Potential Role of Platelet-Derived Growth Factor Receptor Inhibition Using Imatinib in Combination with Docetaxel in the Treatment of Recurrent Non-small Cell Lung Cancer

Introduction:Platelet-derived growth factor receptor (PDGFR) is expressed in lung cancer and is involved in angiogenesis. Preclinical models demonstrated that imatinib (Im) regulates angiogenesis through PDGFR inhibition and enhances efficacy of chemotherapy. Hypothesis: We hypothesized that Im plus docetaxel (D) would have a synergistic effect detectable by an increase in response rate in patients with recurrent non-small cell lung cancer (NSCLC).Methods:A phase II trial to evaluate Im in combination with D in patients with recurrent NSCLC was conducted. The primary end point was response rate, using a Simon two-stage design. Eligible patients had measurable disease and no more than two chemotherapy regimens. D was given at 30 mg/m2/wk intravenously ×3 every 4 weeks and oral Im at 600 mg daily for four cycles. Patients required two cycles to be evaluable for response. Nonprogressors after four cycles continued with Im maintenance until progression or for a total of 12 months.Results:Twenty-three patients were enrolled in the first stage. Toxicity was mainly nonhematologic. We observed one partial response (5.5%), four stable disease (22.2%), and 13 progressed (72.2%). Median time to progression was 1.9 months, and median overall survival was 6.1 months. Two patients who went on Im maintenance had time to progression of 7.78 months and 15.8 months.Conclusion:Im in combination with D did not achieve its primary objective of improving response rate in patients with recurrent NSCLC. An increased understanding of the complex PDGFR pathway in lung cancer and alternative strategies to inhibit it are needed

Emotions, performance and entrepreneurship in the context of fringe theatre

Through a study of small scale independent theatre companies, generally known as ‘fringe’, this article explores how passion is drawn on and activated as company founders seek an outlet for their work. Drawing on a social constructionist approach to emotions, we highlight the multiplicity of passion through its positive and negative dimensions as well as how these may intersect. Further, by positioning passion within a set of power relations we point to its performative role in reflecting and reinforcing contextually specific discursive regimes. We contribute to the literature on the social and emotional performance of entrepreneurialism and to understandings of passion that characterize the affective entrepreneurial condition. © The Author(s) 2013

The Mississippi River source-to-sink system: Perspectives on tectonic, climatic, and anthropogenic influences, Miocene to Anthropocene

© 2015 Elsevier B.V. The Mississippi River fluvial-marine sediment-dispersal system (MRS) has become the focus of renewed research during the past decade, driven by the recognition that the channel, alluvial valley, delta, and offshore regions are critical components of North American economic and ecological networks. This renaissance follows and builds on over a century of intense engineering and geological study, and was sparked by the catastrophic Gulf of Mexico 2005 hurricane season, the 2010 Deep Water Horizon oil spill, and the newly recognized utility of source-to-sink concepts in hydrocarbon exploration and production. With this paper, we consider influences on the MRS over Neogene timescales, integrate fluvial and marine processes with the valley to shelf to deepwater regions, discuss MRS evolution through the late Pleistocene and Holocene, and conclude with an evaluation of Anthropocene MRS morphodynamics and source-to-sink connectivity in a time of profound human alteration of the system. In doing so, we evaluate the effects of tectonic, climatic, and anthropogenic influences on the MRS over multiple timescales.The Holocene MRS exhibits autogenic process-response at multiple spatial and temporal scales, from terrestrial catchment to marine basin. There is also ample evidence for allogenic influence, if not outright control, on these same morphodynamic phenomena that are often considered hallmarks of autogenesis in sedimentary systems. Prime examples include episodes of enhanced Holocene flooding that likely triggered avulsion, crevassing, and lobe-switching events at subdelta to delta scales.The modern locus of the Mississippi fluvial axis and shelf-slope-fan complex was established by Neogene crustal dynamics that steered sediment supply. Dominant Miocene sediment supply shifted west to east, due to regional subsidence in the Rockies. Then, drier conditions inhibited sediment delivery from the Rocky Mountains, and Appalachian epeirogenic uplift combined with wetter conditions to enhance sediment delivery from the Appalachians.Climatic influences came to the forefront during Pleistocene glacial-interglacial cycles. The fluvial system rapidly responded to sea-level rises and falls with rapid and extensive floodplain aggradation and fluvial knickpoint migration, respectively. More dramatically, meltwater flood episodes spanning decades to centuries were powerful agents of geomorphic sculpting and source-to-sink connectivity from the ice edge to the deepest marine basin. Differential sediment loading from alluvial valley to slope extending from Cretaceous to present time drove salt-tectonic motions, which provided additional morphodynamic complexity, steered deep-sea sediment delivery, diverted and closed canyons, and contributed to modern slope geometry.Despite the best efforts from generations of engineers, the leveed, gated, and dammed Mississippi still demonstrates the same tendency for self-regulation that confronted 19th century engineers. This is most apparent in the bed-level aggradation and scour associated with changes in sediment cover and stream power in river channels, and in the upstream migration of channel depocenters and fluvial and sediment outlets at the expense of downstream flow, that will ultimately lead to delta backstepping. Like other source-to-sink systems, upstream control of sediment supply is impacting downstream morphology. Even within the strait-jacketed confines of the modern flood control system, the Mississippi River still retains some independence