Project description:BACKGROUND: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis. METHODS: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years. RESULTS: Fourteen of 47 livers displayed prominent features of inflammation (N=9) or fibrosis (N=5), with the remainder showing similar levels of both simultaneously. Differential profiling of gene expression of the 14 livers displayed a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival. CONCLUSION: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes. Clinical and laboratory data and liver biopies were obtained from 47 infants at diagnosis of biliary atresia and every 3-6 month intervals until 2 years of age as part of a prospective, observational study of the Biliary Atresia Research Consortium. Liver biopsies underwent histological scoring and those specimens classified as inflammation or fibrosis were used to generate a group-specific gene expression profile. The profile was used to assign a molecular stages of inflammation or fibrosis to the entire cohort. Molecular groups were tested for biological plausibility using immunostaining to quantify hepatic inflammatory cells, and quantitative PCR to reproduce the expression of gene groups and the expression of collagen genes. They were also tested for clinical relevance by testing of association with indicators of liver function, complications of disease, and clinical outcome. This dataset is part of the TransQST collection.
Project description:Liver biopsy samples were obtained from 64 infants with biliary atresia at the time of intraoperative cholangiogram. Liver biopsy samples were obtained from 14 age-matched infants with other causes of intrahepatic cholestasis, and from 7 deceased-donor children. GeneChip® Human Gene 1.0 ST Array (Affymetrix, CA) were used to screen mRNAs whose expression was specifically regulated in the livers from patients with biliary atresia. Gene expression profiling: Liver biopsy samples obtained from infantas with other causes of intrahepatic cholestasis were served as diseased control. Liver tissue obtained from deceased-donor children were served as normal control. A molecular signataure of biliary atresia at the time of diagnosis was identified by comparing hepatic gene expression profile from biliary atresia to those from diseased and normal controls. This dataset is part of the TransQST collection.
Project description:BACKGROUND: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis. METHODS: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years. RESULTS: Fourteen of 47 livers displayed prominent features of inflammation (N=9) or fibrosis (N=5), with the remainder showing similar levels of both simultaneously. Differential profiling of gene expression of the 14 livers displayed a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival. CONCLUSION: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes.
Project description:To investigate gene expression profile of human liver MAIT cells from patients with biliary atresia, we isolated human liver MAIT cells from liver tissues of patients with biliary atresia and from adjacent non-tumor liver tissues of hepatoblastoma patients (as control) at the time of diagnosis, and subjected for bulk RNA sequencing.
Project description:We performed single cell 5' RNA sequencing, and B cell receptor and T cell receptor V(D)J sequencing analyses on liver biopsies of nine patients with biliary atresia and three patients with choledochal cyst at diagnosis to generate the liver cell atlas.
Project description:We report label-free quantification of xenobiotic metabolizing enzymes (XME), transporters, redox enzymes, proteases and nucleases in 25 human liver microsomal samples, taken from patients with biliary atresia. Nearly 3500 proteins were identified and quantified. These data can be used in physiologically based pharmacokinetic models to predict appropriate drug doses drugs used in biliary atresia patients.
Project description:We sequenced liver mRNA isolated from biliatresone-treated zebrafish larvae and DMSO-treated controls in order to elucidate the molecular pathways induced by biliatresone, a biliary toxin that is responsible for outbreaks of biliary atresia in Australian liverstock.
Project description:Background & Aims: Age at diagnosis and response to surgery have been correlated with an improved survival with the native liver in children with biliary atresia. However, biological predictors of outcome are largely undefined. We investigated if gene expression profiles at diagnosis predict clinical outcome. Methods: Global gene expression was quantified by RNAseq of liver biopsies from 171 infants with BA at diagnosis and randomly assigned into discovery (N=121), validation (N=50) cohorts and 7 normal controls.