There were no significant differences in thiopurine dose between patients who did and did not carry an ABCC4 2269A allele and all patients had normal TPMT activity.42 However, white blood cell counts were significantly lower and red blood cell 6-TGN concentrations were significantly higher in ABCC4 2269A carriers compared to wild type homozygotes.

Furthermore, the incidence of leucopenia tended to be higher in patients with the variant allele (20.6% vs 8.3% of 2269G homozygotes, P = 0.053).42 These findings suggest that some cases of 6-TGN toxicity, in the absence of TPMT deficiency, may be explained by impaired efflux of this metabolite out of cells. Prospective testing of IBD patients for ABCC4 2269G>A may be useful in Asian populations where this SNP occurs at appreciable frequencies. Methotrexate, CHIR-99021 in vitro an analog of dihydrofolic acid (DHF), enters cells primarily through the reduced folate carrier

1 (RFC1)43 (Fig. 2). Once within the cell, methotrexate (also known as MTX-Glu1 because it is a monoglutamate) is quickly converted to its active polyglutamated forms (MTXGlu2-5) by the enzyme folylpolyglutamate synthase (FPGS).43 This sequential addition of glutamate residues prevents methotrexate efflux selleck kinase inhibitor from the cell via a range of multi-drug resistance proteins.43 Glutamation can be reversed by γ-glutamyl hydrolase (GGH), and the balance between these two enzymes determines how long methotrexate is retained within a cell and its efficacy.43 MTXGlu2-5 inhibit the folate pathway by displacing DHF as the preferred substrate of the folate-dependent enzymes DHF reductase (DHFR),44 thymidylate synthase (TYMS)45 and 5-aminoimidazole-4-carboxamide 4-Aminobutyrate aminotransferase ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC).46 At high dose, MTX has an anti-proliferative effect and this has been attributed to MTXGlu2-5

blocking DHFR and TYMS-mediated nucleic acid methylation and pyrimidine synthesis.46 However, inhibition of these enzymes does not explain the anti-inflammatory effect of low dose MTX. Instead this has been attributed to the inhibition of ATIC which, in turn, leads to the accumulation and eventual release of adenosine from the cell.47 The subsequent binding of extracellular adenosine to adenosine receptors on target cells prevents the production of the pro-inflammatory cytokines while promoting transcription of the anti-inflammatory agents.47 Many genetic polymorphisms have been documented in the folate pathway and an ever-increasing number of studies on patients with rheumatoid arthritis48,49 and patients with hematological malignancies50 have reported association of folate pathway polymorphisms with methotrexate response and toxicity. However, discordance among studies is common, and associations observed in one cohort seldom replicate in another.

The randomized studies are shown in Table 1, whereas the nonrandomized studies involving both angiogenic and nonangiogenic therapies are shown in Tables 2 and 3, respectively. Six randomized studies involving a total of N = 2,464 patients and which compared sorafenib to control in HCC and RCC were identified. Of the HCC patients, 50% were enrolled in either the SHARP study or the Asia-Pacific study. Among the included set of HCC single-arm studies,

there were 19 treated with antiangiogenic therapy and 21 treated with non-antiangiogenic therapy. Eleven of the studies involved sorafenib, four employed bevacizumab, and three studies evaluated sunitinib. The remaining studies involved other agents that are reported to have antiangiogenic effects (brivanib, lenalidomide, TSU68, Nivolumab Selleckchem VX770 linifanib, ramicirumab). There was marked variability across all the studies with regard to the stated laboratory eligibility criteria for entry onto the study. As illustrated in Table 2, the required platelet count ranged from 40 to 150 and international normalization ratio (INR) from 1 to 2.3. The two largest studies, the SHARP and AP studies, allowed for a platelet count of greater than or equal to 60,000. Six of the studies restricted entry to Childs-Pugh A patients only. No

study was identified which mandated endoscopy to exclude patients with varices. However, after the occurrence of gastrointestinal hemorrhage in the course of two studies3, 4 (in one case, a fatal variceal hemorrhage), the protocol was amended to require screening endoscopy prior to inclusion in the study in patients with any evidence Fenbendazole of portal hypertension. Patients found to have esophageal varices on screening examination were eligible for the study following adequate treatment with banding or sclerotherapy and repeat endoscopy showing the varices to be obliterated, minimal, or grade 1. There were four HCC randomized studies involving

sorafenib. The forest plot in Fig. 1A visually depicts the pooled overall estimate of the effect of sorafenib on all bleeding events within HCC randomized studies. The number of events for the sorafenib arm was 48/722 (6.65%) and was 22/653 (3.37%) for the control arm, giving an OR of 1.77 (95% CI 1.04, 3.0) for both the fixed and random effects models. This result provides evidence of a significant (P = 0.04) increase in the odds of bleeding events (all grades) with sorafenib compared to control. Figure 1B visually depicts the pooled overall estimate of the effect of sorafenib on grades 3-5 bleeding events within HCC randomized studies. The number of events for the sorafenib arm was 33/722 (4.57%) and 13/653 (1.99%) for the control arm, giving an OR (95% CI) of 1.76 (0.91, 3.41) for both the fixed and random effects models.

For this experiment, plants were inoculated with inoculum concentration of OD540 = 0.05 (Exp. 1) and 0.1 (Exp. 2). Immediately after sampling, leaf

fragments were weighed and kept in a refrigerator (4°C) until analysis. The fragments were surface sterilized by dipping them in a 50% alcohol solution for 1 min, 2% sodium hypochlorite solution for 40 s, followed by three AG 14699 rinses in sterile deionized water. Leaf segments were ground using a sterile pestle and mortar with 0.85% saline solution (1 : 10, w/v). A total of 10 μl of each leaf macerate was serially diluted in glass vials containing 990 μl of sterile saline solution at 0.85% prepared with 0.02% Tween 80. Aliquots of 10 μl from each dilution series were spread on XTS-agar media (agar, 23 g/l; glucose, 5 g/l; cyclohexamide, 100 mg/ml; gentamycine, 10 mg/ml; and cephalexin, 10 mg/ml) (Schaad et al., 2001). The Petri dishes were kept in a growth chamber at 28°C for 4 days. The number of bacterial colonies was counted in each dilution series and data were transformed to log5 CFU g per leaf. In a separate experiment, the EL was determined according to the methodology described by Lima et al. (2002) with a few modifications. A total of 23 discs (≈8 mm in diameter) were collected from the fourth and fifth leaves from the main tiller from plants of each replication for each

treatment at 0, 1, 2, 3, 4, 6, 8, and 10 d.a.i. For this experiment, plants were inoculated with inoculum concentration of OD540 = 0.05 (Exp. 1) and 0.1 (Exp. 2). Leaf discs were thoroughly washed in deionized sterile water, and then left to float on 60 ml of deionized water in sealed glass vials for 4 h at 25°C. selleck kinase inhibitor The EL was estimated using a conductivity meter Sitaxentan (Tecnopon mCA-150, MS Tecnopon Instrumenação Científica, Brazil) and the values were expressed as the percentage of total conductivity, which was obtained after placing the glass vials in an oven at 90°C for 2 h. In a separate experiment, samples from the second, third, and fourth leaves from plants of each replication for each treatment were collected at 0, 3, 6, 9, and 12 d.a.i. Plants were inoculated with an inoculum concentration of OD540 = 0.05. Leaves were kept in liquid nitrogen

during sampling and then stored at −80°C until further analysis. A representative sample of 0.1 g of leaf sample from each replication and treatment was ground into a fine powder in a pestle and mortar with liquid nitrogen. The fine powder was transferred to a microcentrifuge tube, homogenized with 1.5 ml of 80% methanol, and extracted overnight on a rotary shaker (150 r.p.m.) at room temperature. The homogenate solution was protected from light oxidation by covering the microcentrifuge tube with aluminum foil. The dark-green methanolic extract was centrifuged at 12 000 g for 5 min, the supernatant was transferred to a new microcentrifuge tube and stored at −20°C. The residue was kept at −20°C for further determination of lignin and lignin-like phenolic polymers.

Conclusion: The decreased rate of apoptosis

in the knockout mice correlated with an almost undetectable and significantly decreased level of activated caspase-3 and significantly increased levels of X-linked inhibitor of apoptosis protein, which also correlated with increased levels of nuclear factor kappa B p52 and decreased levels of c-Jun N-terminal kinase; this provides a possible mechanism for the decrease in apoptosis seen in CXCR2 knockout mice. Hepatology 2010 Acute liver failure is common in patients admitted to the intensive care unit; in approximately 20% of acute hepatic selleck failure cases, the liver injury is related to acetaminophen (APAP) toxicity.1 The mechanism of APAP-induced liver injury involves the cytochrome P-450–generated GDC-0980 metabolite N-acetyl-p-benzoquinone imine, which causes glutathione

(GSH) depletion, impairs mitochondrial respiration, and interferes with calcium homeostasis, although the actual events resulting in cell death are not well understood.2 Apoptosis occurs in all cells and is regulated by cellular death and cellular survival signals. Imbalances in these signals can be lethal and likely play SB-3CT a role in many pathophysiological processes. X-linked inhibitor of apoptosis protein (XIAP), which belongs to the inhibitor of apoptosis protein (IAP) family, binds to and inhibits caspase-3 and caspase-9 and protects endothelial cells against tumor necrosis factor-alpha–mediated apoptosis.3 XIAP also inhibits apoptosis

by another mechanism: a positive feedback loop that furthers nuclear factor kappa B (NF-κB) activation.3, 4 This article investigates chemokine (C-X-C motif) receptor 2 (CXCR2) signaling in the apoptotic response to hepatic APAP toxicity in the mouse. The CXC chemokines play a role in many inflammatory and regenerative processes and are the major ligands for the CXCR2 receptor. Studies have demonstrated that CXC chemokines, including interleukin-8, macrophage inflammatory protein-2 (MIP2), and keratinocyte (KC) among others, have direct effects on hepatocytes. The CXCR2 receptor is expressed on hepatocytes,5 and that finding has been confirmed in this study. In models of both partial hepatectomy and APAP toxicity, CXCR2/ligand interactions promote hepatocyte proliferation and liver regeneration.4, 6, 7 In contrast, other investigators have found that CXCR2 ligands can be hepatotoxic.

However, since we did not include a non-temporal description task in our study, we cannot rule out the possibility of a more global deficit in the ability to produce specific descriptions underlying our results. Measures of performance on non-temporal description tasks were included in two recent studies of future thinking in patients with medial-temporal lobe damage (Race et al., 2011) and Parkinson’s disease (de Vito et al.,

2012). Both reported that deficits in future thinking could not be accounted for by narrative construction performances. In the current study, patients were required to construct specific events; however, outside of being plausible and lasting less than a day, there were no demands as to the content of these events. This raises the possibility that participants were able to construct simulations based on well-established check details scripts in semantic memory or more generalized memory for routine events, which do not place demands on episodic memory (Cooper, Vargha-Khadem, Gadian, & Maguire, 2011; Maguire, Vargha-Khadem, & Hassabis, 2010). In line with this suggestion, Race et al. (2011) reported that amnesic patients generated a greater number of details, when imagining more frequent and scripted events (a birthday celebration) than less frequent events (winning the lottery),

although future thinking was impaired for both types of future event construction. These results suggest that, if the TBI patients in the present study indeed relied JAK inhibitor on semantic memory when having to construct future events, this should

have improved their performance relative to what would have been observed under conditions controlling for this option. Thus, in the latter case, their deficits would have been even more pronounced than what we observed here. In short, the specific cognitive and neural deficits that may contribute to the reported difficulties in episodic memory and episodic future thinking in TBI patients include reduced Methocarbamol executive functioning, motivational problems, problem with constructing a narrative, and problems with drawing upon relevant schematic/semantic knowledge. The relative contributions of these different factors cannot be decided based on the present findings, and warrant further investigations. The present study holds two main limitations, which should be taken into account when interpreting the findings. Because of the small sample size, conclusions should be drawn only tentatively, and specifically null findings should be interpreted with caution. A second limitation of the study concerns the relatively short time span between the time of the injury and the memory assessment of the TBI participants (between 39 and 117 days after the injury).

The higher eRVR rate in group C resulted in a higher proportion of patients being assigned to abbreviated treatment (24 weeks) than in groups A or B. The abbreviated regimen was insufficient to selleck sustain an off-treatment response (SVR) in many patients, especially those with difficult-to-cure characteristics, such as cirrhosis or a non-CC genotype. Virologic breakthrough was observed in

some patients during dual Peg-IFNα-2a/RBV therapy after completion of mericitabine therapy. Collectively, these observations can explain the progressively lower overall SVR rates and progressively higher relapse rates in groups A, B, and C, when compared to group D, and the generally poor performance of these regimens in patients with difficult-to-cure characteristics. The lack of correlation between on-treatment VR and SVR is puzzling, given the consistently high barrier to resistance shown by mericitabine. Mericitabine is a prodrug that is converted to a pyrimidine (cytidine) nucleoside analog, which, in turn, is taken up by hepatocytes and sequentially phosphorylated to form the active chain

terminator. When given as monotherapy, mericitabine is associated with a relatively slow first-phase decline in HCV RNA that extends throughout at least 14 days,[12] likely because the first phosphorylation step is thought to be rate selleck chemical limiting in the production of the active triphosphate species.[13] This slow onset of activation as the triphosphate may explain the lack of sustained efficacy observed with only 12 weeks of mericitabine therapy in this trial. Indeed, another investigational Liothyronine Sodium pyrimidine nucleotide analog inhibitor (sofosbuvir), that is formulated as a uridine monophosphate,[14] bypasses the first phosphorylation reaction and has been shown to have more-rapid early-phase kinetics and produce high SVR rates (90%) when administered for 12 weeks together

with Peg-IFNα-2a/RBV.[15] If the rate of activation of mericitabine is critical to achieving an SVR, then one might expect longer treatment durations to offset the slower onset of action of the drug and to be more efficacious. Indeed, a significant increase in SVR-24, compared to a control group, was observed when mericitabine was administered with Peg-IFNα-2a/RBV for 24 weeks in JUMP-C.[16] This result is particularly striking, because more than 60% of mericitabine-treated patients in JUMP-C stopped all treatment after only 24 weeks, compared to the control group, in which all patients received 48 weeks of treatment with Peg-IFNα-2a (40 kD) plus RBV alone.[16] One potential limitation of this study is the lack of stratification by HCV G1 subtype (1a, 1b) and the lack of evaluation of VRs by HCV G1 subtype.

Screening for occult hepatitis B virus infection (by total antibodies against core antigen) and celiac disease (by anti-tissue transglutaminase antibodies, anti-endomysial antibodies, and duodenal biopsy) was also performed in 16 and 10 patients, respectively. Abnormal metabolic parameters and metabolic syndrome were defined according to Adult Treatment Panel III criteria12 with a modified LGK974 waist circumference for the Asia-Pacific region.5 The mean BMI was higher in patients with cryptogenic

cirrhosis (26.06 ± 5.96 kg/m2) versus patients with VCC (22.12 ± 1.71 kg/m2, P = 0.0001). A higher number of patients with cryptogenic cirrhosis had an abnormal waist circumference [38 (58.5%) versus 15 (30%), P = 0.004], type

2 diabetes mellitus [26 (40%) versus 5 (10%), P = 0.0007], and lower serum high-density lipoprotein levels [35 (53.8%) versus 3 (6%), P = 0.0003] in comparison with patients with VCC. Patients with CHCC had a higher BMI (24.35 ± 4 versus 22.5 ± 3.4 kg/m2, P = 0.03) and a higher prevalence of type 2 diabetes mellitus [15 (38.5%) versus 7 (17.9%), P = 0.04] in comparison with patients with VHCC. There was no difference in abnormal high-density lipoprotein, serum triglycerides, or hypertension between patients with CHCC and patients with VHCC. The prevalence of metabolic syndrome was also similar in the two groups MLN0128 chemical structure of patients with cirrhosis and HCC. In conclusion, the higher prevalence of metabolic risk factors, if they are taken as surrogate markers of NAFL, suggests that NAFL is an important cause of both cryptogenic cirrhosis and CHCC and thus contributes to significant liver disease in India. Ajay Duseja M.D., D.M., F.A.C.G*, Balkrishan Sharma M.Sc*, Amit Kumar M.Sc*, Shweta Kapil M.Sc*, Ashim Das M.D., M.R.C.P†, Radha K. Dhiman M.D., D.M., F.A.C.G*, Yogesh K. Chawla M.D., D.M., F.A.C.G*, * Department of Hepatology, Postgraduate Institute of Medical Methane monooxygenase Education and Research, Chandigarh, India, † Department of Histopathology, Postgraduate Institute of Medical Education and Research,

Chandigarh, India. “
“Kim et al.[1] proposed a 65-gene-based risk score classifier of overall survival in hepatocellular carcinoma (HCC). The risk score, derived by multiplying the expression level of a gene by its Cox coefficient, could robustly predict overall survival of HCC patients. Its clinical usefulness was further confirmed in a second test cohort. There were some minor defects in Fig. 1A and Table 2. The article adopted a previous method[2] by simply using Cox’s coefficient from univariate regression analysis, ignoring the inherent correlation between genes. However, as mentioned in the literature,[2] nonlinear relationships may exist between genes, that is, the potential interaction between signature genes.

Endurance capacities were measured on all crabs on horizontal and uphill inclines. Though claw removal had no significant effect on horizontal speeds, removal of the major claw significantly increased uphill speeds of male fiddler crabs at 15 and 30° inclines. Generally, as incline increased, the difference in performance between males with the enlarged claw and those with the claw removed increased. We also found

that clawed males exhibit slower downhill speeds compared to clawless males and that claw removal significantly enhanced endurance on all inclines. This study indicates that an assessment of movement on level surfaces alone may not be entirely ecologically relevant when determining the actual costs of sexually selected ornaments. this website “
“Reconstructing the possible behaviours of long extinct species, and especially those with no close living relatives, are naturally fraught with difficulty: data are often limited and

hard to interpret. However, the field of palaeoethology has not been helped http://www.selleckchem.com/products/AZD1152-HQPA.html by a poor understanding of the range and plasticity of the behaviour of extant organisms, coupled with a tendency to generalize and over-interpret the limited information available. Here we attempt to construct a framework for the establishment of viable hypotheses about the behaviour of extinct organisms and the generation of support for, or testing of, these hypotheses. We advocate that it is preferable to under-interpret available data, than to suggest problematic hypotheses that may become accepted as correct. From the earliest days of palaeontology, hypotheses have been generated about the behaviour of extinct taxa: William Buckland in 1829, for example, suggested that the pterosaur Pterodactylus may have been insectivorous and lived in flocks. However, while palaeontology has developed enormously as a field in this time, the analysis and assessment of the behaviours of extinct animals have not continued apace with the development of ethology

Nutlin-3 nmr as a field. The latter culminated in the sharing of the 1973 Nobel Prize in Physiology or Medicine by K. Lorenz, N. Tinbergen and K. von Frisch. Tinbergen’s ‘four questions’ approach to the study of behaviour (mechanism, development, survival value and evolution), together with the comparative method favoured by Lorenz, has provided a solid framework for interpretation of behaviour from the fossil record. Meanwhile, the foundations of the field of sociobiology were laid in the 1960s by biologists with increasing emphasis being given to understanding how genetic influences may explain behaviour (e.g. Hamilton, 1964). In the intervening decades, our knowledge and understanding of behaviour in extant animals has increased markedly. Neurobiological processes can now be visualized in vivo by scanning techniques, and mechanisms teased apart at the molecular level.

Methods: We analyzed data from 5,015 asymptomatic subjects aged between 50–70 years who had screening colonoscopy conducted at our bowel cancer screening centre between 2008 and 2012. One binary logistic regression analysis was conducted with the presence of advanced neoplasia or colorectal cancer as the outcome. We controlled for APCS, alcohol drinking, BMI, diabetes, hypertension, CHD and cirrhosis as independent variables in the regression model. Results: The average age was 57.7 years (SD = 4.90) and 47.5%

were male. Advanced neoplasms or cancers were found at colonoscopy in 5.6% of all screening participants. From multivariate regression analysis, APCS ≥ 4 (adjusted odds Selleck Pexidartinib ratio [AOR] 1.729, 95% C. I. 1.327–2.254, p < 0.001); BMI ≥ 25 (AOR 1.313, 95% C. I. 1.011–1.705, p = 0.041), the presence of hypertension (AOR 1.652, 95% C. I. 1.264–2.159, p < 0.001) and alcohol drinking (AOR 1.505, 95% C. I. 1.066–2.125, p = 0.020) were associated with colonoscopic findings of these lesions. Diabetes, CHD and cirrhosis were not significant factors. Conclusion: Alcohol drinking, hypertension and BMI could be incorporated into the APCS scoring system to enhance its predictive value for prioritizing asymptomatic Asian subjects for colorectal screening. GSK1120212 mw Key Word(s): 1. colorectal cancer; 2. advanced neoplasia;

3. associated factors; 4. screening; Presenting Author: YINGSIU TUNG Additional Authors: PAULAB POLETTI, THIAGOF SECCHI, ARTUR PARADA Corresponding Author: YINGSIU

TUNG Affiliations: Centro Diagnostico E Terapeutico Endoscopico Objective: AIMS: The aim of this study was determine the prevalence, age distribution, the pattern of disease involvement in the colon and clinical findings of the ischemic colitis. Methods: MATERIAL ANDE METHOD: a total of 2228 colonoscopies (videooscope Pentax and Fujinon) were performed from july 2009 to june 2012 at the endoscopic unit of the hospital 9 de Julho/ são Paulo/ brazil. we diagnosed 69 (3,09%) cases of ischemic colitis with histological confirmation. We reviewed the clinicals and endoscopics reports retrospectively. Results: RESULTS: Over a total of 2228 patients, we diagnosed 69 (3,09%) cases of ischemic colitis. The age ranged Vildagliptin from 32 to 88 years, with a higher prevalence at the 8 decade with 29 cases (42%). Females had a higher prevalence (56,6%). In the evalution of the location of the disease, we observed 41 (59,45) cases in sigmoid colon, 19 (27,5%) in descending colon and 18 (26%)in the rectum. The most common presenting symtoms were hematochezia in 35 (56,6%), abodominal pain in 23 (33,3%) and diarrhea in 19 (27,5%). The endoscopic findings were: edema with erosions in 33 (47,8%), edema with erosions and ulcers in 16 (23,2%), hyperemics areas in 6 (8,7%) and swollen mucosa in 6 (8,7%) Conclusion: RESULTS: Over a total of 2228 patients, we diagnosed 69 (3,09%) cases of ischemic colitis.

14 MFBs also appear capable of providing survival signals, because they reduce the apoptosis of nonmalignant cholangiocytes

in coculture experiments.15 However, information regarding the nature of the cross-talk,and, in particular, the identity of the potential survival signals, remains obscure. Platelet-derived growth factor (PDGF) paracrine signaling between MFBs and cholangiocytes occurs in rodent models of biliary tract inflammation and fibrogenesis.15, 16 Five different ligands of PDGF exist, including PDGF-AA, -BB, -AB, -C, and -D. However, PDGF-BB appears to be the predominant isoform secreted by liver MFBs.17 Of the two cognate receptors, platelet-derived growth factor receptor (PDGFR)-α and -β, PDGFR-β is the cognate receptor for PDGF-BB. PDGFR-β is a receptor tyrosine kinase that is also known to alter plasma-membrane dynamics associated with cell migration by a cyclic adenosine monophosphate (cAMP)-dependent kinase (PKA)-dependent process18; see more thus, PDGF-BB effects on intracellular signaling cascades are pleiotropic. Given an emerging role for PDGF-BB in MFB-to-cholangiocyte cross-talk, a role for PDGF-BB as a survival factor for CCA warrants further investigation. The Hedgehog (Hh)-signaling pathway has been strongly implicated in gastrointestinal tumor biology, including CCA.19, 20 Hh signaling is initiated by any of the three ligands, Sonic (SHH), Indian find more (IHH), and Desert (DHH) hedgehog. These ligands

bind to the Hh receptor, Patched1 (PTCH1), resulting in activation of smoothened (SMO) and, subsequently, the transcription 3-mercaptopyruvate sulfurtransferase factors, glioma-associated oncogenes (GLI) 1, 2, and 3.21 How PTCH1 modulates SMO was enigmatic until quite recently, because

the two proteins do not physically associate. SMO trafficking from an intracellular compartment to the plasma membrane apparently results in its activation.22 Hh ligand binding to PTCH1 increases the concentration of intracellular messengers (i.e., lipid phosphates), which, in turn, promote SMO trafficking to the plasma membrane.23, 24 PKA affects SMO trafficking and activation, raising the unexplored possibility that cues from other ligand-receptor systems, such as PDGF-BB, may also augment SMO activation by facilitating its trafficking to the plasma membrane.22 Interestingly, SHH messenger RNA (mRNA) expression is increased by PDGF-BB in immature cholangiocytes, 16 providing an additional link between Hh signaling and PDGF. Hh signaling may also be a master switch mediating the resistance of CCA cells to TRAIL cytotoxicity.25, 26 Taken together, these observations suggest that MFB-derived PDGF-BB may modulate Hh survival signaling in CCA cells. The aim of this study was to examine the role for MFB-to-CCA cell paracrine signaling in mediating CCA resistance to TRAIL cytotoxicity. The results suggest that PDGF-BB secreted by MFBs protects CCA cells from TRAIL-induced apoptosis. PDGF-BB appears to exert its cytoprotective effects by an Hh-signaling–dependent manner.