IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis

The International Programme on Chemical Safety (IPCS) is leading an activity to harmonize approaches to cancer risk assessment as a part of its larger project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. Through a series of workshops and the evaluation of case studies, a number of key components of risk assessments relating to harmonization were identified: transparency, terminology, weight of evidence, flexibility, and accessibility/communication. A major impediment to harmonization identified in the consideration of weight of evidence was the evaluation of mode of action. To address this need, a conceptual framework was developed, based on the general principles involved in considering the chemical induction of a specific tumor in animals. This is based partly on the Bradford Hill criteria for causality as modified by Faustman et al. (1997) for developmental toxicity. The framework is described in this paper followed by a worked example. It is recognized that the framework addresses only one stage in the overall characterization of hazard to humans of chemical carcinogens. Another important but separate step is the assessment of relevance to humans. This is a priority area for future work in this project.     

Congenital esophageal stenosis: clinical and endoscopic features in adults

BACKGROUND: Congenital esophageal stenosis (CES) is an uncommon anomaly that reportedly rarely goes undiagnosed until adulthood. One variant of CES includes patients with multiple cartilaginous rings described usually in the mid-distal esophagus. METHODS: Ten patients with CES seen over the past 7 years were interviewed and their clinical and endoscopic records reviewed. RESULTS: Eight patients were male and age at time of diagnosis ranged from 21 to 75 years. Meat impaction was the presenting symptom in 8 patients and 3 patients reported a relapsing history. Intermittent solid food dysphagia over extended duration (10-40 years) was reported in all patients with an estimated onset of symptoms at a mean age of 27 years (11-52 years). Endoscopically, all patients had segmental esophageal stenosis (length 2-8 cm, mean = 4.7 cm) due to 'trachea-like' multiple submucosal rings. Pseudodiverticulosis and distal reflux esophagitis were evident in 1 patient. Nine of 10 patients had no macroscopic esophagitis. Dilatation was performed by balloon insufflation (18 mm in 5 patients, 15 mm in 3 patients, 12 mm followed by 15 mm in a patient with a tight stricture) and by Savary dilators in 1 patient, without any complications. No patient had recurrent meat impaction on follow-up (1-7 years, mean = 3 years) after education about the condition. CONCLUSION: (1) We suspect CES is an under-recognized cause for intermittent, long-standing dysphagia in adults. (2) Food impaction is a frequent initial presentation. Recognition of CES is critical for appropriate patient education and planning.     

Hepatitis B virus (HBV) genotype and YMDD motif mutation profile among patients infected with HBV and untreated with lamivudine.

OBJECTIVES: A few reports exist on hepatitis B virus (HBV) genotype distribution in Iran; however the sample sizes of these studies are insufficient. The first objective of this study was to determine the HBV genotype distribution with a large sample size (147 specimens). The second objective was to determine the incidence of the lamivudine-resistant YMDD mutant profile among HBV-infected patients not treated with lamivudine; some studies have reported that YMDD mutants are detectable even before antiviral treatment. METHODS: We used two cost-effective PCR-based methods that have been developed in-house: gap-PCR and artificially created restriction site-PCR (ACRS-PCR). Also, 11 samples were randomly selected and bi-directionally sequenced and subjected to phylogenetic analysis. RESULTS: Gap-PCR results revealed genotype D of HBV in all patients, and ACRS-PCR results disclosed the absence of mutation within the YMDD motif before antiviral therapy in the study population. Phylogenetic analysis supported the former genotyping results with the segregation of all Iranian HBV isolates in the genotype D branch with a high bootstrap value (99%, 1000 replicates). CONCLUSIONS: The present study using two cost-effective methods showed that genotype D of HBV is dominant among Iranian HBV-infected subjects, and HBV lamivudine-resistant strains do not exist naturally among Iranian patients not treated with lamivudine.     

Incidence of Hepatitis C Virus (HCV), Hepatitis B Virus (HBV) and Dual Infection in Egyptian Patients on Haemodialysis

Hepatitis viral infections are important causes of morbidity and mortality in haemodialysis patients. The aim of the present work is to study the prevalence and possible risk factors of hepatitis C virus (HCV), hepatitis B virus (HBV) and dual infection in haemodialysis patients. Three hundred forty patients with end-stage renal disease, 266 males (78.2%) with mean age of 50.9?±?11.6 years and 74 females (21.8%) with mean age of 53.5?±?10.5 years on haemodialysis, were recruited from four haemodialysis units. They were screened for the presence of HCV, HBV and dual HCV and HBV infections and possible risk factors for acquiring these infections in those patients during the period between June 2007 and August 2009. One hundred ninety-six (57.7%) patients were HCV positive while 12 (3.5%) patients had HBV infection. A dual infection with both viruses was observed in 26 patients (7.6%).There was a significant difference in the number of blood transfusions among HCV-positive, HBV-positive and dual infection patients and negative patients (12.4?±?7.6, 13.8?±?6.8, 13.5?±?8.3 vs. 5.2?±?3.4 transfusions, p?<?0.01). HCV, HBV and dual HCV and HBV patients have been on dialysis for a longer period than the negative patients (7.5?±?5, 6.2?±?3.6, 7.5?±?5.4 vs. 4.4?±?4 years, p?<?0.01). Higher HCV was associated with longer haemodialysis duration and history of previous blood transfusion and not associated with dialysis in multicentres. HBV and dual infection is less prevalent than HCV in haemodialysis units.     

Salt content of some fast foods in Casablanca,Morocco: Pilot study

Introduction

High salt intake is associated with high blood pressure. This pilot study aimed to measure the salt content of some fast foods in Casablanca, Morocco.

Design,synthesis, biological evaluations,molecular docking,and in vivo studies of novel phthalimide analogs

A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53–67% of erythromycin activity on the tested bacteria and 60–70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF‐7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad‐spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11 , which showed good activity toward all the tested cell lines except for MCF‐7. The ability of the promising analogs 5 , 8 , and 11 to bind to topoisomerase II DNA gyrase was investigated. Caspase‐3 activation and Bcl‐2 assay of the best active derivatives 8 , 11 in addition to compound 5 were evaluated. The antifibrotic activity was studied in an in vivo model and the histopathological studies revealed that treatment with the new compound 8 improved the fibrotic liver tissues to normality.

     

Co-Delivery of Curcumin and Chrysin by Polymeric Nanoparticles Inhibit Synergistically Growth and hTERT Gene Expression in Human Colorectal Cancer Cells

Nanoparticle (NP)-based combinational chemotherapy has been proposed as a potent approach for improving intracellular drug concentrations and attaining synergistic effects in colorectal cancer therapy. Here, two well-known herbal substances, Curcumin (Cur) and Chrysin (Chr), were co-encapsulated in PEGylated PLGA NPs and investigated their synergistic inhibitory effect against Caco-2 cancer cells.

Characterization of nanoformulated drugs was determined using DLS, FTIR, TEM, and SEM. Drug release study was performed using dialysis method. MTT and real-time PCR assays were applied to evaluate the cytotoxic effects of free and nano-encapsulated drugs on expression level of hTERT in Caco-2 cells.

The results showed that free drugs and nano-formulations exhibited a dose-dependent cytotoxicity against Caco-2 cells and especially, Cur–Chr–PLGA/PEG NPs had more synergistic antiproliferative effect and significantly arrested the growth of cancer cells than the other groups (P < 0.05). Real-time PCR results revealed that Cur, Chr, and combination of Cur–Chr in free and encapsulated forms inhibited hTERT gene expression. Also, it was found that Cur–Chr–PLGA/PEG NPs than free combination forms could further decline hTERT expression in all concentration (P < 0.05).

In summary, our study represents the first report of nano-combinational application of the natural herbal substances with a one-step fabricated codelivery system for effective colorectal cancer combinational chemotherapy.