Conclusion: These results indicate that the HCV core protein pote

Conclusion: These results indicate that the HCV core protein potentiates chemically induced HCC through c-Jun and STAT3 activation, which in turn, enhances cell proliferation, suppresses apoptosis, and impairs oxidative DNA damage repair, leading to hepatocellular transformation. Hepatology 2010 Hepatitis C virus (HCV) causes chronic hepatitis and liver cirrhosis and greatly increases the risk

for hepatocellular carcinoma (HCC).1-3 In both HCC and chronic hepatitis, the transcription factor activator protein-1 (AP-1) is activated and implicated.4 The ectopic expression of HCV core protein in cell cultures also activates AP-1 (c-Jun)5 via the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated Opaganib cost protein kinase,6, 7 and HCV core transgenic (Tg) mice develop liver tumors,8 suggesting the role of c-Jun in core-induced oncogenesis. The transcription activator c-Jun is required for cell proliferation in postnatal hepatocytes.9 Mice deficient in c-Jun die between embryonic days E12.5 and E13.5 from massive apoptosis of hepatoblasts, erythroblasts, and other cell types, indicating the requirement of c-Jun in normal liver development and hematopoiesis.10, 11 To rescue embryonic lethality,

a “floxed” c-jun allele is deleted in a designated cell type upon expression of the Cre recombinase under the control of a cell-type–specific promoter. Using this conditional gene disruption, the requirement for c-jun is also shown for chemically-induced HCC in mice where c-Jun deficiency in hepatocytes reduces both the number and size of check details HCC after tumor initiation with diethylnitrosamine (DEN), while increasing apoptosis.12 HCV

core protein induces reactive oxygen species (ROS), and HCV core Tg mice have higher hepatic levels of 8-oxo-2′-deoxyguanosine (8-oxodG), which is indicative of DNA damage by ROS.13 In fact, HCV core Tg mice show increased mutation frequencies of tumor suppressor and proto-oncogenes.13, 14 ROS also activates c-Jun and signal transducer and activator of transcription 3 (STAT3).15 Therefore, the core protein may increase 上海皓元 the growth and survival of initiated tumor cells via activation of c-Jun and STAT3. However, the mechanisms by which c-Jun and STAT3 specifically contribute to liver oncogenesis induced by interactions of HCV core and environmental carcinogens remain to be elucidated. Furthermore, whether HCV core protein works as a tumor initiator or promoter has not been determined.16 The present study demonstrates that the mitogenic and antiapoptotic effects mediated by c-Jun/AP-1 and STAT3 are both required for hepatocyte susceptibility to HCV core-initiated hepatocellular transformation, and that this is caused by fixation of genetic mutations induced by oxidative stress and impaired DNA repair, resulting from activation of c-Jun and nitric oxide (NO).

3%) out of 21 patients in the Diclofenac suppository

3%) out of 21 patients in the Diclofenac suppository AZD0530 group and whereas in control group pancreatitis was noted in 4 (19.0%) out of 21 patients with non significant P-value > 0.05. Whereas Asymptomatic hyperamylasemia occurred in 1 (4.8%) out of 21 patients in the

diclofenac group and in controlled group 7 (33.3%) out of 21 patients With the significant P-value = 0.045. Conclusion: Prophylactic administration of rectal NSAIDs significantly reduces the incidence of post-ERCP asymptomatic hyperamylasemia P-value0.045, but not reduces the incidence of pancreatitis. Further large randomized controlled trials are required before its introduction into routine care. Key Word(s): 1. Nonsteroidal anti-inflammatory drugs; 2. endoscopic retrograde cholangiopancreatography; 3. Post-ERCP pancreatitis; Presenting Author: WOO HYUN PAIK Additional Authors: DONG WAN SEO, JUN-HO CHOI, YONG-PIL CHO, DO HYUN PARK, SANG SOO LEE, SUNG KOO LEE, MYUNG-HWAN KIM Corresponding Author: DONG WAN SEO Affiliations: Asan Medical AP24534 Center Objective: We evaluated the clinical usefulness of the combination of color Doppler and contrast-enhanced harmonic EUS (CEH-EUS) in diagnosing visceral vascular diseases and in assessing morphological and hemodynamic characteristics required for adequate patient management. Methods: EUS was performed in 12 patients with clinically suspected

visceral vascular disease, as determined by computed tomography (CT) scan between February, 2012, and March, 2013. Conventional B-mode EUS, color Doppler EUS and CEH-EUS was done to evaluate vascular status of celiac artery (CA) and superior mesenteric artery (SMA). Results: We assessed a total of 12 patients. CT suggested dissection of the CA, SMA, and their branch arteries in nine patients; stenosis or occlusion of the splanchnic vessels in two patients; and periarterial MCE soft tissue cuffing surrounding the CA in one patient. EUS correctly

identified all the visceral vascular lesions in 11 patients: eight visceral artery dissection and three mesenteric artery stenosis. One patient in suspicion of SMA dissection on CT was proved to be normal by EUS. EUS also identified one undefined dissection not detected on abdominal CT. EUS showed an intimal flap in five patients and blood flow of the true lumen and thrombi of the false lumen in eight patients. In addition, the stenotic area could be calculated using color Doppler EUS. Two patients underwent surgical thrombectomy and angioplasty because there was total occlusion of SMA on color Doppler and CEH-EUS. EUS showed no flow signal within a long segment of the SMA, indicating its total occlusion, in both patients. Conclusion: The combination of color Doppler and CEH-EUS may be a promising diagnostic modality to assess the splanchnic artery without exposure to radiation. Moreover, EUS is a useful tool in determining appropriate treatments for patients with isolated mesenteric artery dissection. Key Word(s): 1. EUS; 2. Diagnosis; 3.

2D; different letters indicate significance, P < 005) PBA treat

2D; different letters indicate significance, P < 0.05). PBA treatment significantly reduced ER stress–induced formation of apoB-GFP-LC3–positive cells and number of apoB-GFP-LC3 puncta (Fig. 2B, and analysis data shown in Fig. 2C; P < 0.05), and decreased apoB-GFP-LC3-II conversion (Fig. 2D; P < 0.05). Furthermore, PBA treatment markedly inhibited ER stress based on reduced cellular levels of GRP78 and phosphorylated eIF-2α (Fig. 2D). PBA treatment also prevented the loss of newly synthesized cellular and secreted apoB-100 (Fig. 2E) following TM and GLS treatment (different letters indicate significance, P < 0.05). These results strongly indicate that the induction of ER stress

augments autophagic degradation of apoB, whereas suppression of ER stress blocks apoB autophagy. We next assessed whether autophagic degradation

of apoB also occurs in primary hepatocytes. AZD2281 mouse Primary rat hepatocytes were transiently transfected with GFP-LC3 cDNA for 40 hours, and then treated with TM (5 μg/mL) or GLS (5 mM) for 4 hours in the presence or absence of PBA (1 mM). Treatment with TM or glucosamine resulted in substantially increased colocalization of apoB with GFP-LC3 and increased number of apoB-GFP-LC3 puncta (Fig. 3A, panels f and i; analysis of data shown in Fig. 3C; *P < 0.05 versus corresponding control). Similar results were obtained when colocalization of apoB and endogenous LC3 was examined in nontransfected cells (Supporting Fig. 2). Increased apoB-GFP-LC3 MCE公司 puncta were observed together with elevated endogenous AP24534 solubility dmso LC3-II conversion (Fig. 3D; *P < 0.05). Importantly, treatment with TM and glucosamine decreased [35S]-labeled

cellular and secreted apoB100 (Fig. 3E,F; different letters indicate significance, P < 0.05), apoB48 was also slightly reduced but this change did not reach statistical significance suggesting that ER stress induces autophagy of apoB100 in primary rat hepatocytes. Importantly, PBA treatment inhibited colocalization of apoB with GFP-LC3 (Fig. 3B, panels f and i; analysis of data shown in Fig. 3C), reduced the endogenous LC3-II conversion (Fig. 3D; different letters indicate significance, P < 0.05), and led to a significantly increased recovery of [35S]-labeled cellular or secreted apoB100 (Fig. 3E,F; different letters indicate significance, P < 0.05), suggesting that blocking ER stress prevents apoB autophagy. Interestingly, PBA was also found to significantly block colocalization of apoB with GFP-LC3 in primary rat hepatocytes under basal conditions (Fig. 3C; top panel, *P < 0.05 versus corresponding control). However, under basal conditions, PBA did not significantly alter the number of apoB-GFL-LC3 puncta in positive cells (Fig. 3C, bottom panel), or endogenous LC3-II conversion (Fig. 3D).

Per-SVR %point increase in QALE // Per-SVR %point cost saving Dis

Per-SVR %point increase in QALE // Per-SVR %point cost saving Disclosures: Hayley Bennett Wilton – Consulting: BMS Philip McEwan – Consulting: Bristol-Myers Squibb Anupama Kalsekar click here – Employment: Bristol Myers Squibb Yong Yuan – Employment: Bristol Myers Squibb Company The following people have nothing

to disclose: Thomas Ward Background: With the aging HCV cohort in Sweden, the burden of HCV-related disease will probably increase in the coming decade. Until now, approximately 1,100 persons per year were treated with interferon (IFN)-containing regimens. We examined the possible impact of new direct acting antivirals (DAAs) on the future HCV epidemic and the burden of disease from a Swedish perspective. Methods: Treatment strategies PD98059 with new DAAs resulting in higher sustained virologic response (SVR) rates, treating individuals with METAVIR stage ≥F3, were modeled from 2014 to 2030, analyzing the predicted impact on the disease burden and total viremic cases in Sweden. Baseline scenario was IFN-containing therapies including first generation of protease inhibitors as used in 2012 with 1,100 treatments annually. Future scenarios

with increased costs in interferon-free DAA regimens leading to reduction of number of treated due to limited health care budget were modeled. New DAA treatment scenarios were: 1. Maintained budget: reduction to 380 persons treated annually, 2. Doubled maintained budget: 760 persons treated annually, 3. Maintained

number: 1,100 persons treated annually. Results: Using new DAAs, treating 380 persons per year did not impact the future burden of liver disease but resulted in a 17 %increase in the number of viremic cases (n=5,390) by 2030, compared with the baseline scenario. Treating 760 persons decreased the incidence of medchemexpress HCC by 48 %and the number of liver-related deaths by 50%, but the total viremic cases remained the same. Maintaining treatment of 1,100 persons annually, the corresponding figures for HCC and liver-related deaths were 53 %and 58%, with minimal impact (10 %decrease) on the total viremic cases. Conclusions: Significant reduction in mortality and HCC is possible in Sweden with usage of new DAAs, assuming the future availability of potent antivirals for a sufficient number of patients. To reduce the HCV prevalence, higher number of treatments will be needed. These results may facilitate disease forecasting, and the development of rational strategies for HCV management in Sweden.

Zhendao 88 was derived principally from resistance to RSV and con

Zhendao 88 was derived principally from resistance to RSV and controlled by a single dominant gene. Breeding for rice stripe resistance could be accelerated by using cv. Zhendao 88 as a resistant parent if the linked marker for virus resistance were used in a marker-assisted progeny selection programme. “
“Colletotrichum acutatum J.H. Simmonds was identified from fruit clusters of hazelnut (Corylus avellana L.) in Turkey. Pathogenicity tests were conducted under laboratory, greenhouse and field conditions.

Necrotic, sunken lesions and rot were observed on leaves, fruit clusters and pedicels. This is the first report of C. acutatum as a pathogen of hazelnut. “
“Chitosan has recently shown potential for the control of plant diseases and can

act as http://www.selleckchem.com/products/bmn-673.html an elicitor Buparlisib purchase in the induction of defence mechanisms. This study was made to assess the effect of chitosan on bacterial spot control caused by Xanthomonas gardneri in tomato plants. The chitosans used were commercial (Ccom), low molecular weight (Clmw) and medium molecular weight (Cmmw). Chitosans provided disease protection of up to 56%, with best results from Clmw at 3 mg/ml, applied 3 days prior to bacterial inoculation. The spectrophotometric profile of tomato plants that were treated with Clmw showed an increase of absorbance between wavelengths 280 and 300 mm, indicating that the polysaccharide may have induced the plants into synthesizing different compounds as a response to X. gardneri. The analysis of total phenolic compounds and flavonoids supported the results obtained in spectrophotometric scanning, showing a significant increase of those metabolites 3 days after inoculation. Therefore, chitosan has the capability of controlling bacterial spot in tomato plants, which is thought to be attributable to the induction of defence mechanisms in the plant. “
“Downy mildew (DM), caused by Pseudoperonospora cubensis (Berk. & M.A. Curtis) Rostovzev, is a worldwide major disease of PAK5 cucumbers (Cucumis sativus L.). By screening 10 introgression lines (ILs) derived

from interspecific hybridization between cucumber and the wild Cucumis, C. hystrix, through a whole plant assay, one introgression line (IL52) was identified with high DM-resistance. IL52 was further used as a resistant parent to make an F2 population with ‘changchunmici’ (susceptible parent). The F2 population (300 plants) was investigated for DM-yellowing, DM-necrosis and DM-resistance in the adult stage. A genetic map spanning 642.5 cM with 104 markers was constructed and used for QTL analysis from the population. Three QTL regions were identified on chromosome 5 and chromosome 6. By interval mapping analysis, two QTLs for DM-resistance were determined on chromosome 5 (DM_5.1 and DM_5.2), which explained 17.9% and 14.2% of the variation, respectively. QTLs for DM-yellowing were in the same regions as DM-resistance.

In DC patients, survival at 1 year after the first episode of dec

In DC patients, survival at 1 year after the first episode of decompensation (ascites in 78% of cases) was 99% for CPT A, 87% for CPT B and 73% for CPT

C (OI#4). 3% of DC patients had an episode of VB, with survival of 88% after 6 weeks from the VB episode (OI#5) and with recurrence Daporinad cell line rate of 27% (OI#6). 1 9 out of 748 DC patients (3%) had spontaneous bacterial peritonitis, with 79% survival after 6 weeks from the episode (OI#7). In conclusion, the selected OIs performed well in monitoring the rate of decompensation in CC and the accuracy of surveillance for HCC; in DC, OIs were able to capture survival and the efficacy of management of major complications. This study represents the first attempt to identify and test a set of value-based OIs for LC, and provides a reference tool for healthcare policy makers to improve quality of care in patients affected by LC. Disclosures: Michele Colledan – buy Ensartinib Advisory Committees or Review Panels: novartis

The following people have nothing to disclose: Stefano Okolicsanyi, Antonio Ciaccio, Matteo Rota, Maria Gentiluomo, Marta Gemma, Antonella Grisolia, Roberto Scirpo, Paolo A. Cortesi, Luciana Scalone, Lorenzo G. Mantovani, Silvia Pecere, Patrizia Pontisso, Patrizia Burra, Mario U. Mondelli, Luca Fabris, Stefano Fagiuoli, Maria G. Valsecchi, Giancarlo Cesana, Luca S Belli, Mario Strazzabosco Purpose: Based on our Hepatitis Outreach Network (HONE) screening program data, approximately 60% of at-risk foreign-born populations who tested positive for viral hepatitis B and/or C followed up for additional care. The goal of this project was to use theory driven qualitative research

to identify barriers and facilitators to achieving follow-up care after receipt of viral hepatitis diagnosis among community members from the viewpoint of primary care providers (PCPs). As viral hepatitis is a precursor of liver cancer, timely treatment of the virus has the potential to reduce the incidence and burden of liver cancer. Method: With IRB approval, we performed semi-structured new key informant interviews with 20 PCPs who predominantly serve Korean, Chinese, Egyptian, and Russian communities. The 45 minute interviews were audio-taped. Transcriptions were analyzed using Strauss variant grounded theory and a thematic approach, informed by the Andersen Aday and PEN-3 frameworks. These frameworks are conceptual behavioral frameworks that articulate factors that lead to the use of health services and categorize participant responses into domains that can then be applied to an educational message, program format, and content. Results: Median age of the providers was 46, with 55% male. Median time practicing in their current location was 5 years. Responding physicians typically were married and born in their respective country of origin. Barriers detected included cultural factors commonly seen amongst foreign-born populations such as busy work schedules, non-English language, mistrust of the medical system, and high medical cost.

Galectin-9 is not the sole suppressive molecule expressed on HCC-

Galectin-9 is not the sole suppressive molecule expressed on HCC-associated KCs. We have previously demonstrated that KCs express high

levels of B7-H1 (PD-L1) in HCC, interact with PD-1+ T cells, Ferroptosis inhibitor drugs and mediate T-cell exhaustion.17 The pathological relevance of the B7-H1/PD-1 signaling pathway has been observed in many other types of human cancer, and the B7-H1/PD-1 signaling pathway is the justified target for treating human cancer.17 Interestingly, PD-1+ and Tim-3+ T cells are two distinct T-cell populations in HCC. Our studies support the notion that KCs play a negative role in anti-HCC immunity through two distinct molecular pathways, namely, Tim-3/galectin-9 and B7-H1/PD-1. As the expression of B7-H118, 19 and Tim-3 (this work) is negatively associated with HCC patient outcome, it is tempting to speculate B-Raf inhibitor clinical trial that simultaneous blockade of the B7-H1/PD-1 and Tim-3/galectin-9 signaling pathways may synergistically recover T-cell immunity and improve HBV-associated HCC patient outcome. In addition to its clinical relevance, our work raises an important issue that IFN-γ may play dual roles in tumor immunity.41

The immune stimulatory role of IFN-γ has been well appreciated. IFN-γ is elevated in patients with HCC. It is thought that uncontrolled immune activation, including large amounts of IFN-γ, may result in liver damage.42, 43 We have observed that tumor-infiltrating T-cell-derived IFN-γ potently stimulates galectin-3 expression on KCs in HCC. Interestingly, IFN-γ also induces B7-H1 expression on APCs.44, 45 Thus, galectin-3 and B7-H1 induced by T-cell-derived

IFN-γ may be able to fine-tune and temper local immune response, and to avoid over T-cell activation-mediated liver damage. However, this mechanism may be beneficial for tumors to evade tumor immunity. In further support of this possibility, in addition to galectin-3 and B7-H1, IFN-γ can induce the expression of noncognate MHC class I,46 indoleamine-2,3-dioxygenase (IDO),47 and arginase,48 which limit T-cell activation, proliferation, and effector function.49 Furthermore, a recent study has shown that UVB irradiation induces an IFN-γ-associated gene signature in murine melanocytes and results in increased tumorigenesis.50 These immune regulatory roles of IFN-γ are consistent with several studies in patients with cancer. Most clinical trials of IFN-γ treatment this website did not demonstrate clinical efficacy in patients with melanoma.51-54 Multiple clinical trials have demonstrated that IFN-γ-treated patients fare worse than untreated patients.55, 56 Thus, although IFN-γ is a potent immune effector cytokine, it induces B7-H1, IDO, arginase, nonclassical MHC expression, and galectin-3, which may participate in a feedback mechanism to efficiently down-regulate antitumor immunity. In order to achieve clinical efficacy, novel regimens of tumor immune vaccination and therapy may have to maximize beneficial effects and minimize detrimental effects of IFN-γ.

Galectin-9 is not the sole suppressive molecule expressed on HCC-

Galectin-9 is not the sole suppressive molecule expressed on HCC-associated KCs. We have previously demonstrated that KCs express high

levels of B7-H1 (PD-L1) in HCC, interact with PD-1+ T cells, Alvelestat and mediate T-cell exhaustion.17 The pathological relevance of the B7-H1/PD-1 signaling pathway has been observed in many other types of human cancer, and the B7-H1/PD-1 signaling pathway is the justified target for treating human cancer.17 Interestingly, PD-1+ and Tim-3+ T cells are two distinct T-cell populations in HCC. Our studies support the notion that KCs play a negative role in anti-HCC immunity through two distinct molecular pathways, namely, Tim-3/galectin-9 and B7-H1/PD-1. As the expression of B7-H118, 19 and Tim-3 (this work) is negatively associated with HCC patient outcome, it is tempting to speculate Selleckchem Alectinib that simultaneous blockade of the B7-H1/PD-1 and Tim-3/galectin-9 signaling pathways may synergistically recover T-cell immunity and improve HBV-associated HCC patient outcome. In addition to its clinical relevance, our work raises an important issue that IFN-γ may play dual roles in tumor immunity.41

The immune stimulatory role of IFN-γ has been well appreciated. IFN-γ is elevated in patients with HCC. It is thought that uncontrolled immune activation, including large amounts of IFN-γ, may result in liver damage.42, 43 We have observed that tumor-infiltrating T-cell-derived IFN-γ potently stimulates galectin-3 expression on KCs in HCC. Interestingly, IFN-γ also induces B7-H1 expression on APCs.44, 45 Thus, galectin-3 and B7-H1 induced by T-cell-derived

IFN-γ may be able to fine-tune and temper local immune response, and to avoid over T-cell activation-mediated liver damage. However, this mechanism may be beneficial for tumors to evade tumor immunity. In further support of this possibility, in addition to galectin-3 and B7-H1, IFN-γ can induce the expression of noncognate MHC class I,46 indoleamine-2,3-dioxygenase (IDO),47 and arginase,48 which limit T-cell activation, proliferation, and effector function.49 Furthermore, a recent study has shown that UVB irradiation induces an IFN-γ-associated gene signature in murine melanocytes and results in increased tumorigenesis.50 These immune regulatory roles of IFN-γ are consistent with several studies in patients with cancer. Most clinical trials of IFN-γ treatment Inositol monophosphatase 1 did not demonstrate clinical efficacy in patients with melanoma.51-54 Multiple clinical trials have demonstrated that IFN-γ-treated patients fare worse than untreated patients.55, 56 Thus, although IFN-γ is a potent immune effector cytokine, it induces B7-H1, IDO, arginase, nonclassical MHC expression, and galectin-3, which may participate in a feedback mechanism to efficiently down-regulate antitumor immunity. In order to achieve clinical efficacy, novel regimens of tumor immune vaccination and therapy may have to maximize beneficial effects and minimize detrimental effects of IFN-γ.

Our findings reveal that dysregulation of miRNA-122 (miR-122) con

Our findings reveal that dysregulation of miRNA-122 (miR-122) contributes to hepatic insulin resistance through PTP1B induction. Flavonoids are being actively studied Decitabine solubility dmso as potential treatments for components of the metabolic syndrome. In our previous study, treatment with licorice flavonoid ameliorated liver steatosis.12 In the present study, we additionally discovered the effect of c-Jun

N-terminal kinase 1 (JNK1) inhibition by isoliquiritigenin (IsoLQ) or liquiritigenin (LQ) on miR-122 dysregulation using in vivo models and cell-based assays. Here, we report that they have the ability to abolish hepatic insulin resistance by recovering the constitutive expression of miR-122 responsible

for PTP1B down-regulation. Information on the materials used in this study is described in the Supporting Information. Animal studies were conducted in accordance with the guidelines of the Institutional MLN0128 cell line Animal Use and Care Committee. Male C57BL/6 mice at 6 weeks of age were started on a high-fat diet (HFD) for 11 weeks. Detailed information is provided in the Supporting Information. HepG2, H4IIE, C2C12, and 3T3-L1 cell lines were purchased from the American Type Culture Collection (ATCC, Rockville, MD). The isolation of primary rat hepatocytes is described in the Supporting Information. The plasmid containing Luc-PTP1B-3′UTR (3′-untranslated region; Product ID: HmiT015828-MT01) was specifically synthesized (GeneCopoeia, Rockville, MD) and was used in luciferase reporter assay. The plasmid contains firefly luciferase fused to the 3′UTR of human PTP1B, and Renilla luciferase that functions as a tracking gene. pMiR-122a luciferase reporter vector containing the firefly luciferase gene and miR-122 target site at 3′UTR was purchased from Signosis (Sunnyvale, CA). When

miR-122 is expressed, it binds to the sequence and results in repression of the luciferase gene. The sources of other vectors and procedures used in this study for transient transfections and reporter gene assays are provided in the Supporting Information. Total only RNA was extracted with TRIzol (Invitrogen, Carlsbad, CA) and was reverse-transcribed. Quantitative real-time PCR (qRT-PCR) was performed with the Light Cycler 1.5 (Roche, Mannheim, Germany). Chromatin immunoprecipitation assay was done using the EZ ChIP kit (Upstate Biotechnology, Lake Placid, NY) according to the manufacturer’s protocol. HFD feeding increased the mRNA and protein levels of PTP1B (Fig. 1A); the change in the level of PTP1B protein was greater than that in its mRNA, suggesting that a posttranscriptional mechanism might be involved in this event. RNA22 and TargetScan programs enabled us to select miRNAs that potentially bind to the 3′-untranslated region (3′UTR) of PTP1B (PTPN1) mRNA (Fig.

Non-English

Non-English ABT-888 datasheet articles were translated by a medical specialist fluent in the respective languages. All prospective, controlled, experimental (randomized), and observational (nonrandomized) studies in which IL-2Ra induction therapy in liver transplant recipients was compared with placebo or no treatment were included. For comparison

1, we included only studies in which IL-2Ra was compared to placebo or no treatment with otherwise the same immunosuppressive treatment in both study arms. For comparison 2, we included studies with reduced and/or delayed CNI in combination with IL-2Ra; and in comparison 3, we included studies with reduced corticosteroids in combination with IL-2Ra. Other immunosuppressive medication, e.g., mycophenolate mofetil, had to be the same in both treatment arms. Studies with historical controls were also included, but we excluded studies in which both cohorts were assessed retrospectively. We also

excluded noncontrolled studies and pharmacological studies that did not provide data on clinical outcome measures because of their very short follow-up time. With regard to patient selection, we excluded trials with patients undergoing multiorgan transplantation or retransplantation. The primary outcomes analyzed were graft loss, acute rejection, steroid-resistant rejection, and death. Other outcome measures assessed were renal dysfunction BMN-673 (serum creatinine and/or estimated glomerular filtration rate [eGFR]), de novo malignancy (excluding recurrence of hepatocellular

carcinoma), PTLD, infectious complications, including cytomegalovirus (CMV) infection, new onset of metabolic and cardiovascular disorders, such as hypertension, hyperlipoproteinemia, and posttransplant diabetes mellitus (PTDM), and all other adverse reactions (as a direct consequence of drug treatment). There were four reviewers (A.D.G., A.O., N.H., N.B.). The literature search strategy was designed and Tacrolimus (FK506) performed by three reviewers (A.D.G., A.O., N.H.). The search results were combined in an open source reference management software (JabRef v. 2.6.0). Publications were screened independently by three reviewers (A.D.G., N.H., N.B.). Disagreement and any discrepancies were resolved by discussion (A.O. with A.D.G., N.H., N.B.). Data extraction was performed by two reviewers (A.D.G., N.H.), using a standardized form. A training set was used to validate data extraction. Quality of studies was assessed independently by two reviewers (A.D.G., N.H.) without blinding to journal and authorship. The quality items assessed were blinding, randomization, allocation concealment, intention-to-treat analysis (ITT), completeness of follow-up, and the method of handling missing values. Assessment was performed according to definitions stated in the Cochrane Handbook.8 Furthermore, completeness of follow-up was defined as the number of patients that were not lost to follow-up.