Indeed, by attenuating adenosine uptake, and concomitant increases of spontaneously formed extracellular adenosine levels, endogenously generated levels of extracellular

adenosine could become sufficient to trigger immunosuppressive adenosine receptor signaling events within the inflamed liver tissue microenvironments in vivo.[16, 17] In other words, the molecular concept is that pathophysiologically induced elevations of extracellular adenosine can provide better liver protection, if they are elevated over a longer time period, which can be achieved by adenosine uptake inhibitors, or by genetically targeting individual adenosine transporters. Therefore, we combined Pexidartinib ic50 studies of ENT transcript and protein levels in biopsy samples obtained from patients undergoing liver transplantation with pharmacologic and genetic studies in a previously described model of murine partial hepatic ischemia and reperfusion.[8, 9, 18] These studies demonstrated a selective role for ENT1 in elevating hepatic adenosine levels and conveying liver protection from ischemia and reperfusion injury. Liver samples were obtained from patients undergoing orthotopic

liver transplantation (Supporting Table 1). Liver biopsies (I) were taken at the conclusion of cold ischemia time (CIT) during GS-1101 cell line back table preparation of the cadaveric liver allograft (Fig. 1A). A second biopsy (R) was taken immediately prior to closure of the abdomen following

drain placement (Fig. 1A). Importantly, total reperfusion time is defined as the time from portal vein perfusion to abdominal closure at the conclusion of the procedure. All animal protocols were in accordance with the University of Colorado, Denver guidelines. Enzalutamide ic50 Ent1 on the C57BL/6J strain were generated, validated, and characterized as described.[19] Ent2-deficient mice were obtained from Taconic Farms. Conditional hypoxia-inducible factor 1 alpha (HIF1α)loxP/loxP Albumin Cre+ mice were obtained by crossing HIF1αloxP/loxP with Albumin Cre+ mice (Jackson Laboratory). In all control experiments, age-, gender-, and weight-matched littermate controls were used. In an effort to avoid mesenteric congestion, a murine model of partial liver ischemia was employed using a hanging-weight system as described.[18] Ent1 and Ent2 transcript levels were measured by reverse-transcription polymerase chain reaction (RT-PCR) (iCycler, Bio-Rad Laboratories) as described.[20] In both human and mouse tissues Ent1 and Ent2 protein content was determined at different timepoints as described.[20] Liver preparation was performed as described in detail by Wei and colleagues.[21] IFN-γ, IL-6 (R&D Systems), and neutrophil sequestration was quantified according to the manufacturer’s instructions. Livers were removed and immediately snap-frozen after 45 minutes of liver ischemia without reperfusion. Adenosine was measured as described.

Disclosures: Guruprasad P. Aithal – Advisory Committees or Review Panels: Aegerion Pharmaceuticals, Abbott, UK, LtD, Falk Pharma; Consulting: Biogen Idec, OTSUKA PHARMACEUTICAL EUROPE LTD, Basilea Pharmaceutica; Speaking and Teaching: Lilly Indra Neil Guha – AP24534 solubility dmso Grant/Research Support: Pfizer, Conatus The following people have nothing to disclose: David J. Harman, Emilie A. Wilkes, Martin W. James, Stephen D. Ryder Purpose of the study: To measure the disparities in access to liver transplantation across UNOS region 1 using Geographic Information Systems (GIS) software. Methods:

Based on OPTN data, the number of transplant registrations (candidates) and transplants by zip code in November 2012 was obtained. ZIP code listing rate was calculated as the number of candidates performed divided by the ZIP code population. Transplant listing rates by zip code were mapped using ArcGIS software. A choropleth (color-coded) map was generated to display the geographic distribution of 2012 listing rates. The Spatial Scan Statistic (SatScan software) was used to identify geographic areas (clusters) with rates significantly higher or lower than the rest of the region. Spatial

regression analysis was Talazoparib in vitro performed to identify geographic and demographic factors in transplant listing rates. Factors tested included distance from the nearest transplant center, city over 50, 000 and population density. Results: A map of UNOS Region 1 transplant listing rates by zip code is shown in Figure 1 below. The map shows disparities in organ access to organ allocation across the region. SPTLC1 Distance from the nearest transplant facility was the only significant factor in transplant listing rates identified by

spatial regression. More importantly, SatScan cluster analysis identified areas with significantly high (red outlines) or low listing rates (purple outlines) that were not solely a function of distance to the transplant center. Conclusion: GIS represents a new approach to evaluat ing access to liver transplantation within a region, which can be used to guide efforts in alleviating disparities. Disclosures: The following people have nothing to disclose: Rony Ghaoui, Jane Garb Background and Aims: The addition of telaprevir to pegylatedinterferon and ribavirin has improved sustained virologic response (SVR) rates for genotype 1 HCV, but has also increased adverse events (AEs) and costs. We estimated the total management cost of triple therapy in a real-world setting. Methods: Pre-treatment, on-treatment, and post-treatment costs were calculated using 2010 US estimates from Medicare, Agency for Healthcare Research and Quality(AHRQ, ), and Red Book WAC, adjusting for inflation. Resource utilization was based on standard practices and data on 134 patients who initiated telaprevir use at Mount Sinai Medical Center (5/201112/2011).

Its expression in tumors correlates with tumor grade and malignancy. The recapitulation Target Selective Inhibitor Library concentration of the normal developmental process of epithelial-mesenchymal transition (EMT) contributes to tumor cell plasticity. This process is also a characteristic of metastatic cells and vasculogenic mimicry. In the

present study we report functional and structural interactions between Bcl-2 and the EMT-regulating transcription factor Twist1 and the relationship with metastasis and vascular mimicry. Bcl-2 and Twist1 are coexpressed under hypoxia conditions. The Bcl-2 can bind to Twist1 in vivo and in vitro. This interaction involves basic helix-loop-helix DNA binding domain within Twist1 and through two separate domains within Bcl-2 protein. Formation of the Bcl-2/Twist1 complex facilitates the nuclear transport of Twist1 and leads to transcriptional activation of wide ranges of genes that can increase the tumor cell plasticity, metastasis, and vasculogenic mimicry. Finally, nuclear expression of Bcl-2 and Twist1 is correlated with poor survival of these patients in a cohort of 97 cases of human hepatocellular carcinoma. Conclusion: The results describe

a novel function of Bcl-2 in EMT induction, provide insight into tumor progression, and implicate the Bcl-2/Twist1 complex as a potential target for developing chemotherapeutics. (HEPATOLOGY 2011;) Bcl-2 is the founding member of a family of proteins that play important roles during development and disease. Bcl-2 family members exhibit either pro- or antiapoptotic behavior. They include six classical antiapoptotic proteins and three preapoptosis proteins that show canonical Bcl-2 homology Tanespimycin research buy domains (BH1-4). These domains interact to form functional hetero- or homodimers.1 Bcl-2

members interact to exert fine control over cell death. The classically defined interaction between Bcl-2 and Bax proteins at mitochondrial membrane voltage-dependent anion channels results in the release of Ca2+ and cytochrome C. Consequently, a cascade of cell death processes is initiated and leads to apoptosis and necrosis.2, 3 In addition, Bcl-2 family members also interact with other proteins to modify and regulate cellular metabolism, immune response, and autophagy.4-8 Taken together, these observations suggest that the Bcl-2 family operates by way Vildagliptin of diverse mechanisms to regulate cell growth and death. In many malignant tumors, Bcl-2 importantly localizes at the endoplasmic reticulum, nucleus, and other nonmitochondrial sites. The antiapoptotic action of Bcl-2 is also associated with poor prognosis.9, 10 Nevertheless, the functional link of Bcl-2 to the mechanisms of tumor progression remain unclear. Epithelial-mesenchymal transition (EMT) is a normal developmental process wherein phenotypic plasticity alters the properties of cell adhesion and migration. EMT has recently gained considerable attention as a mechanism leading to tumor metastasis.

1C and data not shown). ZEB treatment increased the frequency of SP-derived tumor

spheres relative to non-SP in all cell lines (Fig. 1D,E). Similar effects were observed using fluorescence-based colony-forming assays (data not shown). Thus, epigenetic modulation amplified sphere-forming and clonogenic potential of SP cells, suggesting relative enrichment of CSCs within the SP fraction. In support of this, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed up-regulation of CSCs (ABCG2, CD133, GPC3, and c-KIT) and stemness (OCT4, NANOG, SOX2) associated genes in ZEB-treated SP cells as compared with non-SP cells, albeit to a different degree (Supporting Fig. 1). Limiting

dilution analysis confirmed a higher frequency of tumor-initiating cells within SP fractions from Huh7, WRL68, and KMCH compared with non-SP cells at 8 weeks after subcutaneous selleck transplantation into NOD/SCID mice, although by 10 weeks the differences became less pronounced in untreated cells (Table 1). ZEB remarkably increased the number of tumor-initiating cells in SP fractions (seven-fold, P = 6.12 × 10−5) (Table 1). As few as 100 ZEB-treated SP cells produced tumors, whereas 1,000 non-SP Selleckchem Obeticholic Acid cells gave rise to fewer (KMCH, WRL68) or no tumors (Huh7) (Supporting Table 2). Selected animals injected with non-SP cells from Huh7 and KMCH were followed over 20 weeks after transplantation without tumor growth. Limiting dilution analysis performed at 10 weeks revealed a 14.8-fold increase in tumor-initiating capacity of SP cells compared with non-SP (P = 5.45 × 10−6). Histologically, tumors derived from SP and non-SP cells were similar, and recapitulated features of the parental tumors Orotidine 5′-phosphate decarboxylase regardless of ZEB treatment (Supporting Fig. 2). In addition, ZEB-treated SP cells were analyzed for self-renewal potential. Cells were re-isolated from Huh7 and KMCH

xenograft-tumors established from 100 SP-ZEB cells, propagated in short-term cultures, treated with ZEB for 3 days, and FACS-sorted for SP and non-SP fractions before retransplanting into secondary recipients. In both cell lines, SP cells not only sustained tumorigenic potential in serial transplantations but also increased progressively in frequency (Fig. 2A,B). KMCH secondary tumors developed with a shorter latency. Conversely, the corresponding non-SP cells showed either a dramatic increase in tumor latency and a decrease in tumor incidence (KMCH) or no tumor growth at all (Huh7) (Fig. 2C,D). Together, these data show that ZEB significantly enhanced the tumorigenic potential of SP cells while reducing it in non-SP cells. To provide evidence that the CSC-enriching effect of ZEB was due to inhibition of DNMT-1, we determined the protein levels of DNMT-1, as well as DNMT-3a and DNMT-3b, both in SP and non-SP cells.

Expression of PPAR-α target genes did not change in cells transfected with mutant IRF9 plasmids (Supporting Fig. 6B). When we further overexpressed IRF9 specifically in the liver, we observed up-regulation of PPAR-α target genes in livers of both diet-induced and genetically obese mice (Supporting Fig. 6C,D). www.selleckchem.com/products/DMXAA(ASA404).html Taken together, these results suggest that IRF9 activates PPAR-α target gene expression by interacting with PPAR-α. As expected, primary mouse hepatocytes trasfected with PPAR-α had markedly higher levels of its target genes

than those transfected with GFP controls (Supporting Fig. 7A). To determine the sufficiency of PPAR-α in mediating the metabolic functions of IRF9, we overexpressed PPAR-α specifically in livers of WT mice and IRF9 KO mice. We injected mice with PPAR-α adenovirus through

the jugular vein. Four weeks later, PPAR-α and its target genes were significant increased in the liver (Supporting Fig. 7B,C). After 24 weeks of HFD feeding, IRF9 KO mice displayed aggravated hepatic steatosis, IR, and inflammation, as described earlier. However, after PPAR-α was overexpressed, IRF9 KO mice displayed reduced liver weight (Fig. 7A). H&E and Oil Red O staining BIBW2992 order confirmed less hepatic lipid accumulation (Fig. 7B). Lower hepatic lipid content and preserved liver function indicated attenuated steatohepatitis (Supporting Fig. 7D,E). Fasting serum glucose and insulin levels and the HOMA-IR index in PPAR-α-overexpressed

IRF9 KO mice were similar to those of GFP adenovirus-infected controls (Fig. 7C). Similar results were obtained with IPGTTs and IPITTs (Fig. 7D and 7E). Insulin signaling was also up-regulated upon PPAR-α overexpression (Fig. 7F). Measurement of inflammation- related genes by real-time PCR indicated a shifting macrophage population from M1 to M2 (Supporting Fig. 7F,G). Thus, we demonstrated that liver-specific PPAR-α overexpression rescues insulin sensitivity and ameliorates hepatic steatosis and inflammation in IRF9 Mannose-binding protein-associated serine protease KO mice. IRF9 KO mice have a relatively normal physical appearance, but are susceptible to virus infection because of the crucial role of IRF9 in mediating type I IFN responses.[21, 29] Therefore, most studies on IRF9 have been focused on its involvement in innate immunity and oncogenesis.[11] However, whether IRF9 is involved in the regulation of metabolism is unclear. In the present study, we, for the first time, demonstrated a critical role for IRF9 in hepatic lipid homeostasis. IRF9 expression was lower in livers of both diet-induced and genetic obesity models. On an HFD, IRF9 KO mice exhibited more-severe obesity, hepatic steatosis, IR, and inflammation. When IRF9 was specifically overexpressed in the liver, diet-induced and genetically obese mice displayed attenuated hepatic steatosis, IR, and inflammation, which indicate that IRF9 has an antidiabetic role.

3 ± 4.1 U/L [WT], 266.3 ± 27 U/L [GNMT-KO], 61.8 ± 9.5 U/L [NAM-treated GNMT-KO]; alanine aminotransferase, 24.5 ± 3 U/L [WT], 177.8 ± 10.4 U/L [GNMT-KO], selleck compound 35.6 ± 1.4 U/L [NAM-treated GNMT-KO]; NAM-treated GNMT-KO versus untreated GNMT-KO for both aminotransferases [n = 5; P < 0.05]). Furthermore, histological examination revealed that the livers of 3-month-old GNMT-KO mice treated with NAM lacked signs of steatosis or fibrosis. As reported,6 3-month-old GNMT-KO mice exhibited extensive accumulation of liver fat (hematoxylin-eosin

staining) and fibrosis (Sirius Red staining and α-SMA immunohistochemical analysis) (Fig. 2). In contrast, NAM-treated GNMT-KO mice showed no signs of steatosis or fibrosis (Fig. 2). Liver histology was normal in NAM-treated WT animals. Consistent with the high SAM levels, the liver expression of methionine adenosyltransferase 2A (MAT2A), a gene whose expression is inhibited by SAM,16 was markedly reduced in GNMT-KO mice but was normal in NAM-treated KO animals (Fig. 3E). Similarly, the livers of 3-month-old GNMT-KO mice showed marked alterations in the expression of critical genes involved in lipid metabolism (fatty acid translocase CD36 [CD36], adipose differentiation-related protein [ADFP],

peroxisome proliferator-activated receptor-α [PPARα], and PPARγ), oxidative stress and inflammation (cytochrome P4502E1 [CYP2E1], cytochrome P45039A1 [CYP39A1], cytochrome P4504A10 [CYP4A10], cytochrome P4504A14 [CYP4A14], uncoupling protein-2 [UCP2], PPARγ, interleukin-6 [IL6], and inducible nitric oxide synthase [iNOS]), and extracellular click here matrix regulation (pro-α1-collagen type I [COL1A1], TIMP tissue inhibitor of metalloproteinase-1 [TIMP-1], α-SMA). Furthermore, the treatment of GNMT-KO mice with NAM prevented completely (CD36, ADFP, CYP4A10, CYP4A14, CYP39A1, UCP2, IL6, iNOS, COL1A1, α-SMA) or largely (PPARα, PPARγ, CYP2E1, TIMP-1) the abnormal expression of these genes in the liver (Fig. 3A-E). NAM administration had no significant effect on the expression of these genes in WT mice (Fig. 3A-E),

indicating that the effect of NAM on gene expression in GNMT-KO mice is mediated by its capacity to reduce hepatic SAM content. The hepatic expression of sirtuin-1 (SIRT1), a NAD+-dependent protein deacetylase PRKACG that is an important regulator of energy metabolism modulating many aspects of glucose and lipid homeostasis,17 was similar in WT and GNMT-KO mice and was not modified by NAM administration (Fig. 3A). Finally, the livers of 3-month-old GNMT-KO mice showed marked apoptosis as demonstrated by poly(ADP-ribose) polymerase (PARP) cleavage and TUNEL immunostaining, which was also prevented in NAM-treated GNMT-KO animals (Fig. 4A,B). We have reported the existence of global DNA hypermethylation in the livers of GNMT-KO mice.6 Global DNA methylation, assayed both by the quantification of 5mC groups (Fig. 5A) and by the measurement of the number of unmethylated CpG sites (Fig.

Unfortunately, the intravenous mode of administration will ultimately limit the use of SIL in all-oral DAA combinations. The HCV p7 protein is a viroporin1 critical for the release of infectious virions. When its cation channel activity is pharmacologically blocked, virus production is significantly reduced.47 A number of HCV p7 inhibitors have been identified, such as amantadine, rimantadine,

long-alkylated iminosugar, and amiloride derivatives. GDC-0449 in vivo The in vitro sensitivity to HCV to these drugs is highly genotype-dependent, presumably because of the high sequence variability associated with the p7 genetic region. To date, none of these p7-directed agents has demonstrated any significant clinical activity. Another way to potentially limit acute as well as chronic HCV infection would be to prevent virus entry into the noninfected selleck cells. Ferroquine (FQ), a novel antimalarial currently undergoing clinical evaluation, has been reported recently to inhibit HCV entry in cell culture at the membrane fusion step.48 FQ-resistant HCV was selected with a single resistance-conferring mutation in the E1 envelope protein (S327A). FQ may

therefore represent a novel direct antiviral agent ready to be combined with other DAAs for all-oral therapy. Although there are still some concerns regarding how many of the anti-HCV drugs currently in development will actually hit the market, it is clear we are on the verge of a revolution in Ribociclib manufacturer the treatment of chronic hepatitis C. This revolution, at least for the hard-to-cure HCV genotypes 1 and 4, is likely going to consist of a two- to three-step process that will ultimately lead us to the holy grail of an all-oral, pan-genotypic, IFN-free therapy. The first step forward in anti-HCV therapy will be the introduction of a second-wave

PI to be used in combination with PEG-IFN/RBV. This will be followed by NS5A and NS5B inhibitors to be used with PEG-IFN/RBV in triple therapy regimens or in quadruple therapy regimens in combination with a second-wave PI. Finally, several all-oral combinations will enter the market, likely becoming the standard of care first therapeutic option for all HCV genotypes. One of the main limitations of the first-wave PIs BOC and TVR is tolerability when they are used with PEG-IFN/RBV. This stems both from the induction of specific side effects as well as from the rather impractical assumption mode that both compounds require.49 These first-generation, first-wave PIs need to be taken every 7 to 9 hours with food, causing a significant pill burden that may lead to suboptimal adherence and suboptimal efficacy. First-generation, second-wave PIs such as simeprevir, faldaprevir, and ritonavir-boosted DNV will be able to bypass this issue, as they are being studied in phase 3 trials with once-daily dosing.

Additionally, liver TAG, cholesterol ester and DAG content were significantly decreased in CD36L mice, particularly in lipid species comprising of monounsaturated FAs. CD36L mice on normal diet showed no significant difference in liver lipids compared to controls. However, in CD36L mice on both diets, serum insulin levels were lower and whole body insulin sensitivity was enhanced compared to controls suggesting that there might be metabolic benefits to CD36 ablation independent of liver lipid content. These data suggests that CD36 is important for regulating hepatic lipid content under conditions of elevated circulating FAs. Furthermore the metabolic benefits derived from inhibiting hepatic

CD36 function suggest that Cilomilast research buy it could be a novel therapeutic target for the treatment of hepatic steatosis and the associated inflammation and insulin resistance. Disclosures: Derek Erion – Employment: Pfizer Ethan J. Weiss – Grant/Research

Support: Pfizer The following people have nothing to disclose: Camella Wilson, Jennifer L. Tran, Maria Febbraio Background: Mallory-Denk bodies which represent hepatic inclusions are GW-572016 datasheet observed in diverse chronic liver diseases such as alcoholic and non-alcoholic steatohepatitis and hepatocellular neoplasms; therefore, it is suggested that dysfunction of autophagy is involved in the progression of these liver diseases. Previously, we reported that hepatic steatosis disturbs autophagic proteolysis via suppression of both autophagic induction and lysosomal function. It was shown that lysosomal acidification modulated by the proton-pumping vacuolar ATPase is required for autophagosomal degradative capacity. We investigated the relationship between acidification of autolysosome and vATPase expression in hepatic these steatosis. Methods: Hepatocytes were isolated from male C57BL/C mice (control) and KKAy mice (obese model). Isolated hepatocytes were transfected with GFP-LC3 plasmid and loaded with 10 LysoTracker Red (LTR) for visualization of acidic autolysosomes. LTR-loaded autolysosomes were counted by using laser scanning confocal microscopy. Expression of Lysosomal-associated membrane protein (LAMP)-2

was detected by Western blot analysis. Expression of vacuolar ATPase subunits ATP6v1a, ATP6v1b, ATP6v1d in isolated lysosomes was evaluated by Western blot analysis. Realtime PCR was performed to evaluate mRNA expression of these vacuolar ATPase subunits. Results: More than 80% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, rate of LTR-stained autolysosomes was suppressed in hepatocytes from KKAy mice significantly (45.5 ± 5.82 %). Incubation with rapa-mycin increased in the rate of LTR-positive autolysosomes to 82.2 ± 3.09 % in hepatocytes from KKAy mice. Expression of LAMP-2 was higher in hepatocytes from KKAy mice than control. Treatment with rapamycin enhanced LAMP-2 expression in hepatocytes from both control and KKAy mice.

7A). As described elsewhere,[15,

16, 25] ConA-driven hepatitis was accompanied by up-regulation of interferon-gamma (IFN-γ) and IL-17A RNA transcripts and protein (Supporting Fig. 7). Pretreatment of mice with IL-25 significantly reduced serum levels of both transaminases (Fig. 7A), attenuated histological damage (Fig. 7B), and decreased RNA and protein expression of IFN-γ and IL-17A (Supporting Fig. 7). Induction of liver damage by ConA was associated with infiltration of the liver by GR1+ and CD11b+ cells, and the presence of both these cell types was further increased in hepatitic mice treated with IL-25 (Fig. 7C). FCM analysis revealed that the percentage of GR1/CD11b+ double positive cells was higher in IL-25/ConA-treated mice, compared to mice treated with ConA alone (Fig. 7D). Despite ConA inducing massive damage of the

liver leading to the formation of large areas of necrosis, mice can survive more than KU-60019 price 3 days. This allowed us to test the therapeutic effect of IL-25 by injecting mice 6 hours after ConA administration, a time that was sufficient to cause liver damage (as shown in Fig. 7A,B). Mice treated with ConA and receiving IL-25 showed significantly reduced levels of transaminases, minimal macroscopic lesions, and less necrotic areas (Fig. 7E,F), as compared to mice treated with ConA and receiving PBS. In a final set of studies, we analyzed IL-25 protein expression in paraffin-embedded selleck products liver sections of patients with FH and controls by confocal IF. IL-25-positive cells were clearly evident in control livers, particularly in hepatocytes, SDHB but staining was markedly reduced in liver sections from patients with FH (Fig. 8), thus confirming that acute hepatocyte damage is associated with decreased production of IL-25. IL-25 (also known as IL-17E), a

member of the IL-17 cytokine gene family, is made by several immune and nonimmune cell types and plays a critical role in expansion of Th2 cell responses and negative regulation of both Th1 and Th17 immunity.[8, 9, 13, 14] Deregulation of IL-25 production has been described in many inflammatory disorders and is supposed to contribute to the progression of the pathology.[8, 9, 13, 14] For example, high IL-25 sustains inflammation in airways of patients with asthma, whereas defective IL-25 synthesis helps perpetuate chronic inflammation in the gut of patients with inflammatory bowel disease.[9, 26] This later finding fits with the demonstration that IL-25 delivers negative signals to macrophages and DCs with the downstream effect of suppressing detrimental inflammatory responses in the gut.[9] The data in the present study expand on these data and indicate that IL-25 is produced in both human and mouse liver. Despite its ability to amplify Th2 cell programs, IL-25 does not polarize Th cell responses along the Th2 pathway.[8, 26] Therefore, it is not surprising that expression of IL-25 in the uninjured liver was associated with no induction of Th2 cytokines.

Infrequent asymptomatic ALT elevations were transient, typically occurred by week 1-2 and declined without study drug interruption. Concurrent systemic estrogen use was the main risk factor for ALT elevations. Hemoglobin declines to <10g/dL were infrequent, related to RBV use, and manageable by RBV dose reduction. Less than 0.5% of patients received erythropoietin or red blood cell transfusion. Conclusions: The combination of ABT-450/r/ombitasvir and dasabu-vir with or without RBV is well tolerated in a broad and diverse patient drug discovery population. Disclosures: Michael W. Fried – Consulting: Genentech, Merck, Abbvie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Grant/Research

Support: Genentech, Merck, AbbVie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Patent Held/Filed: HCCPlex Adrian M. Di Bisceglie – Grant/Research Support: Genentech, Gilead, AbbVie, BMS John M. Vierling – Advisory Committees or Review Panels: Abbvie, Bristol-Mey-ers-Squibb, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise, HepQuant, Salix; Grant/Research Ganetespib cost Support: Abbvie, Bristol-Meyers-Squibb, Eisai, Gilead, Hyperion, Intercept, Janssen, Novartis, Merck, Sundise, Ocera, Mochida; Speaking and Teaching: GALA, Chronic Liver Disease Foundation, ViralEd Edward J. Gane – Advisory Committees or Review Panels: Novira, AbbVie, Novartis, Gilead Sciences, Janssen Cilag, Vertex, Achillion, Tekmira, Merck, Ide-nix; Speaking

and Teaching: AbbVie, Novartis, Gilead Sciences, Janssen Cilag Frederik Nevens – Consulting: CAF, Intercept, Gore, BMS, Abbvie, Novartis, MSD, Eumedica, Janssen; Grant/Research Support: Ipsen, Roche, MSD, Astellas Simone I. Strasser – Advisory Committees or Review Panels: Janssen, AbbVie, Roche Products Australia, MSD, Bristol-Myers Squibb,

Histone demethylase Gilead, Norgine, Bayer Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb, MSD, Roche Products Australia, Gilead, Janssen Ola Weiland – Advisory Committees or Review Panels: MSD, BMS, Janssen, Medivir, Gilead, AbbVie; Grant/Research Support, MSD, Roche, BMS; Speaking and Teaching: Novartis, Janssen, Roche, Gilead, AbbVie, Medivir Sandra S. Lovell – Employment: AbbVie Barbara Da Silva-Tillmann – Employment: AbbVie Nancy Shulman – Employment: Abbvie Naoky Tsai – Advisory Committees or Review Panels: BMS, Gilead, AbbVie; Grant/Research Support: BMS, Gilead, AbbVie, Janssen, Beckman; Speaking and Teaching: BMS, Gilead, AbbVie, Janssen, Roche, Merck David R. Nelson – Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen The following people have nothing to disclose: Sorin Rugina Background Ledipasvir (LDV), a potent HCV NS5A inhibitor, is under regulatory review for the treatment of chronic HCV infection as a fixed-dose combination tablet with sofosbuvir.