The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.

β-Carotene (BC) is the most abundant carotenoid in human diet, almost solely as (all-E)-isomer. Significant amounts of (Z)-isomers of BC are present in processed food as well as in mammalian tissues. Differences are described for the activity of various BC isomers in forming retinal and protecting against cancer and cardiovascular diseases. Eccentric cleavage of BC leads to degradation products such as carotenals. A variety of negative consequences were published for the non-vitamin A active BC metabolites, such as inducing the carcinogenesis of benzo [a]pyrene, impairing mitochondrial function, or increasing CYP activity. To increase the knowledge on the antioxidant activity, a variety of BC isomers and metabolites were tested in various in vitro assays.In the present study, no ferric reducing activity (FRAP assay) was observed for the BC isomers. Between the major BC isomers (all-E, 9Z, and 13Z) no significant differences in bleaching the ABTS•+ (αTEAC assay) or in scavenging peroxyl radicals (ROO • ) generated by thermal degradation of AAPH (using a chemiluminescence assay) were detected. However, the (15Z)-isomer was less active, maybe due to its low stability. The degradation to β-apo-carotenoids increased FRAP activity and ROO • scavenging activity compared to the parent molecule. Dependence on chain length and character of the terminal function was determined in αTEAC assay with following order of increasing activity: β-apo-8'-carotenal < β-apo-8'-carotenoic acid ethyl ester < 6'-methyl-β-apo-6'-carotene-6'-one (citranaxanthin). The results indicate that BC does not lose its antioxidant activity by degradation to long chain breakdown products. OPEN ACCESSMolecules 2011, 16 1056

Cancer-associated stromal fibroblasts (CAFs) are the main cellular constituents of reactive stroma in primary and metastatic cancer. We analyzed phenotypical characteristics of CAFs from human colorectal liver metastases (CLMs) and their role in inflammation and cancer progression. CAFs displayed a vimentin ؉ , ␣-smoothmuscle actin ؉ , and Thy-1 ؉ phenotype similar to resident portal-located liver fibroblasts (LFs). We demon-

Progress during the past 15 years has enabled us to perform pediatric liver transplantation with near perfect patient survival. Advances in posttransplant care of the recipients, technical refinements, standardization of surgery and monitoring, and adequate choice of the donor organ and transplantation technique enable these results, which mark a turning point at which immediate survival after transplantation will be considered the norm. The long-term treatment of the transplanted patient, with the aim of avoiding late graft loss and achieving optimal quality of life, will become the center of debate.

No abstract

No abstract

ObjectiveTo assess and compare the value of split-liver transplantation (SLT) and living-related liver transplantation (LRT). Summary Background DataThe concept of SLT results from the development of reducedsize transplantation. A further development of SLT, the in situ split technique, is derived from LRT, which itself marks the optimized outcome in terms of postoperative graft function and survival. The combination of SLT and LRT has abolished deaths on the waiting list, thus raising the question whether living donor liver transplantation is still necessary. MethodsOutcomes and postoperative liver function of 43 primary LRT patients were compared with those of 49 primary SLT patients (14 ex situ, 35 in situ) with known graft weight performed between April 1996 and December 2000. Survival rates were analyzed using the Kaplan-Meier method. ResultsAfter a median follow-up of 35 months, actual patient survival rates were 82% in the SLT group and 88% in the LRT group. Actual graft survival rates were 76% and 81%, respectively. The incidence of primary nonfunction was 12% in the SLT group and 2.3% in the LRT group. Liver function parameters (prothrombin time, factor V, bilirubin clearance) and surgical complication rates did not differ significantly. In the SLT group, mean cold ischemic time was longer than in the LRT group. Serum values of alanine aminotransferase during the first postoperative week were significantly higher in the SLT group. In the LRT group, there were more grafts with signs of fatty degeneration than in the SLT group. ConclusionsThe short-and long-term outcomes after LRT and SLT did not differ significantly. To avoid the risk for the donor in LRT, SLT represents the first-line therapy in pediatric liver transplantation in countries where cadaveric organs are available. LRT provides a solution for urgent cases in which a cadaveric graft cannot be found in time or if the choice of the optimal time point for transplantation is vital.Living-related liver transplantation (LRT) and split-liver transplantation (SLT) are surgical strategies that have led to a reduction in the pretransplant death rate in children from 20% to nearly 0%.1-5 LRT provides a graft of excellent quality by minimizing the cold ischemic time. Primary nonfunction (PNF) after LRT is rare. In addition, this procedure is elective and thus allows flexibility in choosing the optimal time for transplantation with regard to the recipient's clinical status. Because of these advantages, worldwide long-term results of LRT are equal or even superior to those obtained with cadaveric full-size or reduced-size techniques. The actual 1-year graft and patient survival rate after LRT exceeds 80%.6 -10 The expansion of LRT for adult recipients reflects the great expectations of this procedure despite the higher risks for the donor associated with major hepatectomy.Split-liver transplantation (SLT) is technically comparable to LRT. However, as in other cadaveric procedures, it is theoretically susceptible to potential negative effects resulting from...

The technical development of splitting along Cantlie's line is almost complete with the last challenge being the reduction of biliary complications. The key to success is the choice of adequate deceased donors and recipients. Full-right full-left splitting is safely possible and should be considered as a reasonable instrument to alleviate mortality on the adult waiting list and to reduce the need for adult and adolescent living donation.