Interspecies transcriptomic comparison identifies a potential porto-sinusoidal vascular disorder rat model suitable for in vivo drug testing.

Background: Porto-sinusoidal vascular disorder (PSVD) involves a group of rare vascular liver diseases of unknown aetiology that may lead to the development of portal hypertension and its life-threatening complications. Its pathophysiology is not well understood, and animal models described to date do not fully recapitulate human disease.

Methods: We developed three different PSVD rat models by either immunosensitization (repetitive intraportal LPS or intramuscular spleen extract injections) or toxic (Selfox: combination of FOLFOX and a selenium-enriched diet) treatment and characterized them at haemodynamic, histological, biochemical and transcriptional levels.

Lack of endothelial autophagy does not impair liver regeneration after partial hepatectomy in mice.

Liver sinusoidal endothelial cells (LSEC) are key elements in regulating the liver response to injury and regeneration. While endothelial autophagy is essential to protect endothelial cells from injury-induced oxidative stress and fibrosis, its role in liver regeneration has not been elucidated. This study was intended to investigate the role of endothelial autophagy in liver regeneration in the context of partial hepatectomy (PHx).

Hepatocellular Carcinoma in Mongolia Delineates Unique Molecular Traits and a Mutational Signature Associated with Environmental Agents.

Purpose: Mongolia has the world's highest incidence of hepatocellular carcinoma (HCC), with ∼100 cases/100,000 inhabitants, although the reasons for this have not been thoroughly delineated.

Experimental Design: We performed a molecular characterization of Mongolian (n = 192) compared with Western (n = 187) HCCs by RNA sequencing and whole-exome sequencing to unveil distinct genomic and transcriptomic features associated with environmental factors in this population.

Results: Mongolian patients were younger, with higher female prevalence, and with predominantly HBV-HDV coinfection etiology.

The Pathophysiology of Portal Vein Thrombosis in Cirrhosis: Getting Deeper into Virchow's Triad.

Portal vein thrombosis (PVT) is a common complication among patients with cirrhosis. However, its pathophysiology is not well established and there are currently very few predictive factors, none of which are actually useful, from a clinical perspective. The contribution of each of the vertices of Virchow's triad, e.

Spermidine Supplementation Protects the Liver Endothelium from Liver Damage in Mice.

Chronic liver diseases are multifactorial and the need to develop effective therapies is high. Recent studies have shown the potential of ameliorating liver disease progression through protection of the liver endothelium. Polyamine spermidine (SPD) is a caloric restriction mimetic with autophagy-enhancing properties capable of prolonging lifespan and with a proven beneficial effect in cardiovascular disease in mice and humans.

Impact of lifestyle interventions targeting physical exercise and caloric intake on cirrhosis regression in rats.

In patients, advanced cirrhosis only regresses partially once the etiological agent is withdrawn. Animal models for advanced cirrhosis regression are missing. Lifestyle interventions (LIs) have been shown to improve steatosis, inflammation, fibrosis, and portal pressure (PP) in liver disease.

Predicting portal thrombosis in cirrhosis: A prospective study of clinical, ultrasonographic and hemostatic factors.

Background & Aims: Portal vein thrombosis (PVT) is a relatively frequent event in patients with cirrhosis. While different risk factors for PVT have been reported, such as decreased portal blood flow velocity (PBFV) and parameters related with severity of portal hypertension, these are based on retrospective studies assessing only a discrete number of parameters. The aim of the current study was to evaluate the incidence and risks factors for non-tumoral PVT development in a large prospective cohort of patients with cirrhosis.

Autoimmune biomarkers in porto-sinusoidal vascular disease: Potential role in its diagnosis and pathophysiology.

Background And Aims: Porto-sinusoidal vascular disease (PSVD) is a rare disease that requires excluding cirrhosis and other causes of portal hypertension for its diagnosis because it lacks a specific diagnostical test. Although it has been occasionally associated with autoimmune diseases, the pathophysiology of PSVD remains unknown. The aim of this study was to evaluate the potential role of autoimmunity in the pathophysiology and diagnosis of PSVD.

Co-expression gene network analysis reveals novel regulatory pathways involved in porto-sinusoidal vascular disease.

Background & Aims: Porto-sinusoidal vascular disease (PSVD) is a rare vascular liver disease of unknown etiology that causes portal hypertension. It usually affects young individuals and shortens live expectancy. The deregulated pathways involved in PSVD development are unknown and therefore we lack curative treatments.

Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury.

Background & Aims: Endothelial dysfunction plays an essential role in liver injury, yet the phenotypic regulation of liver sinusoidal endothelial cells (LSECs) remains unknown. Autophagy is an endogenous protective system whose loss could undermine LSEC integrity and phenotype. The aim of our study was to investigate the role of autophagy in the regulation of endothelial dysfunction and the impact of its manipulation during liver injury.

Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma.

Background & Aims: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in hepatocellular carcinoma (HCC) and study their intra- and inter-tumor distribution in advanced lesions.

Methods: A total of 151 samples representing the multistep process of hepatocarcinogenesis were analyzed by targeted-sequencing and a single nucleotide polymorphism array.

Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features.

Background & Aims: Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors.

Methods: We analyzed HCC samples from 956 patients.

Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity.

Background & Aims: Mixed hepatocellular cholangiocarcinoma (HCC-CCA) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy.

Methods: Gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 18 patients with mixed HCC-CCA were performed, encompassing the whole histological spectrum of the disease.

Hepatocellular Carcinoma Arising in an HNF-1α-Mutated Adenoma in a 23-Year-Old Woman with Maturity-Onset Diabetes of the Young: A Case Report.

Hepatocyte nuclear factor-1α mutated hepatocellular adenomas (H-HCA) are thought to have no to minimal malignant potential. This report describes a 23-year-old woman with maturity-onset diabetes of the young who developed a 12.5-cm hepatic mass with a radiographically and pathologically distinct 3.

A Systems Approach Identifies Essential FOXO3 Functions at Key Steps of Terminal Erythropoiesis.

Circulating red blood cells (RBCs) are essential for tissue oxygenation and homeostasis. Defective terminal erythropoiesis contributes to decreased generation of RBCs in many disorders. Specifically, ineffective nuclear expulsion (enucleation) during terminal maturation is an obstacle to therapeutic RBC production in vitro.

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression.

Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment.

The exosome complex establishes a barricade to erythroid maturation.

Complex genetic networks control hematopoietic stem cell differentiation into progenitors that give rise to billions of erythrocytes daily. Previously, we described a role for the master regulator of erythropoiesis, GATA-1, in inducing genes encoding components of the autophagy machinery. In this context, the Forkhead transcription factor, Foxo3, amplified GATA-1-mediated transcriptional activation.

FOXO3-mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis.

Ineffective erythropoiesis is observed in many erythroid disorders including β-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3(-/-) erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation.

Chronic β-adrenergic stimulation increases ErbB receptors and cell proliferation in mouse kidney.

Although the sympathetic nervous system is involved in injury caused to the kidney by several stressors such as hypertension or ischemia/reperfusion, little is known about the effect of chronic adrenergic stimulation in the kidneys. Upon injury, however, the kidney possesses a high capacity for tubular cell regeneration and functional recovery. The ErbB1 receptor and its ligands play an essential role in this process.

Expression, localization, and regulation of the neuregulin receptor ErbB3 in mouse heart.

Neuregulins (NRG) belong to the EGF family of growth factors, which are ligands of the ErbB receptors. Their expression in the adult heart is essential, especially when the heart is submitted to cardiotoxic stress such as that produced by anthracyclines. It is considered that ErbB4 is the only NRG receptor expressed by the adult heart.

Heparin-binding EGF-like growth factor in human serum. Association with high blood cholesterol and heart hypertrophy.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) belongs to the EGF family of growth factors which are ligands of the ErbB receptors. Studies in animals suggest the role of HB-EGF in several pathogenic processes such as atherosclerosis and heart hypertrophy. Here, we set up an assay to measure HB-EGF in human serum.

Acute and chronic adrenergic stimulation of submandibular salivary glands. Effects on the endocrine function of epidermal growth factor in mice.

Submandibular salivary glands are the major source of epidermal growth factor (EGF) in mice. Acute secretion of EGF from these glands protects the heart against catecholamine-induced injury. Little is known about chronic adrenergic stimulation of salivary glands and the contribution of accumulated EGF to the adaptive hypertrophic response of the heart to such chronic adrenergic stimulation.

ErbB receptors protect the perfused heart against injury induced by epinephrine combined with low-flow ischemia.

ErbB receptor tyrosine kinases are important in maintaining the long-term structural integrity of the heart and in the induction of hypertrophy. In addition, in vivo activation of ErbB1 by epidermal growth factor (EGF) protects the heart against acute stress-induced damage. We examined here whether the ErbB sytem acutely protects the isolated heart in which stress was induced in vitro by ischemia combined with epinephrine infusion (EPI).