Malformin A1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through stimulation of the p38 signaling pathway.

Malformin A1 (MA1), a cyclic pentapeptide isolated from Aspergillus niger, has been found to possess a range of bioactive properties including antibacterial activity. However, it is unclear whether MA1 exerts an anticancer effect or not. In this study, we conducted in vitro experiments to investigate its anticancer properties in human colorectal cancer cells. The effect of MA1 on human colorectal cancer cells, SW480 and DKO1, was examined by the WST-1 cell viability assay, inverted microscopy, 5-bromo-2-deoxyuridine (BrdU) incorporation, flow cytometry, DNA fragmentation, wound healing, Transwell assays, and western blotting. MA1 treatment showed potent cytotoxic activities on human colorectal cancer cells. MA1 treatment induced apoptosis by activating the poly(ADP-ribose) polymerase (PARP), caspase­3, -7, and -9. MA1 treatment led to the increase in p53 upregulated modulator of apoptosis (PUMA) and the decrease in X-linked inhibitor of apoptosis protein (XIAP) and Survivin. In addition, MA1 treatment induced cell cycle arrest in the sub-G1 phase. The pan-caspase inhibitor, Z­VAD­FMK, attenuated these MA1-induced apoptotic effects on human colorectal cancer cells. Moreover, MA1 treatment suppressed tumor cell migration and invasion. The phosphorylation level of p38 was upregulated by MA1 treatment, and the inhibitor of p38, SB203580, attenuated the MA1-induced p38 phosphorylation as well as caspase­3 and PARP activation. These results indicate that MA1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through the stimulation of the p38 signaling pathway.

The outcome of endoscopic management of bile leakage after hepatobiliary surgery.

BACKGROUND/AIMS: Despite improvements in surgical techniques and postoperative patient care, bile leakage can occur after hepatobiliary surgery and may lead to serious complications. The aim of this retrospective study was to evaluate the efficacy of endoscopic treatment of bile leakage after hepatobiliary surgery. METHODS: The medical records of 20 patients who underwent endoscopic retrograde cholangiopancreatography because of bile leakage after hepatobiliary surgery from August 2009 to September 2014 were reviewed retrospectively. Endoscopic treatment included insertion of an endoscopic retrograde biliary drainage stent after endoscopic sphincterotomy. RESULTS: Most cases of bile leakage presented as percutaneous bile drainage through a Jackson-Pratt bag (75%), followed by abdominal pain (20%). The sites of bile leaks were the cystic duct stump in 10 patients, intrahepatic ducts in five, liver beds in three, common hepatic duct in one, and common bile duct in one. Of the three cases of bile leakage combined with bile duct stricture, one patient had severe bile duct obstruction, and the others had mild strictures. Five cases of bile leakage also exhibited common bile duct stones. Concerning endoscopic modalities, endoscopic therapy for bile leakage was successful in 19 patients (95%). One patient experienced endoscopic failure because of an operation-induced bile duct deformity. One patient developed guidewire-induced microperforation during cannulation, which recovered with conservative treatment. One patient developed recurrent bile leakage, which required additional biliary stenting with sphincterotomy. CONCLUSIONS: The endoscopic approach should be considered a first-line modality for the diagnosis and treatment of bile leakage after hepatobiliary surgery.

Effect of Recepteur d'Origine Nantais expression on chemosensitivity and tumor cell behavior in colorectal cancer.

Recepteur d'Origine Nantais (RON) expression is known to induce oncogenic properties including tumor cell growth, survival, motility, angiogenesis and chemoresistance. In the present study, we evaluated whether RON affects chemosensitivity and oncogenic behavior of colorectal cancer cells and investigated its prognostic value in colorectal cancer. To evaluate the impact of RON on chemosensitivity and tumor cell behavior, we treated colorectal cancer cells with small interfering RNAs specific to RON. This was followed by flow cytometric analyses and migration, Matrigel invasion and endothelial tube formation assays. The expression of RON was investigated by immunohistochemistry in colorectal cancer tissues. TUNEL assay and immunohistochemical staining for CD34 and D2-40 were deployed to determine apoptosis, angiogenesis and lymphangiogenesis. RON knockdown enhanced 5-fluorouracil (FU)-induced apoptosis by upregulating the activities of caspases and expression of proapoptotic genes. Moreover, it enhanced 5-FU-induced cell cycle arrest by decreasing the expression of cyclins and cyclin­dependent kinases and inducing that of p21. Furthermore, RON knockdown augmented the 5-FU-induced inhibition of invasion and migration of colorectal cancer cells. The ß-catenin signaling cascade was blocked by RON knockdown upon 5-FU treatment. RON knockdown also decreased endothelial tube formation and expression of VEGF-A and HIF-1α and increased angiostatin expression. Furthermore, it inhibited lymphatic endothelial cell tube formation and the expression of VEGF-C and COX-2. RON expression was observed to be associated with age, tumor size, lymphovascular and perineural invasion, tumor stage, lymph node and distant metastasis, and poor survival rate. The mean microvessel density value of RON-positive tumors was significantly higher than that of RON-negative ones. These results indicate that RON is associated with tumor progression by inhibiting chemosensitivity and enhancing angiogenesis in colorectal cancer.

Incidence of and risk factors for thyroid dysfunction during peginterferon α and ribavirin treatment in patients with chronic hepatitis C.

BACKGROUND/AIMS: Thyroid dysfunction (TD) is more likely to occur in patients with chronic hepatitis C (CHC) and is particularly associated with interferon (IFN) treatment. The purpose of this study was to investigate the incidence, outcomes, and risk factors for TD during pegylated interferon (PEG-IFN) and ribavirin (RBV) combined therapy in patients with CHC. METHODS: A total of 242 euthyroid patients with CHC treated with PEG-IFN/RBV were included. Thyroid function and autoantibodies were measured at baseline, and virologic response and thyroid function were assessed every 3 months during therapy. RESULTS: TD developed in 67 patients (27.7%) during the PEG-IFN/RBV treatment. The types of TD were subclinical hypothyroidism (50.7%), hypothyroidism (14.9%), thyroiditis (11.9%), subclinical hyperthyroidism (10.4%), and hyperthyroidism (10.4%). Most of the patients with TD recovered spontaneously; however, seven patients (10.4%) needed thyroid treatment. The sustained virological response rate was higher in patients with TD than those without (65.7% vs. 49.1%, p = 0.02). Baseline thyroid stimulating hormone (TSH) concentrations (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.96 to 8.77; p < 0.001), presence of the thyroid peroxidase antibody (OR, 8.81; 95% CI, 1.74 to 44.6; p = 0.009), and PEG-IFNα-2b (OR, 3.01; 95% CI, 1.43 to 6.39; p = 0.004) were independent risk factors for the development of TD. CONCLUSIONS: TD developed in 27.7% of patients with CHC during PEG-IFN/RBV treatment, and 10.4% of these patients needed thyroid treatment. TD is associated with a favorable virologic response to PEG-IFN/RBV. Assessment of TSH and thyroid autoantibodies at baseline and close monitoring of thyroid function during PEG-IFN/RBV therapy are necessary for early detection and management of IFN-induced TD.

Myeloid cell leukemia-1 promotes epithelial-mesenchymal transition of human gastric cancer cells.

Epithelial-mesenchymal transition (EMT) is a critical process that occurs during cancer progression, and cancer stem cells have been shown to acquire the EMT phenotype. Myeloid cell leukemia-1 (Mcl-1) has been implicated in cancer progression and is overexpressed in a variety of human cancers. However, the interaction between Mcl-1 and EMT in human gastric cancer (GC) is unclear. We investigated the impact of Mcl-1 expression levels on EMT and the underlying signaling pathways in human GC cells. We used the human GC cell lines, AGS and SNU638, and small interfering RNAs (siRNAs) to evaluate the effects of Mcl-1 knockdown on cell adhesion, migration and invasion. Expression of Mcl-1 and other target genes was determined using reverse transcription-polymerase chain reaction assays and western blotting. The results revealed that expression levels of Mcl-1 mRNA and protein in the AGS and SNU638 cells were reduced following transfection with Mcl-1 siRNAs. Knockdown of Mcl-1 led to increased cellular adhesion to fibronectin and collagen. Expression levels of vimentin, MMP-2, MMP-9 and Snail protein were decreased following knockdown of Mcl-1. However, expression of E-cadherin was increased in the AGS cells following knockdown of Mcl-1. The expression of cancer stemness markers, such as CD44 and CD133, was not altered by knockdown of Mcl-1. Knockdown of Mcl-1 suppressed tumor cell migration and invasion in both human GC cell lines. Signaling cascades, including the ß-catenin, MEK1/2, ERK1/2 and p38 pathways, were significantly blocked by knockdown of Mcl-1. Our results indicate that Mcl-1 expression induces EMT via ß-catenin, MEK1/2 and MAPK signaling pathways, which subsequently stimulates the invasive and migratory capacity of human GC cells.

Virologic response and safety of tenofovir versus entecavir in treatment-naïve chronic Hepatitis B patients.

BACKGROUND/AIMS: This study aimed to evaluate the antiviral response and safety of tenofovir (TDF) versus entecavir (ETV) in treatment-naïve CHB patients. PATIENTS AND METHODS: We performed a retrospective cohort study of treatment-naive CHB patients who were treated with TDF or ETV. We analyzed virologic, biochemical, and serologic responses at 3, 6, and 12 months. RESULTS: A total of 107 patients (TDF group = 49, ETV group = 58) were included. Baseline characteristics were similar between the two groups. The estimated proportion of complete virologic response (CVR) in the TDF or ETV group was 44.9% versus 39.7% at 6 months and 89.6% versus 83.2% at 12 months, respectively (P = 0.991). Viral breakthrough was not observed in both groups. One patient in the TDF group and two patients in the ETV group experienced HBeAg loss, respectively (P = 0.657). High HBV DNA level at baseline was a significant negative predictor of virologic response by Cox regression analysis (P = 0.007). The safety profile was similar between the two groups. There was no case with serious adverse event. CONCLUSIONS: Both TDF and ETV were effective in achieving CVR and had a favorable safety profile in treatment-naïve CHB patients. High viral load at baseline was a negative predictive factor of CVR.

Cardiogenic shock accompanied by dynamic left ventricular outflow tract obstruction and myocardial bridging after transient complete atrioventricular block mimicking ST-elevation myocardial infarction: a case report.

BACKGROUND: Dynamic left ventricular outflow tract obstruction with or without mitral regurgitation is typically observed in hypertrophic cardiomyopathy, but is also occasionally seen without left ventricular hypertrophy. In this report, we present a case of cardiogenic shock that mimics ST-elevation myocardial infarction, due to dynamic left ventricular outflow tract obstruction with transient mitral regurgitation and myocardial bridging after transient complete atrioventricular block. CASE PRESENTATION: A 65-year-old man with hypertension presented himself at the emergency department with syncope after chest pain. His initial electrocardiography showed inferior ST elevation with profound precordial ST depression and transient complete atrioventricular block. Due to sustained hypotension, an intra-aortic balloon pump was applied. His coronary angiography revealed almost normal right coronary artery and left circumflex artery and only a severe myocardial bridge in the mid-segment of his left anterior descending artery. Instead, severe mitral regurgitation was found without regional wall motion abnormality both in the left ventriculography and the portable echocardiography. However the severe mitral regurgitation completely disappeared in follow up echocardiography the day after. The pressure gradient across the left ventricular outflow tract was measured at 8.95 mmHg during the resting state, and was increased to 38.95 mmHg during the Valsalva state. CONCLUSIONS: The patient presented with a case of cardiogenic shock that mimicked ST-elevation myocardial infarction due to dynamic left ventricular outflow tract obstruction combined with myocardial bridging in the mid-left anterior descending artery.