The generation of Albumin-Cre (Alb-Cre), Trp53F2-10/F2-10 (Trp53flx/flx) and Tgfbr2flx/flx mice has been described.21-23 Tgfbr2flx/flx mice were

crossed with Alb-Cre transgenic mice and Trp53flx/flx mice to generate the following genotypes: Alb-Cre;Trp53flx/flx;Tgfbr2wt/wt (Trp53KO), Alb-Cre;Trp53flx/flx;Tgfbr2flx/flx (Trp53KO;Tgfbr2KO), Alb-Cre;Trp53wt/wt;Tgfbr2flx/flx (Tgfbr2KO), and Trp53flx/flx;Tgfbr2flx/flx (Control). Mice were backcrossed in order to obtain a strain background that was on average C57BL6 (87.5%) / FVB (12.5%). Both Veliparib male and female mice were used for this study. Tissues from nonbreeders were used for quantitative reverse-transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot assays. Genotypes were determined by PCR following published protocols.21, 24 All mice were maintained and cared for using protocols approved

by the Institutional Animal Care and Use Committee (IACUC). Mice that became moribund or reached approximately 15 months of age were sacrificed and necropsied. Total body weight and liver weight were measured. Mouse tissues were either snap-frozen in liquid nitrogen and used for RNA and protein preparations, or fixed in 10% neutral buffered formalin phosphate (Fisher Scientific, Pittsburgh, PA), embedded in paraffin, and PCI 32765 cut into 4-μm sections for hematoxylin and eosin (H&E) staining or immunohistochemistry (see Supporting Information). Gene expression studies were performed as described in the Supporting Information. The results of the qRT-PCR assays were normalized to β-glucuronidase. 上海皓元 Statistical analysis was performed using the GraphPad Prism v. 4.00 software.

The Mann-Whitney test was used for comparisons of quantitative results from the ELISA and qRT-PCR assays. A P value <0.05 was regarded as significant. Total protein lysates were prepared from frozen tumor or nontumor liver tissue. Samples were homogenized on ice with a Dounce Tissue Grinder (Wheaton Science Products, Millville, NJ) in Triton X-100 Lysis Buffer (see Supporting Information). Mouse TGF-β1 was assessed in protein lysates (21 μg per sample) obtained from selected paired frozen tumor and nontumor tissues, as well as from grossly normal-appearing livers. The samples were activated and quantified according to the manufacturer’s instructions (R&D Systems, Minneapolis, MN).

This compound, which corresponds to

the 337.25 m/z band (Fig. 3B), exhibited a modest increment upon UDCA infusion. The instability of GSNO under MS conditions might explain why this band is not predominant in the spectrum. However, FK228 in vitro as shown in Fig. 3B, the relative intensity of a 319.24 m/z band (seemingly corresponding to dehydrated GSNO) was manifestly higher in UDCA-stimulated bile versus basal bile. These data support the concept that UDCA infusion induces an increase of GSNO in bile. We also assessed the involvement of glutathione in the transport of NO to bile by determining biliary NO in rats after depleting their livers of glutathione with BSO. As we previously reported,26 UDCA increased hepatic glutathione levels in normal rats (Fig. 4A). However, in rats that received BSO, liver glutathione was markedly reduced, regardless of UDCA administration (Fig. 4A). An analysis of UDCA in bile from UDCA-infused normal rats and BSO-treated rats showed that biliary UDCA secretion was similar in both situations (Supporting Fig. 2), and this indicates

that the secretion of UDCA to bile is not prevented in the absence of glutathione. In contrast, the secretion of NO species after UDCA infusion does depend on glutathione, as it was virtually abolished in BSO-treated animals (Fig. 4B), even though their hepatic NOS activity was increased IWR-1 to levels similar to those found in UDCA-infused normal rats (data not shown). These findings are consistent with the notion that glutathione has a major role as a carrier for the transport of NO to bile. Glutathione and glutathione conjugates are known to be secreted at the canaliculi through the ABCC/Mrp2 pump. Therefore, we performed UDCA infusion experiments in TR− rats, which exhibit defective canalicular transport of those

compounds because of an ABCC2 mutation.27 In these animals, the levels of biliary glutathione fall 3 logs with respect to normal values, but the compound is still secreted to bile in the micromolar range.28 As shown in Fig. 5A,B, UDCA-infused TR− rats exhibited a significant decrease in both the concentration and biliary output of NO species in comparison with UDCA-infused normal rats. The increment in biliary NO secretion upon UDCA infusion in TR− rats was less than half of that observed in normal animals 上海皓元 (P < 0.05; see the inset in Fig. 5B). In the mutant rats, the levels of both total SNOs and LMw-SNOs increased after UDCA administration, but the values were about one-third of those observed in UDCA-treated normal rats (Supporting Fig. 3). These findings indicate that the glutathione carrier ABCC2/Mrp2 contributes at least partially to biliary NO secretion and provide further support for a role of glutathione as a vehicle for the transport of NO along the biliary tree. To determine whether GSNO could play a role in stimulating ductal secretion in vivo, we performed a retrograde infusion of 150 μL of 250 μM GSNO through the common bile duct in the isPRL model.

In the 240 mg QD/LI group, 59 patients who achieved mRVR were rerandomized to complete 24 or 48 weeks of PegIFN/RBV (total duration); the rate of SVR was significantly higher in patients treated for 48 weeks (72%) compared with those treated for 24 weeks (43%; P = 0.035) and virologic relapse was significantly lower in patients treated for 48 weeks (21%) compared with those treated for 24 weeks (57%; P = 0.0073) (Fig. 2C). Relapse occurred in 27% of patients with 240 mg QD/LI, 12% of patients with 240 mg QD, and 20% of patients with 240 mg BID/LI. The higher relapse rate in the 240 mg QD/LI group was mainly driven by frequent relapses in patients who obtained mRVR and were rerandomized to shortened treatment duration. Breakthrough

was observed in 24% of patients on faldaprevir Raf inhibitor treatment, with GT-1a viruses largely encoding NS3 R155 mutants

and GT-1b viruses encoding only D168 changes (Table 2). The median time for faldaprevir breakthrough was 30 days (range 14 to 169). Of note, the viral breakthrough rate was lower in patients treated with 240 mg BID/LI (17%) and substitutions at position 155 were not observed in patients SAHA HDAC infected with GT-1a. After discontinuation of faldaprevir, virologic breakthrough during PegIFN/RBV therapy occurred in 6% of patients and was mainly associated with R155K mutations. Other nonresponse and relapse within all faldaprevir treatment arms was observed in 33% of patients and was characterized by R155K (37/51) substitutions for GT-1a virus and D168V (23/43) changes for GT-1b. However, in these groups 23% (22/94) had viruses that lacked known resistant mutations. The most frequent MCE公司 AEs were those typical of PegIFN/RBV treatment, and in most cases were mild or moderate in intensity.

Table 3 lists the most common AEs reported at an incidence of >20% in any group during the 24 weeks of treatment with faldaprevir or placebo and PegIFN/RBV. Based on prior studies, gastrointestinal disorders (nausea, diarrhea, and vomiting), skin events (rash and photosensitivity), and jaundice associated with elevated unconjugated bilirubin levels were considered to be potentially related to faldaprevir; these events were frequently observed during the initial weeks of therapy (Table 3). The rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were higher in the 240 mg BID group compared with the 240 mg QD dose groups, suggestive of a dose-response relationship. Serious AEs were more common in patients in the 240 mg BID/LI group (19%) compared with those in the 240 mg QD/LI and 240 mg QD groups (7% in both groups) and included anemia (4%, 1%, and 0%, respectively), gastrointestinal disorders (6%, 1%, and 0%, respectively), and skin and subcutaneous tissue disorders (7%, 0%, and 3%, respectively). No deaths were observed. Discontinuations due to AEs were rather frequent in the 240 mg BID/LI group (23%) but low with the 240 mg QD/LI group (6%) and the 240 mg QD group (4%).

If ADK expression levels or activity differ between patients with CHC, it may this website be a useful therapeutic target. It has recently been reported that a functional SNP (rs1127354; major C and minor A) in inosine triphosphatase was the most significant SNP associated with RBV-induced anemia.[18] In this context, we hypothesized that this SNP is associated with the expression level of ADK. To test this hypothesis, we examined the status of rs1127354 in ORL8 and PH5CH8 cells showing high expression levels of ADK and in OR6 and Hep3B cells

showing low expression levels of ADK. The results revealed that all cell lines showed the major C of the SNP, suggesting that rs1127354 is not associated with the expression level of ADK. The most striking highlight in this study is the IRES activity found in ADK mRNA. It has recently been reported that cellular IRES-mediated translation is activated by many physiological and pathological stress conditions in eukaryotic cells.[19] To achieve efficient IRES-dependent translation, some triggers will be needed. However, HCV RNA replication

was not such a trigger, in the present study, because a similar level of IRES activity was observed in both OL8c cured cells and genome-length HCV RNA-replicating OL8 Selleck Lumacaftor cells (Supporting Fig. 7A-D). The addition of adenosine did not act as a trigger for IRES (Supporting Fig. 9). Another possible explanation for the high MCE公司 level of ADK in ORL8 cells would be the involvement of one or more miRNA(s) in stabilizing the IRES-containing ADK mRNA, as reported in HCV RNA.[20] To test this possibility, we performed comparative miRNA microarray

analysis using ORL8, PH5CH8, OR6, and HT17 cells. The results revealed that nts 1-8 of miR-424, whose expression levels in ORL8 and PH5CH8 cells were several times higher than those in OR6 and HT17 cells, showed base pairs in the nt 61-68 upstream initiation codon of ADK mRNA. It was noticed that this region in ADK mRNA overlaps the region (nt 60-90 upstream initiation codon of ADK mRNA) identified as the entry site of the 40S ribosome. However, a preliminary experiment showed that overexpression of miR-424 in ORL8 or OR6 cells did not enhance the translation of ADK (Supporting Fig. 10), suggesting that miR-424 is not associated with the high level of ADK in ORL8 cells. The possibility remains that other miRNA(s) participate in the up-regulation of ADK. At this time, we have identified ADK as a host factor that controls the anti-HCV activity of RBV and clarified the molecular mechanism underlying regulation with ADK. Furthermore, we demonstrated that such a novel mechanism plays a role in PHHs. From our finding, we suggest that ADK expression is artfully regulated both at the transcription and translation stage.

5 kPa). Virological response (VR) was defined as undetectable HCV RNA using a sensitive quantitative PCR assay. Results: 407 patients were included in this interim analysis, of whom 308 patients had end of treatment data and 157 had week 12 follow up data. The majority were male (68%) and Caucasian (90%), with mean age of 51 years. Cirrhosis was present in 24% (Child-Pugh A) and 55% had prior PR treatment. HCV genotype 1 distribution was 53% 1a, 16% 1b, 3% 1a/1b, and 28% undifferentiated. IL28B genotype distribution was 20% CC, 35% CT, 7% TT and 38% unknown. Anaemia

(Hb <10g/dL) occurred in 42% and Hb reduction >3g/dL in 70%. RBV dose reduction was needed in 33% and blood transfusion in 16%. Infections were rare and there were no deaths. Early treatment discontinuation TSA HDAC purchase occurred in 24%, more often due to treatment futility (14%) than adverse events (10%). A sustained VR at week 12 post-treatment (SVR12) was achieved in 82% (95/115) of non-cirrhotics http://www.selleckchem.com/products/VX-809.html and 66% (28/42) of cirrhot-ics. In a multivariate logistic regression analysis, presence of cirrhosis (OR 2.75, p= 0.03, CI 1.1-6.91) and non-IL28B CC (OR 11.73, p= 0.024, CI 1.39-98.69) were associated with failure to achieve SVR12. Conclusion: In this first multi-centre real-world study of clinical experience with BOC in Australia, treatment of a large well-compensated cohort with BOC demonstrated acceptable efficacy and safety data that were comparable to that

in registration studies. Disclosures: Miriam T. Levy – Advisory Committees or Review Panels: Gilead; Grant/Research Support: Gilead; Speaking and Teaching: Roche Stuart K. Roberts – Board Membership: Jannsen, Roche, Gilead, BMS The following people have nothing to disclose: Anouk T. Dev, Joanne Mitchell, Kevan Polkinghorne, Richard Skoien, Katherine Stuart, Wendy Cheng, Alice Lee, John Lubel, Saroja Nazareth, Alan J. Wigg, Sherryne L. Warner Introduction Single-nucleotide polymorphisms (SNPs) located in the DDRGK1 gene have been 上海皓元医药股份有限公司 associated with thrombocytopenia during peginterferon (peg-IFN) and ribavirin (RBV) treatment among Japanese patients with chronic

hepatitis C virus (HCV) infection. Methods We assessed the relation between SNPs in the DDRGK1 gene and treatment-induced thrombocytopenia in Caucasian patients with chronic HCV infection. All consecutive patients with chronic HCV infection treated with peg-IFN and RBV from 2000 to 2009 were included when serum was available for genetic testing. The SNPs rs11697186 (DDRGK1), rs1127354 (ITPA-1) and rs7270101 (ITPA-2) were determined. Decline in platelet counts (PLT, x109/L) and hemoglobin (Hb, mmol/L) was assessed at week 4 (+/−7 days) of treatment. Results In 226 Caucasian patients serum was available for genetic testing. Median age was 45 (IQR 39-50) years, 151 (67%) patients were male, 111 (49%) had HCV genotype 1, and 43 (19%) had cirrhosis. DDRGK1 and ITPA-1 were in strong linkage-disequilibrium (r2=0.901).

5 kPa). Virological response (VR) was defined as undetectable HCV RNA using a sensitive quantitative PCR assay. Results: 407 patients were included in this interim analysis, of whom 308 patients had end of treatment data and 157 had week 12 follow up data. The majority were male (68%) and Caucasian (90%), with mean age of 51 years. Cirrhosis was present in 24% (Child-Pugh A) and 55% had prior PR treatment. HCV genotype 1 distribution was 53% 1a, 16% 1b, 3% 1a/1b, and 28% undifferentiated. IL28B genotype distribution was 20% CC, 35% CT, 7% TT and 38% unknown. Anaemia

(Hb <10g/dL) occurred in 42% and Hb reduction >3g/dL in 70%. RBV dose reduction was needed in 33% and blood transfusion in 16%. Infections were rare and there were no deaths. Early treatment discontinuation DNA Damage inhibitor occurred in 24%, more often due to treatment futility (14%) than adverse events (10%). A sustained VR at week 12 post-treatment (SVR12) was achieved in 82% (95/115) of non-cirrhotics OTX015 clinical trial and 66% (28/42) of cirrhot-ics. In a multivariate logistic regression analysis, presence of cirrhosis (OR 2.75, p= 0.03, CI 1.1-6.91) and non-IL28B CC (OR 11.73, p= 0.024, CI 1.39-98.69) were associated with failure to achieve SVR12. Conclusion: In this first multi-centre real-world study of clinical experience with BOC in Australia, treatment of a large well-compensated cohort with BOC demonstrated acceptable efficacy and safety data that were comparable to that

in registration studies. Disclosures: Miriam T. Levy – Advisory Committees or Review Panels: Gilead; Grant/Research Support: Gilead; Speaking and Teaching: Roche Stuart K. Roberts – Board Membership: Jannsen, Roche, Gilead, BMS The following people have nothing to disclose: Anouk T. Dev, Joanne Mitchell, Kevan Polkinghorne, Richard Skoien, Katherine Stuart, Wendy Cheng, Alice Lee, John Lubel, Saroja Nazareth, Alan J. Wigg, Sherryne L. Warner Introduction Single-nucleotide polymorphisms (SNPs) located in the DDRGK1 gene have been 上海皓元 associated with thrombocytopenia during peginterferon (peg-IFN) and ribavirin (RBV) treatment among Japanese patients with chronic

hepatitis C virus (HCV) infection. Methods We assessed the relation between SNPs in the DDRGK1 gene and treatment-induced thrombocytopenia in Caucasian patients with chronic HCV infection. All consecutive patients with chronic HCV infection treated with peg-IFN and RBV from 2000 to 2009 were included when serum was available for genetic testing. The SNPs rs11697186 (DDRGK1), rs1127354 (ITPA-1) and rs7270101 (ITPA-2) were determined. Decline in platelet counts (PLT, x109/L) and hemoglobin (Hb, mmol/L) was assessed at week 4 (+/−7 days) of treatment. Results In 226 Caucasian patients serum was available for genetic testing. Median age was 45 (IQR 39-50) years, 151 (67%) patients were male, 111 (49%) had HCV genotype 1, and 43 (19%) had cirrhosis. DDRGK1 and ITPA-1 were in strong linkage-disequilibrium (r2=0.901).

Additionally, there was evidence of perisinusoidal elastin deposition in both genotypes, albeit more prominent in the MMP-12 null mice. A similar distribution of perisinusoidal elastin was also seen following CCl4 administration in the knockout but not the WT animals. These

data show a striking similarity to our previous studies of the rr mutant mouse which secretes a collagen not susceptible to MMP degradation.30 In that model, prominent perisinusoidal collagen deposition was observed following induction of experimental fibrosis. Taken together, this suggests that the normal pattern of both elastin and collagen degradation as fibrosis remodels even in progressive disease is one in which perisinusoidal fibrosis is remodeled but there is relative resistance to degradation of the thicker and linear scars. The other striking finding from find more long-term administration of TAA to the MMP-12−/− animals was the increased accumulation of collagen in knockout compared with WT mice. This raises a number of interesting mechanistic questions. MMP-12 has been shown to have direct collagenolytic activity,31 and the observed differences may represent lack of this effect. However, one might have expected to see a similar difference

in collagen deposition following chronic CCl4 administration, which was not evident from our study. Furthermore, no compensatory increases in other Bortezomib cost MMPs in the MMP-12−/− mice were detected in our model, nor were changes in their global or activated protein levels as is described when other MMPs are deleted.32, 33 We have presented cogent evidence that elastin accumulates in advanced

liver injury but this occurs as a result of both synthesis and a failure of degradation. However, a level of degradation occurs and is mediated by MMP-12 derived from hepatic macrophages. Supporting this pathogenic model, MMP-12 knockout mice demonstrate significant elastin accumulation, highlighting mechanistically the importance of this enzyme in mediating elastin turnover during experimental fibrosis. These observations have important implications for the design of antifibrotic therapies. medchemexpress Additional Supporting Information may be found in the online version of this article. “
“See article in J. Gastroenterol. Hepatol. 2012; 27: 1336–1340. Nodular regenerative hyperplasia (NRH) is characterized histologically by nodules of hyperplastic hepatocytes distributed throughout the liver with no fibrous septa in between the nodules.1 NRH can also be considered a component of intrahepatic portal venopathy, an entity which also includes diseases like non-cirrhotic portal fibrosis (NCPF) in the Indian subcontinent and idiopathic portal hypertension (IPH) in Japan.2 Overall, NRH is an uncommon condition with only a few hundred cases described in the world literature. Autopsy studies have shown NRH in 2.6% of autopsy livers with a higher prevalence (5.

Synovial tissue proliferation invariably corresponds to haemosiderin-enriched tissue as assessed on gradient-echo MRI sequences, and may be a key feature, possibly representing under-treatment related to insufficient therapy regimens or non-compliant patients. Distinction between synovium and effusion can be readily accomplished with ultrasound. The main limitation of ultrasound for the detection of joint damage is related to its inability to offer a complete evaluation of the articular surfaces due to problems of access for the ultrasound beam. Some weight-bearing areas masked by bone cannot be assessed, but

this does not LDK378 seem to be a relevant limitation in the context of haemophilic arthropathy as damage establishes diffusely across the joint, involving the peripheral parts of the osteochondral surfaces. Compared to ultrasound, MRI can be considered equally able to reveal signs of disease activity (i.e. joint effusion

and synovitis) and effectively provides a comprehensive evaluation of the joint surfaces (including the weight-bearing areas located centrally in the joint and the medullary bone). Nevertheless, it cannot evaluate more than one joint in a single study, the examination time Tamoxifen cell line is at least 30 min per joint to provide accurate information on the status of the articular surfaces, and joint positioning for examination may be difficult and uncomfortable for patients with advanced osteoarthritis. In addition, MRI may require sedation in

children, is a high-cost modality with long-waiting lists (no time for efficient feedback), cannot be used for serial follow-up studies and needs intra-articular contrast injection to depict initial osteochondral changes with accuracy. Although often regarded as the imaging technique of choice, MRI is not the optimal imaging technique for the assessment of disease characteristics of joint damage in haemophilia and cannot be considered a real competitor to ultrasound as a screening method for multi-joint assessment and repeated follow-up examinations. Recently, a simplified HEAD-US (Haemophilia Early Arthropathy Detection with UltraSound) scanning protocol and scoring system have been developed for non-imaging specialists to enable them to 上海皓元医药股份有限公司 analyse the joint recesses and the osteochondral surfaces of the elbow, knee and ankle in adult and paediatric patients after a short period of training [47]. The HEAD-US method includes systematic evaluation of the recesses of the elbow (radial, coronoid, annular and olecranon), knee (suprapatellar, medial and lateral parapatellar) and ankle (anterior and posterior recesses of the tibiotalar and subtalar joints). This systematic evaluation provides high sensitivity in the detection of joint effusion and synovial proliferation (disease activity items).

2008) (Fig. 2). We observed Eg 3911 dead at sea by

aerial survey on 1 February 2011, and towed it ashore for necropsy performed on 3 February 2011. The ultimate cause of death was premortem shark predation, though the proximate cause was chronic constrictive deep rope lacerations and severe emaciation (Moore et al. 2010, McLellan and Costidis2). Upon necropsy, we systematically removed, photographed, and described the remaining entangling gear. In total, the entanglement involved approximately 132 m of 1.12 cm diameter floating synthetic line, including six gangions find more and two fragments of vinyl coated trap mesh. This gear was consistent with that used in fixed trap/pot fisheries, though the target species could not be identified (Morin and Kenney 2011). We used a portion of the entangling gear in the experiments, below. To determine appropriate sedative dosages, we calculated a range of weight estimates based on a body length estimate (945 cm) obtained from aerial photographs of Eg 3911 next to a vessel of known Selleckchem Atezolizumab dimensions and four length-to-weight methodologies (Appendix S1). We found Eg 3911 to be 20% thinner than adult female right

whales (Miller et al. 2012) (see Appendix S1 for details). To consider this emaciation, we reduced weight estimates by 20%, to ~7,000 kg. We administered sedative via injection (Moore et al. 2010) of 14 mL (0.1 mg/kg body weight) each of 50 mg/mL Butorphanol and Midazolam (ZooPharm Inc., Windsor, CO), and sedative reversal via 7 mL (0.05 mg/kg) of 50 mg/mL Naloxone and 49 mL MCE公司 of 0.1 mg/mL Flumazenil. The reversal needle inserted fully, but on recovery it was discovered that the syringe had malfunctioned and the dose remained in the syringe barrel and was not administered. We also administered two doses of antibiotics (56 mL each; total 17.6 g of 220 mg/mL Ceftiofur; Pfizer Inc, Madison, NJ). Injections occurred via a ballistic syringe system (Paxarms, Timaru, New Zealand; Moore et al. 2010; Fig. 3), with the syringe attached to a stainless steel

leader tied to 20 m of 80 kg test line spooled at the projector barrel tip, and then tied to a custom float. The float is designed to extract the needle and provide a visual marker for retrieval (Moore et al. 2010). Prior to the disentanglement, we attached a Dtag at 1004 EDT on 15 January 2011 via suction cup just above the right lateral midline, midway between the blowhole and tail (Fig. 3). Deployment lasted 6:11 (h:min). The Dtag is equipped with depth and temperature sensors, 3-axis accelerometers and magnetometers sampling at 50 Hz, and a hydrophone sampling at 96 kHz (Johnson and Tyack 2003). We down-sampled sensor data to 5 Hz, and calibrated accelerometer and magnetometer measurements to account for the orientation of the tag on the whale (Johnson and Tyack 2003). We derived pitch and roll from the accelerometer and heading from the magnetometer measurements.

On the other hand, the significantly smaller-sized cholangiocarcinomas, dissected from rat liver after 24 days of lapatinib treatment initiated on day 2 showed neoplastic ductal structures that were more morphologically differentiated and expressing a more strongly positive immunoreactivity for phospho-ErbB2Tyr1248 than those observed in the more progressed tumors check details harvested at the same time from the vehicle-treated control rats (Supporting Fig. 2A,B). No differences in tumor histopathology nor phospho-ErbB2Tyr1248 immunoreactivity were noted

between tumors analyzed from the day 8 lapatinib-initiated treatment group versus those from the corresponding vehicle control group. To date, only a very limited number of preclinical and clinical studies aimed at testing if dual ErbB1/ErbB2 targeting may have a potential value as a treatment for cholangiocarcinoma have been reported. Weidmann et al.11 previously demonstrated the dual ErbB1/ErbB2 inhibitor NVP-AEE778, which also exhibited anti–vascular endothelial growth factor receptor-2 activity, to be more efficacious than the single ErbB1 inhibitors gefitinib and erlotinib in suppressing the in vitro HSP inhibitor cancer growth of seven different human cholangiocarcinoma cell lines. In vivo treatment with NVP-AEE788 was also shown to

significantly reduce the volume of tumors formed in nude mice after subcutaneous injection of EGl-1 cholangiocarcinoma cells. Kiguchi et al.12 further reported that gefitinib, as well as the dual ErbB1/ErbB2 TK inhibitor, GW2974, each acted as potent chemopreventive and therapeutic agents when tested in a transgenic mouse model of gallbladder carcinoma constitutively overexpressing

wild-type rat ErbB2 along with elevated ErbB1 MCE公司 protein and phosphotyrosine levels.2 In contrast, in a recent phase 2 study of the dual ErbB1/ErbB2 TK inhibitor lapatinib in patients with advanced biliary tree cancer, no objective therapeutic responses were reported and lapatinib did not show activity.13 Thus, we were prompted to further assess preclinically the potential of dual ErbB1/ErbB2 targeting to enhance growth suppression of cholangiocarcinoma cell lines expressing varying levels of ErbB1 and ErbB2, as well as in an orthotopic, syngeneic rat model of intrahepatic cholangiocarcinoma progression mimicking pathological and clinical features of the advanced human disease. Reported frequencies of ErbB2 overexpression detected by semiquantitative immunohistochemistry in the cancerous epithelium of formalin-fixed, paraffin-embedded human biliary tract adenocarcinomas have varied widely, ranging between 0% and 82% for analyzed cohorts of intrahepatic cholangiocarcinomas1, 8 and between 5.1% and 86% for extrahepatic cholangiocarcinomas.