cells after SU9518 (small molecule inhibitor of PDGF receptor tyrosine kinase); (ii) to test the potency und selectivity of the PDGF RTK inhibitor after stimulation with PDGF isoforms (-AB, -AA, -BB) and VEGF+bFGF. In order to simulate in vivo conditions and to understand the role of radiation-induced paracrine PDGF secretion, co-culture models consisting of fibroblasts and endothelial cells were employed. RESULTS: In fibroblasts, radiation markedly activated PDGF signaling as detected by enhanced PDGFR phosphorylation which was potently inhibited by SU9518. In fibroblast clonogenic assay, SU9518 reduced PDGF stimulated fibroblast survival by 57%. Likewise, SU9518 potently inhibited fibroblast and endothelial cell proliferation. In the co-culture model, radiation of endothelial cells and fibroblast cells substantially stimulated proliferation of non irradiated fibroblasts and vice versa. Importantly, the RTK inhibitor significantly inhibited this paracrine radiation-induced fibroblast and endothelial cell activation. CONCLUSION: Radiation-induced autocrine and paracrine PDGF signaling plays an important role in fibroblast and endothelial cell proliferation. SU9518, a PDGFR tyrosine kinase inhibitor, reduces radiation-induced fibroblast and endothelial cell activation. This may explain therapeutic anticancer effects of Imatinib/Gleevec, and at the same time it could open a way of attenuating radiation-induced fibrosis

Review of Underwater and In-Air Sounds Emitted by Australian and Antarctic Marine Mammals

The study of marine soundscapes is a growing field of research. Recording hardware is becoming more accessible; there are a number of off-the-shelf autonomous recorders that can be deployed for months at a time; software analysis tools exist as shareware; rawor preprocessed recordings are freely and publicly available. However, what is missing are catalogues of commonly recorded sounds. Sounds related to geophysical events (e.g. earthquakes) and weather (e.g. wind and precipitation), to human activities (e.g. ships) and to marine animals (e.g. crustaceans, fish and marine mammals) commonly occur. Marine mammals are distributed throughout Australia's oceans and significantly contribute to the underwater soundscape. However, due to a lack of concurrent visual and passive acoustic observations, it is often not known which species produces which sounds. To aid in the analysis of Australian and Antarctic marine soundscape recordings, a literature review of the sounds made by marine mammals was undertaken. Frequency, duration and source level measurements are summarised and tabulated. In addition to the literature review, new marine mammal data are presented and include recordings from Australia of Omura's whales (Balaenoptera omurai), dwarf sperm whales (Kogia sima), common dolphins (Delphinus delphis), short-finned pilot whales (Globicephala macrorhynchus), long-finned pilot whales (G. melas), Fraser's dolphins (Lagenodelphis hosei), false killer whales (Pseudorca crassidens), striped dolphins (Stenella coeruleoalba) and spinner dolphins (S. longirostris), as well as the whistles and burst-pulse sounds of Australian pygmy killer whales (Feresa attenuata). To date, this is the most comprehensive acoustic summary for marine mammal species in Australian waters