8 cm adds specificity to the likelihood that the patient has neoplastic disease. Obviously,

recommendations are only meant to guide an “individualized” approach regarding management decisions that must take into account the variety of unique patient factors. We hope this clarifies our recommendations and check details places them in context vis-à-vis the EASL and AASLD guidelines and provides impetus for further investigations on the subject. Gregory Gores M.D., F.A.C.P.*, Keith D. Lindor M.D.*, Nataliya Razumilava M.D.*, * Division of Gastroenterology and Hepatology, Mayo Medical School, Rochester, MN. “
“ATP8B1 deficiency is a severe autosomal recessive liver disease due to mutations in the ATP8B1 gene characterized by a continuous phenotypical spectrum from intermittent (benign recurrent intrahepatic cholestasis; BRIC) to progressive familial intrahepatic cholestasis (PFIC). Current therapeutic options are insufficient and elucidating the molecular consequences of mutations could lead to personalized mutation-specific therapies. We investigated the effect on pre-messenger RNA splicing of 14 ATP8B1 mutations at exon-intron boundaries using an in vitro minigene system. Eleven mutations, mostly associated find more with a PFIC

phenotype, resulted in aberrant splicing and a complete absence of correctly spliced product. In contrast, three mutations led to partially correct splicing and were associated with a BRIC phenotype. These findings indicate an inverse correlation between the level of correctly spliced product and disease severity.

Expression of modified U1 small nuclear RNAs (snRNA) complementary to the splice donor sites strongly improved or completely rescued splicing for several ATP8B1 mutations located at donor, as well as acceptor, splice sites. In one case, we also evaluated exon-specific U1 snRNAs that, by targeting non-conserved intronic selleck kinase inhibitor sequences, might reduce possible off-target events. Although very effective in correcting exon skipping, they also induced retention of the short downstream intron. Conclusion: We systematically characterized the molecular consequences of 14 ATP8B1 mutations at exon-intron boundaries associated with ATP8B1 deficiency and found that the majority resulted in total exon skipping. The amount of correctly spliced product inversely correlated with disease severity. Compensatory modified U1 snRNAs, complementary to mutated donor splice sites, were able to improve exon definition very efficiently and could be a novel therapeutic strategy in ATP8B1 deficiency as well as other genetic diseases. This article is protected by copyright. All rights reserved. “
“The deregulation of microRNAs (miRNAs) plays an important role in human hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in hepatocellular carcinoma (HCC) cells.