Pain management in LDs needs to be improved to ensure safety while providing better pain control

with zero tolerance for respiratory events. Disclosures: Deforolimus Robert S. Brown – Consulting: Salix, Janssen, Vertex; Grant/Research Support: Gilead, Merck, Vertex, AbbVie, Salix, Janssen, BI; Speaking and Teaching: Genentech, Gilead, Merck The following people have nothing to disclose: Daniela Ladner, Robert A. Fisher, Elizabeth A. Pomfret, Mary Ann Simpson, Amna Daud, Kathryn Waitzman, John R. Joseph, Donna Woods tumors express less CAR protein than normal liver. Conclusions: TCP rescues mice exposed to SFSS after extended liver resections and liver transplantation. Molecular changes induced by CAR activation act on downstream targets of pathways promoting cell cycle progression (Foxm1b) and uncoupling from organ size control (miR375/YAP) to override the regenerative deficits of marginal liver remnants. Reduced CAR expression in tumors suggests a subset of HCCs may not respond to CAR activation, pointing to a patient group amenable to this treatment. Studies in humanized mice and on ex vivo human liver tissue will address the clinical potential of CAR activation by enhancing liver regeneration after extended resections for primarily unresectable liver tumors. Disclosures: check details The following people have nothing to disclose: Christoph Tschuor, Ekaterina Kachaylo,

Perparim Limani, Amedeo Columbano, Andrea Schlegel, Jae Hwi Jang, Dimitri A. Raptis, Emmanuel Melloul, Yinghua Tian, Rolf Graf, Bostjan Humar, Pierre A. Clavien Background: Resectability selleck chemicals llc of liver tumors is limited since patients left with marginal liver remnants are at risk for developing the Small-for-Size Syndrome (SFSS). SFSS is characterized by an insufficient recovery due to delayed regeneration. Strategies are needed to overcome regenerative limits, rendering large liver tumors resectable. Activation of the constitutive androstane receptor (CAR), a nuclear receptor expressed in the liver, induces liver hyperplasia. We investigated the potential of the CAR agonist TCPOBOP (TCP) to ameliorate experimental SFSS, thereby enabling extended oncological liver resections.

Methods: The effects of TCP on liver regeneration were assessed in four murine models: 68% hepatectomy (Hx) (control), 86% Hx (model of SFSS), 91% Hx (lethal model), and 30% liver transplantation (SFSS transplantation model) in BL6 and CAR-/- mice. Serum bilirubin, ALKP, and albumin served as measures of SFSS-like features. Proliferation-associated molecules, including Foxm1b, p21 and miR375/YAP-dependent pathways were analysed. Functional relevance of the molecules was assessed via siRNA knockdown. Humanized mice and human tissue microarrays (TMA) served for evaluation of the translational potential. Results: Reduced survival in SFSS is associated with deficient regeneration due to deregulation of Foxm1b and YAP/miR375 pathways along with p21 upregulation.