However, the exact contribution

However, the exact contribution Idelalisib of Shp/Fgf15 to this suppression, and the associated cell-signaling pathway, is unclear. By using novel genetically modified mice, the current study showed that the intestinal Fxr/Fgf15 pathway was critical for suppressing both Cyp7a1 and Cyp8b1 gene expression, but the liver Fxr/Shp pathway was important for suppressing Cyp8b1 gene

expression and had a minor role in suppressing Cyp7a1 gene expression. Furthermore, in vivo administration of Fgf15 protein to mice led to a strong activation of extracellular signal-related kinase (ERK) and, to a smaller degree, Jun N-terminal kinase (JNK) in the liver. In addition, deficiency of either the ERK or JNK pathway in mouse livers reduced the basal, but not the Fgf15-mediated, suppression of Cyp7a1 and Cyp8b1 gene expression. However, deficiency of both ERK and JNK pathways prevented Fgf15-mediated suppression of Cyp7a1 and Cyp8b1 gene expression. Conclusion: The current study clearly elucidates the underlying molecular mechanism of hepatic versus intestinal Fxr in regulating Selleck Copanlisib the expression of genes critical for bile-acid synthesis and hydrophobicity in the liver. (HEPATOLOGY 2012;56:1034–1043)

Bile-acid synthesis is the major mechanism to remove extra cholesterol from the body. Bile acids are required for the absorption of lipids and lipid-soluble vitamins from the intestine. Bile acids activate members of the nuclear receptor superfamily, including farnesoid X receptor (FXR/Fxr; encoded by the NR1H4/Nr1h4 gene), pregnane X receptor, vitamin D receptor,1-5 and a G-protein-coupled receptor, TGR5,6 which is a critical mechanism for maintaining endobiotic and Idoxuridine xenobiotic homeostasis. Two

enzymatic pathways are responsible for bile-acid synthesis in the liver. The classical pathway generates cholic acid (CA), and the alternative pathway produces chenodeoxycholic acid (CDCA). The cholesterol, 7α-hydroxylase, encoded by the cytochrome P450 (CYP) 7A1/7a1 (CYP7A1/Cyp7a1) gene, is the rate-limiting enzyme in the classical pathway. The sterol, 12α-hydroxylase, encoded by the CYP8b1/Cyp8b1 gene, mediates the production of CA, and cholesterol is converted only to CDCA when CYP8b1/Cyp8b1 is deficient. Because CA is less hydrophobic than CDCA, CYP8B1/Cyp8b1 is critical in regulating the hydrophobicity of the bile-acid pool by regulating the CA/CDCA ratio. Bile-acid synthesis is tightly regulated because disruption of bile-acid homeostasis leads to hepatobiliary and intestinal disorders, including cholestasis, gallstone disease, and inflammatory bowel disease, as well as systemic diseases, such as atherosclerosis.7 Feedback suppression of CYP7A1/Cyp7a1 and CYP8B1/Cyp8b1 gene transcription by nuclear receptors and inflammatory cytokines is the most important mechanism in maintaining bile-acid homeostasis in humans and mice.

For mixed-sex samples, data were extracted for the total sample a

For mixed-sex samples, data were extracted for the total sample and also disaggregated

by sex, if possible. If disaggregation by detainee type or sex resulted in a sample size of less than 40, that subsample was excluded. For sources reporting incidence data, the sample size, number of incident HCV cases, person-years of observation, and incidence rate were extracted. For prevalence sources, the sample size, number of anti-HCV positive participants, and prevalence were extracted. Some sources did not report all incidence or prevalence variables; this website in these cases, missing variables were calculated from other reported values (i.e., numerator calculated from reported denominator and prevalence). Study design and sampling variables (geographical region; type of closed setting; prospectively or retrospectively defined cohort; random or convenience sampling; restriction of recruitment to serving inmates or new entrants; year/s of data collection; percentage of sample male and percentage injecting) were extracted in order to explore heterogeneity in reported click here HCV incidence and prevalence. Geographical regions were defined consistent with other recent global epidemiological reviews.[4, 5] Data analyses were conducted in Stata v. 12 (StataCorp, College Station, TX) using the metan[23]

and metareg[24] commands. Given the expected heterogeneity between studies, all meta-analyses were performed using random effects models, which account for interstudy variation. Meta-analyses of HCV incidence were undertaken for sources reporting on general population detainees and detainees with a history of IDU. Heterogeneity was assessed using the I2 statistic, which describes the percentage of variation between studies that is due to heterogeneity rather than chance.[25] Interpretation of I2 was as in Higgins et al.[25] The small number of sources of incidence Cyclooxygenase (COX) data prevented further stratification or meta-regression. Meta-analyses of anti-HCV prevalence were

conducted for general population detainees and detainees with a history of IDU, stratified by geographical region. Heterogeneity was assessed using the I2 statistic, as above, and also explored through meta-regression. Variables used in meta-regressions were cohort ascertainment (prospective versus retrospective); sampling (random versus convenience); detainee status at the time of recruitment (current detainees or current detainees and new entrants versus new entrants only); type of HCV antibody test undertaken (blood/sera versus saliva); mean or median age of the sample; percentage of the sample that was male; percentage of the sample with a history of IDU; and year of completion of data collection.

Liver and spleen sections were stained with Perls’ Prussian blue,

Liver and spleen sections were stained with Perls’ Prussian blue, and hepatic and splenic

iron concentrations were determined. qRT-PCR was used to assess mRNA expression. Results: Wild type and Mdr2-/- mice fed an iron deficient diet developed severe systemic anaemia evidenced by reduced haemoglobin (Hgb) (WT: 67 ± 11; Mdr2-/-: 84 ± 10 g/dL). No significant differences in haematological parameters were seen in wild type or Mdr2-/- mice following 1% carbonyl iron feeding however Mdr2-/- mice had significantly elevated serum iron levels (Mdr2-/-: 463 ± 30 Selleckchem BMS907351 vs WT: 252 ± 14 μg/dL). Mdr2-/- mice fed a control diet had a lower hepatic iron concentration than wild type mice (7.3 ± 1.8 vs 11.2 ± 1.8 μmol Fe/g dry wt, P = 0.08) with redistribution of stainable iron

to the reticuloendothelial this website system. Both wild type and Mdr2-/- mice fed 1% carbonyl iron had significant hepatic iron accumulation however the degree of iron loading was greater in wild type mice (HIC: 57 ± 4 vs 23 ± 2 μmol Fe/g dry wt, P < 0.001). Perls’ Prussian blue staining indicated that iron accumulation was predominantly in reticuloendothelial macrophages in contrast to a hepatocellular distribution seen in wild types. Splenic iron concentration was similar in wild type and Mdr2-/- mice fed a control diet (38.5 ± 3.0 vs 36.7 ± 1.8 μmol Fe/g dry wt) however was significantly higher in Mdr2-/- when compared to wild type mice following 1% carbonyl iron (64.4 ± 2.0 vs 54.3 ± 2.4 μmol Fe/g dry wt). Both hepatic and splenic iron concentration were significantly

lower in wild type and Mdr2-/- mice following an iron deficient diet. Hamp1 mRNA was upregulated in both wild type and Mdr2-/- mice following 1% carbonyl iron feeding and downregulated following an iron deficient diet. Mdr2-/- had 2.8-fold higher Tfr1 expression than wild Mannose-binding protein-associated serine protease type mice when fed a control diet. Tfr1 was further upregulated in both wild type and Mdr2-/- mice following an iron deficient diet. Discussion/Conclusions: The reduced hepatic iron concentration, redistribution of iron to the reticuloendothelial system and resistance to hepatic iron loading when fed a 1% carbonyl iron diet suggests that hepatocyte iron uptake is impaired in Mdr2-/- mice. This work may explain the paucity of iron loading in biliary cirrhosis and suggests that iron homeostasis depends upon an appropriately functioning biliary system. 1. Stuart et al. Hepatology 2000;32(6):1200–1207. 2. Ludwig et al. Gastroenterology 1997;112:882–888.

Disclosures: Tomoaki Kato – Grant/Research Support: Novartis The

Disclosures: Tomoaki Kato – Grant/Research Support: Novartis The following people have nothing to disclose: Andrew Wehrman, Nadia Ovchinsky, Adam Griesemer, Steven J. Lobritto, Mercedes Martinez, Jean C. Emond Background The role

of the PET-CT for clinical staging of HCC, patient selection for liver transplantation, recurrence and prediction of survival is controversial. Aim To evaluate the relation between FDG positivity and recurrence, survival Selleck Ibrutinib and histopathology in living donor liver transplantation. Methods All patients with HCC who underwent living donor liver transplantation (LDLT) between June 2011 and December 2013 were retrospectively analyzed. Imaging data, differantiation, AFP, number of tumors and size, recurrence and survival were reported and correlated to FDG-PET CT scanning. Results There were

62 patients, in a mean age of 54 years and the mean follow-up of all patients was 20.4±11.9 months. The comparison of the results between PET-CT negative and positive patients have shown that the maximum tumor size was larger in PET-CT positive vs negatives (p= 0.04), PET-positive patients had higher mortality and recurrence rates than PET-CT negative patients (p<0.05), figure 1. One-year survival was significantly lower in PET-CT positive patients vs negatives (82% vs 100%, p=0.04), figure 1. However, there were no differences according to AFP, grade and microvasculare invasion (p>0.05). Conclusion The present study has shown that pre-transplant PET-CT positivity is a marker of poor prognosis of HCC and shows lower survival and higher tumor recurrence rates after LDLT. However, especially in pre-transplant setting, its role should be studied with higher Liothyronine Sodium number of patients. Disclosures:

The following people have nothing to disclose: Murat Akyildiz, Arzu Oezcelik, Gokhan Gungor, Nergis Ekmen, Necdet Guler, Onur Yaprak, Yalcin Erdogan, Gulen B. Dogusoy, Murat Dayangac, Yildiray Yuzer, Yaman Tokat Background: Gilbert’s syndrome is a benign inherited status, which is characterized by mild unconjugated hyperbilirubinemia episodes in absence of haemolysis or liver disease. The data in the literature is very limited to answer the question whether is it safe to accept donors with Gilbert’s syndrome for living donor liver transplantation or not. Aim: The aim of our study was to evaluate the safety of donors with Gilbert’s syndrome and to compare the outcome of their recipience with recipience of none-Gilbert’s donors. Methods: Between 2004 and May 2014, 600 living donor liver transplantation were performed in our center. The pre-, intra- and postoperative data of these patients and theirs donors were retrospectively analyzed. Donors with serum bilirubin level greater than 1,2 mg/dL (20,5 ^mol/L) were identified as a Gilbert’s syndrome.

In contrast, only two of seven organ transplant recipients with c

In contrast, only two of seven organ transplant recipients with chronic hepatitis E had detectable HEV-specific CD4+ responses and only one patient showed HEV-specific CD8+ T-cell responses. In addition, the strength (average sum of stimulation index/patient) and breadth (number of recognized pools/patient) of HEV-specific proliferative responses were much lower in viremic patients as compared with both groups of HEV-recovered subjects (Table 3). No HEV-specific proliferative responses were detectable in seronegative healthy subjects. Thus, these data demonstrate a clear

correlation between recovery from HEV infection and detectability of HEV-specific T-cell responses in the peripheral blood, even in patients receiving immunosuppressive medications. High

levels of interferon-gamma (IFN-γ) responses were observed in subjects with resolved hepatitis Ruxolitinib solubility dmso E (transplant or healthy seropositive) to most of the peptide pools, whereas IFN-γ production was not observed in any post-transplant patient with chronic hepatitis E (Fig. 2A). In contrast to IFN-γ levels, interleukin (IL)-10 production was found only in HEV RNA-positive patients (Fig. 2B). IL-17 click here production was detected in all groups with no obvious differences (Fig. 2C). In addition, intracellular cytokine staining for IFN-γ, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-1β was performed in a total of 23 subjects. Strong and significant IFN-γ levels were observed in both CD4+ and CD8+ T-cells of seropositive healthy subjects in response to most of the peptide pools. This was in contrast to transplanted

patients with chronic or resolved HEV infection where intracellular IFN-γ responses were much weaker (Fig. 3A,D). HEV-specific TNF- and MIP-1β secretion of CD8+ T-cells is shown in Fig. 3B,C and did not reveal clear differences between the different groups of patients. We also had the chance to study proliferative T-cell responses longitudinally in transplanted patients with chronic HEV infection before and after HEV clearance. As indicated above, CD4+ and CD8+ T-cell responses were undetectable in PRKACG five and six of seven chronic hepatitis E patients respectively at baseline (Fig. 1c). These weak HEV-specific T-cell responses could be confirmed in three subjects who were tested at a second independent timepoint when the subjects were still HEV-RNA positive (LTxC2; HTxC6; KTxC7). During further follow-up, five patients cleared HEV RNA: two of them by reducing immunosuppressive medication (LTxC1 and KTxC7) and three during treatment with ribavirin (HTxC3, HTxC4, and HTxC5). Of note, multispecific CD4+ and CD8+ T-cell responses against all different HEV peptide pools became detectable rapidly (within 4 weeks) after viral clearance in four of the five patients (Fig. 4). In patient LTxC1 HEV-specific T-cell responses appeared only 8 weeks after viral clearance.

Forty-four rust-infected

Forty-four rust-infected selleck sunflower leaf samples were collected from 25 geographical locations. Freshly produced spores were used to study physiological race differentiation on a set of nine differentials. Race 300 was the most prevalent race observed over all locations with a 59% frequency followed by races 735, 310, 500, 724 and 737. To evaluate hybrids and varieties for resistance screening, spores of race 300 were used to inoculate 65 hybrids, and five open-pollinated varieties selected from breeding programmes and from the seed market. None of the confection hybrids and open-pollinated varieties was immune to race 300. Conversely, among oilseed hybrids, 3% of them showed immunity,

12% highly resistant, 59% resistant and 26% showed susceptible reactions. Open-pollinated varieties were the most click here susceptible to race 300 followed by confection and oilseed sunflower hybrids. Results from this study are projected to assist breeders in selection of hybrids and varieties against prevalent race as our results showed a diversity of resistance levels to race 300. “
“Royal Palms (Roystonea regia) with symptoms such as

severe chlorosis, stunting, collapse of older fronds and general decline were observed in the state of Selangor, Malaysia. Using polymerase chain reaction (PCR) amplification with phytoplasma universal primer pair P1/P7 followed by R16F2N/R16R2 and fU5/rU3 as nested PCR primer pairs, all symptomatic plants tested positively for phytoplasma. Results of phylogenetic and virtual RFLP analysis of the 16S rRNA gene sequences revealed that the phytoplasma associated with Royal Palm yellow decline (RYD) was an isolate of ‘Candidatus Phytoplasma asteris’ belonging to a new 16SrI-subgroup. These results show that Roystonea regia is a new host for the aster yellows phytoplasma (16SrI). This is the first report on the presence of 16SrI phytoplasma on Royal Palm trees in Malaysia. second

poae is one of the Fusarium species isolated from grains associated with Fusarium head blight (FHB), whose occurrence has increased in the last years. In this study, a total of 105 F. poae isolates from Argentina, Belgium, Canada, England, Finland, France, Germany, Hungary, Italy, Luxembourg, Poland, Switzerland and Uruguay were evaluated using sequence-related amplified polymorphism (SRAP) to analyse the capacity of this molecular marker to evaluate the F. poae genetic variability. The molecular analysis showed high intraspecific variability within F. poae isolates, and a partial relationship was revealed between variability and the host/geographic origin. Analysis of molecular variance (amova) indicated a high genetic variability in the F. poae collection, with most of the genetic variability resulting from differences within, rather than between American and European populations.

Early diagnosis and treatment typically permit the best clinical

Early diagnosis and treatment typically permit the best clinical outcome. Liver transplantation is an important intervention to consider for advanced disease since it can sometimes treat the underlying metabolic derangement as well as liver failure. “
“Aim:  One major cause of hepatic see more sinusoidal obstruction syndrome (HSOS) is the consumption of products

containing pyrrolizidine alkaloids (PA). As the use of herbal preparations has increased in China, so has the number of reports of HSOS induced by ingesting PA-containing herbs. The aim of the present study was to investigate the mechanisms by which prednisone and the related factors, transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF), prevent liver fibrosis and the pathogenesis of HSOS. click here Methods:  A murine model of HSOS was created by oral gavage with Gynura segetum with or without prednisone for 30 days. Histological changes in liver tissue were evaluated by a scoring system in tissue slices subjected to hematoxylin–eosin and Masson trichrome staining. Hepatic expression of TGF-β1 and CTGF mRNA and protein was detected by immunohistochemistry, reverse transcription polymerase chain reaction (RT–PCR) and Western blot analysis.

RT–PCR was also used to detect tumor necrosis factor (TNF)-α and nuclear factor (NF)-κBp65 mRNA expression. Activation of NF-κBp65 was detected by immunohistochemistry. Results:  Intervention with prednisone diminished the symptoms of HSOS in mice treated with G. segetum. Prednisone

treatment significantly inhibited expression of TGF-β1 and CTGF mRNA and protein (P < 0.05), and inhibited expression of TNF-α and NF-κBp65 mRNA (P < 0.05) in the liver tissue of HSOS mice. Conclusion:  Prednisone suppresses the development of liver fibrosis in HSOS mice by inhibiting TGF-β1, CTGF, TNF-α and NF-κBp65 expression. "
“Antiviral interferons (IFNs) provide one of the first lines of defense against virus infections. Whether produced endogenously in response to virus or used clinically in antiviral therapies, IFNs establish an “antiviral state” by transcriptionally inducing interferon-stimulated genes (ISGs) acetylcholine through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The signaling events upstream of IFN induction and downstream of IFN receptor engagement are complex and subject to various levels of positive and negative regulation. For example, STAT molecules are themselves induced by IFN, enforcing a positive feedback loop. By contrast, IFN also triggers production of suppressor of cytokine signaling (SOCS)1 and SOCS3, which dampen IFN signals in a classic negative feedback loop. Thus, multiple levels of regulation exist solely within the IFN pathway. Outside of the IFN cascade, other signaling pathways have been shown to cross-talk with IFN, including interleukin-6 and IFN-γ.[1] In addition to these, Lupberger et al.

Briefly, daily diary

entries included 11 questions and an

Briefly, daily diary

entries included 11 questions and an optional comment section. The first question asked “Did you have a headache today?” Questions 2 to 7 mirror PedMIDAS questions[5] but were modified buy GSI-IX to address disability for each daily diary entry. Questions 2 to 4 addressed missing school (Q2), missing partial school days due to leaving early or arriving late (Q3), and functioning at less than half ability in school (Q4) because of a headache. Question 5 asked if activities at home such as homework or chores were affected by headache. Questions 6 and 7 addressed missed participation in social or recreational activities (Q6) and functioning at less than half ability during activities because of headache (Q7). In keeping with the PedMIDAS structure, patients could not choose more than one form of disability for school or for social activities for a given headache day. For example, if Q2 (“missed school”) was selected, then Q3 and Q4 were automatically Selleck A 769662 blocked. Question 8 provided a headache intensity rating scale that ranged from 1 to 10. Questions 9 to 11 addressed medicine compliance. Patients were asked to complete a diary entry each day. Study

investigators had an administrative login feature that allowed review of all daily diary entries upon submission and monitoring of daily compliance. Daily e-mail reminders were sent to parents and patients when entries were missed. Families were contacted by telephone after 5 consecutive missed days. Patients were asked to complete all missed entries by describing headache disability and intensity in the comment section of the subsequent entry or by relaying information to the study coordinator by e-mail or telephone. A disability score was calculated for each headache day. The score ranged from 0 to 3 based on the sum of affirmative responses to three PedMIDAS disability categories: school

(Q2-Q4); home activities (Q5); and leisure/recreational activities (Q6-Q7). Patients distinguished school days from weekends and holidays when answering school-related questions (ie, Did you miss school today because of a headache?) GNE-0877 as “yes,” “no,” or “weekend or school holiday.” Weekend and holiday designations were confirmed by comparing the date-stamped diary entry to the school-district calendar. The school year was defined as all school days (including weekends and school holidays) beginning from the first school day through the last school day of the calendar year. The summer holiday comprised all calendar days not included in the school year. To assess the evidence for systematic differences in headache disability, intensity, and frequency, we tested the null hypothesis of no difference between means for school days vs non-school days and for the school year vs the summer holiday. The 90-day observation period contained weekdays during the school year, weekends during the school year, and (for n = 32 patients) days during the summer holiday.

6% vs 804%,

grade cut off ≥ 2; 457% vs 63%)21 Likewise

6% vs 80.4%,

grade cut off ≥ 2; 45.7% vs 63%).21 Likewise, Kim et al. showed a statistically significant difference in sensitivity between Multistix and Uriscan strips (50% vs 67%).20 In the present series, we compared all validity scores among the three reagent strips, at the lowest cut off ≥ 1, we confirmed that Multistix strip gave the lowest sensitivity (80% vs 90%). In our series, the prevalence of SBP was not lower or higher (12%) than standard series.1–3 Clinical suspicion level plays important role on the prevalence and PPV of SBP positive cases in our study. The PPV by strip test was excellent in symptomatic patients (> 95.5–100%) whereas in BVD-523 asymptomatic patients with a low suspicion for SBP, as expected, the PPV was much poorer (20–22%) (data not shown). It has been speculated in the past that prior antibiotic use may result in false negative and positive results.22 However, none of our patients with false negative result reported history of recent or current antibiotic uses. Our previous study showed that the smaller number of PMN cells in the specimens (close to 250 PMN/mm3) may contribute to a false negative result.13 However, in the present series, we observed that all false negative specimens from the strip test always had PMN higher than 1000 PMN/mm3

by manual count. In summary, our false negative rates from Aution Mutistix, and Combur strips were quite significant (10%, 20% and 10%, respectively). Although there were some discrepancies in the range of PMN number between automated reading and manual reading, the specimen number 11 was the only one that this discrepancy resulted in Palbociclib concentration the different interpretation and caused false positive. If we lowered our cut off value for SBP diagnosis by the automated system to 200 cells/mm3, Bcl-w we would not have any false negative case. It has been reported that the agreement between manual and automated cerebrospinal fluid cell counts was suboptimal if the PMN count was less than 200

cells/mm3.23 In addition, there was a certain lower limit for PMN detection by each automated system. For instance, based on coefficient of variation, the Iris iQ200 automated microscopy analyzer Body Fluids Module (Iris Diagnostics, Chatsworth, CA), has a limitation at 35 PMN cells/mm3.24 Therefore, further study on the threshold for clinical diagnosis of SBP form ascitic fluid analysis by each automated cell count is required. At the critical threshold of manual PMN count to diagnose SBP (250 > PMN < 1000) cells/mm3 (n= 12), there were another five specimens (specimen number 2, 17, 20, 22, 23) that had a significant discrepancy of cell count by the two methods but this was not affecting SBP diagnosis interpretation by the automated cell count (Table 2). A better correlation between the two methods was demonstrated by a study from Rome.25 Riggio et al. reported the limits of agreement of the two methods were +124 cells/mm3[95% confidence interval (CI): +145 to +103] and −108 cells/mm3 (95% CI: −87 to −129).

51 cell transfection) using siRNA and a PKR expression plasmid,

5.1 cell transfection) using siRNA and a PKR expression plasmid, and then assessed cancer-related genes by real-time PCR and Western blotting. Cell lines were further analyzed using wound healing

and MTS (proliferation) assays. The modulation of genes by PKR was also assessed in 34 specimens of human HCC. Results: The expression of c-Fos and c-Jun genes was altered in parallel by PKR. An increase in PKR resulted in the upregulation of phosphorylated c-Fos and c-Jun that was related to levels of phosphorylated Erk1/2 and JNK1, namely the MAPK pathway, which is associated with cell proliferation. We therefore assessed cell proliferation in mono-layer wound-healing experiments. We found that JFH1 and H77s cells recovered more slowly buy GDC-0068 after PKR knockdown than controls. Cell proliferation determined by MTS assays significantly decreased and increased after PKR knockdown and PKR upregulation, respectively, and cell proliferation

Wnt inhibitor was dependent on PKR-modulated c-Fos and c-Jun expression. We also confirmed the coordinate expression of c-Fos and c-Jun with PKR in human HCC specimens with HCV infection. The amounts of c-Fos and c-Jun and their phosphorylation levels were increased in specimens with high levels of PKR expression. Conclusions: The activities of c-Fos and c-Jun were upregulated by PKR through the activation of Erk1/2 and JNK1, respectively. Such modulations resulted in HCC cell proliferation with HCV infection. These findings suggest that PKR-related proliferation pathways could Ixazomib cell line serve as an attractive therapeutic target. Disclosures: Raymond T. Chung – Advisory Committees or Review Panels: Idenix; Consulting: Enanta; Grant/Research Support:

Gilead, Merck, Mass Biologic, Gilead The following people have nothing to disclose: Takao Watanabe, Yoshio Tokumoto, Masashi Hirooka, Masanori Abe, Morikazu Onji, Yoichi Hiasa Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide, but molecular mechanisms of its pathogenesis are not well understood. Recent studies suggest that extracellular ATP-mediated activation of P2Y2 purinergic receptor induces hepatocyte proliferation in response to partial hepatectomy and ATP treatment alone was sufficient to induce hepatocyte proliferation in vitro. The purpose of this study was to characterize extracellular nucleotide effects on HCC cell proliferation and to examine the role of P2 purinergic signaling in the pathogenesis of HCC in patients and Mst1/2-/-, a mouse model of HCC. Hypothesis: Dysregulation of purinergic signaling facilitates aberrant cell proliferation underlying hepatocellular carcino-genesis. Methods. HCC human-derived Huh7 cells, maintained in serum free media for 24h, were treated with ATPγS, or ADP (100μM) for different time intervals. SP600125 pretreatment was used to inhibit c-Jun N-terminal Kinase (JNK) signaling. Western blotting, qRT-PCR and 5-Bromo-2′-deoxy-uridine (BrdU) incorporation analysis were done.