miRNome Profiling and Functional Analysis Reveal Involvement of hsa-miR-1246 in Colon Adenoma-Carcinoma Transition by Targeting AXIN2 and CFTR

Regulatory changes occurring early in colorectal cancer development remain poorly investigated. Since the majority of cases develop from polyps in the adenoma-carcinoma transition, a search of early molecular features, such as aberrations in miRNA expression occurring prior to cancer development, would enable identification of potentially causal, rather than consequential, candidates in the progression of polyp to cancer. In the current study, by employing small RNA-seq profiling of colon biopsy samples, we described differentially expressed miRNAs and their isoforms in the adenoma-carcinoma transition. Analysis of healthy-adenoma-carcinoma sequence in an independent validation group enabled us to identify early deregulated miRNAs including hsa-miR-1246 and hsa-miR-215-5p, the expressions of which are, respectively, gradually increasing and decreasing. Loss-of-function experiments revealed that inhibition of hsa-miR-1246 lead to reduced cell viability, colony formation, and migration rate, thereby indicating an oncogenic effect of this miRNA in vitro. Subsequent western blot and luciferase reporter assay provided evidence of hsa-miR-1246 being involved in the regulation of target AXIN2 and CFTR genes’ expression. To conclude, the present study revealed possible involvement of hsa-miR-1246 in early colorectal cancer development and regulation of tumor suppressors AXIN2 and CFTR.     

A topic network analysis of the system turn in the environmental sciences

Scientometrics - The concept of Earth system science denotes a shift in the scientific discourse from disciplinary accounts of isolated components of the global environment towards the holistic and...     

Camelina oil‐ and linseed oil‐based polymers with bisphosphonate crosslinks

Natural oils are the attractive biobased alternatives for petroleum derived chemicals in the production of polymers. A series of new biodegradable polymers based on epoxidized camelina oil was synthesized and investigated. The thermal, mechanical, swelling properties, hydrolysis, biodegradation, and bioresistance of the camelina oil‐based polymers with bisphosphonate crosslinks were studied and compared with those of the analogous polymers based on epoxidized linseed oil. The dependence of the polymer properties on the density of crosslinks was observed. The obtained results showed that the properties of the camelina oil‐based polymers are comparable with those of the linseed oil‐based polymers and that camelina oil is a promising starting material for the synthesis of polymers. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40683.     

Dependence of ceramics physical–mechanical properties on chemical and mineralogical composition

To determine the dependence of physical–mechanical properties of ceramics on chemical and mineralogical composition, the appropriate raw materials have been tested and five batches of ceramic specimens have been formed. The aforementioned specimens have been made of the following components: fusible clay, quartz sand, chamotte, sawdust and crushed window glass. The specimens differed by the amount of the components (differences in burning regime were insignificant). After having formed and burned the specimens, their X-ray phase analysis has been carried out, elemental chemical composition has been defined and the composition of chemical oxides has been calculated. Moreover, the following physical–mechanical properties have been determined: density, general contraction and compressive strength. The test results showed that the physical–mechanical properties of ceramics mostly depend on the amount carbon, silicon and aluminum. The mineralogical structure of specimens under testing was practically unchanged.     

Copolymers of glycerol and propylene glycol diglycidyl ethers with aromatic dithiols

Monomers derived from renewable recourses have the potential to become the biobased alternatives for petroleum derived chemicals in the production of polymers. Glycerol, the byproduct of biodiesel refining, and propylene glycol derived from glycerol are promising candidates which can be used in the synthesis of polymers as they are or after chemical modification. The new copolymers of glycerol and propylene glycol diglycidyl ethers with aromatic dithiols were synthesized and investigated in this study. Their chemical structures were confirmed by IR, ¹H‐NMR spectroscopy, and gel permeation chromatography. The dependencies of the mechanical, thermal properties, swelling in the different solvents, biodegradability, and bioresistance of synthesized copolymers on their chemical structures were studied. The properties of some synthesized copolymer films were found to be comparable with those of commodity polymer films. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 4367–4374, 2013     

Measurement of Nanomolar Dissociation Constants by Titration Calorimetry and Thermal Shift Assay �C Radicicol Binding to Hsp90 and Ethoxzolamide Binding to CAII

The analysis of tight protein-ligand binding reactions by isothermal titration calorimetry (ITC) and thermal shift assay (TSA) is presented. The binding of radicicol to the N-terminal domain of human heat shock protein 90 (Hsp90αN) and the binding of ethoxzolamide to human carbonic anhydrase (hCAII) were too strong to be measured accurately by direct ITC titration and therefore were measured by displacement ITC and by observing the temperature-denaturation transitions of ligand-free and ligand-bound protein. Stabilization of both proteins by their ligands was profound, increasing the melting temperature by more than 10 ºC, depending on ligand concentration. Analysis of the melting temperature dependence on the protein and ligand concentrations yielded dissociation constants equal to 1 nM and 2 nM for Hsp90αN-radicicol and hCAII-ethoxzolamide, respectively. The ligand-free and ligand-bound protein fractions melt separately, and two melting transitions are observed. This phenomenon is especially pronounced when the ligand concentration is equal to about half the protein concentration. The analysis compares ITC and TSA data, accounts for two transitions and yields the ligand binding constant and the parameters of protein stability, including the Gibbs free energy and the enthalpy of unfolding.     

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the K_d was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.