Project description:Liver disease alters the gut microenvironment by liver-gut axis. To investigate the composition and transcriptome changes of various intestinal cell populations in liver cirrhosis, we delineated a single-cell atlas of the colon from mice treated CCl4 for 6 weeks.
Project description:Gene profiling of hepatocytes in early and advanced cirrhotic Rats Two-condition experiment, Advanced cirrhosis vs Control liver, Advanced cirrhosis vs Early cirrhosis. Biological replicates: 5 Advanced cirrhosis, 5 Early cirrhosis, 5 control liver. Each hepatocyte was isolated independently. One replicate per array.
Project description:Cirrhosis, advanced liver disease, affects 2-5 million Americans. While most patients have compensated cirrhosis and may be fairly asymptomatic, many decompensate and experience life-threatening complications such as gastrointestinal bleeding, confusion (hepatic encephalopathy), and ascites, reducing life expectancy from 12 to less than 2 years. Among the patients with compensated cirrhosis, identifying patients at high risk of decompensation is critical to optimize care, reduce morbidity and mortality. This is important to preferentially direct them towards specialty care which cannot be provided to all patients with cirrhosis. We used discovery Top-down Proteomics (TDP) to detect differentially expressed proteoforms (DEPs) in the plasma of patients with cirrhosis with the goal to identify candidate biomarkers of disease progression. 663 DEPs were identified across three stages of cirrhosis (compensated, compensated with portal hypertension, and decompensated), of which 115 derived from proteins enriched in the liver at a transcriptional level and discriminated the progressive stages of cirrhosis. Enrichment analyses demonstrated DEPs are involved in numerous metabolic, oxidative, immunological, and hematological processes known to be impacted by cirrhosis progression. We have preliminarily defined the plasma proteoform signatures of cirrhosis patients, setting the stage for ongoing discovery and validation of biomarkers for early diagnosis, risk stratification, and disease monitoring.
Project description:Cirrhosis and cancers of the upper digestive tract, colorectal and ENT share common risk factors. Liver cirrhosis can change the elimination of cancer drugs.
Precise data on management and outcome of patients with liver cirrhosis undergoing chemotherapy are lacking. Most patients have been excluded from clinical trials evaluating conventional therapies.
The study of tolerance, side effects, and outcome in patients with cirrhosis could help improve chemotherapy management for better tolerance and efficacy.
The main objective is to estimate the frequency of liver cirrhosis among patients evaluated in CPR for ENT, upper digestive or colorectal cancer.
Secondary objective includes the evaluation ofthe impact of cirrhosis on the management of chemotherapy by comparing cirrhotic patients’ outcomes with a control group of matched non-cirrhotic patients.
Project description:Dysregulation of the gut microbiome has been implicated in the progression of nonalcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, stool microbiomes were compared across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles using the Random Forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, AUC). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species may offer universal utility as a non-invasive diagnostic test for cirrhosis.
Project description:One in five heavy drinkers develop alcohol-associated cirrhosis. Metabolism, inflammation, signaling, gut microbiome and genetic variations have all been tied to pathogenesis but alcohol-associated cirrhosis (AC) models in rodents are limited by differences between rodent species and humans in genetic background and bioenergetics. Here, we used iPSC derived hepatocytes (iHLCs) as a tool to understand mechanisms of AC injury, hypothesizing that iHLC’s derived from patients would preserve genetic and bioenergetic differences leading to AC, and as compared to iHLC’s from patients free of liver disease. Bioenergetically, AC iHLCs had lower spare capacity for mitochondrial respiration and produced less ATP. Metabolic capacities of AC iHLC mitochondria for glutamine and fatty acids were reduced. Together with genome wide association (GWAS) studies, these metabolic and histologic profiles of AC derived iHLCs suggest that differences in mitochondrial oxidative phosphorylation and lipid droplet formation predispose to AC.
Project description:This is a pilot project to assess the genomic landscape of liver cirrhosis. Non-cancer cirrhotic liver tissue biospies will undergo LCM to look for clonality across the entire liver and cancer driver mutations. Furthermore this will be compared to previous CASM studies and on normal liver samples.