In more severely immune compromised patients, fungal, viral, and bacterial esophagitis can be seen, sometimes simultaneously. An accurate diagnosis usually requires endoscopic biopsy and viral culture. The most common stomach infections are caused by H. pylori and community-acquired viruses; otherwise, gastric infections in healthy people are rare. In the immune compromised patient, Cytomegalovirus is the most common gastric pathogen. Diagnosis

is by endoscopic biopsy. Treatment is available for almost all esophageal and gastric infections. “
“Background and Aims:  The binucleation DAPT mouse of hepatocytes, which was known as an important feature of liver growth and physiology, has been reported to be increased during the chronic oxidative injury stage and has been regarded as an age-related change of hepatic structures. Therefore, we investigated the binuclearity pattern in the livers of senescence marker proteins-30 (SMP30) knock-out (KO) mice compared with wild-type (WT) mice and vitamin C-treated KO (KO + VC) mice. Methods:  The WT, KO and KO + VC mice were fed a vitamin C free diet and VC(+) group

mice were given vitamin C water containing 1.5 g/L of vitamin C, whereas VC(−) group was given normal drinking water without vitamin C, for 16 weeks. Results:  In microscopic examination, the livers of KO mice showed a significantly increased number of binuclear hepatocytes compared with that of WT mice and KO + VC mice. KO mice also showed the most increased expression level of CYP2E1 and PCNA determined by immunohistochemistry and immunoblot analysis. Moreover, KO mice indicated the highest level Carfilzomib purchase of serum alanine aminotransferase and aspartate aminotransferase level in serum biochemical analysis. Accordingly, significantly decreased levels of reactive oxygen species, MDA (malondialdehyde) and HAE (4-hydroxyalkenals) were detected in KO + VC mice compared with KO mice. Conclusion:  Therefore, it is concluded that vitamin Tideglusib C deficiency induces an increase of CYP2E1 expression and elevated ROS production, which causes oxidative liver injury and the elevation of hepatocyte binucleation

in SMP30 KO mice. “
“Hepatitis C virus (HCV) genotype is an important criteria in determining duration of therapy and predictor of sustained virologic response (SVR) to pegylated interferon (PEG IFN) and ribavirin (RBV) therapy. Optimal duration of therapy for patients with HCV genotype 6 is not known. We conducted a multicenter, open-label randomized controlled trial of patients with HCV genotype 6 at five gastroenterology clinics in the western U.S. Patients were stratified by viral load and histologic stage and assigned to receive PEG IFN-α2a 180 μg subcutaneously weekly and weight-based oral RBV 800 to 1,200 mg daily for 24 or 48 weeks. Primary outcome measurement was SVR rate by intention-to-treat analysis. From February 2005 to October 2007 a total of 60 patients (age 51 ± 10 years, 47% male, log HCVRNA 6.

8 Unfortunately, the methods used by Hu and Colletti preclude the evaluation of the relevant cell death pathways, but might have

led to the misinterpretation of apoptosis as the principal mechanism of APAP hepatotoxicity. First, the authors show that a caspase inhibitor, which was solubilized in dimethylsulfoxide (DMSO), prevented terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining in hepatocytes. TUNEL is an unspecific marker that cannot distinguish between apoptotic and necrotic DNA fragmentation. Moreover, a DMSO control was not presented but is mandatory, because DMSO is a radical scavenger and by itself exerts cytoprotective effects.9 Second, although the authors show that APAP-induced DNA fragmentation was prevented, it remains unclear whether caspase inhibition indeed improves the survival of mice. There are many cases known in which caspase inhibitors prevent apoptotic

PLX-4720 research buy alterations but do not affect cell survival. Finally, on the basis of the assessment of proteolytic caspase fragments, the authors suggest that caspase-9 is activated by APAP. However, they do not present data mTOR inhibitor on the enzymatic caspase activity. Indeed, caspase-9 does not require cleavage to be activated. Moreover, calpains that are activated by APAP can induce proteolytic cleavage of caspase-9.10 These cleavages generate fragments of Thalidomide similar size but occur at sites that render the caspase-9 proteolytically inactive. Hence, the mere cleavage of caspase-9 cannot be taken as sufficient evidence for its activation. Altogether, we have serious concerns regarding the interpretation of the results

by Hu and Colletti. Apoptosis is certainly of major importance in many chronic liver diseases. APAP-induced ALF is, however, one of the few examples where necrosis but not apoptosis predominates. An understanding of the cell death processes will be essential for effective interventions in ALF and other liver diseases. Klaus Schulze- Osthoff M.D*, Heike Bantel M.D†, * Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany, † Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany. “
“An 80 year old woman presented as an emergency with a two week history of progressively worsening diffuse abdominal pain, bilious vomiting and diarrhoea. There was no history of trauma. She was commenced on Warfarin three weeks before this admission for paroxysmal atrial fibrillation. She previously had undergone a right hemicolectomy for poorly differentiated adenocarcinoma in 2008. Her past history was also significant for hypertension, chronic renal failure and breast cancer. Initial examination revealed normal vital signs. The abdomen was soft but diffusely tender, without guarding or rigidity. Normal bowel sounds were present. There was no lymphadenopathy.

However, the effects of EGCG on intestinal inflammation

and the molecular mechanisms responsible are poorly understood. The aim of this study was to evaluate the therapeutic effects of EGCG on colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS) in rats, and its possible mechanisms. Methods: Colitis was induced by intrarectal instillation of TNBS in 50% ethanol in Sprague-Dawley male rats. 12 hours after colonic instillation of TNBS, EGCG with this website several doses (25, 50, 7 g/kg) was given by gastric gavage once daily for 7 days. The disease activity index (DAI), macroscopic score, microscopic score, myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels in colon tissues were subsequently

evaluate. Caspase-1 expression in colonic mucosa was also detected by immunohistochemistry. Furthermore, the levels of interleukin-1β (IL-1β) and IL-18 in the serum were measured Protein Tyrosine Kinase inhibitor by enzyme-linked immunosorbent assay (ELISA). Results: Comparing with the 0.9% NaCl-treated rats with TNBS-induced colitis, EGCG-treated rats with TNBS-induced colitis were shown improvements of DAI, macroscopic score, microscopic score, MPO activity and MDA levels. Consistent with these findings, caspase-1expression in colonic mucosa was also suppressed in the EGCG-treated group. Moreover, treatments with EGCG decreased the up-regulated levels of IL-1βand IL-18 in the serum caused by TNBS. However, these parameters were found to be significantly ameliorated in rats treated with EGCG at given doses, especially at 50 mg/kg and 75 mg/kg. Conclusion: Our results suggested that, at the appropriate dose, EGCG could ameliorate colonic inflammation of TNBS-induced colitis. The therapeutic effect of EGCG in treating colitis might be related to the reduction of the colonic caspase-1 expression, and the decrease in the serum levels of IL-1β and IL-18. Key Word(s): 1. caspase-1; 2. colitis; 3. interleukin-1β;

4. interleukin-18; Presenting Author: HU ZHANG Additional Authors: JANE GOODALL, JAMES LEE, MILES PARKES Corresponding Author: HU ZHANG Affiliations: Department of Gastroenterology, West China Hospital, Sichuan University; Department Hydroxychloroquine chemical structure of Rheumatology, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; IBD research group, Department of Gastroenterology, University of Cambridge, Cambrdige, United Kingdom; Director of GastroenterologyAddenbrooke’s HospitalCAMBRIDGE Objective: The focal SNP rs7746082 is located in a confirmed Crohn’s disease (CD) susceptibility locus on 6q21. Within 500 kb of this locus only two genes, PRDM1 encoding BLIMP1 and ATG5 (a key autophagy gene), are present. Both of them have been implicated in CD susceptibility.

Particularly, we focused on the endoscopic findings and clinicopathological characteristics of colonic schistosomiasis. Methods: All cases with intestinal

schistosomiasis diagnosed between October 2004-October 2010 in West China Hospital were included in the study. A total of 179 cases of colonic schistosomiasis diagnosed by colonoscopy and pathological examination were collected for analysis, and the demographics, the selleck screening library presence of symptoms, endoscopic findings, clinicopathological characteristics were retrospectively evaluated. Results: Of the 179 colonic schistosomiasis patients, 32 cases (male = 24, 75%) aged 44–85 years old combined with colorectal cancer (CRC) were detected. 32 lesions

were classified as 12 as endophytic/ulcerative (37.5%), 10 as exophytic/fungating (31.2%), 4 as annular (12.5%), 3 asIIa (superficial elevated type) (9.4%), 3 asIIc (superficial depressed type) (9.4%). The segments of rectum and sigmoid colon were involved in 19 patients (59.4%) and 6 patients (18.8%), respectively. The histopathologic type was classified as follows:30 well-differentiated adenocarcinomas, one mucinous adenocarcinoma, one poorly differentiated adenocarcinomas. The pathological findings have suggested that colorectal malignancy with schistosome ova deposited. Conclusion: Chronic schistosomal infestation is a probable etiological role in promoting carcinogenesis of colorectal neoplasms. Proposing that CP 690550 patients diagnosed as intestinal schistosomiasis undergo colonoscopy and pathological examinations regularly if necessary STK38 medical infrastructures are available. Assuring the periodical administration

of anthelminthics is essential to promote the control of schistosomiasis in endemic countries. Key Word(s): 1. colonoscopy; 2. pathology; 3. colorectal carcinoma; 4. schistosomiasis; Presenting Author: SHOMRON BEN-HORIN Additional Authors: TANIA BERDICHEVSKI, NATI KELLER, GALIA RAHAV, SIMON BAR-MEIR, RAMI ELIAKIM Corresponding Author: SHOMRON BEN-HORIN Affiliations: Sheba Medical Center Objective: Although pseudomembranes are the hallmark manifestation of Clostridium difficile-associated diarrhea (CDAD), there are scant data specifically addressing their impact on the clinical outcome. We investigated whether the formation of pseudomembranes predicts a worse CDAD outcome. Methods: CDAD patients hospitalized during 2010 underwent sigmoidoscopy and were followed prospectively. In addition, all hospitalized CDAD patients in 01/2000–12/2009 who underwent lower endoscopy were retrospectively identified and their charts reviewed. Patients with detectable pseudomembranes on endoscopy were compared to those in whom pseudomembranes were absent.

S2). Furthermore, in metastatic H2M cells that express a high level of EIF5A2 endogenously, treatment of specific siRNA against EIF5A2 suppressed stress fiber

formation. The level of total RhoA and Rac1 remained the same between LO2-EIF5A2 and LO2-Vec cells, indicating that EIF5A2 did not affect the expression of Rho/Rac GTPases. https://www.selleckchem.com/products/torin-1.html Rho-GTPase activity is determined by the amount of the GTP-bound form, which is regulated by RhoGAP (Rho-GTPase activating protein), RhoGEF (Rho-GTPase guanine exchange factors), as well as RhoGDI (Rho GDP dissociation inhibitor). Thus, EIF5A2 may target members of GEF, GAP, or GDI to increase GTP-bound Rho in EIF5A2 overexpressing cells. Further study is needed to identify which Rho regulator is targeted by EIF5A2 that leads to Rho-GTPase activation. A previous study has implicated DHPS as one of the metastasis signature genes.3 To date, EIF5A and EIF5A2 are the only known proteins that require posttranslational modification by DHPS. It is therefore a logical hypothesis that one or both of the proteins may be involved in the pathogenesis of cancer metastasis. EIF5A and EIF5A2 share 83% amino acid identity. Although the lethal effect of EIF5A disruption

could be partially rescued by EIF5A2, evidence is accumulating that they are not functionally redundant.30 EIF5A is ubiquitously expressed at a high level in all tissues, whereas EIF5A2 is normally undetectable except

in testis and brain.12 Moreover, amplification Morin Hydrate NVP-BKM120 manufacturer and overexpression of EIF5A2 was frequently detected in various malignancies,11, 20–22 indicating its unique role in cancer development and progression. In our HCC sample set analyzed for EIF5A2 mRNA expression, 43 cases (23 of which with overexpression of EIF5A2) were also analyzed for potential EIF5A2 gene copy number change. We did not detect any significant copy number change in these HCC samples using semiquantitative genomic PCR (data not shown), suggesting that EIF5A2 gene amplification may not be the major reason for its overexpression found in the current study. However, we could not rule out the possibility that small copy number changes may exist that were not detected by the assay used. Although DHPS was suggested to be a metastatic signature gene,3 overexpression of DHPS was not reported in HCC. In this study we screened the DHPS mRNA expression status in 45 HCCs by qPCR. The result showed that overexpression of DHPS (fold change >2) was detected in 6/45 (13.3%) of HCCs, indicating that EIF5A2 overexpression frequently detected in HCC could not be explained by the DHPS expression level alone. Other factors yet to be defined may also be involved in the regulation of EIF5A2 expression at the level of transcription, translation, and posttranslational modification.

case age sex Cirrhosis CT triple phase MRI Histology Art E Ven W Size (cm) Art E Ven W 1 = yes, 0 = no, x = not done, E = enhancement,

W = wash out, R = regenerative, corr dx = correct diagnosis Comparing the characteristics of these cases with the group of correctly diagnosed HCC using Fisher’s exact test or t test, (only the age mean reached statistical significance with age 63.88 vs. 51.20, p = 0.025). Only 2 of 5 patients with a false diagnosis showed typical radiological features of an HCC. In the group with a correct diagnosis of HCC, application of the AASLD guidelines would have resulted in liver biopsy for 26 of 50 patients with atypical imaging features. Conclusion: 1) A false

diagnosis of HCC was 9%. 2) A younger age was the only statistically significant patient characteristic RG7420 supplier associated with a false diagnosis of HCC. 3) Following AASLD guidelines liver biopsies could have prevented unnecessary hepatic resection in 2 patients with atypical imaging features, but would have resulted in unnecessary biopsies for 26 patients with correctly diagnosed HCC. TM GOODSALL,1 M MENON,2,3 S BOLLIPO,1,3 JK FERGUSON2,3,4 1Department of Gastroenterology, John Hunter Hospital, Newcastle, Australia, 2Department of Microbiology, Pathology North-Hunter, Newcastle, Australia, 3Faculty of Health and Medicine, The University of Newcastle,

Newcastle, Australia, 4School of Rural Medicine, PD-0332991 mouse University of New England, Armidale, Australia Introduction: Patients with cirrhosis and diuretic resistant ascites may require regular elective therapeutic abdominal paracentesis, which can be performed in an ambulatory setting. International ascites management guidelines recommend routine bedside inoculation of blood culture bottles for all paracentesis procedures as an adjunct to cell count to exclude spontaneous bacterial peritonitis (SBP); this recommendation is based on cohort second studies of patients selected for clinical features of SBP and/or neutrocytic ascites (Level 2a).1,2 The benefit of blood culture bottle inoculation when performing therapeutic paracentesis of otherwise well patients in an ambulatory setting has not previously been investigated. Methods: Data for all ascitic fluid samples received in our health care network over a twelve month period was extracted and de-identified. Samples were designated “inpatient” if collected during an admission to the emergency department or wards and “ambulatory” if collected at a gastroenterology clinic or day procedure unit. A positive result was defined as the growth of an organism in a blood culture bottle. For every positive result the medical records were reviewed for documentation of the relevant encounter.

41-43 Moreover, HCV infection induces apoptosis through the caspase-3-dependent pathway.44 In contrast, NS5A is involved in anti-apoptotic effects mediated by NF-κB activation in Huh-7 cells.45 Of interest, the role of NS4B in the regulation of NF-κB activity is influenced by the cellular microenvironment. NS4B HKI-272 mouse increases baseline NF-κB activity in the absence of TNF-α; however, the same protein suppresses NF-κB activity in the presence

of TNF-α. The mechanism by which NS4B regulates NF-κB activity needs to be elucidated in future molecular studies. HCV is known to efficiently evade the intracellular host defense system in various ways. Therefore, we questioned whether HCV has an advantage in viral replication by the inhibition of TNF-α-induced NF-κB activation.

From the viewpoint of viral persistence, TNF-α-induced cell death is not advantageous to the virus. Increased cell death in HCV-infected cells may hamper viral replication. Instead, we suggest that this mechanism may help HCV to escape from proinflammatory responses triggered by NF-κB. NF-κB controls the expression of many inflammatory proteins, including chemokines and adhesion molecules. Thus, suppression of TNF-α-induced NF-κB activation may enhance HCV persistence by limiting inflammation this website and further immune responses. At the same time, however, suppression of NF-κB activation also disrupts the balance between the survival and death of infected cells and sensitizes infected cells to TNF-α-induced cell death. In the current study, we demonstrated that HCV infection enhanced TNF-α-induced cell death through the suppression of NF-κB activation by the action of core, NS4B,

and NS5B. In the HCV-infected L-NAME HCl liver, TNF-α might be one of the major cytokines. TNF-α can be secreted by a range of immune cells, including T cells, NK cells, and monocytes and macrophages. Without HCV infection, TNF-α activates both signaling pathways (i.e., the anti-apoptotic NF-κB pathway and the proapoptotic JNK pathway), resulting in a cellular response that reflects a balance between survival and death. In HCV infection, however, TNF-α-induced NF-κB activation is suppressed by core, NS4B, and NS5B, and HCV-infected hepatocytes become vulnerable to TNF-α-induced cell death. This mechanism may explain the cause of liver injury in hepatitis C, which often progresses to liver cirrhosis and HCC. Additional Supporting Information may be found in the online version of this article. “
“The contribution of humoral immune responses to spontaneous control of hepatitis C virus (HCV) infection remains unclear. We assessed neutralizing antibody (nAb) responses during acute HCV infection to determine whether infection outcome is associated with the nAb response, specifically, its timing or breadth (neutralization of multiple genotype-matched variants).

18 Flow cytometry at day 11 confirmed depletion efficiencies of >95%. Following cardiac perfusion with phosphate-buffered saline, livers were aseptically removed and mechanically disrupted between sterile frosted microscope slides. Cell suspensions were passed twice through 70 μm filters before cell isolation. Liver CD11b+ cells were isolated using anti-CD11b magnetic beads and positive selection columns (Miltenyi) per the manufacturer’s protocol. Gr1+ cells were isolated using phycoerythrin-tagged

anti-Gr1 (RB6-8C5; eBioscience) and positive immunomagnetic separation using a phycoerythrin selection kit (StemCell Technologies, Inc.). CD11b+Ly6GhiLy6Clo cells were isolated via positive selection employing biotinylated anti-Ly6G and anti-biotin find more magnetic microbeads (Miltenyi). CD11b+Ly6G−Ly6Chi cells were isolated by negative selection of Ly6G− cells followed by positive selection with biotinylated anti-Ly6C and anti-biotin magnetic microbeads (Miltenyi). Flow cytometry verified that all cell isolations yielded >90% pure populations. Bead-isolated CD4+ T cells were

cultured for 3 days with plate-bound anti-CD3ε (10.0 μg/mL), soluble anti-CD28 (1.0 μg/mL; BD Biosciences) recombinant interleukin-12 (IL-12) (10 ng/mL; Peprotech) and anti-IL-4 (10 μg/mL; NCI). Th1 effector development was confirmed by intracellular IFN-γ staining. Cells were incubated with Fc Block (anti-CD16/CD32; eBioscience)

for 20 minutes at 4°C then washed twice. Cells were stained with antibodies to CD4, CD11b, Gr1, F4/80, programmed Quizartinib ic50 death ligand 1 (PD-L1; eBioscience, San Diego), Ly6G (Clone 1A8), Ly6C (Clone 1G7.G10), major histocompatibility complex class II (BD Biosciences), or CD14 (Biolegend) and acquired on either BD FACSCalibur (eBiosciences) or Accuri C6. Data analysis was performed with FlowJo, version 8.8.6 (Tree Star) software. Cells obtained from suppression assay cultures at 48 hours were surface stained as described above, fixed and permeabilized (CytoFix/CytoPerm; BD Biosciences), stained with rabbit anti-mouse iNOS (BD Biosciences), followed Tyrosine-protein kinase BLK by blocking with 10% normal goat serum, and secondary staining with goat anti-rabbit (Jackson ImmunoResearch). Surface-marker-appropriate isotype and intracellular staining with secondary antibody alone served as negative control. RAW 264.7 cells cultured for 24 hours with lipopolysaccharide and IFN-γ served as positive control. Cells were acquired by flow cytometry. Prior to inclusion in cocultures, bead-isolated CD4+ or CD8+ T cells from wild-type mouse spleens were stained with 5.0 μM 5-(and-6)-carboxyfluorescein diacetate, succinimidyl ester (CFSE; Invitrogen) for 10 minutes and quenched by washing twice in Roswell Park Memorial Institute medium 1640/10% fetal bovine serum. Isolated Tgfb1+/− or Tgfb1−/− CD11b+ cells were added at 3.0 × 105 (“300K”) or 1.

29–31 For instance, Theise et al.31 demonstrated that cells morphologically and immunohistochemically resembling hepatic progenitor cells merged with the HCC and CC components and with mature-appearing hepatocytes within some combined HCC-CC, supporting the notions that carcinogenesis of this unique neoplasm may be explained by the malignant transformation of the hepatic progenitor cells. Furthermore, a recent study32 demonstrated the cell of origin of cholangiolocellular carcinoma (Fig. 6), a very rare neoplasm accounting for less than 1% of primary liver cancer,33,34

may also be the hepatic progenitor cells. Because the HCC (Fig. 6a) and CC (Fig. 6b) components altogether comprised less Doxorubicin ic50 than

10% of the neoplasm and the cholangiolocellular carcinoma area (mixture of small monotonous glands, antler-like anastomosing pattern, selleck chemicals Fig 6c) occupied more than 90% of the neoplasm in this study, although these three histological components showed transitions between each other, the exact relationship between this unique neoplasm and the typical combined HCC-CC remains to be clarified. It is possible they may overlap to some degree and belong to a spectrum of the primary liver neoplasm arising from the hepatic progenitor cells. For the purpose of diagnosis, combined HCC-CC needs to be distinguished from conventional

HCC or CC. Pseudoglands (Fig. 7) reflecting rapid and active neoplastic replication are very common in HCC and they should not be confused with the true glandular formation in CC. In fact, Popper and Schaffner in 1957 stated that with careful examination most primary hepatic carcinomas could be found to have both hepatocellular and ductal elements,7 PJ34 HCl but Edmondson in the following year pointed out that in the majority of cases these ductal elements were from hepatocyte-like tumor cells and that such tumors are in fact a variant of HCC.3 Retrospectively, most of these ductal elements likely represent pseudoglands in HCC. In this regard, detection of mucin by a mucin stain in the CC component or identification of bile in the HCC component can be very helpful. As mentioned previously, it has been recognized that the expression of CK7 and CK19 in HCC is not uncommon from several series and therefore a diagnosis solely based on immunohistochemistry may not be fully reliable.23–25 In fact, a recent study using a comparative functional genomics approach has demonstrated that the CK19-associated gene expression signature may predict poor patient survival.35 Whether this poorer outcome can be largely attributed to the progenitor cell lineage of the carcinoma awaits further investigation.

14 Especially

because of the variability in species-specific hepatocyte tropism for candidate gene therapy vectors, such models also provide a useful platform for the exploration of directed gene therapy of the liver.15 Thus, although the extent to which this new model can be harnessed by the hepatological research community remains to be seen, a wide range of areas will potentially be advanced by successfully utilization of this experimental system. “
“The cell death receptor Fas plays a role in the establishment of fulminant hepatitis, a major cause of drug-induced liver failure. Fas activation elicits extrinsic apoptotic and hepatoprotective signals; however, the mechanisms by which these signals are integrated during disease are unknown. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls the critical sheddase a disintegrin and metalloproteinase 17 (ADAM17) and selleck Ibrutinib nmr may dictate stress signaling. Using mice and cells lacking TIMP3, ADAM17, and ADAM17-regulated cell surface molecules, we have found that ADAM17-mediated ectodomain shedding of TNF receptors and EGF family ligands controls activation of multiple signaling cascades in

Fas-induced hepatitis. We demonstrated that TNF signaling promoted hepatotoxicity, while excessive TNF receptor 1 (TNFR1) shedding in Timp3−/− mice was protective. Compound Timp3−/−Tnf−/− and Timp3−/−Tnfr1−/− knockout conferred complete resistance to Fas-induced toxicity. Loss of Timp3 enhanced metalloproteinase-dependent EGFR signaling due to increased release of the EGFR ligands TGF-α, amphiregulin, and HB-EGF, while depletion of shed amphiregulin resensitized Timp3−/− hepatocytes to

apoptosis. Finally, adenoviral delivery of Adam17 prevented acetaminophen-induced liver failure in a clinically relevant model of Fas-dependent fulminant hepatitis. These findings demonstrate that TIMP3 and ADAM17 cooperatively dictate cytokine signaling during death receptor activation and indicate that regulated metalloproteinase activity integrates survival and death signals during acute hepatotoxic stress. Murthy STK38 A, Defamie V, Smookler DS, Di Grappa MA, Horiuchi K, Federici M, et al. Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. J Clin Invest 2010;120:2731-2744. (Reprinted with permission.) Significant hepatocyte loss due to apoptosis accompanies most causes of liver injury.1 Apoptosis is the highly regulated process of programmed cell death and is essential to liver development, normal homeostasis, and disease.2 Apoptosis is the pathological hallmark of acute liver injury: in an unchecked manner, it can result in massive hepatocyte loss and fulminant acute liver failure.