Src and ADAM-17-Mediated Shedding of Transforming Growth Factor-alpha Is a Mechanism of Acute Resistance to TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) has emerged as a promising anticancer agent. However, resistance to TRAIL is likely to be a major problem, and sensitization of cancer cells to TRAIL may therefore be an important anticancer strategy. In this study, we examined the effect of the epidermal growth factor receptor (EGFR)tyrosine kinase inhibitor (TKI) gefitinib and a human epidermal receptor 2 (HER2)-TKI (M578440) on the sensitivity of human colorectal cancer (CRC) cell lines to recombinant human TRAIL (rhTRAIL). A synergistic interaction between rhTRAIL and gefitinib and rhTRAIL and M578440 was observed in both rhTRAIL-sensitive and resistant CRC cells. This synergy correlated with an increase in EGFR and HER2 activation after rhTRAIL treatment. Furthermore, treatment of CRC cells with rhTRAIL resulted in activation of the Src family kinases (SFK). Importantly, we found that rhTRAIL treatment induced shedding of transforming growth factor-alpha (TGF-alpha) that was dependent on SFK activity and the protease ADAM-17. Moreover, this shedding of TGF-alpha was critical for rhTRAIL-induced activation of EGFR. In support of this, SFK inhibitors and small interfering RNAs targeting ADAM-17 and TGF-alpha also sensitized CRC cells to rhTRAIL-mediated apoptosis. Taken together, our findings indicate that both rhTRAIL-sensitive and resistant CRC cells respond to rhTRAIL treatment by activating an EGFR/HER2-mediated survival response and that these cells can be sensitized to rhTRAIL using EGFR/HER2-targeted therapies. Furthermore, this acute response to rhTRAIL is regulated by SFK-mediated and ADAM-17-mediated shedding of TGF-alpha, such that targeting SFKs or inhibiting ADAM-17, in combination with rhTRAIL, may enhance the response of CRC tumors to rhTRAIL. [Cancer Res 2008;68(20):8312-21]

El significado de la prosopopeya de las Leyes en el "Critón" de Platon

El objeto de este trabajo es realizar un estudio iusfilosófico sobre la aparición de las Leyes (nómoi) personificadas de Atenas en el Critón de Platón. La prosopopeya de las Leyes resulta ser un aspecto central para poder comprender la obra, ya que éstas entablan un diálogo imaginario con Sócrates en el cual instalan diversos argumentos filosóficos para fundamentar la autoridad de la pólis. A los fines de identificar el valor argumentativo de este recurso en la obra, analizaré el significado del nómos en la Atenas del siglo V a. C. y la naturaleza de las Leyes en el contexto general del diálogo. Se busca demostrar la importancia que tienen aquéllas para explicar la decisión de Sócrates de beber la cicuta.

Accumulation of knowledge and accumulation of capital in early ‘theories’ of growth and development

This paper argues that prior to Adam Smith economic progress was largely conceived as being based on the accumulation of knowledge. The development by Turgot and Smith of a concept of capital that subsumed other factors contributing to development led their followers to focus on capital to the neglect of the independent role of knowledge. The paper demonstrates that this paradigmatic shift was identified and challenged by Bentham, Hodgskin and Rae who argued for the independent role of innovation but without lasting impact. © The Author 2009. Published by Oxford University Press on behalf of the Cambridge Political Economy Society. All rights reserved.