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464A AASLD ABSTRACTS HEPATOLOGY, October, 2015 ERK1/2 were more robustly activated in RA-primed regenerating livers than controls. Conclusion: Priming mice with RA resulted in a lean microbiota composition and hydrophilic bile acid profile, which are associated with facilitated metabolism and enhanced cell proliferation. Disclosures: The following authors have nothing to disclose: Hui-Xin Liu, Ying Hu, Lili Sheng, Yu-Jui Yvonne Wan 509 Pre-operative plasma glypican-3 levels detected by a novel ELISA system predict the risk of post-operative recurrence in patients with stage I hepatocellular carcinoma Kazuya Ofuji 1,2 , Keigo Saito 1 , Yasunari Nakamoto 2 , Tetsuya Nakatsura 1 ; 1 Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan; 2 Second Department of Internal Medicine, University of Fukui, Fukui, Japan Background: Prognosis of post-operative hepatocellular carcinoma (HCC) patients remains unsatisfactory due to the high risk of recurrence. Glypican-3 (GPC3) is specifically overexpressed in HCC and has been recognized as a novel prognostic factor after curative resection of HCC. Recent <strong>studies</strong> have shown the usefulness of GPC3 as a biomarker for the diagnosis of early HCC. However, the diagnostic value of GPC3 as a predictive marker for recurrence of postoperative early-stage HCC remains unclear. Here, this study was undertaken to evaluate the detection of plasma GPC3 using a novel sandwich enzyme-linked immunosorbent assay (ELISA) system in early-stage HCC patients after surgical resection. Methods: Plasma samples were collected from 25 patients with stage I HCC who underwent for surgical resection between 2008 and 2010. The ELISA system for detection of plasma GPC3 levels was established, by use of a newly-generated anti-GPC3 mouse monoclonal capture antibody and a biotinylated detection antibody and recognized with streptavidin-conjugated horseradish peroxidase. GPC3 expression of surgical specimens was analyzed by immunohistochemical staining. Results: HCC recurrence was observed in 14 cases after surgical resection (51.8%) during follow-up period (median, 738 days). In the immunohistochemical analysis, GPC3 positive rate of resected specimen was 53% (13/23). There was a tendency towards a shorter recurrence-free survival (RFS) in GPC3 positive cases than in GPC3 negative cases (p 0.233). In the ELISA system, the mean ± standard deviation (SD) of plasma GPC3 concentrations was 110.12 ± 37.70 ng/ml in control subjects, and cut-off value was determined to be 132 ng/ml (mean + 1.5 SD). In stage I HCC, the sensitivity and specificity were 40.7% and 92%, respectively. GPC3-positive rate at the time of recurrence was 64.3%. In the recurrence group, pre-operative plasma GPC3 levels were significantly higher than in the non-recurrence group (median, 191.7 ng/ml vs 29.7 ng/ml, p = 0.029). There was a tendency of shorter RFS in the pre-operative plasma GPC3-positive patients group compared with the negative group (median RFS, 769 days vs. not reached, p = 0.147). However, there was no significant difference in overall survival. The recurrence rate of patients with post-operative plasma GPC3 positive was significantly higher than GPC3 negative patients (p = 0.012). Conclusions: We have established a novel ELISA system for detecting plasma GPC3 levels and evaluated the utility of GPC3 as a diagnostic marker of HCC. This study suggests pre-operative plasma GPC3 levels may help in identification of stage I HCC patients at high risk of post-operative recurrence. Disclosures: Tetsuya Nakatsura - Consulting: Ono Pharmaceutical co.Ltd.; Grant/Research Support: Ono Pharmaceutical co.Ltd., MEDINET co.Ltd., Sysmex co. Ltd. The following authors have nothing to disclose: Kazuya Ofuji, Keigo Saito, Yasunari Nakamoto 510 Evaluation of Glyoxylate and Hydroxyproline Metabolic Pathways Through the Use of Dicer-Substrate Small Interfering RNA Nicole Avitahl-Curtis 1 , Benjamin Holmes 1 , Luciano Apponi 2 , Rohan Diwanji 1 , Marita S. Larsson Cohen 2 , Chaitali Dutta 1 , Natalie W. Pursell 1 , Dongyu Chen 2 , Xue Shui 2 , Purva Pandya 2 , Utsav H. Saxena 2 , Martin Koser 2 , Abrams Marc 2 , Weimin Wang 2 , Hank Dudek 2 , Chengjung Lai 1 , Bob D. Brown 2 ; 1 Translational Biology, Dicerna Pharmaceuticals, Inc., Cambridge, MA; 2 Dicerna Pharmaceuticals, Inc., Cambridge, MA Primary Hyperoxaluria (PH) results from genetic mutations which affect glyoxylate metabolism, causing overproduction of oxalate. Three types of Primary Hyperoxaluria have been described to date, and the genetic lesions underlying disease have been identified. PH1, PH2 and PH3 are caused by mutations in the genes, AGXT, GRHPR and HOGA1, respectively, which encode the metabolic enzymes alanine: glyoxylate aminotransferase (AGT), glyoxylate reductase (GRHPR), and 4-hydroxy-2-oxoglutarate adolase (HOGA). The roles of AGT and GRHPR in glyoxylate metabolism have been explored utilizing mouse strains harboring a germline disruption of the Agxt or Grhpr gene. Agxt- and Grhpr-deficient mice develop hyperoxaluria, consistent with the proposed roles of AGT and GRHPR in glyoxylate metabolism. Dicer-substrate siRNAs (DsiR- NAs) are potent and specific RNAi triggers that inhibit the expression of disease-relevant targets at the mRNA level, and are currently in clinical development. In this work, we describe the use of DsiRNAs to silence the expression of Agxt and Grhpr in mice to generate PH1 and PH2 animal models that phenotypically mimic Agxt- and Grhpr-deficient mice. DsiRNA-induced PH disease models were further explored for their utility to identify effective therapeutics. This approach was also used to investigate the dysregulation of the glyoxylate and hydroxyproline metabolic pathways occurring in each type of primary hyperoxaluria. Finally, we describe the utility of siRNA as an efficient and powerful method for generating models of liver disease in rodents and, potentially, other species. Disclosures: Nicole Avitahl-Curtis - Employment: Dicerna Pharmaceuticals, Inc. Benjamin Holmes - Employment: Dicerna Pharmaceuticals; Stock Shareholder: Dicerna Pharmaceuticals Luciano Apponi - Employment: Dicerna Pharmaceuticals Rohan Diwanji - Employment: Dicerna Pharmceuticals; Stock Shareholder: Dicerna Pharmceuticals Chaitali Dutta - Employment: Dicerna Pharmaceuticals Utsav H. Saxena - Employment: Dicerna Pharmaceuticals Martin Koser - Employment: Dicerna Pharmaceuticals Abrams Marc - Employment: Dicerna Pharmaceuticals Hank Dudek - Employment: Dicerna Chengjung Lai - Employment: Dicerna Pharmaceuticals Bob D. Brown - Employment: Dicerna Pharmaceuticals The following authors have nothing to disclose: Marita S. Larsson Cohen, Natalie W. Pursell, Dongyu Chen, Xue Shui, Purva Pandya, Weimin Wang
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 465A 511 Cell-Type-Specific Expression Profile of Repopulating Hepatocytes by Translating Ribosome Affinity Purification (TRAP) Kirk J. Wangensteen 1,2 , Amber W. Wang 2 , Monica Teta-Bissett 2 , Klaus H. Kaestner 2 ; 1 Gastroenterology, University of Pennsylvania, Philadelphia, PA; 2 Genetics, University of Pennsylvania, Philadelphia, PA Understanding the genetic regulation of liver regeneration could help in the development of new treatments for liver disease. Much of the research on liver regeneration has focused on the partial hepatectomy model in rodents; however, the lack of cell necrosis and immune response calls for the development of novel paradigms that recapitulate human liver diseases. Fah - /- mice, a model of hereditary tyrosinemia, are suitable for the study of liver repopulation after injury because repopulating hepatocytes can be genetically traced. We first injected Fah - /- mice with plasmids that co-express Fah and GFP, and found that we could isolate GFP-positive hepatocytes by fluorescence activated cell sorting, but met challenges in isolating pure populations of repopulating hepatocytes in the setting of injury. We then employed a different approach, the Translating Ribosome Affinity Purification (TRAP) system, to isolate mRNA specifically from repopulating hepatocytes. We injected Fah -/- mice with a plasmid that co-expresses Fah and a fusion of GFP and the ribosomal subunit L10a, and then induced liver injury for 1 or 4 weeks. Liver tissue harvested from these mice was immediately lysed and polysomes were extracted. Anti-GFP antibodies were then used to affinity-purify the mRNAs bound to the GFP- L10a fusion protein expressed within repopulating hepatocytes (Figure). No RNA was obtained from wildtype control liver, as expected. We performed high throughput mRNA sequencing (RNA-seq) to identify differentially expressed genes during repopulation as compared to quiescent hepatocytes. Gene ontology analysis showed that the genes were enriched in metabolic pathways and in c-Myc-responsive genes. In conclusion, this represents the first analysis of the differential expression of repopulating hepatocytes in an injury model. Intriguingly, liver repopulation involves differential regulation of metabolic genes, likely to maintain metabolic homeostasis in the setting of widespread liver injury. Bioanalyzer tracings of affinity-purified RNA from mice treated with (Green and Red), or without (Blue) the TRAP vector, illustrating the specificity of the system. 512 In vivo distribution of exosome packaged extracellular miRNA-155 to the liver, hepatocytes and Kupffer cells and its functional effects Shashi Bala 1 , Timea Csak 1 , Fatemah Momen-Heravi 1 , Dora Lippai 1 , Karen Kodys 1 , Donna Catalano 1 , Abhishek Satishchandran 1 , Victor Ambros 2 , Gyongyi Szabo 1 ; 1 Medicine, UMass Medical School, Worcester, MA; 2 Molecular Medicine, UMass Medical School, Worcester, MA Purpose: Circulating miRNAs are gaining increasing interest as new biomarkers of diseases and means of intercellular communication. Previously, we showed induction of miR-155 in the plasma and found that miR-155 was associated with extracellular vesicles (EVs). However, little is known about the half-life and biodistribution of EVs associated miRNAs in vivo. Here, we established an exosome-based miR-155 mimic delivery system to study the biodistribution and half-life of EV associated miR- 155 using a miR-155 knock out (KO) mouse model. Methods: Female wild type (WT) (C57/BL6J) or miR-155 KO mice were used. Exosomes were isolated from murine B cells using filtration method and characterized by electron microscopy, Nanosight and Western blot analyses. Electroporation was used to introduce miR-155 mimic into exosomes. Purified miR-155 or control mimic loaded exosomes were administered intravenously to miR-155 KO mice. Mice were perfused to eliminate blood contamination. The Mann-Whitney test was employed for statistical analysis. Results: Our results indicate that administration of exosomes loaded with miR-155 mimic resulted in a rapid accumulation of miR-155 in the plasma of recipient miR- 155 KO mice with subsequent distribution in the liver, adipose tissue, lung, muscle and kidney (highest to lowest, respectively). At the cellular level, miR-155 was detected in hepatocytes and liver mononuclear cells of recipient miR-155 KO mice in vivo, suggesting successful uptake of exosomal miR-155 by various cell populations of the liver. Functionally, exosomes-mediated restoration of miR-155 in Kupffer cells isolated from miR-155 KO mice resulted in the induction of pro-inflammatory cytokines (MIP2 and MCP1) after LPS challenge in an in vitro co-culture system. To mimic the half-life and distribution of miRNA naturally present in the plasma, we administered (iv) WT plasma (donor) to miR-155 KO (recipient) mice. WT plasma was generated from CpG+LPS treated WT mice and was enriched in miR- 155. Our results indicate detection of donor miR-155 in plasma of recipient miR-155 KO mice and distribution to the liver and adipose tissue. Induction of pro-inflammatory cytokines was found in recipient miR-155 KO mice suggesting some biological activity. In summary, our results demonstrate tissue biodistribution and biologic function of EV-associated miR-155. Conclusion: Exosome packaged miR-155 is readily distributed to the liver in a cell–specific manner resulting in KC activation. These observations will aid in developing new exosome-mediated miRNA delivery and investigating biological function of other extracellular miRNAs in vivo. Disclosures: The following authors have nothing to disclose: Shashi Bala, Timea Csak, Fatemah Momen-Heravi, Dora Lippai, Karen Kodys, Donna Catalano, Abhishek Satishchandran, Victor Ambros, Gyongyi Szabo Disclosures: The following authors have nothing to disclose: Kirk J. Wangensteen, Amber W. Wang, Monica Teta-Bissett, Klaus H. Kaestner
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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