MicroRNA profiling in cancer

The diagnosis of cancer has undergone major changes in the last 40 years. Once based purely on morphology, diagnosis has come to incorporate immunological, cytogenetic and molecular methods. Many cancers, especially leukaemias, are now defined by molecular markers. Gene expression profiling based on mRNA has led to further refinement of the classification and diagnosis of cancer. More recently, miRNAs (microRNAs), among other small non-coding RNA molecules, have been discovered and found to be major players in cell biology. miRNAs, having both oncogenic and tumour-suppressive functions, are dysregulated in many types of cancer. miRNAs also interfere with metastasis, apoptosis and invasiveness of cancer cells. In the present review, we discuss recent advances in miRNA profiling in human cancer. We discuss both frequent and rare tumour types and give an outlook on future developments.     

A pilot study of nuclear instability in archived renal and upper urinary tract tumours with putative ochratoxin aetiology

DNA ploidy measurement has been applied uniquely to wax-embedded tissue of primary renal cell and metastatic tumours of a key experimental researcher on porcine ochratoxicosis, a control, and four transitional cell carcinomas from cases of Balkan endemic nephropathy. Primary renal tumour was diploid, and hyperdiploid metastasis was within the lower ploidy range for typical renal cell carcinoma. Three Balkan primary tumours showed extensive aneuploidy indicating marked nuclear instability, similar to model rat renal carcinoma caused by ochratoxin A. In contrast, much less nuclear instability in the putative occupational ochratoxicosis case fitted poorly with the ochratoxin A model.     

Synthesis, biological evaluation and molecular modeling of GW 501516 analogues

Eleven analogues of GW 501516 (1) were prepared and subjected to biological testing in a semi-high throughput human skeletal muscle cell assay. The assay testing indicated that all analogues elicited oxidation of oleic acid. Among the most potent agonists, 2e (2-{2-ethyl-4-[(4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl)methylthio]phenoxy}-2-methylpropanoic acid), was also subjected to a luciferase-based transfection assay, which showed that this compound is a potent agonist against PPARδ and a moderate agonist against PPARα. Docking of compound 2e into PPARδ revealed that it occupied the agonist binding site and exhibited key hydrogen bonding interactions with His323, His449, and Tyr473.     

Experimental Study Regarding the Behavior at Different pH of Two Types of Co-Cr Alloys Used for Prosthetic Restorations

Cobalt-chromium (Co-Cr) alloys are widely utilized in dentistry. The salivary pH is a significant factor, which affects the characteristics and the behavior of dental alloys through corrosion. This study aimed to evaluate the corrosion behavior in artificial saliva with different pH values (3, 5.7, and 7.6) of two commercial Co-Cr dental alloys manufactured by casting and by milling. Corrosion resistance was determined by the polarization resistance technique, and the tests were carried out at 37 ± 1 °C, in Carter Brugirard artificial saliva. After the electrochemical parameters, it can be stated that the cast Co-Cr alloy has the lowest corrosion current density, the highest polarization resistance, and the lowest speed of corrosion in artificial saliva with pH = 7.6. In the case of milled Co-Cr alloy, the same behavior was observed, but in artificial saliva with pH = 5.7, it recorded the most electropositive values of open circuit potential and corrosion potential. Although both cast and milled Co-Cr alloys presented a poorer corrosion resistance in artificial saliva with a more acidic pH value, the milled Co-Cr alloy had better corrosion behavior, making this alloy a better option for the prosthetic treatment of patients suffering from GERD.     

Resistance of Akt kinases to dephosphorylation through ATP-dependent conformational plasticity

Phosphorylation of a threonine residue (T308 in Akt1) in the activation loop of Akt kinases is a prerequisite for deregulated Akt activity frequently observed in neoplasia. Akt phosphorylation in vivo is balanced by the opposite activities of kinases and phosphatases. Here we describe that targeting Akt kinase to the cell membrane markedly reduced sensitivity of phosphorylated Akt to dephosphorylation by protein phosphatase 2A. This effect was amplified by occupancy of the ATP binding pocket by either ATP or ATP-competitive inhibitors. Mutational analysis revealed that R273 in Akt1 and the corresponding R274 in Akt2 are essential for shielding T308 in the activation loop against dephosphorylation. Thus, occupancy of the nucleotide binding pocket of Akt kinases enables intramolecular interactions that restrict phosphatase access and sustain Akt phosphorylation. This mechanism provides an explanation for the "paradoxical" Akt hyperphosphorylation induced by ATP-competitive inhibitor, A-443654. The lack of phosphatase resistance further contributes insight into the mechanism by which the human Akt2 R274H missense mutation may cause autosomal-dominant diabetes mellitus.