Arsenic trioxide-induced cytotoxicity in small cell lung cancer via altered redox homeostasis and mitochondrial integrity.

Arsenic trioxide (ATO) has demonstrated anticancer activity in different malignancies, especially acute promyelocytic leukemia, with a wide array of putative mechanisms. In this study, we aimed to elucidate the activity and mechanisms of ATO in small cell lung cancer (SCLC). A panel of SCLC cell lines (H841, DMS79, H526, H69 and H187) was employed to demonstrate the activity of ATO. Cell viability, apoptosis and mitochondrial membrane depolarization were assessed. Western blotting was performed to determine the alteration of pro-apoptotic and anti-apoptotic mediators. Reactive oxygen species (ROS) (hydrogen peroxide and superoxide) and intracellular glutathione (GSH) were measured. Antioxidants, N-acetyl-L-cysteine (NAC) and butylated hydroxyanisole (BHA), were applied to restore GSH content and reduce production of ROS. All SCLC cell lines were relatively sensitive to ATO with IC50 values below 10 µM. ATO induced cell death mainly through apoptosis in H841 cells in a dose-dependent manner. Hydrogen peroxide was the major ROS in SCLC cells induced by ATO. Along with GSH depletion and Bcl-2 downregulation, mitochondrial membrane permeabilization was enhanced, followed by release of AIF and SMAC from mitochondria to initiate different cell death pathways. NAC reversed cell death and molecular changes induced by ATO via restoring GSH and reducing ROS content. BHA inhibited hydrogen peroxide production completely and partially restored GSH content accounting for partial reversal of cell inhibition and mitochondrial dysfunction. Nonetheless, ATO reduced both reduced and oxidized form of thioredoxin 1 (Trx1) with no effect on Trx1 redox potential. ATO led to cell death in SCLC mainly through mitochondrial dysfunction, resulting from altered cellular redox homeostasis, namely, hydrogen peroxide generation, GSH depletion and Trx1 downregulation.published_or_final_versio

The Effect of Tumor Microenvironment on Autophagy and Sensitivity to Targeted Therapy in EGFR-Mutated Lung Adenocarcinoma

Lung cancer is the top cancer killer worldwide. Tyrosine kinase inhibitors (TKIs), for example erlotinib, are commonly used to target epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC). Autophagy is a cellular response to stress, serving as a protective mechanism during anticancer therapy. The tumor microenvironment (TME) is composed of non-tumor cells that include fibroblasts. Our study aimed to investigate the effect of TME on autophagy and TKI sensitivity. Following cell sorting after direct co-culturing, autophagy and cytokine production were observed in both HCC827 and MRC-5 cells. The synergistic combination of erlotinib and chloroquine (autophagy inhibitor) was observed under TME. Tumor growth was significantly suppressed with combined erlotinib/chloroquine compared with erlotinib in HCC827 xenografts.published_or_final_versio

E2F1 Downregulation by Arsenic Trioxide in Lung Adenocarcinoma

Lung cancer is one of the most common cancers worldwide. Arsenic trioxide (ATO) has been approved by the U.S. Food and Drug Administration for the treatment of acute promyelocytic leukemia. Nonetheless preliminary data have suggested potential activity of ATO in solid tumors including lung cancer. This study aimed to examine the underlying mechanisms of ATO in the treatment of lung adenocarcinoma. Using a panel of 7 lung adenocarcinoma cell lines, the effects of ATO treatment on cell viability, expression of E2F1 and its downstream targets, phosphatidylserine externalization, mitochondrial membrane depolarization and alteration of apoptotic/anti-apoptotic factors were studied. Tumor growth inhibition in vivo was investigated using a nude mouse xenograft model. ATO decreased cell viability with clinically achievable concentrations (8 uM) in all cell lines investigated. This was accompanied by reduced expression of E2F1, cyclin A2, skp2, c-myc, thymidine kinase and ribonucleotide reductase M1, while p-c-Jun was upregulated. Cell viability was significantly decreased with E2F1 knockdown. Treatment with ATO resulted in phosphatidylserine externalization in H23 cells and mitochondrial membrane depolarization in all cell lines, associated with truncation of Bid, downregulation of Bcl-2, upregulation of Bax and Bak, caspase-9 and caspase-3 activation and PARP cleavage. Using a H358 xenograft model, the tumor growth was suppressed in the ATO treatment group during 8 days of treatment, associated with downregulation of E2F1 and upregulation of truncated Bid and cleaved caspase-3. In conclusion, ATO has potent in vitro and in vivo activity in lung adenocarcinoma, partially mediated through E2F1 downregulation and apoptosis.published_or_final_versio

Hybrid meshless/displacement discontinuity method for FGM Reissner's plate with cracks

Growing applications of non-homogenous media in engineering structures require the application of powerful computational tools. A novel hybrid Meshless Displacement Discontinuity Method (MDDM) for cracked Reissner's plate in Functionally Graded Materials (FGMs) is presented in this paper. The fundamental solutions of slope and deflection discontinuity for an isotropic homogenous media are chosen as a part of general solutions to create the gaps between the crack surfaces. The governing equation is satisfied by using the meshless methods such as the Meshless Local Petrov-Galerkin (MLPG) and the Point Collocation Method (PCM) with Lagrange series interpolation and mapping technique. The Stress Intensity Factors (SIFs) are evaluated analytically with the Chebyshev polynomials. The accuracy is verified by comparison of numerical and analytical results

A guide to chemokines and their receptors

The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G‐protein coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behaviour, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many non‐leukocytic cell types. Chemokines are profoundly affected by post‐translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical ‘atypical’ chemokine receptors that regulate chemokine localisation and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarises the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focussing particularly on their ability to direct leukocyte migration

Do patients with non-ulcer dyspepsia respond differently to Helicobacter pylori eradication treatments from those with peptic ulcer disease? A systematic review

Aim: It is controversial whether patients with non-ulcer dyspepsia (NUD) respond differently to Helicobacter pylori (H pylori) eradication treatment than those with peptic ulcer disease (PUD). To review the evidence for any difference in H pylori eradication rates between PUD and NUD patients. Methods: A literature search for full articles and meeting abstracts to July 2004 was conducted. We included studies evaluating the efficacy of a proton pump inhibitor (P) or ranitidine bismuth citrate (RBC) plus two antibiotics of clarithromycin (C), amoxicillin (A), metronidazole (M), or P-based quadruple therapies for eradicating the infection. Results: Twenty-two studies met the criteria. No significant difference in eradication rates was found between PUD and NUD patients when treated with 7-d RBCCA, 10-d PCA or P-based quadruple therapies. When the 7-d PCA was used, the pooled H pylori eradication rate was 82.1% (431/525) and 72.6% (448/617) for PUD and NUD patients, respectively, yielding a RR of 1.15 (95%CI 1.01-1.29). However, the statistically significant difference was seen only in meeting abstracts, but not in full publications. Conclusion: There is no convincing evidence to suggest that NUD patients respond to H pylori eradication treatments differently from those with PUD, although a trend exists with the 7-d PCA therapy. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio

Service-based analysis of biological pathways

Background: Computer-based pathway discovery is concerned with two important objectives: pathway identification and analysis. Conventional mining and modeling approaches aimed at pathway discovery are often effective at achieving either objective, but not both. Such limitations can be effectively tackled leveraging a Web service-based modeling and mining approach. Results: Inspired by molecular recognitions and drug discovery processes, we developed a Web service mining tool, named PathExplorer, to discover potentially interesting biological pathways linking service models of biological processes. The tool uses an innovative approach to identify useful pathways based on graph-based hints and service-based simulation verifying user's hypotheses. Conclusion: Web service modeling of biological processes allows the easy access and invocation of these processes on the Web. Web service mining techniques described in this paper enable the discovery of biological pathways linking these process service models. Algorithms presented in this paper for automatically highlighting interesting subgraph within an identified pathway network enable the user to formulate hypothesis, which can be tested out using our simulation algorithm that are also described in this paper

Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: A meta-analysis

Aim: To systematically evaluate the efficacy of H2-receptor antagonists (H2RAs) and proton pump inhibitors in healing erosive esophagitis (EE). Methods: A meta-analysis was performed. A literature search was conducted in PubMed, Medline, Embase, and Cochrane databases to include randomized controlled head-to-head comparative trials evaluating the efficacy of H2RAs or proton pump inhibitors in healing EE. Relative risk (RR) and 95% confidence interval (CI) were calculated under a random-effects model. Results: RRs of cumulative healing rates for each comparison at 8 wk were: high dose vs standard dose H2RAs, 1.17 (95%CI, 1.02-1.33); standard dose proton pump inhibitors vs standard dose H2RAs, 1.59 (95%CI, 1.44-1.75); standard dose other proton pump inhibitors vs standard dose omeprazole, 1.06 (95%CI, 0.98-1.06). Proton pump inhibitors produced consistently greater healing rates than H2RAs of all doses across all grades of esophagitis, including patients refractory to H2RAs. Healing rates achieved with standard dose omeprazole were similar to those with other proton pump inhibitors in all grades of esophagitis. Conclusion: H2RAs are less effective for treating patients with erosive esophagitis, especially in those with severe forms of esophagitis. Standard dose proton pump inhibitors are significantly more effective than H2RAs in healing esophagitis of all grades. Proton pump inhibitors given at the recommended dose are equally effective for healing esophagitis. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio

Effects of L-arginine on intestinal development and endogenous arginine-synthesizing enzymes in neonatal pigs

This study aimed to investigate the effects of dietary L-arginine supplementation on the intestinal development of neonatal piglets and the underlying mechanisms. 36 neonatal piglets were randomly allocated into three diet groups: control group (supplemented with 0% L-arginine), 0.4 and 0.8% Larginine groups. When compared with the control, dietary supplementation with L-arginine decreased (P<0.05) blood urea nitrogen (BUN), and improved (P<0.05) serum T3 and insulin level of the piglets on day 11. Arginine and its metabolites (citrulline and ornithine) were elevated, additionally, dietary supplementation with 0.8% L-arginine markedly enhanced jejunal villus height, villus area on day 11 and D-xylose absorption rate on day 19. Dietary supplementation with 0.8% L-arginine increased (P<0.05) activities of maltose and lactose on day 18, respectively. This effect correlated with profound change in enzyme activities as inducible nitric oxide synthetase (iNOS), glutamine synthetase (GS) and ornithine decarboxylase (ODC) were elevated on day 18. The concentrations of spermine was increased (P<0.05) by L-arginine supplementation on day 18. These results collectively suggest that dietary  Larginine supplementation improves protein synthesis and intestinal development of the neonatal pigs, the underlying mechanism includes dietary L-arginine supplementation which regulated the productions of intestinal polyamine in jejunum, and stimulated endogenous arginine-synthesizing enzymes in neonatal piglets.Key words: Neonatal pig, L-arginine, intestinal development, arginine-synthetases