Perturbations in XXXX mutant signaling pathways after drug-induced @entity879 and their reversal during rescue of animals by cell therapy.

@entity32 @entity19 @entity6560 @entity879 @entity409 @entity1578 @entity3174 @entity1215 @entity1129 @entity2155 @entity74 @entity3230
Superior insights into molecular mechanisms of @entity1578 , which are not fully understood, will help strategies for inducing @entity409 . We examined hepatotoxic mechanisms in @entity19 homozygous for the severe combined @entity3230 mutation in the protein kinase, DNA-activated, catalytic polypeptide. @entity19 were treated with @entity1215 , @entity3174 , and @entity6560 . The ensuing @entity879 was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with @entity1578 . We found extensive @entity409 in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, @entity32 , DNA damage-repair, and @entity1129 mutant ( @entity2155 ) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with @entity1578 . @entity74 rapidly reversed, including in hepatic @entity2155 and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that @entity2155 signaling played critical roles in the pathological features of @entity1578 . These studies should help redirect examination of pathophysiologic and therapeutic mechanisms in @entity1578 .
