Some patients

Some patients Sirolimus price had more than one AE at the time of discontinuation. Changes in laboratory

values were generally consistent with those commonly reported for PegIFN/RBV. Decreases in hemoglobin, platelets, and white blood cell count were observed at frequencies similar to those observed with PegIFN/RBV and descriptive analysis did not reveal any clinically relevant differences between dose groups (no statistical analyses were conducted; Table 4).10 Erythropoietin was received by 6% to 14% of patients (two patients received transfusions; one in the 240 mg QD arm and one in the 240 mg BID/LI arm). Increases in total bilirubin, characterized by predominance GDC-0068 purchase of the unconjugated (indirect) fraction, were common during faldaprevir therapy and rapidly returned to pretreatment levels in all patients after faldaprevir was discontinued. Elevations in bilirubin were not associated with

increases in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, or other markers of liver injury (Supporting Table 1). Treatment with the PI, faldaprevir 240 mg QD, in combination with PegIFN and RBV, led to virologic cure (SVR) in □35% and 50% of HCV GT-1 patients with strictly defined prior null or partial response to PegIFN/RBV. Interestingly, higher SVR rates were not observed in patients treated with 3-day LI of PegIFN/RBV compared with those treated

with all three drugs simultaneously from the start. check details While 240 mg BID/LI was associated with lower rates of virologic breakthrough, the SVR rate achieved with this regimen was lower than the rate achieved with 240 mg QD, largely due to higher rates of treatment discontinuation due to AEs. This trial excluded patients with liver cirrhosis and used a more stringent definition of null (<1 log10 reduction in HCV RNA at any time during previous treatment) and partial response (≥1 log10 reduction in VL but never undetectable on treatment) than clinical trials with other HCV PIs plus PegIFN/RBV in treatment-experienced patients.3, 4, 11 The manner in which prior HCV treatment response was collected in this study did not permit retrospective analysis of the current definitions of null (<2 log10 reduction in HCV RNA at week 12) and partial response (≥2 log10 reduction in HCV RNA at week 12 but with detectable HCV RNA at week 24). Accordingly, cross-study comparison of these data with other published studies is not possible.12 A phase 3 trial of faldaprevir plus PegIFN/RBV in treatment-experienced patients classified according to current definitions of null and partial response is ongoing. Prior relapsers are also being assessed in the phase 3 study.

2, 4-7 Third, IL-22 treatment may overturn corticosteroid-mediate

2, 4-7 Third, IL-22 treatment may overturn corticosteroid-mediated or TNF-α inhibitor-mediated inhibition of liver regeneration, as IL-22 can stimulate hepatocyte proliferation and promote liver regeneration.10, 11 Fourth, IL-22 is not elevated, whereas expression of IL-22R1 is up-regulated in the liver from mice treated with chronic-binge ethanol (Fig. 8). Just like in our animal model, IL-22 is not detected, whereas expression

of IL-22R1 is elevated (five-fold) Venetoclax manufacturer in the liver of patients with alcoholic hepatitis (Fig. 8). A potential limitation of these clinical samples is that we only include patients with severe alcoholic hepatitis. Further studies should evaluate if the results obtained in these patients are also found in the livers with mild to moderate liver injury. Collectively, these findings suggest that patients with alcoholic hepatitis may be sensitive to IL-22 treatment due to low levels of endogenous IL-22 and elevated levels of IL-22R1 in the liver. Finally, side effects from IL-22 treatment may be minimal as IL-22 receptor expression is restrictedly to epithelial cells such as hepatocytes.8 In summary, IL-22 treatment

appears to have multiple beneficial effects on alcoholic hepatitis, such as preventing hepatocellular damage, promoting hepatocyte proliferation, and inhibiting bacterial infection. Clinical trials examining combination therapy with IL-22 plus corticosteroids or plus TNF-α inhibitor for patients with severe

buy Cobimetinib alcoholic hepatitis is warranted. Additional Supporting Information may be found in the online version of this article. “
“Background and Aims:  Cyclosporin A (CSA), an immunosuppressive agent, is highly efficacious in patients with refractory ulcerative colitis (UC). We retrospectively investigated patients with refractory UC treated with CSA therapy to elucidate the efficacy and the prognostic factors. Methods:  Forty-one patients (26 men and 15 women) were see more enrolled. The efficacy of CSA was assessed at three time points: short- and mid-term assessments took place 2 weeks and 1 year after CSA administration, respectively, and long-term assessments at the end of the observation period. Results:  The short-term response rate was 71%. Background analysis revealed risk factors for CSA unresponsiveness: (i) more than 10 000 mg of prednisolone used before CSA treatment; (ii) the presence of circulating (C7-HRP); and (iii) disease duration more than 4 years. The mid-term relapse-free survival rate was 51.0%. The addition of azathioprine (AZA) after CSA treatment significantly suppressed the incidence of relapse at 1 year (72.5% vs 26.7%, P = 0.0237). The overall colectomy-free survival rate was 46.4%, and the induction of AZA after CSA treatment significantly reduced the colectomy rate (66.7% vs 30.5%, P = 0.0419).

We examined about age, sex, gastrointestinal (GI) symptoms, GI le

We examined about age, sex, gastrointestinal (GI) symptoms, GI lesions, HCS assay treatments. 6 cases are observed in small intestines by capsule endoscopy and double baloon endoscopy. Results: Age at onset ranged from 21 to 86 years

(median 63.5). 5 patients were male and 3 patients were female. GI symptoms included abdominal pain (100%), diarrhea (37%), nausea (14%), distension of abdomen (14%). GI lesions were located in terminal ileum (88%), duodenum (100%), stomach (63%), jejunum (37%), and colon (37%). The lesions were described as irregular ulcer, erosion, redness. The most common lesion was multiple irregular ulcer in terminal ileum (75%). Other patients had redness in terminal ileum. 4 patients developped nephritis. 4 patients had Helicobacter pylori (HP) antibody. Steroid remitted GI symptoms and improved GI lesion in all patients. Conclusion: These results suggest that steroids may reduce abdominal resion of SHP in adults. 6 of 8 patients had multiple irregular ulcer in terminal ileum and all patients had small intense lesions. Key Word(s): 1. Schönlein-Henoch purpura Table 1. Case Age Sex Compliant GI lesion Treatment Nephritis HP S: Stomach, D: Duodenum,

J: Jejunum, I: Ileum, C: Colon. Presenting Author: YU YU OMATA Additional Authors: AKIHIKO TSUCHIYA, AZUMA WATANABE, TAKAHIRO SASAMOTO, KO NISHIKAWA, MASAMI YAMANAKA Corresponding Author: OMATA YU YU Affiliations: Ageo Central General Hospital, Ageo Acalabrutinib order Central General Hospital, Ageo Central General Hospital, Ageo Central General Hospital, Ageo Central General Hospital Objective: As the Japanese population continues to age, the number of FOBT-positive elderly individuals detected by medical screening

is increasing. However, as these individuals have various underlying diseases, colonoscopy may not be the best option because of the risk of complications. We performed colonoscopy in FOBT-positive elderly individuals and investigated the final diagnoses and treatments offered. Methods: A total of 43 FOBT-positive elderly patients (85 years old) who visited our department between June 2010 Telomerase and June 2014 were examined by colonoscopy. Those with visible blood in the stool were excluded. Final diagnosis based on colonoscopy findings and subsequent treatments were investigated. Results: Subjects included 21 men and 22 women (average: 88.1/88.5 years). Colonoscopy revealed no abnormalities (hemorrhoid) in 14 patients, ischemic colitis in 3 patients, colon polyps £ 5 mm in 12 patients (1 treated by EMR and 11 untreated), colon polyps 6–10 mm in 10 patients (5 treated by EMR and 5 untreated), colon polyps 11–20 mm in 3 patients (2 treated by EMR and 1 untreated), and advanced colon cancer in 1 patient (laparotomy). Among the patients who underwent EMR, adenocarcinoma was found in only 1 patient with 20 mm polyps.

6–10 HRS is pathogenically related to a marked arterial vasodilat

6–10 HRS is pathogenically related to a marked arterial vasodilation of the splanchnic circulation, due to portal hypertension, that causes impairment of the effective arterial blood volume with activation of systemic vasoconstrictor factors that lead to marked reduction of renal blood flow and glomerular BIBW2992 filtration rate.1–5 In recent years, several studies have shown that the administration of terlipressin, a vasopressin analogue that is not available in all countries

(including the United States), together with intravenous albumin improves renal function in patients with HRS. Other vasoconstrictor drugs, including midodrine and norepinephrine, have also been investigated, yet the information available is limited.1–4, 11, 12 The results of the studies show that not all patients with HRS respond to terlipressin

and albumin. A recent meta-analysis indicates that 52% of patients with HRS respond to treatment with terlipressin.13 In the remaining patients, terlipressin therapy is not associated with improvement Ipilimumab in vitro of renal function. So far, no specific studies have been published investigating predictive factors of response to therapy in patients with HRS treated with terlipressin and albumin. The identification of patients with low likelihood of response to treatment is of important clinical interest, particularly in patients awaiting transplantation, and also in the design of new therapies for HRS. In the current study, we assessed predictive factors of response to terlipressin and albumin in patients with cirrhosis and type 1 HRS treated with the same therapeutic protocol in a single institution. CVP, central venous pressure; HRS, hepatorenal syndrome; MAP, mean arterial pressure; MELD, Model for End-Stage Liver Disease. Since 1998, all patients with cirrhosis and renal failure admitted to the Liver Unit of the Hospital Clínic of Barcelona (Catalunya, Spain) were evaluated using the same diagnostic

algorithm,14 which includes diuretic withdrawal, assessment of possible causes of hypovolemia, a trial of plasma tuclazepam expansion with intravenous albumin to rule out the existence of renal failure due to volume depletion, and evaluation of possible drug nephrotoxicity, infection, or renal parenchymal diseases. Patients meeting the criteria of type 1 HRS, as proposed by the International Ascites Club,15 were treated with terlipressin and albumin. The new criteria for definition of HRS were not used because patients included in this study were treated before the new criteria were published.3 Reasons for not receiving treatment include terminal condition (death expected in less than 48 hours), presence of severe cardiovascular diseases, advanced hepatocellular carcinoma, and active infection.

The role that GhLOX2 may have in the defence strategy of cotton t

The role that GhLOX2 may have in the defence strategy of cotton to Xcm is discussed Talazoparib cell line regarding the HR. “
“Understanding on actinomycetes-mediated stress tolerance in plants is very limited. This study demonstrated for the first time some stress tolerance mechanisms in chickpea via mediation of an actinomycetes strain Streptomyces rochei SM3. Here, we used the strain SM3 for treating chickpea seeds and plants raised from such seeds were challenged with Sclerotinia sclerotiorum and NaCl. Chickpea mortality due to Sc. sclerotiorum infection was suppressed by nearly 48%, and biomass accumulation

was increased by nearly 20% in the salt-stressed condition in SM3-treated plants compared to non-treated plants. Physiological responses in chickpea under the challenging conditions showed that phenylalanine ammonia lyase activities increased in SM3-treated plants. This is followed by accumulation of higher concentrations of phenolics that led to enhanced lignifications in SM3-treated plants compared to non-SM3-treated plants challenged with the same stresses. Antioxidant activities, as assessed through catalase activities and proline accumulation, also increased in SM3-treated plants challenged with both the stresses

compared to non-SM3-treated plants. Investigation at genetic level further showed that the strain Tofacitinib SM3 triggered the ethylene (ET) responsive ERF transcription factor (CaTF2) under the challenged conditions. Thus, from this study, we conclude that actinomycetes St. rochei SM3 trigger the ET-mediated defence pathway in chickpea and activates the phenylpropanoid pathway for alleviating the stresses caused by Sc. sclerotiorum and salt in chickpea. “
“The objective of this study was to examine the impact of free

environmental moisture, such as from rainfall, on disease development and mycotoxin production and accumulation in planta. In greenhouse experiments in 2009, two single Fusarium graminearum isolates were used to inoculate spikes of three wheat cultivars: ‘Alsen’, ‘2375’ and ‘Wheaton’ at anthesis. On each wetting event/sampling day (7, 14, 21 or 28 days after inoculation), FHB severity was assessed and five pots of each of the two cultivar/isolate treatments were subjected Methocarbamol to a wetting event. At the end of the wetting event, the spikes were sampled both from the plants that received the wetting treatment and those that did not and analysed for mycotoxins. Run-off water samples were also taken 3 h after the start of irrigation and immediately after the wetting treatment concluded and analysed for mycotoxins. The results showed despite statistically similar FHB severity, the levels of DON and other mycotoxins detected were significantly lower in the plants receiving a single wetting event compared to the control. The levels of DON in wetted plants were lower up to 36% in ‘Alsen’, 52% in ‘2375’ and 41% in ‘Wheaton’ compared to that of corresponding controls.

Written informed consent was obtained from all subjects at the ti

Written informed consent was obtained from all subjects at the time of health check-up, and the study was conducted in accordance with the Helsinki Declaration. NAFLD was diagnosed using abdominal ultrasonography. Serum fetuin-A was measured by ELISA. IMT was assessed using a high-resolution ultrasound PF01367338 scanner. Using recombinant human fetuin-A, we investigated the effects of fetuin-A on HSCs. Results: Serum fetuin-A concentration

was significantly correlated with platelet count (R=0.19, P<0.01), NAFLD fibrosis score (R=−0.25, P<0.01), and mean IMT (R=−0.22, P<0.01). Next, we analyzed the correlation between the serum fetuin-A level and mean IMT in four groups segmented by mean IMT value quartile (range of mean IMT; group 1: <0.7, group 2: 0.7-0.8, group 3: 0.8-1.0, group 4: 1 mm). Interestingly, the serum fetuin-A level did not change in the three normal groups, but significantly decreased only in the

abnormal group (mean IMT ≥ 1 mm). Multivariate analysis revealed that fetuin-A concentration was a significant and independent determinant of platelet count, NAFLD fibrosis score, and mean IMT. Recombinant fetuin-A suppressed TGF-β1 signaling and fibrosis-re-lated gene expression and increased the expression of TGF-β1 pseudoreceptor bone morphogenic protein and activin membrane-bound inhibitor (BAMBI). Conclusions: Serum fetuin-A level is associated with liver/vessel fibrosis-related selleckchem markers in NAFLD patients. Circulating fetuin-A could be a useful

serum biomarker for predicting liver and vascular fibrosis progression in NAFLD patients. Disclosures: Tetsuo Takehara – Grant/Research Support: Chugai Pharmaceutical Co., MSD K.K. The following people have nothing to disclose: Yoshihiro Kamada, Motoya Sato, Yuri Takeda, Sachiho KIda, Yuka Ohara, Hironobu Fujii, Maaya Akita, Kayo Mizutani, Yuichi Yoshida, Makoto Yamada, Hidetaka Hougaku, Eiji Miyoshi Background. The diagnosis and staging of NASH still relies on liver histology. However, histological classifications of NAFLD Demeclocycline are based on morphology, thus empirical, with undetermined clinical relevance and correlates. Aim. To investigate whether different histological categories according to the FLIP algorithm and the SAF score reflect distinct patient profiles and are predicted by relevant clinical/biological features. Methods. 140 liver biopsies of patients (pts) with suspected NAFLD based on metabolic risk factors (cohort 1) and 78 liver biopsies from a multicentric therapeutic trial of ASP9831 in NASH (cohort 2) were reassessed with the FLIP algorithm (identifying NASH and non-NASH, NAFL) and the SAF score (S=Steatosis; A=Activity; F=Fibrosis; Hepatology 2012;56:1751, identifying histolog-ically severe forms, HSF, as A≥3 and/or F≥3) by a single liver pathologist, blinded to clinical data. Results. In cohort 1, 60 pts (43%) were diagnosed with NASH according to the FLIP algorithm.

Tubulogenesis was visualized with a Zeiss Axiovert 40 CFL inverte

Tubulogenesis was visualized with a Zeiss Axiovert 40 CFL inverted microscope (×4 magnification; Carl Zeiss, Ltd.), captured with a charge-coupled device digital camera (Jenoptix, Jena, Germany) after 3 or 6 hours of culturing in the presence of either vehicle or 1 μg/mL LPS13, 20 at 37°C with

5% CO2, and quantified with Image Pro Software as previously selleck products described.15 Cell viability was measured with calcein AM (Invitrogen). Anesthetized TLR4-WT and TLR4-MT mice received 300-μL injections of sterile Matrigel (growth factor reduced; catalog no. 356231, BD Biosciences)21 and vascular endothelial growth factor (VEGF; 50 ng/mL; R&D Systems, Minneapolis, MN) into the subcutaneous layer in two locations. Matrigel plugs were removed 14 days after implantation, photographed, and divided into two blocks. One Matrigel plug was allowed to liquefy at 4°C, and the hemoglobin content was determined by the Drabkin method according to the manufacturer’s protocol (Sigma, St. Louis, MO). Absorbance was measured at 540 nm, and the hemoglobin concentration was calculated and normalized to the plug weight. The other Matrigel block was fixed overnight in formalin and embedded in paraffin. Sections (6 μm) were stained

with hematoxylin and eosin (H&E) and were visualized by traditional light microscopy. Proteins from cellular extracts were subjected to denaturing 12% sodium dodecyl sulfate–polyacrylamide LY294002 datasheet gels and transferred to nitrocellulose membranes. After blocking, the blots were probed with anti-TLR4 (1:1000) and anti-MyD88 (1:1000; Imgenex). The blots were washed Evodiamine and incubated for 1 hour at room temperature with appropriate horseradish

peroxidase–conjugated secondary antibodies. Protein bands were detected with an enhanced chemiluminescence detection system (ECL Plus, Santa Cruz). After the nitrocellulose sheets were exposed to Kodak XAR film, the autoradiographs were scanned. Equal protein loading was verified by the reprobing of the membrane with an anti–β-actin antibody (1:5000). For immunostaining, murine and human LECs were cultured to approximately 50% confluence on gelatin-coated cover slips in 24-well plates. Frozen liver sections from sham, BDL, olive oil–treated, and CCl4-treated TLR4-WT and TLR4-MT mice were fixed with ice-cold acetone and were blocked with 10% goat serum for 2 hours at room temperature to eliminate nonspecific background signals. Cells or tissue sections were then incubated with antibodies against TLR4 (Sigma; 1:400), von Willebrand factor (vWF; Sigma; 1:400), F4/80 (Abcam; 1:150), CD11b (Abcam; 1:200), aquaporin-1 (Alpha Diagnostics International; 1:500), and platelet-derived growth factor receptor β (Cell Signalling; 1:100) at 4°C overnight (recent studies22 have shown that aquaporin-1 stains LECs, including cirrhotic neovessels).

T-cell differentiation leads to cells that can be distinguished b

T-cell differentiation leads to cells that can be distinguished by functional assays and their production of characteristic cytokines. This cellular differentiation is commonly viewed as a kind of lineage commitment associated with the expression of master regulators within this process, i.e. the transcription factors T-bet, Gata-3, RorγT, Bcl6, and FoxP3 that drive differentiation of Th1, Th2, Th17, follicular T helper (Tfh), and regulatory Treg cells, respectively. However, Selleckchem Fulvestrant there is growing evidence for plasticity

in this process, and in the context of Th cell function in chronic infections such as H. pylori, one should keep in mind that subtype populations may not be as committed as generally believed [38]. The generation and maintenance of a T-cell response depends on DC, and it has been a longstanding challenge to decipher whether DCs are present in noninflamed gastric mucosa. Studies in mice had shown that H. pylori-specific responses might be induced more

distally in the gastrointestinal system, in Peyer’s patches, by passing H. pylori, implying that this was a functional consequence of the gastric mucosa lacking DC [39,40]. Several groups have now re-addressed this issue. Bimczok et al. [41] showed that cells with typical DC markers such as MHC HSP inhibitor review II, CD11c, DC-SIGN, and CD206 can be isolated from biopsies taken from both normal and H. pylori-infected patients. The frequency of these cells increased around fivefold in biopsies from infected patients in which DCs also exhibited an activated phenotype and molecules which act as co-stimulatory ligands to T cells, such as CD86, were upregulated. In vitro, these gastric DCs phagocytose and process H. pylori. DCs secreted IL-6, -8, and

-10 as well as triggering expansion of Th1 cells. Presence of DCs in normal human gastric mucosa and their increase in H. pylori colonized mucosa were confirmed by Necchi et al. [42]. It is interesting in this context that Khamri et al. also detected monocyte-derived DCs in inflamed mucosa, and using DCs derived by IL-4 and GM-CSF from blood monocytes, they found that these cells express IL-23 and IL-12, but the former was produced earlier [43]. IL-23 is a positive regulator of Th17 cells, and Kamzi et al. could visualize IL-23 Selleck Baf-A1 expressing DCs as well as Th17 cell in inflamed gastric mucosa. They also showed that in vitro stimulated CD4+ T cells produce more IL-17 in response to H. pylori exposed DCs, a process mediated by IL-23 and IL-1. Kao et al. reported essentially similar findings when analyzing mice [44]. They showed that bone marrow-derived DCs (which are more accessible) preferentially induced Treg and Th17 cells. Differentiation of these CD4+ subsets requires TGF-β, but Th17 cells also need IL-6 and are further promoted by IL-23 and IL-1. The bias toward Treg cells in the murine system was probably because H.

Caucasians were the predominant ethnic population in this study (

Caucasians were the predominant ethnic population in this study (n = 1443) with the frequency of the good responder IFN-λ3 rs12979860 CC and rs8099917 TT genotypes being 32% and 52%, respectively. These results were very similar to that found in Caucasians from the pivotal GWAS from North America and Australia-Europe selleck compound reporting on the IFN-λ3 rs12979860 and rs8099917 SNPs, respectively.[1, 2] Asian subjects, in contrast, had a higher prevalence of good

responder genotypes, and both SNP responder alleles were of similar prevalence. The overall frequency of the IFN-λ3 rs12979860 CC was 80%, while the rs8099917 TT genotype frequency was 86%. These findings were similar to that reported in other Asian cohorts with HCV Gt1 infection, including those from Taiwan (rs12979860 CC 90%, rs8099917 TT 90%),[11] China (rs12979860 CC 88%, rs8099917 TT 85%),[12, 13] and Korea (rs8099917 TT 85%).[14] Reports from Japan have been mixed, however, with the prevalence of the rs8099917 TT genotype in HCV Gt1 varying from 71% to 86%.[3, 15] The high prevalence of good responder IFN-λ3 polymorphisms along with recent data linking favorable IFN-λ3 genotype

to improved viral clearance and kinetics[16, 17] among Asians explains much of why Asian subjects have high response rates to PEG-IFN plus RBV. To our knowledge, this study is the first to report the distribution of IFN-λ3 polymorphisms among Australian Selleckchem EPZ-6438 (or non-Australian) Aboriginals with CHC. Interestingly, we found that the prevalence of favorable IFN-λ3 genotypes among the 33 Aboriginals tested was similar to that of Caucasians with the frequency of the IFN-λ3 rs12979860 CC and rs8099917 TT genotypes being 33% and 63%, respectively. Limited data exists, however, on the outcomes of PEG-IFN and RBV therapy in Aboriginal Australians with CHC to determine whether our findings have a clinical corollary. Indeed, the only relevant study of note evaluating this issue involved Aboriginal Canadians who had similar response rates to PEG-IFN plus RBV therapy compared with non-Aboriginal

Canadians.[18] Further studies are therefore needed to address the issue of the relationship of IFN-λ3 genotype and IFN responsiveness among this important ethnic GPX6 group. Our study is also the first to describe the distribution of IFN-λ3 polymorphisms in native New Zealanders and Pacific Islanders. Although subject numbers were small (n = 17), Maoris and Pacific Islanders both had a relatively high prevalence of good responder genotypes, with the frequency of IFN-λ3 rs12979860 CC being 75% and 78%, and rs8099917 TT genotype 88% and 89%, respectively. Thus, the IFN-λ3 distribution of both ethnic groups appears to resemble far more closely that of Asians rather than indigenous Australians.

In the EPLBD without EST group, there were 36 patients in the EPL

In the EPLBD without EST group, there were 36 patients in the EPLBD with a larger balloon (>15 mm) group and 129 patients in the EPLBD with a smaller balloon (12–15 mm) group. The safety variables did not differ significantly between the two groups, and no severe to fatal adverse event occurred in either group. Conclusion: Our study shows selleck chemical that EPLBD with a larger balloon (>15 mm) tends to have more risk of severe to fatal adverse events compared with a smaller balloon (12–15 mm) for removing

large bile duct stones. Large multicenter trials will be needed to reveal the statistical relationships between adverse events and balloon size. Key Word(s): 1. endoscopic large balloon dilation (EPLBD); 2. adverse events; 3. balloon size Presenting Author: YOUN JOO KIM Additional Authors: JIN SUN SHIN, KI YOUNG YANG Corresponding Author: YOUNJOO KIM Affiliations: Korea Cancer Center Hospital,

Korea Cancer Center Hospital Objective: Despite improvements in chemoradiation, local control remains a major KU-57788 clinical trial clinical problem in locally advanced or R1 resected cholangiocarcinoma (CC). The Hedgehog (HH) pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Methods: We evaluated the radiosensitizing effects of a targeted Hedgehog inhibitor (Cyclopamine) or SMO RNA interference on proliferation, migration of cholangiocarcinoma cell lines in vitro. In vivo nude mice experiments were conducted using two groups: HuCCT-1-single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2. Results: In 4 CC cell lines in vitro, cyclopamine showed little

C-X-C chemokine receptor type 7 (CXCR-7) or no effect on radiosensitivity. By contrast, In co-cultured with Lx-2, LI 90 (human hepatic stellate cell lines), HH signal inhibition increased cancer cell suppression effect of radiation. In the human tumor xenograft models, cyclo pamine enhanced radiation efficacy and delayed tumor growth in CX, but not in SX. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased apoptosis in the CX group, but not in the SX group. Conclusion: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in cholangiocarcinoma preclinical models. This effect is associated with pathway suppression in tumor-stroma interaction. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced cholangiocarcinoma. Key Word(s): 1. hedgehog; 2. cholangiocarcinoma; 3.