Results: 2

1.
Fig. 2

Fig. 2. From: A multipathway phosphoproteomic signaling network model of idiosyncratic drug- and inflammatory cytokine-induced toxicity in human hepatocytes.

Inflammatory cytokine-associated idiosyncratic drug hepatotoxicity as a “network toxicity”. The multipathway modeling approach presented here suggests that an integration of multiple intracellular signaling pathway -- namely the MEK–ERK, mTOR–p70 S6K, Akt, and p38–HSP27 pathways -- activities is necessary for hepatocytes to specify death responses to hepatotoxic drug/cytokine co-treatment conditions. This provides motivation of the network-level consideration of multiple survival, stress, and apoptosis signaling pathways in evaluating the hepatotoxicity mechanisms of context-dependent hepatotoxic drugs. Schematic reproduced from [10].

Benjamin D. Cosgrove, et al. Conf Proc IEEE Eng Med Biol Soc. 2009;2009:5452-5455.
2.
Fig. 1

Fig. 1. From: A multipathway phosphoproteomic signaling network model of idiosyncratic drug- and inflammatory cytokine-induced toxicity in human hepatocytes.

OPLSR modeling demonstrates accurate predictions of drug- and cytokine-induced hepatotoxicity across human hepatocyte donors. Phosphoprotein signaling and response data from two human hepatocyte donors [10]. An OPLSR model was trained on the 66-condition (only a subset of 6 conditions shown here), 6-phosphoprotein CSR data compendium from donor #1. This OPLSR model generated quantitatively accurate predictions of cell death responses in donor #1 and donor #2, even though donor-specific signaling network activation profiles and cell death responses were observed under the same drug/cytokine treatments. Compare clarithromycin (CLA) ± cytokine mix across the two donors. The predictive accuracy of this OPLSR model suggests that a common-effector processing mechanism (f(x) = y) encompassing the integration of the survival and stress signaling network (x) yields quantitatively concerted cell death responses (y) to toxic drug/cytokine conditions exists and is shared between hepatocytes from different human donors. Data and schematic reproduced from [10].

Benjamin D. Cosgrove, et al. Conf Proc IEEE Eng Med Biol Soc. 2009;2009:5452-5455.

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