13 These differences between studies reflect the complexity of the HCV entry mechanisms and the fact that current in vitro systems may not completely reproduce the virus life cycle in a human liver.14 Liver transplant patients undergo frequent liver biopsies, allowing in vivo assessment of the potential changes in the expression CP-868596 purchase of such HCV

receptors over time. The aim of this study was to evaluate the potential changes in tight junction proteins claudin-1 and occludin following HCV graft infection and to analyze if their expression could influence early HCV kinetics. CH, cholestatic hepatitis; CMV, cytomegalovirus; CyA, cyclosporine A; DDLT, deceased donor liver transplantation; FFPE, formalin-fixed and paraffin-embedded; FK, tacrolimus; HCV, hepatitis C virus; HCVpp, HCV pseudoparticle; HVPG: hepatic venous pressure gradient; LDLT, living donor liver transplantation; LT, liver transplantation; MR, mild hepatitis C recurrence; SR-B1, scavenger receptor B1. Forty-two HCV-infected patients undergoing LT from January 2000 to January 2008 were included in the study. Selection of patients was based on the type of hepatitis C recurrence and individuals at both extremes of the disease spectrum (mild and severe) were selected. Mild disease mTOR inhibitor recurrence was defined as absent (F0) or mild (F1) fibrosis 1 year after transplantation, and a normal hepatic venous pressure

gradient (HVPG). Severe disease recurrence was defined as the presence of advanced fibrosis (F ≥3) and/or clinically Molecular motor significant portal hypertension (HVPG ≥10 mmHg) 1 year after transplantation. Nineteen HCV-negative liver transplant recipients served as controls.15,

16 All patients were followed in our Liver Unit and underwent standard immunosuppression protocols.15 Induction immunosuppression consisted of cyclosporine A or tacrolimus and prednisone. After hospital discharge patients visited the outpatient clinic monthly for 3 months for complete recording of clinical and analytical data and every 2 or 3 months thereafter. Liver biopsies were obtained after graft reperfusion (revascularization of the graft during the surgical procedure) and at 3 and 12 months after LT in accordance with the standard protocol. Patients whose liver disease was likely caused by another reason (rejection, cytomegalovirus [CMV] infection) were excluded. The study was previously approved by the Investigation and Ethics Committee of the Hospital Clinic of Barcelona following the ethical guidelines of the 1975 Declaration of Helsinki. We obtained informed consent from all patients included in the study. Percutaneous liver biopsies were performed by expert radiologists. HVPG measurements and transjugular liver biopsies were performed at the Hepatic Hemodynamics Laboratory as described.16 Liver samples were processed by the Pathology Department.

Approximately half EMD 1214063 purchase of the potential target genes in both healthy and obese mice were unique to each, suggesting that potential FXR target genes and biological pathways are altered in obesity. Moreover, a large fraction of the potential FXR target genes examined were repressed by ligand-activated FXR, suggesting that direct gene repression by FXR might be more common than previously thought. Additional studies will be required to elucidate the molecular mechanisms by which FXR directly represses these potential genomic targets. The authors are grateful to Dr. Grace L. Guo (University of Kansas Medical Center) for her helpful suggestions

for the ChIP-seq analysis. The authors also thank Ms. Ting Fu for kindly performing Oil Red staining of liver sections. The authors also thank Byron Kemper for his critical comments on the manuscript for this article. Additional Supporting Information may be found in the online version of this article. “
“Defects in human hemochromatosis protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential

complications check details from HFE-related hereditary hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Patients (n = 18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30

nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (±99) μg/L. Magnetic resonance imaging showed that iron overload was absent in nine patients, mild in one patient with metabolic syndrome, and high (180 μmol/g) in one patient with hereditary spherocytosis discovered after LT. At the end of follow-up, serum hepcidin was normal in 10 patients Cyclin-dependent kinase 3 (11.12 ± 7.6 nmol/L; P < 0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. Conclusion: In HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients who received LTs for other liver diseases. (Hepatology 2014;59:839–847) "
“Pancreatic exocrine insufficiency (PEI) is one of the long-term consequences of chronic pancreatitis (CP). Majority of patients with PEI were undiagnosed or undertreated.

Safety assessments were based on reported AEs and the results of vital sign measurements, physical examinations, ECGs, and clinical laboratory tests. The incidences of AEs were tabulated and reviewed for their clinical relevance. Serial blood samples for PK analysis were obtained on day 1 for 24 hours after the morning dose and on day 14 for 72 hours after the last dose. PK samples for the once-daily dosing groups were collected on day 1 and day 14 predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose. buy Torin 1 In addition, PK samples were collected 48 hours (day 15) and 72 hours (day 16)

postdose. PK samples for the 30 mg twice-daily dosing group were collected using the same PK sampling schedule as the once-daily dosing groups, but a second dose

was not administered on day 14. Blood samples for trough concentrations (Ctrough), minimum observed plasma concentration (Cmin), and steady-state assessment were obtained on days 2, 3, 4, 5, 7, 9, 11, and 13 prior to the morning dose. The PK parameters derived from the plasma SCH772984 purchase concentration versus time data by noncompartmental methods were: maximum observed plasma concentration (Cmax), Cmin, time of maximum observed plasma concentration (Tmax), area under the concentration curve (AUC) over 12-hour dosing interval for 30 mg twice daily (AUC(TAU)), half-life (T1/2), and apparent total body clearance (CLT/F). The AUC(0-24) for the 30 mg twice-daily dosing group was determined by multiplying the AUC(0-12) by 2. In addition, accumulation index, degree of fluctuation, and time to steady-state were assessed. Additional blood samples were collected on day 14 immediately prior to and 2 hours after the morning dose for ex vivo protein binding determination. Protein binding in human plasma was assessed in

triplicate at both timepoints. Plasma samples for BMS-790052 were prepared by a liquid-liquid extraction procedure and assayed by Tandem Histone demethylase Labs (West Trenton, NJ) using a validated liquid chromatography/tandem mass spectrometry (LC-MS/MS) method during the period of known analyte stability. The lower limit of quantitation of the assay in human plasma was 0.0500 ng/mL. Chromatographic separation was achieved using a Genesis C8, 50 × 2.1 mm, 4 μm column (Grace Vydac, Hesperia, CA) with a gradient mobile phase of 10 mM ammonium acetate in water with 0.1% formic acid / 0.1% formic acid in acetonitrile. Mass spectrometry data were acquired using an API 4000 mass spectrometer (MDS Sciex, Thornhill, ON, Canada) operated in a positive electrospray ionization mode. The selected reaction monitoring transitions (±0.3 amu) were 370.4 > 130.2 for BMS-790052 and 375.4 > 130.2 for BMS-790052-13C. The intraassay precision for BMS-790052 was within 12.1% coefficient of variation (CV) and the interassay precision was within 11.9% CV.

We accepted HCV antibody, viral load and genotype tests as evidence of HCV screening. We calculated HCV screening rates, confirmatory HCV RNA testing rates, anti-HCV prevalence and HCV infection prevalence. Results: Among 5,500, 392 Veterans in VA care in 2012, 54.7% had VA HCV screening at least once: 41.5% of those born before 1945, 64.2% of those born during 1945-1965 and 58.0% of those born after 1965.Confirmatory

HCV RNA testing was performed for 95.1% of Veterans with positive antibody results. In over 2.9 million Veterans screened, anti-HCV and HCV infection prevalence were 2.9% and 1.7% respectively for those born before 1945, 13.1% and 9.9% for those born during 1945-1965 and 1.9% and 1.1% for Ruxolitinib mouse those born AG-014699 price after 1965.For those in the 1945-1965 birth cohort in VA care in 2012, HCV infection prevalence based on the year HCV screening first occurred declined sharply from 33.2% to

10.3% for those first screened between 1999 and 2003 and then gradually from 9.5% to 5.7% for those first screened between 2004 and 2012.Extrapolating the most recent HCV infection prevalence to Veterans in the 1945-1965 birth cohort not yet screened (n = 905, 751) suggests that up to 51,000 additional Veterans would be identified with HCV infection with full birth cohort screening. Conclusions: Among Veterans in recent VA care, HCV screening rates were highest among those born during 1945-1965.Anti-HCV and HCV infection prevalence were

markedly elevated among those born during 1945-1965 compared to those born before or after this birth cohort supporting the CDC’s emphasis on birth cohort testing. Given the observed HCV infection prevalence, full adoption of birth cohort screening may reveal substantial numbers of Veterans with previously unknown HCV infection. Disclosures: The following people have nothing to disclose: Lisa I. Backus, Pamela S. Belperio, Timothy P. Loomis, Troy A. Shahoumian, Larry A. Mole HCV is increasingly prevalent among patients PRKACG over age 65; however, this population is underrepresented in Phase III trials of boceprevir (BOC) and telaprevir (TVR). The aim of this study is to evaluate the impact of age on safety and efficacy of current HCV regimens. Methods: The HCV-TARGET consortium of investigators utilizes novel, standardized data abstraction and a common database to enroll sequential patients treated with regimens that contain at least one direct-acting antiviral. Demographic, clinical, adverse events (AE), and virological data are collected throughout treatment and post-treatment follow-up. Results: In this ongoing study, 2212 patients have been enrolled and are at varying stages of treatment. Of 970 patients (mean age = 56yrs, range 18-76yrs) who started triple therapy regimens prior to July, 2012, 74 patients (8%) are ≥65yrs: 53 (72%) TVR and 21(28%) BOC.

Consistent with the significant reduction of hepatic superoxide dismutase activity and marked downregulation of the gene expression of hepatic antioxidant enzymes, the hepatic TBARS level and the plasma level of alanine aminotransferase

were only increased in SHR on CD diet. Conclusions:  Spontaneously hypertensive rats receiving CD diet showed severe hepatic steatosis associated with reduction AZD4547 of hepatic anti-oxidant capacity, leading to increased hepatic oxidative stress and tissue damage. Accordingly, hypertension might have a potential effect on the progression of NASH. “
“Although interferon (IFN) treatment in elderly patients with chronic hepatitis C virus (HCV) infection has increased with the aging Japanese population, few studies have examined the efficacy and safety of IFN treatment in this population. We investigated the efficacy and safety of IFN treatment in elderly patients with chronic HCV infection using the Japanese Interferon Database. Records of IFN treatment in 36 prefectures in Japan from December 2009 to April 2013 were examined. Patients with HCV

infection who received IFN treatment were selected. We compared the sustained virological response (SVR) rate and the withdrawal from treatment proportion Epacadostat among elderly patients (≥75 years) with those among younger patients (<65 years, 65–74 years). We identified 15 267 patients with chronic HCV infection as the study cohort from the database. Of these, 310 patients were elderly with a mean age of 76.7 ± 1.95 years (2.03%; men, 155; women, 155), and the majority (87%) were treated with pegylated IFN. Lower SVR rates (aged <64 years, 65.3%; aged 65–74 years, 49.6%; aged ≥75 years, 46.5%; P < 0.001) and higher withdrawal from treatment proportions (aged <64 years, 15.0%; aged 65–74 years, 21.5%; aged ≥75 years, 32.4%; P < 0.001) were observed

with aging. We learn more conclude that elderly patients with chronic HCV infection taking IFN therapy achieved lower SVR rates and a higher withdrawal from treatment proportion than younger patients. “
“The Centers for Disease Control and Prevention recommends hepatitis B surface antigen (HBsAg) testing to identify chronic hepatitis B virus infection for foreign-born persons from countries or regions with HBsAg prevalence of ≥2%. However, limited data exist to indicate which countries meet this definition. To address this data gap, we estimated the HBsAg prevalence among refugees entering the United States between 2006 and 2008. We contacted state refugee health coordinators and asked them to report the number of refugees, country of origin, and HBsAg prevalence among refugees screened in their jurisdiction during the most recently available 12-month period prior to August 2008.

MesP1Cre, Wt1CreERT2, Rosa26lacZflox, Rosa 26mTmGflox mice were described previously.16-19 Tamoxifen (Sigma) dissolved in ethanol was emulsified in sesame oil at 12.5 mg/mL and 2 mg of tamoxifen was injected intraperitoneally to the pregnant mice from E10.5. Before E10.5 embryos, we failed to

induce lacZ expression in the STM by injection of 2 mg tamoxifen, despite the strong expression of Wt1 in the STM. Before E9.0 embryos, a fetal-placental circulation is yet to be established and tamoxifen injected into the mother may not be delivered efficiently to the embryos. We also experienced that tamoxifen treatment before E10.5 embryos often results in LDK378 ic50 abnormal bleeding in utero and termination of embryogenesis. Thus, we injected a reduced tamoxifen dose of 1.5 mg twice at

E7.5 and E8.5 and examined the embryos at E9.5 and E11.5. Although some embryos still died by this method, surviving embryos did not show any signs of abnormalities. Mice were used in accordance with protocols approved by the Institutional Animal Care and Use Committee of the University of Southern California. Embryos SCH727965 were fixed with 4% paraformaldehyde. Cryosections (7 μm) were stained with X-gal followed by counterstaining with Nuclear Fast Red or Eosin (Sigma).13 To quantify the number of the lacZ+ cells in the livers from E11.5 to E13.5, the images were captured under a microscope (Nikon Eclipse 90i) and the lacZ signals were counted in the median lobe (ML) and left lobe (LL) (n = 6). The areas of the ML and LL were measured with imaging software (Nikon NIS-Elements). The number of the lacZ signals inside the liver was quantified in every six (E11.5) or 10 sections

(E12.5, E13.5). Immunohistochemistry was performed as described.13 The antibodies used in immunostaining are listed in Supporting Table 1. The primary antibodies were detected with secondary antibodies conjugated with AlexaFluor dyes (Invitrogen). The sections were counterstained with DAPI (Invitrogen). For immunostaining of the Rosa26mTmG embryos, we bleached the tomato fluorescence with 3% H2O2 in methanol 10 minutes before Sirolimus immunostaining. To quantify the percentages of lacZ+ or green fluorescent protein (GFP)+ cells in desmin+ HSCs and PMCs inside the liver, the images in every six (E11.5) or 10 section (E12.5, E13.5, E18.5) were captured and the lacZ+, GFP+, and desmin+ cells inside the livers were counted (n = 5). To quantify the labeling efficiency of MC/SubMCs by tamoxifen treatment, E9.5 or E11.5 liver sections were stained with antibodies against Alcam and lacZ in every sixth section. The images were captured as above and the lacZ+ MC/SubMCs and Alcam+ cells in the STM or MC/SubMCs were counted (n = 5).

“
“Over the past two decades, the advances in molecular cell biology have led to significant Nutlin-3a chemical structure discoveries about the pathophysiology of portal hypertension (PHT). In particular, great progress has been made in the study of the molecular and cellular mechanisms that regulate the increased intrahepatic vascular resistance (IHVR) in cirrhosis. We now know that the increased

IHVR is not irreversible, but that both the structural component caused by fibrosis and the active component caused by hepatic sinusoidal constriction can be, at least partially, reversed. Indeed, it is now apparent that the activation of perisinusoidal hepatic stellate cells, which is a key event mediating the augmented IHVR, is regulated by multiple signal transduction pathways that could be potential therapeutic targets for PHT treatment. Furthermore, the complexity of the molecular physiology of PHT can also be appreciated when one considers the complex signals capable of inducing vasodilatation and hyporesponsiveness to vasoconstrictors in the splanchnic vascular bed, with several vasoactive molecules, controlled at multiple levels, working together to mediate these circulatory abnormalities. Added to the complexity is the occurrence of pathological angiogenesis during the course of disease check details progression, with recent emphasis

given to understanding its molecular machinery and regulation. Although much remains to be learned, with the current availability of reagents and new technologies and the exchange of concepts and

data among collaboratory, multidisciplinary teams, our knowledge on the molecular basis of PHT will doubtless continue to grow, accelerating the transfer of the know-how generated by the basic research to the clinical practice. That will hopefully permit a better future for patients with PHT. (Hepatology 2014) “
“Interest in the role of 25-hydroxyvitamin D3 [25(OH)D3] in the pathogenesis of metabolic disturbances (i.e., insulin resistance, type 2 diabetes, cardiovascular Dimethyl sulfoxide disease, and liver abnormalities of different etiologies) has been growing in recent years.1-4 The study by Petta et al.1 might suggest the importance of 25(OH)D3 as a common marker of both metabolic abnormalities and hepatic damage in a sample of individuals with chronic hepatitis C. Patients suffering from chronic hepatitis C presented with low levels of 25(OH)D3. Concentrations of vitamin D were associated with characteristics of metabolic syndrome (i.e., a high waist circumference, ferritin, and low high-density lipoprotein cholesterol levels) and with severity of inflammation and fibrosis. A relative vitamin deficiency was associated with reduced expression of a cytochrome P450 isoform (cytochrome P450 27A1). Importantly, the authors proposed low levels of 25(OH)D3 as serum markers of fibrosis to be validated in external populations. Targher et al.

To simulate wear, specimens were inserted and separated horizonatally 3285 times in wear equipment with artificial saliva. Retention forces and weights of the double

crowns were then remeasured. Data were analyzed using paired t-tests and Wilcoxon tests, and the groups were compared using Mann–Whitney U-tests. Results: In group A, the wear test had a significant influence on the retentive force (p < 0.05), but wear produced no significant difference in weight (p > 0.05). In group B, the STA-9090 price wear test had a significant influence on the retentive force (p < 0.05), and wear produced a significant difference in weight (p < 0.05). Conclusions: The results of this study indicated that the use of different combinations of galvanoforming and casting techniques in the fabrication of conical crowns significantly affected retention force. "
“The purpose of this study was to retrospectively evaluate implant survival rates in patients treated with the All-on-Four™ protocol according to edentulous jaws, gender, and implant orientation (tilted vs. axial). All Brånemark System implants placed in patients following the All-on-Four™ protocol in a single private practice were separated into multiple classifications (maxilla Galunisertib manufacturer vs. mandible; male vs. female; tilted vs. axial) by retrospective patient chart

review. Inclusion criteria consisted of any Brånemark System implant placed with the All-on-Four™ protocol from the clinical inception (May 2005) until December 2011. Life tables were constructed to determine cumulative implant survival rates (CSR). The arches, genders, and implant orientations were statistically

compared with ANOVA. One hundred fifty-two patients, comprising 200 arches (800 implants) from May 2005 until December 2011, were included in the study. Overall implant CSR was 97.3% (778 of 800). Two hundred eighty-nine of 300 maxillary implants and 489 of 500 mandibular implants survived, for CSRs of 96.3% and 97.8%, respectively. In male patients, 251 of 256 implants (98.1%) remain in function while 527 of 544 implants (96.9%) in female patients survived. Regarding implant orientation, 389 of 400 tilted implants and 389 of 400 axial implants osseointegrated, for identical Casein kinase 1 CSRs of 97.3%. All comparisons were found to be statistically insignificant. The prosthesis survival rate was 99.0%. The results from this study suggest that edentulous jaws, gender, and implant orientation are not significant parameters when formulating an All-on-Four™ treatment plan. The high CSRs for each variable analyzed demonstrate the All-on-Four™ treatment as a viable alternative to more extensive protocols for rehabilitating the edentulous maxilla or mandible. “
“Purpose: This study analyzed the surface roughness and weight loss in Plex Glass specimens caused by dentifrices, one conventional (Sorriso) and three specific for dentures.

In particular, canopy structure may influence assemblage production by affecting the distribution of light to photosynthetic tissues in the assemblage and consequent efficiency of light utilization (Binzer

and Sand-Jensen 2002a,b). Varying functional trait composition in assemblages is known to directly regulate ecosystem STA-9090 mw processes (Díaz and Cabido 2001, McGill et al. 2006) and has been recently incorporated in biodiversity-ecosystem functioning relationships (e.g., Griffin et al. 2009, Roscher et al. 2012) rather than species richness per se. Additionally, the individual performance of species (i.e., identity effects) has been proposed to affect the magnitude of an ecosystem process in macroalgal assemblages (Arenas et al. Smad inhibitor 2009, Griffin et al. 2009), indicating a high degree of interspecific variation in macroalgal productivity (Littler and Littler 1980). A few laboratory studies have also incorporated an assemblage perspective using natural communities (Arenas et al. 2009, Tait and Schiel 2011). Examining different components of biodiversity (e.g., biomass, richness, evenness), Arenas et al. (2009) described a positive relationship for biomass and species richness with productivity on macroalgal assemblages

on small boulders bearing intertidal macroalgal assemblages. Recently, experimental studies on marine communities have analyzed photosynthesis within intact, in situ macroalgal assemblages (e.g., Miller et al. 2009,

Noël et al. 2010, Tait and Schiel 2010). For example, Tait and Schiel (2010) tested for primary production in intertidal macroalgal assemblages dominated by fucoid algae and described increased primary productivity of these macroalgal assemblages with a combination of greater biomass and greater numbers of macroalgal species. Marine coastal ecosystems are strongly affected by invasions of NIS, which together with anthropogenic disturbances can create highly altered habitats. Nonetheless, to date, there have been virtually no studies which have focused on the functional consequences of increases in species richness due to the presence of invaders in marine habitats (but see Stachowicz and Byrnes 2006). Marine macroalgae are a significant component Casein kinase 1 of introduced NIS (Schaffelke et al. 2006), highlighting the importance of studies addressing interactions at this level, particularly using strong invaders, sensu Ortega and Pearson (2005). This study aimed to investigate assemblage-level impacts of macroalgal invasions and discriminate the mechanisms promoting its impact. In particular, we intended to understand the role of a strong invader, S. muticum (Yendo) Fensholt, and assemblage structure on the dynamics of respiration and light-use efficiency of assemblages. We used synthetic assemblages of marine macroalgae, resembling those from intertidal rock pools, with varying levels of functional diversity and invader biomass.

5 hours after Jo2 administration (Fig. 5C). At 5 hours after Jo2 administration, marked phosphorylation and subsequent degradation of BimEL and reduction of the cytochrome c level in the mitochondrial fraction were seen in WT mice, whereas these changes were significantly suppressed in ASK1−/− mice (Fig. 5D). As reported,19 administration of a JNK inhibitor reduced Jo2-induced BimEL phosphorylation and serum ALT elevation. However, administration of a p38 inhibitor had no detectable effect on BimEL phosphorylation

or liver injury (Fig. 5E,F). These results suggest that ASK1 plays an important role in Fas-induced activation of the JNK–Bim–mitochondrial apoptotic pathway. Next, check details to examine whether ASK1 may be involved in a Fas-induced mitochondria-independent apoptotic pathway, we used primary thymocytes, which are independent of mitochondria for Fas-induced apoptosis (so-called type I cells). Fas-induced activation of JNK and p38 was reduced in ASK1−/− thymocytes, whereas caspase-3 activation and cell viability were comparable between WT and ASK1−/− thymocytes (Supporting Fig. 1A,B), suggesting that ASK1 is not required for the mitochondria-independent

apoptotic pathway. Recently, Fas signaling was reported to play a role in not only cancer cell apoptosis, but also cancer cell proliferation.26 JNK has also been shown to be one of the main mediators of Fas-mediated proliferative learn more signals. To investigate whether ASK1 participated in Fas-mediated hepatocyte proliferation, we injected Jo2 to WT and ASK1−/− mice after partial hepatectomy, which is known to convert

Fas signaling from Atezolizumab mouse apoptotic to proliferative.27 As reported,26, 27 Jo2 injection after partial hepatectomy induced JNK phosphorylation and accelerated hepatocyte proliferation without liver injury (Supporting Fig. 2A,B). Although liver regeneration after partial hepatectomy and Jo2-induced JNK phosphorylation were slightly impaired in ASK1−/− mice (especially the upper band corresponding to JNK2), there was no significant difference in Jo2-mediated acceleration of hepatocyte proliferation (Supporting Fig. 2A,B). Thus, ASK1 seemed to regulate the apoptotic, but not proliferative, function of JNK in Fas signaling. To further confirm the involvement of ASK1 in Fas-induced hepatocyte apoptosis, we examined whether the reintroduction of ASK1 to ASK1−/− mouse liver restored sensitivity to Fas. We injected an adenoviral vector encoding either Ad-ASK1 or LacZ into the tail vein of ASK1−/− mice. ASK1 protein was successfully expressed in ASK1−/− mouse liver, as much as that in WT mouse liver, at 48 hours after Ad-ASK1 injection (Fig. 6A). Immunohistochemical analysis using anti-HA antibody revealed that ≈70%-80% of hepatocytes were transduced with the ASK1 gene (Fig. 6B). The reintroduction of ASK1 did not affect the serum ALT level or liver histology.