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Background and Aims: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) is increasingly accepted as an effective treatment option in patients who require drainage for acute cholecystitis. A newly designed lumen-apposing metal stent (LAMS) has been introduced recently in this procedure. In this study, we evaluated the feasibility and safety of the newly designed LAMS in patients with acute cholecystitis who were unsuitable for cholecystectomy.Methods: Between Mar 2017 and Oct 2017, 22 patients with acute cholecystitis who were unsuitable for cholecystectomy underwent EUS-GBD with the newly designed LAMS. We evaluated the technical and clinical success and the adverse event profiles.Results: EUS-GBD with newly designed LAMS was technically and clinically successful in 21 of the 22 patients. EUS-GB stenting was performed at urgent setting in 17 patients, while 5 patients, who had undergone initial PTGBD, underwent EUS-GB stenting to remove PTGBD tube. The median procedure time was 11.5 (range 8.8-17.0) min. A late adverse event of stent occlusion developed in one patient. Stent migration was not observed during follow-up (median 318.0 days, range 39.0-398.0 days) and cumulative stent patency rate at 1 year was 95%.Conclusion: EUS-GBD with newly designed LAMS is feasible and shows acceptable safety profiles for both the urgent drainage of acute cholecystitis and elective internalization following PTGBD in patients with high surgical risk. [ABSTRACT FROM AUTHOR]

Abstract: Taurine, a non essential sulfur-containing amino acid, plays a critical role in cardiovascular functions. We here examined the effect of taurine on angiogenesis and its underlying signal pathway. Taurine treatment increased angiogenesis in vitro and in vivo, which was followed by activation of the phosphatidylinositol 3-kinase (PI3K)/Akt, MEK/ERK, and Src/FAK signaling pathways. Further, taurine promoted endothelial cell cycle progression to the S and G2/M phases by up-regulating the positive cell cycle proteins, particularly cyclins D1 and B, as well as down-regulating the negative cell cycle proteins, p53 and p21WAF1/CIP1, resulting in Rb phosphorylation. This angiogenic event was inhibited by inhibitors of PI3K and MEK. In addition, a PI3K inhibitor blocked the activation of Akt and ERK, while Akt knockdown did not affect taurine-induced ERK activation, indicating that PI3K is an upstream mediator of both MEK and Akt. Taurine-induced endothelial cell migration was suppressed by Src inhibitor, but not by other inhibitors, suggesting that the increase in cell migration is regulated by Src-dependent pathway. Moreover, inhibition of cellular taurine uptake by β-alanine and taurine transporter knockdown promoted taurine-induced cell proliferation, ERK and Akt activation, and in vivo angiogenesis, suggesting that extracellular taurine induces angiogenesis. However, taurine did not induce vascular inflammation and permeability in vitro and in vivo. These data demonstrate that extracellular taurine promotes angiogenesis by Akt- and ERK-dependent cell cycle progression and Src/FAK-mediated cell migration without inducing vascular inflammation, indicating that it is potential use for the treatment of vascular dysfunction-associated human diseases. [Copyright &y& Elsevier]

Background and Aims: Segregated right intrahepatic duct dilatation (IHD) results from complete obstruction of the biliary tract proximal to the hilar level. We aimed to evaluate long‐term efficacy and safety of endoscopic ultrasound (EUS) hepaticoduodenostomy (HDS) in segregated right IHD. Methods: Consecutive patients who had undergone EUS‐guided HDS with a fully covered self‐expandable metal stent (FCSEMS) in an academic tertiary center were recruited. All patients had segregated right hepatic duct and failed drainage by endoscopic retrograde cholangiopancreatography (ERCP). Demographic data, endoscopic findings, procedure details, and outcome data were extracted from a prospectively maintained database. Results: From 2013 to 2017, there were 35 patients who had undergone EUS‐guided HDS with a median follow‐up duration of 169 (3–2091) days. Malignancy accounted for 71.4% of the ductal segregation, followed by surgical complication (17.1%). Technical and clinical success rate was 97.1% and 80%, respectively. Early adverse event (AE) happened in seven patients (20%), two of them required endoscopic reintervention, and no percutaneous transhepatic biliary drainage (PTBD) or surgery was performed because of AE. The median stent patency duration was 331 (3–1202) days. The median duration of fistula tract keeping was 1280 (3–1280) days. There was no significant difference in terms of patency rate with respect to whether the underlying pathology was benign or malignant (P = 0.776). EUS‐guided HDS for right posterior sectional duct segregation was associated with higher 3‐month stent patency rate when compared with right anterior sectional duct (79.1% vs 38.1%, P = 0.012). Conclusion: Endoscopic ultrasound‐guided HDS with an FCSEMS appears to be a safe and effective treatment as a viable alternative option to PTBD after failed ERCP. It creates a durable and reliable fistula tract for permanent access to an isolated ductal system, and this application deserves more attention. [ABSTRACT FROM AUTHOR]

Background: Type 1 autoimmune pancreatitis (AIP), as a pancreatic manifestation of IgG4-related disease, shows a favorable prognosis in the short term. However, disease relapse is common in long-term follow-up, despite a successful initial treatment response. This study aimed to identify the predictors of relapse and long-term outcomes in patients with type 1 AIP.Methods: Patients with more than 2 years of follow-up who met the International Consensus Diagnostic Criteria for type 1 AIP were included. Patients who had undergone pancreatic operations associated with AIP or who lacked sufficient clinical data were excluded.Results: All 138 patients achieved clinical remission with initial steroid therapy, and 66 (47.8%) experienced relapse during a median 60 (range 24-197) months follow-up. Among the relapsed patients, about 74% (49/66) relapsed within 3 years. About 60% (82/138) had other organ involvement (OOI), most commonly in the proximal bile duct (26.8%). At first diagnosis, OOI, and especially OOI of the proximal bile duct, was a significant independent predictor of relapse (hazard ratio 2.65; 95% confidence interval 1.44-4.89; p = 0.002), according to multivariate analysis. During the follow-up period, 16 (11.6%) patients experienced endocrine/exocrine dysfunction and 32 (23.2%) patients developed de novo pancreatic calcifications/stones. No pancreatic cancer occurred in any patients.Conclusions: Type 1 AIP has common relapses, and patients with OOI, especially OOI of the proximal bile duct, appear to be at increased risk for relapse. Long-term sequelae, including pancreatic insufficiency and pancreatic calcifications/stones, are common in patients with relapse. To reduce the relapse, longer maintenance treatment may be needed especially for patients at high risk for relapse. [ABSTRACT FROM AUTHOR]

Background and Aim: Endoscopic snare papillectomy (ESP) is an effective treatment for ampullary adenoma. Argon plasma coagulation (APC) is widely used as an additional method to control bleeding or ablate the residual tumor. However, the efficacy of this procedure has not yet been fully evaluated. This study aimed to evaluate the usefulness of APC as an additional method to ESP. Methods: Patients who underwent ESP for ampullary adenoma between September 2005 and September 2015 were retrospectively reviewed. Using propensity score matching, we compared short‐ and long‐term outcomes between the ESP‐with‐additional‐APC group (ESP + APC group) and the ESP‐only group. Primary outcome was early post‐ESP adverse events (AE), and secondary outcomes were late AE and recurrence. Results: Among 109 patients, additional APC was carried out in 59 (54.1%) patients. After matching, 41 patients were included in both groups, respectively. Bleeding rate was significantly lower in the ESP + APC group than in the ESP‐only group (7.3% vs 31.7%, odds ratio = 0.180, P < 0.01). However, there were no significant differences in other procedure‐related early AE such as pancreatitis (12.2% vs 19.5%, P = 0.365), cholangitis (2.4% vs 9.8%, P = 0.198), and perforation (2.4% vs 2.4%, P = 1.000) between the ESP + APC group and the ESP‐only group. During the follow‐up period (mean 904 ± 868 days), papillary stricture (9.8% vs 4.9%, P = 0.405) and recurrence rates (24.4% vs 24.4%, P = 0.797) were not significantly different between the ESP + APC group and the ESP‐only group. Conclusion: Additional APC during ESP may have a beneficial effect by decreasing bleeding rate without harmful effects. [ABSTRACT FROM AUTHOR]

Background: Recent research has shown that a substantial number of patients with primary sclerosing cholangitis (PSC) can also have elevated serum/tissue IgG4. The aim of our study was to develop a simple scoring system for the discrimination of IgG4-related sclerosing cholangits (IgG4-SC) from PSC.Methods: Patients with IgG4-SC (n = 39) and PSC (n = 76) who had intrahepatic/hilar strictures were included. Candidate-differentiating variables included patient age, other organ involvement (OOI), inflammatory bowel disease, serum IgG4, and cholangiographic features. A scoring system was developed on the basis of these variables, and its performance was internally validated using a bootstrapping-based method.Results: The scoring system in the final model included age (<30 years, 0 points; 30-39 years, 1 point; 40-49 years, 2 points; 50-59 years, 3 points; ≥60 years, 4 points), OOI (no, 0 points; yes, 3 points), and beaded appearance (yes, 0 points; no, 2 points). The patients were classified according to their total score into three categories: 0-4 points, probable PSC; 5-6 points, indicating diagnostic steroid trial; 7-9 points, probable IgG4-SC. The discrimination between IgG4-SC and PSC using the scoring system was excellent (area under the receiver operating characteristic curve, 0.986).Conclusions: A reliable differentiation of IgG4-SC from PSC can be made using the scoring system presented here. We suggest the diagnosis of IgG4-SC at a cutoff of 7 points or higher and the indication of diagnostic steroid trial at 5 or 6 points. External validation of our scoring system is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Keap1 is a cytoplasmic repressor of the transcription factor Nrf2, and its degradation induces Nrf2 activation, leading to upregulation of antioxidant phase II genes. We investigated the roles of phase II genes in vascular inflammation and septic injury using Keap1 siRNA and elucidated its underlying mechanism. Selective knockdown of Keap1 with siRNA promoted Nrf2-dependent expression of phase II genes in endothelial cells, such as heme oxygenase-1 (HO-1), glutamate–cysteine ligase (GCL), and peroxiredoxin-1 (Prx1), resulting in the elevation of cellular glutathione levels and suppression of tumor necrosis factor (TNF)-α-induced intracellular H2O2 accumulation. Keap1 knockdown inhibited TNF-α-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by suppressing NF-κB activation via inhibition of its upstream modulators, Akt, NIK, and IKK, resulting in the elevation of monocyte adhesion to endothelial cells. Importantly, these events were reversed by HO-1 and GCL inhibitors and Prx1-specific siRNA. Keap1 knockdown also inhibited endotoxin-induced expression of inducible nitric oxide synthase (iNOS) and TNF-α by upregulating HO-1, GCL, and Prx1 expression in macrophages. Moreover, in vivo Keap1 knockdown increased the expression of phase II genes and suppressed the expression of ICAM-1, VCAM-1, iNOS, and TNF-α in an endotoxemic mouse model, resulting in significant protection against liver and lung injuries and lethality. Our results indicate that Keap1 knockdown prevents NF-κB-mediated vascular inflammation and endotoxic shock by suppressing NF-κB-mediated inflammatory gene expression via upregulation of Nrf2-mediated antioxidant genes. Thus, siRNA targeting Keap1 may provide a new therapeutic approach for inflammation-associated vascular diseases and sepsis. [Copyright &y& Elsevier]

Abstract: Although it has been suggested that smad7 blocks downstream signaling of TGF-β, the role of smad7 in the EGF signaling pathway has not been fully elucidated. We determined the effect of smad7 on EGF-induced MMP-9 expression in SKBR3 breast cancer cells. The expression of smad7 and MMP-9 was increased by EGF or TGF-β1, respectively, and further increased by EGF and TGF-β1 co-treatment. EGF induced the phosphorylation of EGFR, smad3, ERK, and JNK, and MMP-9 expression was decreased by the EGFR inhibitor, AG1478. In addition, EGF-induced MMP-9 expression was inhibited by UO126 (a MEK1/2 inhibitor) or SIS3 (a smad3 inhibitor), but not by SP600125 (a JNK inhibitor). Interestingly, EGF-induced smad3 phosphorylation was completely blocked by smad7 over-expression, but not the phosphorylation of ERK and JNK. EGF- or TGF-β1-induced MMP-9 expression was completely decreased by adenoviral-smad7 (Ad-smad7) over-expression. We also investigated the role of smad3 on EGF-induced MMP-9 expression and showed that EGF-induced MMP-9 expression was decreased by smad3 siRNA transfection, whereas EGF-induced MMP-9 expression was further increased by smad3 over-expression, as expected. This study showed that EGF-induced smad3 phosphorylation mediates the induction of MMP-9, whereas smad7 inhibits TGF-β1 as well as the EGF signaling pathway in SKBR3 cells. [Copyright &y& Elsevier]

Cyclooxygenase-2 (COX-2) has been reported to be elevated in many cancers, including breast and colorectal cancers, resulting in accumulation of prostaglandin E2 in the cancer cell environment. In this study, we investigated the effect of pifithrin (PFT)-α, an inhibitor of p53 transactivation, on COX-2 expression in breast and fibrosarcoma cells. Our results showed that COX-2 expression was dose-dependently increased by PFT-α in MDA-MB231 breast cancer cells with mutant p53. In addition, the expression level of COX-2 was also increased by PFT-α in normal fibroblasts as well as in HT1080 fibrosarcoma cells with p53 wild-type cells. To verify the regulatory mechanism of COX-2 in response to PFT-α, we pretreated cells with a mitogen-activated protein kinase (MAPK) kinase (MEK)1/2 inhibitor (UO126) and a phosphoinositide-3 (PI-3K) inhibitor (LY294002). PFT-α-induced COX-2 expression was significantly decreased by UO126 and LY294002 in MDA-MB231 cells. However, the phosphorylation of extracellular signal-regulated kinase (ERK) was increased by PFT-α, but not Akt phosphorylation. Finally, we confirmed the correlation of the MEK and PI-3K pathway and COX-2 expression using the constitutively active (CA)-MEK and myr-Akt adenovirus systems. COX-2 expression was increased by CA-MEK transfection, but not by myr-Akt. Taken together, we have demonstrated that PFT-α-induced COX-2 expression is regulated through a MEK/ERK pathway in MDA-MB231 human breast cancer cells. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents a case study of a 47-year-old man who was diagnosed with monomorphic-type post-transplant lymphoproliferative disorder.