5%, Group B 2/37, 5.4%) were not different

between group A and group B. Conclusion: Tumor size was difficult factor to procedure colorectal ESD. In case of large size tumor, more caution is needed during submucosal dissection. Key Word(s): 1. ESD; 2. colon; Presenting Author: LIJUAN QIAN Additional Authors: RUIHUA SHI Corresponding Author: LIJUAN QIAN, RUIHUA SHI Affiliations: the First Affiliated Hospital of Soochow University; the First Affiliated Hospital of Nanjing Medical University Objective: To investigate the risk factors for the development of proximal tissue hyperplasia after stenting in patients with malignant and benign esophageal strictures. Methods: Consecutive patients of malignant and benign esophageal strictures who received esophageal stents were enrolled in this retrospective analysis. Endoscopy follow-up was performed one month after stenting to evaluate the severity of proximal Selleckchem Everolimus tissue hyperplasia. We evaluated the significance of patient age, sex, stent

diameter, and stent length as factors contributing to the development of proximal tissue hyperplasia. Results: A total of 168 patients were included. Technical success was achieved in all patients. Different GSK458 datasheet severity of tissue hyperplasia occurred in all patients one month after stenting. Stent diameter in patients of benign strictures was larger than those of malignant strictures (20.5 ± 2.9 mm versus 18.3 ± 2.1 mm, P < 0.001). Regression analysis revealed that tissue hyperplasia was significantly Celecoxib more severe in patients with large stent diameter (Odds Ratio 1.202, 95%CI 1.045–1.383, P = 0.010). No significant relationship was identified between the severity of tissue hyperplasia and age, sex, or stent length. Conclusion: Patients of benign esophageal strictures usually insert stents with large diameter to expand the stricture effectively. Large stent diameter is important factors that contribute to severe tissue hyperplasia after esophageal stenting. Key Word(s): 1. esophageal

stent; 2. tissue hyperplasia; 3. esophageal stricture; Presenting Author: LIJUAN QIAN Additional Authors: RUIHUA SHI Corresponding Author: RUIHUA SHI Affiliations: he First Affiliated Hospital of Soochow University; the First Affiliated Hospital of Nanjing Medical University Objective: To compare the efficacy and safety of pneumatic dilation with stenting, a less reported modality for the treatment of achalasia. Methods: Patients with newly diagnosed achalasia were allocated for treatment with pneumatic dilation or stenting. Clinical symptoms were assessed with the use of Eckardt score. Timed barium esophagram and esophageal manometry were performed at pre-treatment and post-treatment follow-up visits. Data such as patient demographics and complications were collected. The Eckardt score drop to ≤3 was defined as treatment success. Results: A total of 151 patients were enrolled for treatment with pneumatic dilation (N = 76) or stenting (N = 75).

[9-14] This

scarcity of kinase mutations suggests that HCC might be rarely susceptible to the dramatic responses to kinase inhibitors that are observed in other cancer types.[34, 35] In contrast, the frequent mutation of MLL histone methyltransferases—as well as ARID ATP-dependent nucleosome remodeling enzymes identified in previous studies—suggests that epigenetic regulatory enzymes may represent important target genes in HCC. Because most studies to date have been conducted on surgically resected tumors, we have little knowledge about the genetic Poziotinib manufacturer alterations that occur in either very early lesions treated with ablative modalities as well as later stages of HCC progression that are not amenable to surgical treatment. Our understanding of tumor evolution could be improved by more-sensitive technologies that could sequence gDNA FDA-approved Drug Library screening from core biopsy specimens. Another confounding issue with genomic profiling is the high rate of intratumor heterogeneity. Indeed,

a pioneering study demonstrated considerable clonal heterogeneity within a single tumor lesion, with allelic frequencies as low as 13%.[10] In this series, we present the whole-exome sequencing analysis of a large diverse series of HCC tumors and matching normal liver tissue. Our results support the genetic heterogeneity of HCC in that most genes were mutated in few (<20%) of the samples analyzed; however, analysis of gene families have indicated potentially important pathways, including MLL and NFE2L2-KEAP1, that are altered in subsets of tumors. Overexpression of several genes of interest were observed in tumors with identified mutations, but also in adjacent nontumor liver samples, which suggests a role of these genes in the premalignant “field effect” Anacetrapib that is observed in the unaffected liver of HCC patients.[36] We observed phenotypic differences in HCC according to gene

mutation status, including p53 mutation status as an independent predictor of recurrence-free survival. Several other genes of interest demonstrated trends in time and risk of recurrence; these observations were limited by sample size and require further investigation in larger studies. The lack of correlation between traditional prognostic features, such as tumor size, number, and vascular invasion, indicates that mutational profiling may enhance our ability to develop more-predictive models of tumor behavior. Further investigation is required to enhance our understanding of the full breadth of gene mutations in HCC and identify clinically relevant genes and pathways that can enhance our understanding of hepatocarcinogenesis and develop individualized therapy based on HCC genetic signatures. The authors thank Bert O’Neil for a critical revision of this manuscript. Additional Supporting Information may be found in the online version of this article. “
“We estimated the global burden of hepatitis E virus (HEV) genotypes 1 and 2 in 2005.

IBD; 2. Glucocorticoids; 3. SNP; 4. Susceptibility; Ridaforolimus Presenting Author: SIEWC NG Additional Authors: HOYEE HIRAI, SUNNYH WONG, FRANCISKL CHAN, JUSTINCY WU Corresponding Author: SIEWC NG Affiliations: CUHK Objective: Background: Intestinal tuberculosis (ITB) and Crohn’s

disease (CD) share very similar clinical, pathologic, radiologic and endoscopic findings. Distinguishing between the two conditions can be a challenge in tuberculosis-endemic countries. Aim: We conducted a meta-analysis to evaluate the usefulness of Interferon-gamma releasing assay (IGRA) and anti-Saccharomyces cerevisiae antibody (ASCA) in the differential diagnosis of ITB and CD. Methods: Methods: Publications in English and non-English literatures in OVID, MEDLINE and EMBASE were searched up to February 2013 for studies evaluating the performance of IGRAs (QuantiFERON-TB Gold and T-SPOT. TB) or ASCA in distinguishing ITB from CD. Forest plots and pooled estimates using random effects models were created. Results: Fifteen studies fulfilled the inclusion criteria. Mean age of patients was 37 years and 58% were male. The positive rate for IGRA in patients with ITB was significantly higher than in patients

with CD (78% versus 14%; P < 0.001), and the positive rate of ASCA in CD was higher than ITB (37% versus 18%; p < 0.05). Pooled sensitivities and specificities of IGRA for the diagnosis of ITB was78% (95% confidence interval, CI, 73%–82%) and 86% (95% CI, 82%–89%), respectively. Pooled sensitivities Amylase Gefitinib order and specificities of ASCA for the diagnosis of CD was 37% (95% CI, 32%–42%) and 85% (95% CI, 80%–89%), respectively. Subgroup analysis showed that QuantiFERON had higher specificity than TB Spot in the diagnosis of ITB.

Conclusion: IGRA and ASCA have a discriminatory role in the differential diagnosis between ITB and CD. These non-invasive serum markers may be useful in clinical practice when diagnosis remains uncertain. Key Word(s): 1. tuberculosis; 2. crohn’s disease; 3. IGRA; 4. meta-analysis; Presenting Author: LIN-YUN XUE Additional Authors: QIN OUYANG Corresponding Author: LIN-YUN XUE Affiliations: First Hospital of Putian City; West China Hospital, Sichuan University Objective: IBD are characterized by the loss of tolerance of the intestinal immune system towards the intestinal microbiota. The aim of this study was as followes: 1) to analyze the effects of VSL#3 and 5ASA on intestinal microbiota and immune regulation in experimental colitis; 2) to investigate the correlation between the intestinal microbiota and immune factors. Methods: 32 Balb/c mice were randomly assigned into 4 groups: control group, colitis group, VSL#3-fed group and 5ASA-fed group. Colitis was induced by oxazolone. The community composition was analyzed by T-RFLP. The expression of Occludin, TLR2, TLR4 and NF-kBp65 proteins were measured by Immunohistochemistry and Western blot; The level of TNF-α was measured by ELISA.

M., grant no. 18591055) from the Japan Society for the Promotion of Science. “
“Stress-induced soluble major histocompatibility complex class I–related chains A/B (MIC A/B) are increased in chronic liver diseases and hepatocellular malignancy. We investigated

the impact of these molecules on liver injury, apoptosis, and fibrosis in nonalcoholic steatohepatitis (NASH). Blood and liver tissue were obtained from 40 patients with NASH undergoing bariatric surgery for obesity. The control group consisted of 10 healthy individuals. We also investigated 10 patients with nonalcoholic fatty liver (NAFL). Polymerase chain reaction was used to measure messenger RNA (mRNA) transcripts of MIC A/B, natural killer cell receptor G2D (NKG2D), this website CD95/Fas, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–death receptor

signaling pathway 5 (DR5). Apoptosis was quantified by way of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) (intrahepatic) and M30/M65 (systemic). Liver injury was assessed histopathologically and serologically (alanine aminotransferase/aspartate aminotransferase). Fibrosis was identified by Sirius red staining, quantitative morphometry, and α-smooth muscle actin and collagen 1α transcripts. Compared with controls, patients with NASH revealed significant increases in (1) NKG2D mRNA (13.1-fold) and MIC A/B mRNA (3.6-fold and 15.8-fold, respectively); (2) TRAIL–DR5 and CD95/Fas mRNA (2.7-fold and 3.6-fold, respectively); (3) TUNEL-positive hepatocytes (4.0-fold); and (4) M30 and M65 levels (4.6-fold and 3.4-fold, respectively). We found relevant correlations between MIC protein expression rates and NAS and fibrosis stages. In contrast, NKG2D and MIC A/B transcripts were attenuated in Sclareol patients with NAFL compared with NASH. Histopathologically, NASH patients revealed increased NAS scores, an accumulation of natural killer cells, and 2.7-fold increased hepatic fibrosis by quantitative morphometry. Conclusion: Our findings suggest an important role for

MIC A/B in liver injury. Therapeutic intervention aimed at reducing MIC A/B levels may beneficially affect the progression of NASH. (HEPATOLOGY 2009.) With the increasing prevalence of the metabolic syndrome in western and westernized countries, the diagnosis of nonalcoholic fatty liver disease (NAFLD) has greatly increased in clinical practice. NAFLD is the most common cause of elevated liver enzymes and probably the most common liver disease in these countries, with an overall prevalence of up to 30%.1, 2 Hepatocellular apoptosis is a prominent feature of liver injury in the pathogenesis of nonalcoholic steatohepatitis (NASH).3 Recently, soluble forms of major histocompatibility complex class I–related chains A and B (MIC A/B) were reported to be increased in the sera of patients with chronic liver disease and hepatocellular malignancy.

In Japan, Hashimoto et al. followed up the clinical course of 247 patients with non-alcoholic fatty liver disease (NAFLD) and noted concurrent hepatocellular carcinoma in 10 patients with cirrhosis. The 5-year cumulative incidence of hepatocellular carcinoma was 20% in F3–4 patients showing progression to liver fibrosis (LF1210229 level FDA approved Drug Library 2b). Each of the above risk factors has been shown to independently

increase the risk of development of liver cancer, and the incidence of hepatocellular carcinoma is assumed to increase with an increasing number of risk factors. While it would be ideal to score these risk factors and quantitatively evaluate them, there is, at present, no adequately examined system for such quantitation. Furthermore, it would be desirable to specify a threshold for the annual rate of carcinogenesis at which screening should be started,

but that is also difficult at this point. Consequently, we select patients with usual type B or C chronic liver disease and patients with Selleck Sirolimus cirrhosis of various etiologies as the target population for hepatocellular carcinoma screening. CQ5 Does regular screening of patients having risk factors for hepatocellular carcinoma improve the prognosis of hepatocellular carcinoma? Regular hepatocellular carcinoma screening leads to early detection of hepatocellular carcinoma, and in turn provides an opportunity for radical treatment. It may also Nintedanib (BIBF 1120) lead to improvement of the prognosis. (grade B) One RCT reported that regular hepatocellular carcinoma surveillance might have the effect of improving the prognosis of hepatocellular carcinoma (LF106251 level 1). Among patients with HBV infection, hepatocellular carcinoma was more frequently detected in the small nodule stage, the number of patients in whom hepatectomy was feasible was significantly higher, and the survival rate was significantly higher

in the group that underwent regular surveillance every 6 months by serum α-fetoprotein (AFP) measurement and ultrasonography as compared with the results in the group in whom such surveillance was not undertaken. The mortality rate also improved by 37%. Although not an RCT, a prospective study conducted only in patients with cirrhosis (LF019822 level 2a) also demonstrated that regular surveillance by ultrasonography and serum AFP measurement prolonged survival. Retrospective studies adjusted for lead-time bias (LF100863 level 2b, LF108494 level 2b, LF102745 level 2b) also reported that regular surveillance improved the survival rate; therefore, they demonstrated that regular surveillance might have a favorable effect on the prognosis.

2%), 0-IIc in 9 lesions (37.5%), selleck and 0-IIa+IIb in 1 lesion (4.2%). The median tumor size was 10 (range, 1.5–38) mm. En bloc resection was performed for 22 lesions (91.7%). Aspiration pneumonia occurred in one patient after ESD, but the patient was successfully treated by intravenous antibiotics. There were no treatment-related deaths. On pathological examination, 17 were tubular adenocarcinoma, and 7 were tubular adenoma. Histologically, curative resection was obtained in 21 of the 24 lesions (87.5%). There were no differences in gross type (elevated type/flat and depressed type), tumor size, or histology between primary and metachronous lesions. However, location (U/M/L)

was significantly different (P = 0.037). Furthermore, there were significant differences in U/M (P = 0.016) and U/L (P = 0.038). Therefore, there was a slightly higher frequency of metachronous lesions in the U area.

Conclusion: Metachronous lesions tended to develop in the U area. These results suggest that it is necessary to carefully observe the U area by surveillance endoscopy after ESD for gastric neoplasms. Key Word(s): 1. metachronous gastric neoplasms; 2. after endoscopic submucosal dissection Presenting Author: HYUN SEOK LEE Additional Authors: SEONG WOO JEON Corresponding Author: HYUN SEOK LEE Affiliations: Kyungpook National University Medical Center Objective: Colorectal laterally spreading tumors (LST) >20 mm are usually treated by endoscopic mucosal resection Progesterone (EMR) or endoscopic Ibrutinib research buy submucosal dissection (ESD). Endoscopic piecemeal mucosal resection (EPMR) is sometimes required. The aim of our study was to compare the effectiveness of EMR (including EPMR) and ESD for such LST. Methods: A total of 309 patients with a colorectal LST > 20 mm were treated endoscopically at our hospital. We retrospectively evaluated the clinical outcomes of EMR and ESD for large colorectal LST. Results: A total of 232 colorectal LSTs were treated by EMR and 77 were treated by ESD. EMR was

associated with a lower en bloc resection rate (72.8%/94.8%; p < 0.001) and smaller tumor size (26.8 ± 9 mm/37.7 ± 12 mm; p < 0.001) than ESD. Between-group differences in perforation rates (5.2%/9.1%; p = NS) and delayed bleeding rates (3.4%/3.9%; p = NS) were not significant. One ESD case of perforation was managed by surgical operation and the others of perforation were managed effectively treated endoscopically. Additional colectomy rates due to non-curative resection were 6 (2.6%) in EMR and 4 (5.2%) in ESD, respectively and no significant differences (p = NS). One (1.4%) recurrence was detected in EMR, whereas there were no recurrences observed in ESD during a mean endoscopic follow-up period of 13.0 months. The one recurrence case was managed endoscopically. Conclusion: ESD is a feasible technique for en bloc resection and showed no local recurrences.

An episode was considered new if the patient was pain free for at least 24 hours. Secondary study end points included number of headache days per month, headache intensity, headache disability (assessed using Headache Impact Test-6 and the Migraine Disability Assessment score

scales), acute headache medication use, resource utilization, and allodynia pain. Adverse events were reported. Results.— A total of 25 patients (24 women, mean age 50.5 years; mean age of disease onset 21.9 years) were RXDX-106 research buy enrolled in the study. Patients experienced improvement in cervical dystonia symptoms with significant reductions from baseline in Toronto Western Spasmodic Torticollis Rating Scale scores at 30, 60, 90, 120, 150, and 180 days (−9.84 ± 8.49, −12.67 ± 8.22, −13.63 ± 7.27, −14.92 ± 7.05, −14.76 ± 6.97, −14.49 ± 6.14, respectively,

P < .0001 at all time points from a baseline of 31.03 ± 3.61). Changes from baseline were assessed using the t-test. Reductions in the number of headache episodes from baseline on concurrent onabotulinumtoxinA treatment for coexistent chronic migraine did not attain significance. However, patients PF 2341066 experienced significant reductions from baseline in the number of headache days at 90, 120, and 180 days (−3.39 ± 6.78, P = .0289; −4.29 ± 7.94, P = .0194; −4.38 ± 7.99, P = .0178, respectively, from a baseline of 15.33 ± 6.76). Changes from baseline were assessed using the t-test. The change from baseline in Headache Impact Test-6 Methane monooxygenase total scores was significant at 30, 60, 90, 150, and 180 days (3.21 ± 4.14, P = .0009; −3.04 ± 4.04, P = .0012; −2.41 ± 2.79, P = .0006; −2.59 ± 3.87, P = .0050; −3.09 ± 3.80, respectively, from a baseline of 22.68 ± 3.20). Changes from baseline were assessed using the t-test. The change from baseline in Migraine Disability Assessment was significant at 120,

150, and 180 days (−38.09 ± 47.87, P < .0001, Wilcoxon signed rank test; −16.91 ± 62.69, P = .0358, Wilcoxon signed rank test; −23.73 ± 40.57, P = .0122, t-test, respectively, from a baseline of 56.68 ± 50.41). There were no serious adverse events or treatment-related discontinuations. Conclusions.— Concurrent treatment with onabotulinumtoxinA is effective and well tolerated in controlling the symptoms of cervical dystonia complicated by concurrent migraine. "
“(Headache 2010;50:955-962) Introduction.— Migraine is thought to be genetically complex. There is evidence of an X-linked dominant genetic component. A locus at Xq24-q28 has already been described supporting this hypothesis. Methods.— The X chromosome in 61 migraine families was screened using markers spanning the entire chromosome. Alleles were assigned using the GeneScan Analysis software, analysis for affected relative allele sharing and linkage was performed using Genehunter X and ALLEGRO. For linkage analysis we chose a model based on epidemiological data as well as assumptions drawn on other complex disorders.

[273] New medical therapies for A-1ATD are being investigated.[274] Inborn errors resulting in bile acid synthesis disorders (BASD) most commonly present as neonatal cholestasis or neonatal hepatitis, but can present as chronic liver disease in older children.[275-277] These diseases are characterized by a failure to produce normal bile acids and www.selleckchem.com/products/fg-4592.html an accumulation of unusual bile acids and bile acid intermediaries.[278] Unlike most cholestatic diseases, patients with inborn errors of bile acid synthesis generally present with the hallmark features

of normal or low serum levels of primary bile acids, normal GGT concentrations, and the absence of pruritus.[279] For a definitive diagnosis, fast atom bombardment-mass spectrometry (FAB-MS) and gas chromatography-mass spectrometry (GC-MS) analyses of serum and urine is recommended, but is only available in a few specialized referral laboratories.[280] Early diagnosis of some defects of bile acid synthesis can be treated effectively with cholic acid and/or chenodeoxycholic acid, which down-regulate endogenous bile acid synthesis resulting in clinical, biochemical, and histologic improvement if therapy is initiated before significant liver disease is established.[281, 282] LT is indicated for progression to endstage liver disease.[283]

Selleckchem Palbociclib 63. Bile acid replacement therapy should be initiated as early as possible in children with a confirmed bile acid synthetic disorder; LT should Bcl-w be considered only in patients with progressive endstage liver disease due to inborn errors of bile acid synthesis or those known to be refractory to medical therapy. (1-B) Hereditary tyrosinemia type 1 (HT) is a multisystem disorder often presenting in infancy with a profound coagulopathy despite minimally elevated or normal serum aminotransferase levels.[284] Older

children and even adults can present with features of chronic liver disease. Treatment with NTBC (2-(2nitro-4-fluoromethybenzoyl)−1,3-cyclohexanedione) results in rapid clinical and biochemical improvement, manifested by undetectable levels of succinylacetone in the urine within 24 hours, and has reduced early complications as well as the need for LT. There has been an increase in mean age at transplantation from 1.82 ± 2.86 years between 1988-1998 to 3.70 ± 4.42 years between 1999-2008.[285] Failure to respond to NTBC within a week may be due to noncompliance or subtherapeutic NTBC, manifested by persistence of succinylacetone in the urine, or a fulminant course despite therapy. The child that survives initial presentation without LT can experience an extended interval of good health. Hepatic nodules, if present initially, may persist, regress, or disappear on a combination of NTBC therapy and a low tyrosine / low phenylalanine diet. The AFP is elevated at presentation, but will normalize or fall to levels less than 10 ng/L on NTBC therapy.

05) in KO livers. Consistently, in Nogo-B KO mice fed ethanol, expression of M2-type macrophage markers, such as MRC2, CD163 and IL10, was significantly

up-regulated (p<0.05), compared to WT mice. In vitro, Kupffer cells isolated see more from Nogo-B KO mice demonstrated significantly decreased inducible nitric oxide (iNOS), interleukin 1beta (IL1β) and TNFβ expression in response to ethanol/LPS (p<0.05), all of which are known as NFkB response genes. Interestingly, KO Kupffer cells decreased translocation of p65 protein (an active form of NFkB) to the nucleus, compared to WT Kupffer cells, suggesting that Nogo-B may regulate NFkB activity in response to ethanol. Conclusion: These results indicate that Nogo-B promotes alcohol-induced

hepatic steatosis by modulating Kupffer cell function. Given that iNOS, IL1β and TNFβ are known to enhance hepatic Selisistat lipid accumulation, Nogo-B might exert this role by increasing release of these cytokines from Kupffer cells through its regulation of NFkB activity. Specific deletion of Nogo-B in Kupffer cells may be a therapeutic potential for alcohol-induced steatosis/steatohepatitis. Disclosures: The following people have nothing to disclose: Jin-Kyu Park, Teruo Utsumi, Yirang Jung, Yasuko Iwakiri “
“To evaluate the feasibility of the real-time virtual needle tracking system for percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). An electromagnetic field created by an ultrasound (US) machine

detected the tracking bracket mounted onto the RFA needle. When the needle tip was confirmed to be in the accurate plane extracorporeally, the needle was inserted into the liver using the virtual navigation US system, and RFA was performed. Eight patients with eight liver lesions underwent click here percutaneous RFA under ultrasound for HCC from October to November 2012 using the real-time electromagnetic virtual needle tracking system (VirtuTRAX). The average size of the tumors was 11.5 mm with one lesion in S4, two in S5, two in S7 and three in S8. Sufficient margins were obtained in a single session in all cases. Using only B-mode, the needle tip was obscured due to the condition of the surrounding liver or subcutaneous fat tissue, but it was identifiable with the use of the virtual needle tracking device in all cases. In one case where the lesion was large, the needle was placed twice deliberately, but the second puncture was made difficult by the ablation artifact of the first puncture. With the tracking device, however, it was possible to perform the second puncture accurately. The virtual tracking system is useful in cases where the needle tip is obscured due to surrounding liver conditions or when multiple punctures are necessary due to the ablation artifact’s obscuring the needle tip. Freehand puncturing may be possible in the future using this technique with further improvements in the system.

In fully activated cells, expression of PPAR isoforms was not detected, whereas expression of α-SMA and COL1A2 dramatically increased. Similar to the progression in the expression pattern of these genes and consistent with activated HSCs being a major PARP inhibitor source of ADAMTS1, ADAMTS1 mRNA expression was undetectable in quiescent HSCs (days 1-4), enhanced in cultured HSCs (10±0.75-fold increase at day

11) and strongly increased after 4 passages (150- to 200-fold increase; Fig. 2C). In contrast, thrombospondin, previously reported to be present in isolated rat HSCs,22 was expressed early in culture and reached an increase of 11.58±0.24-fold at day 11, but its levels were strongly diminished in myofibroblast-like cells. To avoid interference from thrombospondin activity, human HCSs were routinely used between passages 4 and 10 in all subsequent learn more experiments. Up-regulation of ADAMTS1 expression was confirmed by western blotting in both activated HSCs and fibrotic liver tissues relative

to normal livers. The processed 87-kDa ADAMTS1 active form (see Fig. 2D) was recovered mainly in cell extracts and HSC-conditioned media (Fig. 2E) and was clearly induced in liver fibrosis (Fig. 2F). The 110-kDa unprocessed form was only present in cell extracts, and the 65-kDa shorter form was recovered only in conditioned media (Fig. 2E). A major feature of ADAMTS1 is the presence of three thrombospondin type 1 motifs (TSP1), with the proximal TSP1 being separated from the two carboxy-end TSP1 motifs by a “spacer sequence” rich in cysteine residues (Fig. 2D). Next to the proximal TSP1 sequence, we identified a KTFR motif that aligns with the active KRFK sequence of the human thrombospondin TSP1 repeats previously shown to be involved in the interaction with TGF-β (Fig. 3A).23 A tryptophan-rich peptide (WxxW), described as a docking site that promotes the interaction of KRFK sequences with LAP-TGF-β, is also present in the proximal TSP1 motif of ADAMTS1. The WxxW and KxFx motifs are not present in the two carboxy-end TSP1 motifs of ADAMTS1 (not shown). Because the proximal TSP1-containing domain of ADAMTS1 resembles that of Quinapyramine thrombospondin, we asked whether it

might display a structural organization, allowing for interactions with TGF-β (Fig. 3B). An “hhsearch” against the Protein Data Bank (see Supporting Information) identified the following candidate structural templates for ADAMTS1 TSP-like and thrombospondin domains (P values < 10−15): ADAMTS23 (PDB:3ghm); ADAMTS5 (PDB:2rjq); the TSP1 type 1 repeat (PDB:1lsl); F-spondin (PDB:1vex, 1szl); the thrombospondin anonymous protein, Trap (PDB:2bbx); VAP1 (PDB:2ero); Properdin (PDB:1w0r); Catrocollastatin (PDB:2dw0), and the Vitelline membrane outer layer protein I (PDB:1vmo). Except for 2dw0, 2ero, and 1vmo, all matching structural templates have a triple-strand organization, suggesting that this TSP1-like structure is shared by both the TSP1 repeat from thrombospondin and the motif found in ADAMTS1 (Fig. 3C).