Therefore, it is speculated that the miRNAs described above play an important role in regulating immune responses and that their expression profiles in xenograft rejection is significantly different from those in allograft rejection; this Pictilisib implies that the mechanism of xenograft rejection is more complex. In this study, our data showed that miR-146a and miR-155 were simultaneously upregulated after

xenotransplantation. In support of this finding, miR-155 was also found upregulated in acute rejection following renal and small bowel transplantation.[9, 12] In the recent years, some studies have shown that miR-155 and miR-146a are the most important two miRNAs critically involved in immune and inflammatory responses. For example, it has been reported that miR-155 and miR-146a are considered as a new class of immunoregulatory factors and

can be abundantly expressed in macrophages.[13, 14] The researchers found that the human mononuclear cell line THP-1 with lipopolysaccharide (LPS) stimulation developed upregulation of three types of miRNA, including miR-146a/b, miR-132, and miR-155.[15, 16] Further studies also demonstrated that miR-146a/b expression can be induced by the TLRs (TLR2, TLR4, and TLR5) ligand for recognition of bacterial components on the cell surface.[16] Moreover, the expression of miR-146 induced by TLR ligand, TNF-α, and IL-1β suggests the dependence of NF-κB activation in regulating the immune response.[15] Selleckchem AZD0530 More importantly, second two important molecules, TRAF6 and IRAK1, have been proved to be the direct targets of miR-146 in the TLR/IL-1β pathway.[17] It suggests that as a negative regulator, miR-146a/b rely mainly on the complementary combination of IRAK1 or TRAF6 in the 3′-UTR region at the post-transcriptional level to inhibit TRAF6 and IRAK1, and thus play a feedback regulation of the immune signal transduction in order to regulate the body’s immune response to inflammatory stimuli.[17] Bhaumik et al.[18] also believed

that it is the IL-1 receptor signal that starts miR-146a/b upregulation and secretion of cytokines. Furthermore, miR-146a/b expression in response to the elevated levels of inflammatory cytokines is a negative feedback loop process; higher miR-146a/b expressions would thereby inhibit IL-6 and IL-8 secretion.[18] Unlike miR-146, miR-155 can be induced by TLR3 ligand with the body of the poly(I:C) and IFN-β/γ.[19] Connell et al.[19] have found that miR-155 gene expression is significantly upregulated with stimulation of IFN-β, IFN-γ, poly-inosinic acid, and LPS and that cytokine stimulation can cause changes of miR-155 level in the immune cells. Tili et al.[20] have also reported that LPS could induce miR-155 upregulation in macrophages. In addition, TNF-α-stimulation changes miR-155 expression level in murine Raw264.

8% in 2008).[16] In the Australian dialysis population, infection accounted for 11% of mortality, the third most common cause of death following dialysis withdrawal (35%) and cardiac disease (43%)[17] Of the 11% (n = 148), approximately 25% was secondary to bacterial septicaemia. Similarly, 17% of mortality was attributed to infection in the New Zealand dialysis population. CRI has an enormous adverse impact, not only at individual level of increased morbidity and mortality, but also financial implications with the costs of hospital admissions, antibiotics use and catheter change. Cost-per-infective-episode has been estimated to be between US$3703 and US$29 000 in the USA from non-tunnelled catheters in intensive care

units.[18] With the high incidence of catheter use in incident haemodialysis patients, it is imperative to develop strategies to prevent Rucaparib manufacturer and treat CRI. There have been studies examining the application of topical agents to the exit site to prevent both local and systemic infections. Intense interests have been concentrating on the use of antimicrobial lock solutions (ALS) to reduce CRI in recent years. Once bacteraemia has occurred, catheter removal, with or without delay in insertion of a new vascular catheter, is often indicated. Alternative therapy such as combining systemic antibiotics and ALS, without changing the catheter, has been evaluated in the literature. The objective of this guideline is to identify appropriate recommendations for central Trametinib venous catheter insertion and catheter care, as well as prevention and treatment of CRI in dialysis patients with tunnelled catheters in-situ. Dressing type, frequency of dressing changes and cleansing solutions will be addressed. The use of topical agents or intraluminal lock solutions will be investigated as will be the various treatment strategies for CRI. The use of real-time ultrasound guidance is strongly recommended for the placement of haemodialysis catheters and results in improved rates of successful catheter

placement, and reduced rates of both haematoma formation and inadvertent arterial puncture. (Level 1 evidence) (Suggestions are based on Level III and IV evidence) The adherence to strict aseptic technique is proven to reduce the catheter related bacteraemia rate and all units should therefore audit this practise. Tunnelled haemodialysis GBA3 catheters should be used as they are associated with lower rates of catheter related bacteraemia, catheter dysfunction and vascular damage (venous trauma, and stenosis) compared with temporary non-tunnelled catheters. The right internal jugular vein is the preferred insertion site with respect to ease of access and lower rates of short and long-term complications. In ICU settings, subclavian catheter placement has excellent short-term outcomes compared with jugular and femoral approaches but has significant long-term sequelae recommending against their use.

, Shanghai, China) and stimulated with HspX, Ag85B, purified protein derivative selleck and Mpt64190–198, respectively, with ConA and PBS as positive and negative controls, for 36 h at 37 °C, 5% CO2. The cells were then removed, and 200 μl/well ice-cold deionized water was added to lyse the remaining cells. The plates were incubated on ice for 15 min, after which they were washed 10 times with PBST. Next, biotinylated detector antibody solution was added and the plates were incubated

for 1 h at 37 °C. The plates were washed five times with PBST, after which 100 μl/well streptavidin–horseradish peroxidase was added. The plates were again incubated for 1 h at 37 °C and washed five times with PBST. One hundred microlitres of AEC (3-amino-9-ethylcarbazole) substrate was added to each well. The plates were developed for 25 min at room temperature in the dark. The wells were washed with distilled water to stop development when the stained cells were counted on an automated ELISPOT reader and analysed with ImmunSpot software (Bio-sys, GmbH, Karben, Germany). Protective

efficacy assay.  Mice were sacrificed for bacterial CFU count at 6th week post-challenge with H37Rv. The lower left lobe of the lungs from infected mice (n = 7) was harvested, homogenized in 0.05% PBS-Tween 80 and planted in 10-fold dilutions (10–1000) www.selleckchem.com/products/RO4929097.html on Middlebrook 7H11-OADC agar (BD, Franklin Lakes, NJ, USA) containing ampicillin (10 μg/ml) to prevent contamination. Bacterial colonies were counted 3 weeks after incubation Selleck ZD1839 at 37 °C. Histopathology of the lung tissues.  Each upper lobe of the left

lung of infected mice (n = 5) was harvested 6 weeks after challenge. The lobes were fixed with 10% neutral buffered formalin. After 2 weeks, each lobe was bisected with 5 μm thick to examine the same area of the lung in all mice. The sections were stained with haematoxylin and eosin (HE) and Ziehl–Neelsen Method. Granulomas area was divided by total section area to determine the affected area in a section. Histopathology was evaluated by three pathologists independently. Statistical analysis.  The results were expressed as means ± standard deviation (SD) and analysed by SPSS10.0 software (Statistical Product and Service Solutions Company, Chicago, IL, USA). The significance of differences among the groups was determined by analysis of variance (anova). Independent-samples t-test was used for Ziehl–Neelsen stain. Probability values (P < 0.05) were considered as statistically significant. The correct DNA sequence for the recombinant fusion protein, AMH was confirmed by sequencing and was found to encode a protein with molecular weight of 54.6 kDa. AMH was overexpressed in E. coli in inclusion bodies, which were subsequently dissolved and purified with Ni-NTA His affinity chromatography.

16 Although the role of eosinophils in the immune response to fungal infections has not been extensively studied, there are some results suggesting that Coccidioidomycosis, caused by the fungus Coccidioides immitis, may be accompanied by an

increase in peripheral blood eosinophils of the order of 3–10%.17 Moreover, during TSA HDAC Paracoccidioidomycosis in humans, Wagner et al.18 have shown a clear association among the presence of Paracoccidioides brasiliensis, infiltration of the lesion by eosinophils and deposition of myelin basic protein (MBP) on the fungus. In this regard, Feldmesser et al.19 have demonstrated in vitro that rat eosinophils phagocytose opsonized C. neoformans yeasts, and they also observed a direct

interaction between eosinophils and C. neoformans in vivo during an experimental murine intratracheal infection. Even though eosinophils are unlikely to be the predominant effector cells in the immune response to this organism, their occurrence, in intimate association with C. neoformans, suggests a potential function for eosinophils as effector cells. The aim of this study was to evaluate the ability of rat peritoneal eosinophils to be activated by C. neoformans yeasts in order to present fungal antigens to T cells, thereby promoting the development of an immune response to this pathogen. The results presented here show that eosinophils became activated by C. neoformans, increasing the surface expression of MHC class I and class II and of CD80 and CD86, resulting in Sorafenib mouse the secretion of proinflammatory cytokines, such as IL-12, IFN-γ and tumour necrosis factor-α (TNF-α). Finally, this work demonstrated that these fungal-activated eosinophils induce the development of a C. neoformans-specific T-helper 1 (Th1) immune response. For cell cultures, RPMI-1640 supplemented with 10% fetal bovine serum (FBS), 2 mm glutamine and 50 μg/ml of gentamycin (Sigma-Aldrich Co., St Louis, MO) was used. The mouse monoclonal antibodies (mAbs) anti-rat SSR128129E CD32 (FcγRII), CD18 (WT.3), MHC class II (RT1b),

MHC class I (RT1a), CD80 (B7-1), CD86 (B7-2), OX-62, CD11b/c, CD4, CD8a, CD25, IFN-γ (DB-1), IL-4 (OX-81) and IL-10 (A5-4) were obtained from BD Biosciences (San Jose, CA). The glucuronoxylomannan-specific mAb, 3C2 (mouse IgG1), was a generous gift from Thomas R. Kozel (Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557). Recombinant rat GM-CSF was obtained from BioSource (Camarillo, CA), and 2′,7′-dichlorodihydrofluorescein diacetate (DCF) was obtained from Sigma-Aldrich. Male, 7- to 8-week-old Wistar rats, weighing 250 g, were housed and cared for in the animal resource facilities of the Department of Clinical Biochemistry, Faculty of Chemical Sciences, National University of Cordoba, following institutional guidelines.

15, 23 In this study, we examined whether ICC and HCC are distinct at the transcriptomic levels. Using two independent transcriptomics approaches, we found that ICC cases from Asian patients can be mainly divided into two subgroups with one resembling of stem-like HCC and other mature hepatocyte-like HCC. Consistently, we found that several known hepatic stem/progenitor cell-specific genes such as POU5F1 (Oct4), NANOG, MYC, TGFB1, NCAM1, and PROM1 are more abundantly expressed in stem-like ICC than mature hepatocyte-like ICC.29 Alectinib clinical trial Moreover, both ICC-specific

mRNA and microRNA signatures could independently predict HCC survival as well as ICC prognosis in Caucasian patients. These results are consistent with our recent finding that a subset of HCC may share an ICC-like gene expression trait.15 Integrative pathway analyses revealed that an altered miR-200c signaling pathway linked to EMT may be responsible for the maintenance of stem-like ICC associated with poor prognosis. For example, we found that two significant microRNAs, i.e., miR-200c and miR-141, encoded by the same transcript, were negatively correlated with

genes in the TGF-β, NF-κB, and Smad signaling pathways. These two microRNAs share the same seed sequences and are predicted to have Selleckchem BAY 73-4506 similar cellular functions. EMT is an important biological process contributing to embryogenesis and organ development.30 Recently, components of EMT have been shown to be critical in promoting cancer invasion and metastasis.31 TGF-β is essential for the induction of EMT during various stages of embryogenesis and plays an important role in carcinoma progression into an invasive state.32-34 Smad signaling is essential for TGF-β-induced EMT.35 Furthermore, miR-200 family members including miR-141 and miR-200c induce epithelial differentiation, thereby suppressing EMT by inhibiting Carnitine palmitoyltransferase II translation of mRNA for the EMT-activators ZEB1 and ZEB2.36, 37 miR-200 family members are functionally linked to EMT, in part by way of targeting ZEB1

and ZEB2, as well as cell migration, invasion, and tumorigenicity.36, 38 These results suggest that the ZEB1-miR-200 feedback loop is critical for maintaining aggressive tumor features. In addition, we also found that miR-200c directly targets NCAM1. NCAM1 is highly expressed in hepatic stem cells and its function has been tightly linked to EMT.29, 39 Our results are consistent with the hypothesis that the miR-200-EMT gene axis may be functional critical to the development of stem-like ICC. Shared molecular activities including EMT and microRNA among HCC and ICC have been noted in recent publications.40, 41 Interestingly, abnormal regulation of EMT-related genes has been reported to be linked to HCC development.42-44 However, no evidence has linked miR-200 to HCC development. Consistently, we found no evidence that miR-200c is silenced in stem-like HCC (data not shown).

The advantages of CE include non-invasiveness, better tolerance, and handiness, which appeals to clinicians managing OGIB patients. However, CE cannot indicate the precise location of the bleeding lesion, nor can it be used to perform a therapeutic procedure. Also, during CE, the capsule is advanced forward with irregular velocity by peristalsis, and cannot be controlled by

the endoscopist because of its passiveness; this might lead the endoscopist to miss the lesion or mistake its identity. CE has recently been evolving a result of new technologies, such as controlling CE movement, equipping therapeutic or tissue biopsy function, and a transcutaneous power delivery system. These novel technologies selleck compound could expand the role of CE, but at present, if the bleeding lesion in the small bowel is found with CE, other therapeutic procedures

should be considered. DBE can examine the small bowel through either or both the oral or anal route. Many studies on DBE have reported that diagnostic rate to be in the range of 43–81%, and the treatment success rate in the range of 43–84%.3,4 It is therefore clear that DBE is a useful tool for the diagnosis and treatment of OGIB, but it is more invasive than CE, requires sedation, and can be laborious. It also takes time to learn DBE, and complications, such as small bowel perforation, ileus, and pancreatitis are reported to in the range of 0.8–4%.5 These C-X-C chemokine receptor type 7 (CXCR-7) risks lead endoscopists to use DBE VX-809 in specific circumstances,

particularly to take biopsies or for therapeutic intervention, and not to use DBE as a screening modality. Diagnostic guidelines5,6 suggested by evidence-based data have reflected these fundamental differences between CE and DBE. Non-invasiveness, tolerance, high diagnostic yield, and a high negative predictive value of CE have led to the conclusion that CE should be used as an initial diagnostic choice in OGIB. It is further suggested that DBE should be considered as a second-line approach for OGIB patients with a positive CE examination who require tissue biopsy or intervention. Comparative studies and meta-analysis comparing CE and DBE specifically in OGIB have been relatively small. Arakawa et al.4 reported that the overall diagnostic yield between DBE (64%) and CE (54%) was not significantly different. They suggested that in most OGIB cases, CE should initially be selected for lesion detection, and after disease detection, DBE should be selected for management. Teshima et al.2 also estimated that the diagnostic yield for CE (62%) and DBE (56%) was not significantly different, and that the yield for DBE after positive CE was 75%.

The potent effect on cell-to-cell transmission and viral spread also opens a perspective of SR-BI–based entry inhibitors for treatment of chronic infection. Small molecules and mAbs targeting SR-BI and interfering with HCV infection have been described.12, 17, 26 A human anti–SR-BI mAb has been reported to inhibit HDL binding, to interfere with cholesterol efflux and to decrease HCVcc entry during attachment steps without having a relevant impact on SR-BI–mediated postbinding steps.20, 26 A codon-optimized version of this mAb has been demonstrated to prevent HCV spread in vivo,9 underscoring the potential of SR-BI as an antiviral target. The mAbs generated in our study are highly novel in their

function, as they do not interfere with sE2–SR-BI selleckchem Roxadustat manufacturer binding but inhibit HCV entry during postbinding steps of cell-free infection and cell-to-cell transmission. Furthermore, in contrast to described anti–SR-BI mAbs,26 these mAbs do not hinder HDL–SR-BI binding and only partially inhibit lipid transfer at concentrations significantly inhibiting HCV infection. Given their novel mechanism of action and their potential differential toxicity profile, QQ-4A3-A1, QQ-2A10-A5, QQ-4G9-A6, and NK-8H5-E3 define a novel class of anti–SR-BI mAbs for prevention and treatment of HCV infection. We thank R. Bartenschlager (University of Heidelberg, Germany) for providing Luc-Jc1 expression vector; T. Wakita (National Institute of Infectious

Diseases, Tokyo, Japan) for the JFH1 construct; S. K. H. Foung (Stanford University, Palo Alto, CA) for anti-E2 antibody CBH23; and C. M. Rice (The Rockefeller University, New York, NY) and F. V. Chisari (The Scripps Research Institute, La Jolla, CA) for Huh7.5 and Huh7.5.1 cells, respectively. We also thank A. H. Patel (MRC-University of Glasgow Centre for Virus Research,

Glasgow, UK) for Huh7.5-GFP cells and AP33 antibody; J. Ball (University of Nottingham, Nottingham, UK) for providing plasmids for production of different HCVpp genotypes; and D. Trono (Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland) for pWPI plasmid. We also acknowledge E. Schnober (University of Freiburg, Freiburg, Germany) for contributing to sE2 binding assays and S. Durand (INSERM U748, RG7420 manufacturer Strasbourg, France), C. Bach (INSERM U748, Strasbourg, France), J. Barths (INSERM, University of Strasbourg, Strasbourg, France), C. Granier (INSERM U758, France), and S. Glauben (Aldevron Freiburg, Freiburg, Germany) for technical assistance. Additional Supporting Information may be found in the online version of this article. “
“Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. To aid the development of novel immunological interventions, we studied the breadth, frequency, and tumor-infiltration of naturally occurring CD8+ T-cell responses targeting several tumor-associated antigens (TAA).

After 25 weeks of CCl4 administration, CCl4-PlGF+/+ mice exhibited centro-portal fibrotic septae and centro-central fibrotic linkages (Fig. 4A,C). Remarkably, the lack of the PlGF gene in cirrhotic PlGF−/− mice (Fig. 4B) substantially decreased the severity and extent of

the fibrotic changes, as illustrated by a 36% reduction in fibrosis score compared with wild-type CCl4-treated mice (39,316 μm2 versus 61,034 μm2 fibrotic area, respectively; P < 0.05). In addition, CCl4-treated wild-type mice given αPlGF for 8 weeks (from week 12 to week 20) also showed less fibrosis compared with IgG1-treated cirrhotic mice (53,676 versus 90,357 μm2 fibrotic area, respectively;

PKC412 supplier P < 0.05) (Fig. 4D). The effect of αPlGF treatment to decrease the extent of fibrosis in cirrhotic mice was further confirmed by macroscopic and stereomicroscopic evaluation, which revealed loss of nodularity after αPlGF treatment (Fig. 4E-H). On the other hand, no changes in the fibrosis score were detected when end-stage cirrhotic mice (week 18 to week 25 of CCl4 treatment) were treated with αPlGF. These results point to a therapeutic window during which the antifibrotic effect of αPlGF can be successful. To understand why a decrease in PlGF activity was associated with a reduction in fibrosis severity, we studied the intrahepatic expression of PlGF by immunofluorescence in livers of control (rats, n = 10; mice, n = 10) and CCl4-treated rats (n = 10) and mice (n = 10). A PlGF signal was weakly observed in the livers www.selleckchem.com/products/ink128.html of control animals (Fig. 5A). PlGF-positive cells, however, were quite evident in CCl4-treated animals. The livers of PlGF-deficient mice were totally devoid of PlGF immunoreactivity (data not shown).

In an attempt to identify the cellular source of PlGF expression, we measured PlGF protein and mRNA levels in mouse HSCs (Supporting Information Fig. 7). Activation of HSCs was associated with increased αSMA expression, a finding that reached significance from day 8 onward (Supporting Information Fig. 7A), and with a significant PlGF increase in the cell supernatants (Supporting to Information Fig. 7B). These data were further confirmed in primary HSCs isolated from control and cirrhotic rats (Supporting Information Fig. 7C). In these cells, an intense up-regulation of PlGF was observed in activated HSCs and, to a lesser extent, in hepatocytes and endothelial cells isolated from cirrhotic rats. Considering the major pathophysiological role that HSCs play in fibrogenesis, the effect of PlGF on rat and human activated HSCs was studied. As shown in Fig. 5B, there was a significant overexpression of VEGFR1 receptors in primary HSCs from cirrhotic rats and in the LX-2 human HSC cell line.

FODMAPs in enteral formulas may also be responsible for diarrhoea induced

by enteral nutrition. Conclusion:  Dietary restriction of FODMAPs is an effective therapy in the majority of patients with functional bowel symptoms and, provided https://www.selleckchem.com/products/bay80-6946.html dietitians are trained in the technique, should be first line therapy. “
“Results from a phase II study (COSMOS) suggested that HCV G1 infection can be treated effectively with a combination of sofosbuvir (SOF) and simeprevir (SMV) with or without rib-avirin (RBV) for 12 weeks. The regimen is suitable for IFN ineligible patients and those who have failed prior treatment with advanced fibrosis. Objective: To report the experience of treating patients who were IFN ineligible/prior treatment failures with SOF/ SMV combination in 3 U.S. liver transplant (LT) centers. Results: We identified 127 patients with G1 disease who required this IFN-free treatment. To date 91 (71.7%) have initiated

treatment. Of the 91 patients, 60.4% were male, 89% were Caucasian. 55% had failed prior treatment, 15% relapsed and 30% were treatment naïve. 82.4% had cirrhosis and of those 36% are listed for LT. (median www.selleckchem.com/products/Deforolimus.html MELD was 9, range 6-22). To date, 19 have completed 12 weeks of therapy treatment; 70% were HCV RNA negative at week 4; all were HCV RNA negative at week 12. So far, no treatment relapses have occurred in these patients; 1 patient received a LT 6 weeks after she became virus negative and remains virus Casein kinase 1 negative 2 weeks post-LT. No serious adverse

events or episodes of hepatic decompensation have been observed. Four patients have reported self-limited vertigo on treatment. Conclusion: SMV/SOF combination has been well tolerated in our difficult to treat population of patients a majority of whom are cirrhotic, and who are ineligible, previously intolerant or non-responsive to IFN-based therapy. No episodes of hepatic decompensation have been documented with this regimen to date. A major barrier to initiating SMV/SOF combination treatment is the slow approval process, even in patients with advanced liver disease. SVR 12 data will be presented as it becomes available that will allow better characterization of the benefit of SMV/ SOF therapy in cirrhotic patients. Disclosures: Surakit Pungpapong – Grant/Research Support: BMS, Gilead Hugo E. Vargas – Advisory Committees or Review Panels: Eisai; Grant/Research Support: Merck, Gilead, Idenix, Novartis, Vertex, Janssen, Bristol Myers, Ikaria, AbbVie The following people have nothing to disclose: Bashar Aqel, K Tuesday Werner, Amy E. Chervenak, Jorge Rakela, Kymberly D. Watt, Michael D. Leise, Jennifer L. Murphy, Tanisha M.

Nevertheless, immunosuppressive agents show little therapeutic efficacy, whereas daily administration of ursodeoxycholic acid (UDCA), the only U.S. Food and Drug Administration–approved treatment for PBC, improves the prognosis in a majority of patients when started in early stages of the disease.1, 5-7 Among its multiple effects, which include poorly defined immunomodulatory properties, the hydrophilic bile acid, UDCA, is known to induce bicarbonate-rich hypercholeresis in humans.1, 6, 7 Interestingly, PBC patients who had not yet initiated the treatment with UDCA were shown to exhibit impaired biliary

bicarbonate secretion in response to secretin administration, and this defect was restored in patients under UDCA therapy.8 As smartly illustrated by the bicarbonate-umbrella hypothesis, mTOR inhibitor secretin-stimulated biliary bicarbonate secretion may be crucial in humans to prevent the biliary epithelium from becoming injured by hydrophobic bile acids.9, 10 Secretin-stimulated biliary bicarbonate secretion is mediated by Cl−/HCO anion exchanger 2 (AE2),11-13 a widely expressed protein involved in hydroionic fluxes and intracellular pH (pHi) homeostasis, which, in the biliary epithelium, is located on the apical surface of lining cholangiocytes.14 In cholangiocytes of PBC patients, both the expression of AE2 and the level of find more exchange activity after stimulation with cyclic adenosine monophosphate

(cAMP) (the second messenger of secretin signaling) are decreased.15, 16 Of interest, the observed restoration of the secretin response in PBC patients under treatment with UDCA appeared to run parallel with increased expression of AE2 in PBC livers.8, 15 These previous data supported the hypothesis that AE2 dysfunction may have an important pathogenic role in PBC.17 In fact, common genetic variations of the AE2/SLC4A2 gene have been associated with disease susceptibility

and/or progression and AMA status among PBC patients.18-20 Additional evidence for a pathogenic role of AE2 dys-regulation was recently obtained with our Ae2a,b-deficient mice, a model that develops biochemical, histological, and immunologic alterations that recapitulate acetylcholine many PBC features (including development of serum AMA).21 Thus, though the deficient expression of AE2 in cholangiocytes of patients with PBC appears to be involved in the pathogenesis of the disease, the mechanisms responsible for AE2 down-regulation remain unclear. MicroRNAs (miRNAs) are a subclass of small, noncoding RNAs that have recently attracted a lot of attention because of their ability to post-transcriptionally regulate the expression of numerous genes into their encoded proteins.22-24 Moreover, abnormal protein expression contributing to the pathogenesis of a variety of diseases has increasingly been recognized to be caused by alterations of specific miRNAs involved in regulating those proteins.