Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development.
Cancer Cell 30(2):308 (2016)
Hepatocellular carcinoma (HCC) represents a classic example of inflammation-linked cancer. To characterize the role of the immune system in hepatic injury and tumor development, we comparatively studied the extent of liver disease and hepatocarcinogenesis in immunocompromised versus immunocompet...
Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.
Journal of Hepatology 65(2):325 (2016)
Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability ...
A universal system to select gene-modified hepatocytes in vivo.
Science Translational Medicine 8(342):342ra79 (2016)
Many genetic and acquired liver disorders are amenable to gene and/or cell therapy. However, the efficiencies of cell engraftment and stable genetic modification are low and often subtherapeutic. In particular, targeted gene modifications from homologous recombination are rare events. These obst...
Methylation Status of the Chromosome Arm 19q MicroRNA Cluster in Sporadic and Androgenetic-Biparental Mosaicism-Associated Hepatic Mesenchymal Hamartoma.
Pediatric and Developmental Pathology 18(3):218 (2015)
The C19MC gene on chromosome band 19q13.4 encodes a cluster of 46 microRNAs; those microRNAs are normally only expressed from the paternal allele and in the placenta. Placental expression correlates with selective demethylation of the paternal C19MC promoter, in contrast to methylation of both m...
An infant with a diagnostically challenging hepatic teratoma, hypofibrinogenemia, and adrenal neuroblastoma: case report.
Pediatric and Developmental Pathology 18(3):251 (2015)
Teratomas of the liver are exceedingly rare. Neuroblastoma is the most common, extracranial solid tumor of infancy. We describe the case of a 2-month-old, female infant who presented with an abdominal mass arising in the right lobe of the liver, and a severe coagulopathy, which necessitated cryo...
Pediatric and Developmental Pathology 18(6):530 (2015)
Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.
Journal of Pediatric Gastroenterology and Nutri... 59(1):17 (2014)
Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastroint...
Angiosarcoma successfully treated with liver transplantation and sirolimus.
Pediatric Transplantation 18(4):E114 (2014)
Malignant liver tumors represent approximately 1% of malignancies in children. HA is a high-grade tumor of endothelial cells that is even more rare in the pediatric population. HA has a limited response to chemotherapy, radiation and resection with universal tumor recurrence with LT and nearly 1...
Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors.
Human Gene Therapy 24(8):761 (2013)
Helper-dependent adenoviral vectors (HDAd) have been shown to mediate a considerably longer duration of transgene expression than first-generation adenoviral vectors. We have previously shown that transgene expression from HDAd-transduced hepatocytes can persist at high levels for up to 2.6 year...
Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer.
Hepatology 57(3):1098 (2013)
One of the early events in the development of liver cancer is a neutralization of tumor suppressor proteins Rb, p53, hepatocyte nuclear factor 4α (HNF4α), and CCAAT/enhancer binding protein (C/EBP) α. The elimination of these proteins is mediated by a small subunit of proteasome, gankyrin, which...
Balloon catheter delivery of helper-dependent adenoviral vector results in sustained, therapeutic hFIX expression in rhesus macaques.
Molecular Therapy 20(10):1863 (2012)
Hemophilia B is an excellent candidate for gene therapy because low levels of factor IX (FIX) (≥1%) result in clinically significant improvement of the bleeding diathesis. Helper-dependent adenoviral (HDAd) vectors can mediate long-term transgene expression without chronic toxicity. To determine...
Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy.
Clinical Gastroenterology and Hepatology 9(4):357 (2011)
Pathologists participating in the National Institutes of Health-sponsored Biliary Atresia Research Consortium (BARC) developed and then evaluated a standardized system for histologic reporting of liver biopsies from infants with cholestasis.
A set of 97 anonymous liver biopsy samples was sent to...
Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption.
Cell Metabolism 13(1):35 (2011)
All organisms have devised strategies to counteract energy depletion and promote fitness for survival. We show here that cellular energy depletion puts into play a surprising strategy that leads to absorption of exogenous fuel for energy repletion. The energy-depletion-sensing kinase AMPK binds,...
Epigenetic silencing of beta-spectrin, a TGF-beta signaling/scaffolding protein in a human cancer stem cell disorder: Beckwith-Wiedemann syndrome.
Journal of Biological Chemistry 285(46):36112 (2010)
Hereditary cancer syndromes provide powerful insights into dysfunctional signaling pathways that lead to sporadic cancers. Beckwith-Wiedemann syndrome (BWS) is a hereditary human cancer stem cell syndrome currently linked to deregulated imprinting at chromosome 11p15 and uniparental disomy. Howe...
Chromosomal integration of adenoviral vector DNA in vivo.
Journal of Virology 84(19):9987 (2010)
So far there has been no report of any clinical or preclinical evidence for chromosomal vector integration following adenovirus (Ad) vector-mediated gene transfer in vivo. We used liver gene transfer with high-capacity Ad vectors in the FAH(Deltaexon5) mouse model to analyze homologous and heter...
Epigenetic changes play critical role in age-associated dysfunctions of the liver.
Aging Cell 9(5):895 (2010)
CCAAT/Enhancer Binding Proteins family proteins are important regulators of liver functions. Here, we show the critical role of C/EBPα-mediated chromatin remodeling in the age-associated dysfunctions of the liver and in the maintenance of physiological homeostasis. Because ph-S193 isoform of C/E...
Therapeutic liver reconstitution with murine cells isolated long after death.
Gastroenterology 139(3):1019 (2010)
Due to the shortage of donor organs, many patients needing liver transplantation cannot receive one. For some liver diseases, hepatocyte transplantation could be a viable alternative, but donor cells currently are procured from the same sources as whole organs, and thus the supply is severely li...
Elimination of C/EBPalpha through the ubiquitin-proteasome system promotes the development of liver cancer in mice.
Journal of Clinical Investigation 120(7):2549 (2010)
Despite significant advancements in our understanding of cancer development, the molecular mechanisms that underlie the formation of liver cancer remain largely unknown. C/EBPalpha is a transcription factor that regulates liver quiescence. Phosphorylation of C/EBPalpha at serine 193 (S193-ph) is...
Reprogramming the posttranslational code of SRC-3 confers a switch in mammalian systems biology.
PNAS 107(24):11122 (2010)
Here we demonstrate that reprogramming steroid receptor coactivator-3 (SRC-3) function by changing its posttranslational modification (PTM) code drastically influences systems biology. These findings support the physiological importance of PTMs in directing in vivo functions of a master coregula...
Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease.
Science 322(5906):1395 (2008)
Hepatic glucose production is critical for basal brain function and survival when dietary glucose is unavailable. Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serves as a terminal gatekeeper for hepatic glucose release into the plasma. Mutations in G6Pase result in V...