Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=3699 KeY WORDSCHK1, CHK2, EXEL-9844, XL844, S-phase checkpoint, gemcitabine ABBReviATiONS ATRATM and Rad3-related kinase TGI tumor growth inhibition MBP myelin basic protein ABSTRACTChk1 and Chk2 kinases are critically involved in modulating DNA damage checkpoints. In particular, Chk1, a key activator of the S-phase DNA damage response, may be involved in resistance to genotoxic therapies that target DNA synthesis. We studied the in vitro and in vivo effects of EXEL-9844 (XL844), a potent, orally available, and specific inhibitor of Chk1 and Chk2, in combination with gemcitabine. In clonogenic assays using multiple cell lines in vitro, EXEL-9844 had only minor effects as a single agent but substantially enhanced gemcitabine-induced cell killing. Correspondingly, in PANC-1 cells, EXEL-9844 increased gemcitabine-induced H2AX phosphorylation, blocked Cdc25A phosphorylation, and induced premature mitotic entry. In a PANC-1 xenograft model, EXEL-9844 significantly enhanced gemcitabine antitumor activity but had limited effect as a single agent. Together, these data show that cell cycle checkpoint inhibitors may have significant clinical utility in potentiating the activity of gemcitabine.

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Distributional properties of emerging market returns may impact on investor ability and willingness to diversify. Investors may also place greater weighting on downside losses, compared to upside gains. Using individual equities in a range of emerging Asian markets, we investigate the potential contribution of downside risk measures to explain asset pricing in these markets. As realized returns are used as a proxy for expected returns, we separately examine conditional returns in upturn and downturn periods, in order to successfully identify risk and return relationships. Results indicate that co-skewness and downside beta are priced by investors. Further testing confirms a separate premium for each measure, confirming that they capture different aspects of downside risk. Robustness tests indicate that, when combined with other risk measures, both retain their explanatory power. Tests also indicate that co-skewness may be the more robust measure.

This paper tests the volatility spillovers between the Shanghai market and the main developed stock markets abroad, namely New York, Tokyo, London, and Frankfurt, as well as between the Shanghai market and the emerging stock markets, namely Hong Kong, and Korea. The tests cover the period of 11 July 2005-12 July 2007 and 1 August 2007-10 July 2009, since the financial crisis started from July 2007. To account for asymmetries in the volatility transmission mechanism, we have used the GARCH and EGARCH model. The main findings are as follows. First, the degree of the Leverage Effect of the Shanghai market changes in the opposite direction from most of the other sample markets after the financial crisis began in July 2007. This change implies that investors in the Shanghai markets began to pay close attention to bad news. Secondly, reciprocal spillovers exist for some market pairs before the crisis, as the Shanghai A-share market has unidirectional influence on the emerging markets. After the onset of the financial crisis, the stock markets in developed countries have bidirectional influences on each other. The financial crisis brings the developed markets closer together than before, but they do not receive volatility spillover from the Shanghai A-share market. The financial crisis also influences the Asian emerging markets so as to decrease the volatility transmission that comes from the Shanghai A-share market. The Chinese mainland market is still not a vital security market in the world, although it has become the third largest one. Thirdly, the risk-precautionary role of the Shanghai B-share market is not as significant as expected.volatility spillover, financial crisis, GARCH, leverage effect,