Liver transplantation for pediatric genetic and metabolic disorders.

Pediatric genetic and metabolic liver diseases comprise a broad spectrum of conditions and represent the second most common indication for liver transplantation following biliary atresia. The decision to transplant can be challenging and requires consideration of several factors including hepatic involvement, extra-hepatic manifestations, and anticipated post-transplant outcomes. This review examines pediatric genetic and metabolic liver diseases, their pathophysiology, clinical presentation, and the role of liver transplantation.

Germline Genetic Associations for Hepatobiliary Cancers.

Hepatobiliary cancers (HBCs) include hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma, which originate from the liver, bile ducts, and gallbladder, respectively. They are responsible for a substantial burden of cancer-related deaths worldwide. Despite knowledge of risk factors and advancements in therapeutics and surgical interventions, the prognosis for most patients with HBC remains bleak.

Aspirin is associated with a reduced incidence of liver disease in men.

Background: The hepatoprotective effects of aspirin have been observed in individuals with viral hepatitis; however, its impact on the general population remains uncertain. Understanding the association between aspirin use and the development of liver diseases is crucial for optimizing preventive strategies.

Methods: We identified individuals with aspirin use in the UK Biobank and the Penn Medicine Biobank, as well as propensity-score-matched controls.

Development of an Electronic Health Record-Based Clinical Decision Support Tool for Patients With Lynch Syndrome.

Purpose: To develop an electronic health record (EHR)-based clinical decision support (CDS) tool to promote guideline-recommended cancer risk management among patients with Lynch syndrome (LS), an inherited cancer syndrome that confers an increased risk of colorectal and other cancer types.

Materials And Methods: We conducted a cross-sectional study to determine the baseline prevalence and predictors of guideline-recommended colonic surveillance and annual genetics program visits among patients with LS. Multivariable log-binomial regressions estimated prevalence ratios (PRs) of cancer risk management adherence by baseline sociodemographic and clinical characteristics.

Emerging and potential use of CRISPR in human liver disease.

CRISPR is a gene editing tool adapted from naturally occurring defense systems from bacteria. It is a technology that is revolutionizing the interrogation of gene functions in driving liver disease, especially through genetic screens and by facilitating animal knockout and knockin models. It is being used in models of liver disease to identify which genes are critical for liver pathology, especially in genetic liver disease, hepatitis, and in cancer initiation and progression.

Large-scale identification of undiagnosed hepatic steatosis using natural language processing.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports.

Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.

Association of Statin Use With Risk of Liver Disease, Hepatocellular Carcinoma, and Liver-Related Mortality.

Importance: Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed.

Objective: To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population.

Design, Setting, And Participants: This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020.

Comparing telemedicine and in-person gastrointestinal cancer genetic appointment outcomes during the COVID-19 pandemic.

Background: The study purpose is to compare outcomes associated with completion of genetic testing between telemedicine and in-person gastrointestinal cancer risk assessment appointments during the COVID-19 pandemic.

Methods: Data was collected on patients with scheduled appointments between July 2020 and June 2021 in a gastrointestinal cancer risk evaluation program (GI-CREP) that utilized both telemedicine and in-person visits throughout the COVID-19 pandemic, and a survey was administered.

Results: A total of 293 patients had a GI-CREP appointment scheduled and completion rates of in-person versus telemedicine appointments were similar.

Lipid Nanoparticle Delivery of Small Proteins for Potent RAS Inhibition.

Mutated RAS proteins are potent oncogenic drivers and have long been considered "undruggable". While RAS-targeting therapies have recently shown promise, there remains a clinical need for RAS inhibitors with more diverse targets. Small proteins represent a potential new therapeutic option, including K27, a designed ankyrin repeat protein (DARPin) engineered to inhibit RAS.

A Therapeutically Targetable TAZ-TEAD2 Pathway Drives the Growth of Hepatocellular Carcinoma via ANLN and KIF23.

Background & Aims: Despite recent progress, long-term survival remains low for hepatocellular carcinoma (HCC). The most effective HCC therapies target the tumor immune microenvironment (TIME), and there are almost no therapies that directly target tumor cells. Here, we investigated the regulation and function of tumor cell-expressed Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HCC.

MYC and MET cooperatively drive hepatocellular carcinoma with distinct molecular traits and vulnerabilities.

Enhanced activation of the transcription factor MYC and of the receptor tyrosine kinase MET are among the events frequently occurring in hepatocellular carcinoma (HCC). Both genes individually act as drivers of liver cancer initiation and progression. However, their concomitant alteration in HCC has not been explored, nor functionally documented.

Cellular origins of regenerating liver and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the predominant primary cancer arising from the liver and is one of the major causes of cancer-related mortality worldwide. The cellular origin of HCC has been a topic of great interest due to conflicting findings regarding whether it originates in hepatocytes, biliary cells, or facultative stem cells. These cell types all undergo changes during liver injury, and there is controversy about their contribution to regenerative responses in the liver.

Uptake and outcomes of small intestinal and urinary tract cancer surveillance in Lynch syndrome.

Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome associated with increased risk of multiple cancers. While colorectal cancer surveillance decreases mortality in LS and is recommended by guidelines, there is lack of evidence for the efficacy of surveillance for extra-colonic cancers associated with LS, including small intestinal cancer (SIC) and urinary tract cancer (UTC). Given the limited evidence, guidelines do not consistently recommend surveillance for SIC and UTC, and it remains unclear how often individuals will choose to undergo and follow through with extra-colonic surveillance recommendations.

EUS-based Pancreatic Cancer Surveillance in Carriers Without a Family History of Pancreatic Cancer.

Carriers of a pathogenic/likely pathogenic (P/LP) variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)-based PDAC surveillance in carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP carriers who underwent EUS at a tertiary care center.

Multigene Panel Testing in Individuals With Hepatocellular Carcinoma Identifies Pathogenic Germline Variants.

Unlabelled: Hepatocellular carcinoma (HCC) has well-defined environmental risk factors. In addition, epidemiologic studies have suggested hereditary risk factors. The goals of this study were to determine the rate of pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes in patients with HCC, possible enrichment of P/LP variants in particular genes, and potential impact on clinical management.

MRGPRX4 in Cholestatic Pruritus.

Pruritus (itch) is a debilitating symptom in liver diseases with cholestasis, which severely affects patients' quality of life. Limited treatment options are available for cholestatic itch, largely due to the incomplete understanding of the underlying molecular mechanisms. Several factors have been proposed as pruritogens for cholestatic itch, such as bile acids, bilirubin, lysophosphatidic acid, and endogenous opioids.

Aspirin in Hepatocellular Carcinoma.

Preclinical and clinical studies provide evidence for aspirin as a preventative agent for cancer. Compelling direct evidence supports a chemopreventive effect of aspirin in individuals at high risk of developing colorectal cancer due to Lynch syndrome, while indirect evidence indicates that aspirin may reduce the risk of and mortality from sporadic colorectal cancer. There is weaker evidence for a protective effect of aspirin against all cancers taken as a group.

Upper Endoscopic Surveillance in Lynch Syndrome Detects Gastric and Duodenal Adenocarcinomas.

Lynch syndrome is a prevalent hereditary cancer predisposition syndrome. While colorectal cancer is the most common gastrointestinal (GI) cancer in Lynch syndrome, there is also increased risk of gastric and small intestinal cancers. Recommendations for upper GI cancer surveillance in Lynch syndrome vary widely with limited data supporting effectiveness.

Multiple Roles for Hepatitis B and C Viruses and the Host in the Development of Hepatocellular Carcinoma.

Chronic hepatitis B and C viral infections are major risk factors for hepatocellular carcinoma (HCC) in the United States and worldwide. Direct and indirect mechanisms of viral infection lead to the development of HCC. Chronic viral infection leads to inflammation and liver damage, culminating in cirrhosis, the penultimate step in the progression toward HCC.

A High-Content Screen Identifies MicroRNAs That Regulate Liver Repopulation After Injury in Mice.

Background & Aims: Liver regeneration is impaired in mice with hepatocyte-specific deficiencies in microRNA (miRNA) processing, but it is not clear which miRNAs regulate this process. We developed a high-throughput screen to identify miRNAs that regulate hepatocyte repopulation after toxic liver injury using fumarylacetoacetate hydrolase-deficient mice.

Methods: We constructed plasmid pools encoding more than 30,000 tough decoy miRNA inhibitors (hairpin nucleic acids designed to specifically inhibit interactions between miRNAs and their targets) to target hepatocyte miRNAs in a pairwise manner.