Hepatic Cell News Volume 3.42 | Nov 8 2019

TOP STORY

Epigenetic Remodeling Licences Adult Cholangiocytes for Organoid Formation and Liver Regeneration

Investigators describe that ductal cells undergo a transient, genome-wide, remodeling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licenses differentiated ductal cells to initiate organoids and activated the regenerative program through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signaling. [Nat Cell Biol] Abstract

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Reproducing Human and Cross-Species Drug Toxicities Using a Liver-Chip

Researchers applied micro-engineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. [Sci Transl Med] Abstract | Press Release

Hepatocytes Delete Regulatory T Cells by Enclysis, a CD4⁺ T Cell Engulfment Process

Enclysis is selective for CD4⁺ but not CD8⁺ cells, independent of antigen-specific activation, and occurs in human hepatocytes in vitro, ex vivo, and in vivo. Intercellular adhesion molecule 1 facilitated T cell early adhesion and internalization, whereas hepatocytes formed membrane lamellipodia or blebs to mediate engulfment. [Cell Rep] Full Article | Graphical Abstract

A Novel AKR1C3 Specific Prodrug TH3424 with Potent Anti-Tumor Activity in Liver Cancer

The prodrug TH3424, which releases a DNA alkylating reagent upon reduction by AKR1C3, was developed to target tumors with overexpression of AKR1C3. TH3424 showed specific killing of liver cancer cells with AKR1C3 overexpression both in vitro and in vivo. [Clin Pharmacol Ther] Abstract

Hepatocyte-Derived Exosomal MiR-194 Activates PMVECs and Promotes Angiogenesis in Hepatopulmonary Syndrome

Researchers found that hepatopulmonary syndrome rat serum exosomes (HEs) significantly enhance PMVEC proliferation, migration, and tube formation. They further identified miR-194 was the most notably increased miRNA in HEs compared to serum exosomes. [Cell Death Dis] Full Article

miR-223 Overexpression Inhibits Doxorubicin-Induced Autophagy by Targeting FOXO3a and Reverses Chemoresistance in Hepatocellular Carcinoma Cells

The potential role of miR-223 in modulating doxorubicin-induced autophagy and sensitivity were evaluated in four transfected human hepatic cell carcinoma (HCC) cell lines, and the in vivo relevance was assessed using a mouse xenograft model of HCC. The authors found that the well-defined miR-223 was expressed at low levels in doxorubicin treated HCC cells and that miR-223 overexpression inhibited the doxorubicin-induced autophagy that contributed to chemoresistance. [Cell Death Dis] Full Article

Disruption of the Mouse Shmt2 Gene Confers Embryonic Anemia via Fetal Liver-Specific Metabolomic Disorders

The authors elucidated the potential mechanisms by which the disruption of the gene serine hydroxymethyltransferase 2 (SHMT2) induces mitochondrial respiration defects and embryonic anemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. [Sci Rep] Full Article

LncRNA GABPB1-AS1 and GABPB1 Regulate Oxidative Stress during Erastin-Induced Ferroptosis in HepG2 Hepatocellular Carcinoma Cells

Scientists demonstrated that erastin upregulated the lncRNA GABPB1-AS1, which downregulated GABPB1 protein levels by blocking GABPB1 translation, leading to the downregulation of the gene encoding Peroxiredoxin-5 peroxidase and the eventual suppression of the cellular antioxidant capacity. Such effects critically inhibited the cellular antioxidant capacity and cell viability. [Sci Rep] Full Article

Potent Repression of C-Reactive Protein (CRP) Expression by the JAK1/2 Inhibitor Ruxolitinib in Inflammatory Human Hepatocytes

Ruxolitinib was found to fully inhibit lipopolysaccharide (LPS)-induced CRP secretion and mRNA expression, at concentrations achievable in human blood. It similarly repressed CRP up-regulation due to several Toll-like receptor agonists or pro-inflammatory cytokines and counteracted LPS-mediated induction of serum amyloid A, fibrinogen, haptoglobin and serpin. [Inflamm Res] Abstract

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Emerging Agents and Regimens for Hepatocellular Carcinoma

The combination of an anti-PD-1 antibody and an anti-angiogenesis agent has shown more potent anti-tumor effects in early phase clinical trials and is now the hot-spot in clinical studies. Furthermore, these agents are investigated in combination treatment with surgery or other loco-regional therapies in patients with early or intermediate-stage hepatocellular carcinoma. [J Hematol Oncol] Full Article

Recreating Tumor Complexity in a Dish: Organoid Models to Study Liver Cancer Cells and Their Extracellular Environment

Primary liver cancer-derived organoids have opened up new avenues due to their patient-specificity, self-organizing ability and potential recapitulation of many of the tumor properties. Organoids are solely of epithelial origin, but incorporation into co-culture models can enable the investigation of the cellular component of the tumor micro-environment. [Cancers] Abstract | Download Full Article

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Celsion Reports Unanimous Independent Data Monitoring Committee Recommendation to Continue the Phase III OPTIMA Study of ThermoDox^® in Primary Liver Cancer

Celsion Corporation announced that the independent Data Monitoring Committee has unanimously recommended the OPTIMA Study continue according to protocol. The recommendation was based on a review of blinded safety and data integrity from 556 patients enrolled in the company’s multinational, double-blind, placebo-controlled pivotal Phase III study with ThermoDox^® plus radiofrequency ablation in patients with hepatocellular carcinoma, or primary liver cancer. [Celsion Corporation] Press Release

AB Science Granted Authorization to Initiate Phase III Confirmatory Study of Masitinib in Indolent Systemic Mastocytosis

AB Science SA announced that it has been authorized by the French Medicine Agency, ANSM, to initiate the Phase III confirmatory study evaluating masitinib in indolent systemic mastocytosis. This study is a multicenter, randomized, double blind, placebo-controlled, Phase III study to compare the efficacy and safety of masitinib dose titration up to 6 mg/kg/day with that of placebo in treatment of patients with severe indolent systemic mastocytosis, unresponsive to optimal symptomatic treatment. [AB Science SA] Press Release

Spring Bank Announces Interim Top-Line Results from the First Cohort of the Phase II Trial Evaluating Low-Dose Inarigivir Plus Vemlidy^® in Chronic Hepatitis B Patients

Spring Bank Pharmaceuticals, Inc. announced interim top-line results at 12 weeks from the first cohort of the ongoing Phase II trial evaluating the safety, efficacy and pharmacodynamics of escalating doses of the investigational compound inarigivir co-administered with Gilead Sciences’ Vemlidy^® for the treatment of chronic hepatitis B virus infection. [Spring Bank Pharmaceuticals, Inc.] Press Release

CohBar Completes Phase Ia and Initiates Phase Ib Stage of Clinical Trial of CB4211 Under Development for NASH and Obesity

CohBar, Inc. announced the completion of the Phase Ia stage of the company’s ongoing Phase Ia/Ib study evaluating the safety, tolerability, and activity of CB4211, and the initiation of recruitment for the Phase Ib stage. CB4211 is under development as a potential treatment for nonalcoholic steatohepatitis (NASH) and obesity, and is the first therapeutic candidate based on a mitochondrial-derived peptide to enter clinical testing. [CohBar, Inc.] Press Release

Texas Voters Approve Second Life for State Cancer Funding Agency

On 5 November, Texas voters approved (64% to 36%) a ballot measure to extend the life of its pioneering state cancer research funding agency, CPRIT, by doubling, to $6 billion, the amount of bonds that can be issued to support the agency. [ScienceInsider] Editorial

Report Sketches Vision for UK Research After Brexit

An eagerly awaited external report, commissioned by the government, lays out research priorities and options if those relationships with Europe are severed. It calls for increased spending on R&D nationwide, a new research fellowship program, and larger chunks of money for universities to quickly target research opportunities. [ScienceInsider] Editorial

NEW Liver Cancer: Advances in Science and Clinical Management
December 13, 2019
New York, New York, United States

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NEW Postdoctoral Fellow – Drug-Induced Liver Injury (Johnson & Johnson)

Postdoctoral Researcher – Liver Disease Treatment (University of Southern Denmark)

Postdoctoral Researcher – Personalized Medicine (Mayo Clinic Center for Individualized Medicine)

Postdoctoral Researcher – Liver Plasticity (University of Southern Denmark)

Postdoctoral Scientist – RAS Cancer Biology (Genetech, Inc.)

Assistant Professor – Liver Research (The University of Hong Kong)

Research Associate – Pluripotent Stem Cells in Liver Development (The Wellcome Institute)

Research Scientist – Fibrosis (Gilead Sciences, Inc.)

Postdoctoral Researcher – Liver Cell-Cell Interactions (Flanders Institute for Biotechnology)

Principal Researcher – Systems Disease Biology (Boehringer Ingelheim)

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