Sprawozdanie z I Spotkania Konsorcjum Akademickich Zakładów Studiów Strategicznych, Warszawa, 10 kwietnia 2017 r.

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Qualitative analysis of Adenomatous Polyposis Coli promoter: Hypermethylation, engagement and effects on survival of patients with esophageal cancer in a high risk region of the world, a potential molecular marker

<p>Abstract</p> <p>Background</p> <p>Squamous cell carcinoma of esophagus (SCCE) occurs at a high incidence rate in certain parts of the world. This feature necessitates that different aspects of the disease and in particular genetic characteristics be investigated in such regions. In addition, such investigations might lead to achievement of molecular markers helpful for early detection, successful treatment and follow up of the disease. Adenomatous Polyposis Coli (<it>APC</it>) promoter hypermethylation has been shown to be a suitable marker for both serum and solid tumors of adenocarcinoma of esophagus. We investigated the status of <it>APC </it>promoter hypermethylation in Iranian patients, compared the results with the former studies, and evaluated its applicability as a candidate molecular marker by examining association between survival of SCCE patients and <it>APC </it>promoter methylation.</p> <p>Methods</p> <p>For evaluating the status of <it>APC </it>promoter hypermethylation and its association with SCCE, a qualitative methylation specific PCR (MSP) was used. DNA was extracted and digested with an appropriate restriction enzyme, treated with sodium bisulfite in agarose beads and amplified in two-step PCR reaction by applying either methylated or unmethylated promoter specific primers. Universally methylated DNA and methylase treated blood DNA of healthy donors were used as positive controls as well. Survival of patients was followed up for two years after treatment and survival rate of patients with methylated <it>APC </it>promoter was compared with that of unmethylated patients.</p> <p>Results</p> <p>Assessment of <it>APC </it>promoter methylation revealed that normal tissues were unmethylated, while twenty out of forty five (44.4%) tumor tissues were hypermethylated either in one or both alleles of <it>APC</it>. Among the tissues in which methylation was detected, seven were hypermethylated in both alleles while the other thirteen were hypermethylated in one of the two alleles of <it>APC</it>. Analyzing two-year survival rate of patients with respect to promoter hypermethylation showed a lower rate of survival for patients with methylated <it>APC </it>promoter following their treatment. Further investigation into the association between promoter hypermethylation and tumor differentiation status indicated that patients with well differentiated tumors were more likely to develop promoter hypermethylation.</p> <p>Conclusion</p> <p>Observing similar level of <it>APC </it>promoter hypermethylation in patients with SCCE in this high risk region and comparing it with other parts of the world could support the hypothesis that a common molecular mechanism might be involved in tumorigenesis of SCCE. In addition, the higher rate of two-year survival for patients with unmethylated <it>APC </it>promoter as well as its relationship with tumor differentiation would suggest that this tumor suppressor could be an appropriate candidate molecular marker for evaluating tumor malignancy and predicting survival of patients subsequent to treatment.</p

p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus

Background: Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings: We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett’s esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions: The results of this study suggest the environment of the esophagus in BE patients can both generate an

The Cumulative Effects of Polymorphisms in the DNA Mismatch Repair Genes and Tobacco Smoking in Oesophageal Cancer Risk

The DNA mismatch repair (MMR) enzymes repair errors in DNA that occur during normal DNA metabolism or are induced by certain cancer-contributing exposures. We assessed the association between 10 single-nucleotide polymorphisms (SNPs) in 5 MMR genes and oesophageal cancer risk in South Africans. Prior to genotyping, SNPs were selected from the HapMap database, based on their significantly different genotypic distributions between European ancestry populations and four HapMap populations of African origin. In the Mixed Ancestry group, the MSH3 rs26279 G/G versus A/A or A/G genotype was positively associated with cancer (OR = 2.71; 95% CI: 1.34–5.50). Similar associations were observed for PMS1 rs5742938 (GG versus AA or AG: OR = 1.73; 95% CI: 1.07–2.79) and MLH3 rs28756991 (AA or GA versus GG: OR = 2.07; 95% IC: 1.04–4.12). In Black individuals, however, no association between MMR polymorhisms and cancer risk was observed in individual SNP analysis. The interactions between MMR genes were evaluated using the model-based multifactor-dimensionality reduction approach, which showed a significant genetic interaction between SNPs in MSH2, MSH3 and PMS1 genes in Black and Mixed Ancestry subjects, respectively. The data also implies that pathogenesis of common polymorphisms in MMR genes is influenced by exposure to tobacco smoke. In conclusion, our findings suggest that common polymorphisms in MMR genes and/or their combined effects might be involved in the aetiology of oesophageal cancer

9th International Conference on Fracture Mechanics of Concrete and Concrete Structures STUDY OF SHRINKAGE RESTRAINT EFFECTS AT EARLY-AGE IN ALKALI- ACTIVATED SLAG MORTARS

Abstract: Alkali-activated materials are being increasingly studied nowadays as hydraulic binders. In order to be enrolled in different civil engineering applications, several properties must be characterized. This study focuses on their cracking risk by shrinkage restraints. The current paper summarizes the experimental and numerical results of a project assessing the development of early age properties of an alkali-activated slag mortar. First, an experimental campaign was held in order to quantify hydration heat release and hydration kinetics, to determine the time evolution of the Young modulus and the tensile strength and to measure free shrinkage strains, all in autogenous conditions. Second, two modelling approaches for mechanical properties and shrinkage development were compared. The results showed that the classical approach to characterize the hydration kinetics based on semi-adiabatic calorimetry results isn&apos;t suitable for the studied binder because of slow hydration and low heat release. Numerical work was finally conducted in order to predict stress development of a massive structure of alkali-activated slag mortar subjected to internal (self) and external strains&apos; restraints (at mesoscopic and macroscopic scales)

UNGG Waste Retrieval Comparison of general and galvanic corrosion of Magnesium alloy coupled to graphite in ordinary Portland cement and alkali-activated slag binders

International audienceGraphite and magnesium alloys wastes were generated during the reprocessing phase of spent fuel assemblies of the former nuclear reactors in France. Conditioning of these low to intermediate level wastes in cementitious materials is being addressed here. The study is aiming to develop a numerical model able to predict the generation of stresses in such waste packages during their lifetime. Magnesium is one of the most reactive metals with a standard potential of -2.37V/SHE [1]. Once embedded in a hydraulic binder with alkaline pH and high internal humidity, oxidation reactions occur. The subsequent formation of corrosion products around the alloy may result in tensile stresses development in the surrounding binder that could lead to cracking risks. Thus, general and galvanic corrosion (when coupled with graphite) of the metal in the packages should be properly addressed.Hence, weight losses, electrochemical techniques and microscopic observations together with chemical analysis methods (Raman and SEM/EDX) are used to characterize the metal's corrosion in three binders. These latter consist of two different ordinary Portland cement and an alkali-activated blast furnace slag mortars [2]. The results prove that the use of alkali-activated slag (AAS) is beneficial for the metal's galvanic corrosion while the general corrosion behavior is comparable in all studied mortars.Additionally, the electrical conductance of the hydraulic binders was determined using electrochemical impedance spectroscopy technique (EIS). These tests were performed on graphite and magnesium electrodes embedded in the binders, from 7 to 180 days of hydration. The analysis of the results, using an equivalent electrical circuit, showed that the electrical conductance of AAS binder was lower than ordinary Portland cement binders, at a given hydration age.In order to explain this lower conductance of the AAS binder, an investigation of its porosity (total porosity and porosity size distribution) and a characterization of the pore solution are undertaken. Therefore, on one hand, mercury intrusion porosimetry and BET nitrogen adsorption tests are performed on the different binders in order to compare the pore structure. On the other hand, pH measurements and liquid ion chromatography techniques are used to monitor the evolution of the AAS binder's pore solution. The latter results are compared to those for OPC binders found in the literature

Early-age cracking tendency of Alkali-activated slag binders compared to Ordinary Portland Cement

International audienceGround granulated blast furnace slag (GGBFS) is a by-product of steel manufacturing, increasingly used as an alkali-activated hydraulic binder. The substitution of Ordinary Portland Cement (OPC) based binders by this type of materials represents essentially an ecological advantage due to the reduction in CO2 emissions. Additionally, these materials constitute relevant alternative of OPC binders in some specific industrial applications [1] [2]. Hydration advancement and microstructural properties' evolution of alkali-activated slag materials have been extensively studied in the literature. However, a large dependency both on the chemical and physical properties of the activated GGBFS, and the type and concentration of the alkaline activator used, can be observed. Additionally, few studies have addressed the evolution of the mechanical properties of these binders and the early-age creep and shrinkage characteristics. Thus cracking tendency of this type of materials, especially at early ages when the volumetric changes of the hydraulic binders are the most important, needs to be investigated in order to study the durability of any structural application. In this context, the current paper describes, first, an experimental campaign comparing the early-age behavior of an alkali-activated slag mortar to that of an OPC mortar, then thermo-chemo-mechanical simulations allowing comparing the cracking tendency of both materials.The developed experimental campaign covers the delayed strains (autogenous shrinkage and creep) and the mechanical properties (mechanical strengths and Young's modulus) evolutions of the mortars. Results show that the alkali-activated mortar undergoes autogenous shrinkage strains higher then OPC mortar and showing an increase even at long term. However, its basic creep strains are more important than OPC mortar ones tested in the same conditions. This implies a higher capacity of stress relaxation for the alkali-activated slag mortar. Regarding the evolution of mechanical properties, Young modulus, compressive and tensile strengths of the alkali-activated mortar are lower of those of OPC based mortar at all ages. A simplified cracking index comparison applied at this stage of study shows comparable cracking risks of both materials at 7 and 28 days.The performed numerical simulations are performed by the means of a thermo-chemo-mechanical model developed based on the experimental study. The equivalent time approach model is adopted in order to describe the early-age evolution of the binders. Basic creep strains are expressed using a visco-elastic model combining a Kelvin-Voigt chain and dashpot [3]. This model is revisited to add a time-equivalent evolution for the ageing parameters. Finally, finite element calculations are performed on a bar fixed at both ends in order to compare the cracking tendency of the studied mortars