- Genomic Analysis Revealed New Oncogenic Signatures inTP53-Mutant Hepatocellular Carcinoma. [Journal Article]
- FGFront Genet 2018; 9:2
- TheTP53gene is the most commonly mutated gene in human cancers and mutations inTP53have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer ...
TheTP53gene is the most commonly mutated gene in human cancers and mutations inTP53have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum ofTP53mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures inTP53-mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found thatTP53somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinctTP53-mutant subsets, three of which were defined byCTNNB1mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred withTP53mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T>C substitutions, was prevalent in HCCs with wild-typeTP53or with missenseTP53mutations, but not in HCCs with deleteriousTP53mutations. Finally, whereas patients with HCCs harboring deleteriousTP53mutations had worse overall and disease-free survival than patients withTP53-wild-type HCCs, patients with HCCs harboring missenseTP53mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity amongTP53-mutant HCCs in studies of biomarkers and molecular characterization of HCCs.
- Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis. [Journal Article]
- TJTohoku J Exp Med 2018; 244(2):123-131
- Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Its histological characteristics, such as progressive intrahepatic bile duct destruction, cholestasis, and liver cirrhosis, are caused ...
Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Its histological characteristics, such as progressive intrahepatic bile duct destruction, cholestasis, and liver cirrhosis, are caused by the body's autoimmune disorders. Interleukin (IL)-35 has two subunits (p35 and Ebi3) and is a member of the IL-12 family of heterodimeric cytokines. IL-35 has immunosuppressive functions and plays an important role in many autoimmune diseases. In this study, we compared plasma levels of IL-35 and relative mRNA expression levels of p35 and Ebi3 in peripheral blood mononuclear cells (PBMCs) from 70 PBC patients and 70 healthy individuals. The results showed that the relative expression levels of Ebi3 mRNA were lower in PBMCs from PBC patients than in PBMCs from healthy individuals, whereas the levels of p35 mRNA were similar in both groups. Plasma IL-35 concentrations were lower in patients with PBC than in healthy individuals. Plasma levels were higher in PBC patients at an advanced stage compared to patients at an early stage. Variable plasma levels with different stages were also found in transforming growth factor beta (TGF-β), which is mainly produced by regulatory T cells (Tregs). IL-35 and TGF-β levels were positively correlated with each other, and IL-35 was capable of promoting the inhibitory functions of Tregs in PBC patients at both the early and late stages of disease. Lower plasma IL-35 levels were accompanied by higher levels of typical clinical parameters, such as alkaline phosphatase, or of proinflammatory cytokines, such as interferon-gamma (IFN-γ), in PBC patients (P < 0.05 for each). We propose that IL-35 may be involved in the pathogenesis of PBC and could be a potential biomarker for diagnosing this disease.
- Percutaneous transhepatic vs. endoscopic retrograde biliary drainage for suspected malignant hilar obstruction: study protocol for a randomized controlled trial. [Journal Article]
- TTrials 2018 Feb 14; 19(1):108
- CONCLUSIONS: The INTERCPT trial is designed to determine whether PTBD or ERC is the better initial approach when managing a patient with suspected MHO, a common clinical dilemma that has never been investigated in a randomized trial.
- Pediatric Intestinal Failure-Associated Liver Disease: Challenges in Identifying Clinically Relevant Biomarkers. [Journal Article]
- JJJPEN J Parenter Enteral Nutr 2018; 42(2):455-462
- CONCLUSIONS: Numerous challenges made it difficult to apply the DILI criteria to children with IFALD. Direct bilirubin, fractionated ALP, and perhaps GGT may be more suitable. Given its complex etiology and the age-based differences due to hepatic immaturity and growth, a more suitable composite marker needs to be developed to assess IFALD in this population.
- Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A. [Journal Article]
- CSCold Spring Harb Perspect Med 2018 Feb 12
- Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute l...
Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (<1%), intensive care and urgent decision on liver transplantation are required. Liver injury during hepatitis A is not directly caused by HAV but is known to be caused by immune-mediated mechanisms. In this review, the natural history and clinical manifestations of hepatitis A are described. In addition, mechanisms of immunopathogenesis in hepatitis A are discussed.
- Transcriptome analysis to assess the cholestatic hepatotoxicity induced by Polygoni Multiflori Radix: Up-regulation of key enzymes of cholesterol and bile acid biosynthesis. [Journal Article]
- JPJ Proteomics 2018 Feb 10; 177:40-47
- CONCLUSIONS: To the best of our knowledge, this is the first transcriptome analysis to highlight the main molecular changes occurring in rats chronic exposed to PMR. We have identified 39 specific differentially expressed genes (DEGs) that were present in various comparisons. A total of 14 of these altered gene transcripts were associated with cholesterol biosynthesis. Another factor of great importance in our opinion seemed to be the enhancement of bile acid (BA) biosynthesis, which were closely linked to cholesterol biosynthesis or metabolism. Our findings suggested that the disturbance on balance of BA formation and elimination might lead to a BA overload in hepatocytes, thereby resulting in liver injury.
- The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. [Journal Article]
- UEUnited European Gastroenterol J 2018; 6(1):112-122
- CONCLUSIONS: Patients with PSC-IBD had distinct microbiota and microbiota-stool bile acid correlations as compared with inflammatory bowel disease. Whether these changes are associated with, or may predispose to, an increased risk of colorectal neoplasia needs to be further clarified.
- Open-label study of ademetionine for the treatment of intrahepatic cholestasis associated with alcoholic liver disease. [Journal Article]
- MGMinerva Gastroenterol Dietol 2018 Feb 08
- CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.
- Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility. [Journal Article]
- AJAm J Hum Genet 2018 Feb 01
- Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three fam...
Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
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- Protective effects of yangonin from an edible botanical Kava against lithocholic acid-induced cholestasis and hepatotoxicity. [Journal Article]
- EJEur J Pharmacol 2018 Feb 07; 824:64-71
- Accumulation of toxic bile acids in liver could cause cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of yangonin, a product isolated from an...
Accumulation of toxic bile acids in liver could cause cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of yangonin, a product isolated from an edible botanical Kava against lithocholic acid (LCA)-induced cholestasis, and further to elucidate the involvement of farnesoid X receptor (FXR) in the anticholestatic effect using in vivo and in vitro experiments. The cholestatic liver injury model was established by intraperitoneal injections of LCA in C57BL/6 mice. Serum biomarkers and H&E staining were used to identify the amelioration of cholestasis after yangonin treatment. Mice hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying yangonin hepatoprotection. The results indicated that yangonin promoted bile acid efflux and reduced hepatic uptake via an induction in FXR-target genes Bsep, Mrp2 expression and an inhibition in Ntcp, all of which are responsible for bile acid transport. Furthermore, yangonin reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1, which are involved in bile acid synthesis and metabolism. In addition, yangonin suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α and IL-1β. In vitro evidences showed that the changes in transporters and enzymes induced by yangonin were abrogated when FXR was silenced. In conclusions, yangonin produces protective effect against LCA-induced hepatotoxity and cholestasis due to FXR-mediated regulation. Yangonin may be an effective approach for the prevention against cholestatic liver diseases.