Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran

Background: Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. Methodology/Principal Findings: Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40 at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. Conclusion/Significance: ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis

Suppression of colitis-related mouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands

BACKGROUND: It is generally assumed that inflammatory bowel disease (IBD)-related carcinogenesis occurs as a result of chronic inflammation. We previously developed a novel colitis-related mouse colon carcinogenesis model initiated with azoxymethane (AOM) and followed by dextran sodium sulfate (DSS). In the present study we investigated whether a cyclooxygenase (COX)-2 inhibitor nimesulide and ligands for peroxisome proliferator-activated receptors (PPARs), troglitazone (a PPARγ ligand) and bezafibrate (a PPARα ligand) inhibit colitis-related colon carcinogenesis using our model to evaluate the efficacy of these drugs in prevention of IBD-related colon carcinogenesis. METHODS: Female CD-1 (ICR) mice were given a single intraperitoneal administration of AOM (10 mg/kg body weight) and followed by one-week oral exposure of 2% (w/v) DSS in drinking water, and then maintained on the basal diets mixed with or without nimesulide (0.04%, w/w), troglitazone (0.05%, w/w), and bezafibrate (0.05%, w/w) for 14 weeks. The inhibitory effects of dietary administration of these compounds were determined by histopathological and immunohistochemical analyses. RESULTS: Feeding with nimesulide and troglitazone significantly inhibited both the incidence and multiplicity of colonic adenocarcinoma induced by AOM/DSS in mice. Bezafibrate feeding significantly reduced the incidence of colonic adenocarcinoma, but did not significantly lower the multiplicity. Feeding with nimesulide and troglitazone decreased the proliferating cell nuclear antigen (PCNA)-labeling index and expression of β-catenin, COX-2, inducible nitric oxide synthase (iNOS) and nitrotyrosine. The treatments increased the apoptosis index in the colonic adenocarcinoma. Feeding with bezafibrate also affected these parameters except for β-catenin expression in the colonic malignancy. CONCLUSION: Dietary administration of nimesulide, troglitazone and bezafibrate effectively suppressed the development of colonic epithelial malignancy induced by AOM/DSS in female ICR mice. The results suggest that COX-2 inhibitor and PPAR ligands could serve as an effective agent against colitis-related colon cancer development

Phospholipase D signaling: orchestration by PIP2 and small GTPases

Hydrolysis of phosphatidylcholine by phospholipase D (PLD) leads to the generation of the versatile lipid second messenger, phosphatidic acid (PA), which is involved in fundamental cellular processes, including membrane trafficking, actin cytoskeleton remodeling, cell proliferation and cell survival. PLD activity can be dramatically stimulated by a large number of cell surface receptors and is elaborately regulated by intracellular factors, including protein kinase C isoforms, small GTPases of the ARF, Rho and Ras families and, particularly, by the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 is well known as substrate for the generation of second messengers by phospholipase C, but is now also understood to recruit and/or activate a variety of actin regulatory proteins, ion channels and other signaling proteins, including PLD, by direct interaction. The synthesis of PIP2 by phosphoinositide 5-kinase (PIP5K) isoforms is tightly regulated by small GTPases and, interestingly, by PA as well, and the concerted formation of PIP2 and PA has been shown to mediate receptor-regulated cellular events. This review highlights the regulation of PLD by membrane receptors, and describes how the close encounter of PLD and PIP5K isoforms with small GTPases permits the execution of specific cellular functions

On the residual strength of aging cast iron trunk mains: physically-based models for asset failure

Worldwide, a significant proportion of the large diameter (trunk) mains within water networks are still made of aging cast iron material. With corrosion seeming to be the most significant cause of deterioration in cast iron trunk mains, the traditional structural view of the residual strength of the pipe has been based on the strength of the remaining wall thickness, i.e. a loss-of-section approach. In some situations this may lead to an over-estimate of the residual strength and better predictions can be made using an approach based on fracture mechanics. The present research has shown how loss-of-section models of residual strength can be used alongside fracture mechanics models in a twin approach to provide boundaries to the failure envelope for a “ring element” subjected to combined bending and direct (tensile or compressive) forces. When the application of such a failure envelope to a ring from a pipe under combined vertical loading and internal pressure is considered, it was found that in addition to its size, the angular position of a corrosion defect can have a significant effect on the residual strength of the pipe

Managing water infrastructure: Corrosion models for cast iron trunk mains

Distribution networks are critical in providing continuous potable water supplies to households and businesses. Trunk mains are the major arteries of the distribution network and convey large volumes of water over long distances. Worldwide, much of this infrastructure is made of ageing cast iron and is deteriorating at different rates. Many of these mains are beginning to approach the end of their service lives (with some already exceeding their design life) and consequently out of large populations of pipes, some are failing, although some still have considerable residual life. Trunk main failures can have significant social, health and safety, environmental and economic impacts. It is therefore imperative to prevent the wide-scale failure of trunk mains through the implementation of proactive asset management strategies. Such approaches require accurate condition assessment data across the network in conjunction with deterioration modelling to predict how the assets' condition and performance changes over time. This work, being part of a wider collaborative project, has outlined a deterioration modelling framework on the basis of existing physical probabilistic failure models and research focussing on residual mechanical properties, corrosion and the NDT detection of flaws. The developed deterioration model can be used to characterise individual pipes (deterministic approach), as well as the cohort/network modelling of pipes (probabilistic approach). Deterioration is assumed to be predominantly based on corrosion. Previously this has been dealt with in a rather simplistic manner. The broader work has, on the one hand,shown that corrosion mechanisms are rather different than previously thought and, on the other, that their effect on a given pipe can be variable. A corrosion model capable of simulating the distribution of corrosion properties of the primary defects is to be incorporated within the proposed modelling framework and the development of important aspects of this model are discussed here. © 2014 WIT Press