Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.     

Resveratrol as Chemosensitizer Agent: State of Art and Future Perspectives

Resistance to chemotherapy still remains a major challenge in the clinic, impairing the quality of life and survival rate of patients. The identification of unconventional chemosensitizing agents is therefore an interesting aspect of cancer research. Resveratrol has emerged in the last decades as a fascinating molecule, able to modulate several cancer-related molecular mechanisms, suggesting a possible application as an adjuvant in cancer management. This review goes deep into the existing literature concerning the possible chemosensitizing effect of resveratrol associated with the most conventional chemotherapeutic drugs. Despite the promising effects observed in different cancer types in in vitro studies, the clinical translation still presents strong limitations due to the low bioavailability of resveratrol. Recently, efforts have been moved in the field of drug delivery to identifying possible strategies/formulations useful for a more effective administration. Despite the necessity of a huge implementation in this research area, resveratrol appears as a promising molecule able to sensitize resistant tumors to drugs, suggesting its potential use in therapy-refractory cancer patients.     

Preliminary Evidence on the Diagnostic and Molecular Role of Circulating Soluble EGFR in Non-Small Cell Lung Cancer

Assessment of biological diagnostic factors providing clinically-relevant information to guide physician decision-making are still needed for diseases with poor outcomes, such as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a promising molecule in the clinical management of NSCLC. While the EGFR transmembrane form has been extensively investigated in large clinical trials, the soluble, circulating EGFR isoform (sEGFR), which may have a potential clinical use, has rarely been considered. This study investigates the use of sEGFR as a potential diagnostic biomarker for NSCLC and also characterizes the biological function of sEGFR to clarify the molecular mechanisms involved in the course of action of this protein. Plasma sEGFR levels from a heterogeneous cohort of 37 non-advanced NSCLC patients and 54 healthy subjects were analyzed by using an enzyme-linked immunosorbent assay. The biological function of sEGFR was analyzed in vitro using NSCLC cell lines, investigating effects on cell proliferation and migration. We found that plasma sEGFR was significantly decreased in the NSCLC patient group as compared to the control group (median value: 48.6 vs. 55.6 ng/mL respectively; p = 0.0002). Moreover, we demonstrated that sEGFR inhibits growth and migration of NSCLC cells in vitro through molecular mechanisms that included perturbation of EGF/EGFR cell signaling and holoreceptor internalization. These data show that sEGFR is a potential circulating biomarker with a physiological protective role, providing a first approach to the functional role of the soluble isoform of EGFR. However, the impact of these data on daily clinical practice needs to be further investigated in larger prospective studies.     

Changes in pain perception and pain-related somatosensory evoked potentials in humans produced by exposure to oscillating magnetic fields

cDNA selection was used to isolate coding sequences from cosmids mapping to the gene-rich telomeric region of human chromosome 21q. A novel cDNA, termed SMT3A, was isolated and mapped between the loci PFKL and D21S171, about 2.2 Mb proximal to the telomere. The predicted protein of 103 amino acids appears to be a homologue of the Saccharomyces cerevisiae SMT3 protein, whose gene was previously isolated as a suppressor of mutations in the MIF2 gene. The yeast MIF2 gene encodes an essential centromeric protein and shows homology to mammalian CENP-C, an integral component of active kinetochores. SMT3A was found to be highly homologous to two other recently isolated human genes, suggesting the presence of a new gene family. Homologous sequences were also found in protozoa, metazoa, and plants. Moreover, all predicted proteins show significant homology to ubiquitin. The proposed role of yeast SMT3 as centromeric protein and the strong evolutionary conservation of the SMT3A gene suggest an involvement of the encoded protein in the function and/or structure of the eukaryotic kinetochore.     

Watermarked 3-D Mesh Quality Assessment

This paper addresses the problem of assessing distortions produced by watermarking 3D meshes. In particular, a new methodology for subjective evaluation of the quality of 3D objects is proposed and implemented. Two objective metrics derived from measures of surface roughness are then proposed and their efficiency to predict the perceptual impact of 3D watermarking is assessed and compared with the state of the art. Results obtained show good correlations between the proposed objective metrics and subjective assessments by human observers     

Simultaneous detection of HPV and other sexually transmitted agents in chronic urethritis

Three tests are routinely done to assess blood status of selenium in cattle: serum selenium, whole blood selenium, and glutathione peroxidase. The objective of this study was to compare the various analytical methods for determining blood selenium status in groups of mature cows and beef calves. Twenty to 30 blood samples per herd were collected from 8 beef herds in central Alberta and 1 dairy in Alberta herd twice a year from the spring of 1992 through the fall of 1995, and once from 185 spring calves in 2 beef herds in Saskatchewan. Serum and whole blood samples were submitted to 1 laboratory and whole blood samples were submitted to a 2nd laboratory. Samples for glutathione peroxidase determinations were submitted to a 3rd laboratory. Pearson's correlation coefficients and Cohen's kappa were calculated for each possible comparison among the different measures. The best agreement was observed between serum and whole blood analysis within Laboratory A. The remaining comparisons reflected poor agreement. Comparison of herd-level assessment resulted in better agreement than comparison of individual sample results among laboratories and procedures for all combinations tested. Serum selenium analysis was the only laboratory procedure for which external reference material was utilized. Serum selenium, whole blood selenium, and glutathione peroxidase measure different compartments of the blood selenium pool. The time frame of interest, supplementation practices, and the stability of recent dietary intake determine the optimum assessment method for individual animals or herds. Determination of the serum status or of blood selenium is more consistently measured at the herd-level than for individual samples.     

An exploratory study of the impact of antipatterns on class change- and fault-proneness

Antipatterns are poor design choices that are conjectured to make object-oriented systems harder to maintain. We investigate the impact of antipatterns on classes in object-oriented systems by studying the relation between the presence of antipatterns and the change- and fault-proneness of the classes. We detect 13 antipatterns in 54 releases of ArgoUML, Eclipse, Mylyn, and Rhino, and analyse (1) to what extent classes participating in antipatterns have higher odds to change or to be subject to fault-fixing than other classes, (2) to what extent these odds (if higher) are due to the sizes of the classes or to the presence of antipatterns, and (3) what kinds of changes affect classes participating in antipatterns. We show that, in almost all releases of the four systems, classes participating in antipatterns are more change-and fault-prone than others. We also show that size alone cannot explain the higher odds of classes with antipatterns to underwent a (fault-fixing) change than other classes. Finally, we show that structural changes affect more classes with antipatterns than others. We provide qualitative explanations of the increase of change- and fault-proneness in classes participating in antipatterns using release notes and bug reports. The obtained results justify a posteriori previous work on the specification and detection of antipatterns and could help to better focus quality assurance and testing activities.     

Cushing’s Syndrome Effects on the Thyroid

The most known effects of endogenous Cushing’s syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus–pituitary–thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the “central hypothyroidism”. These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus–pituitary–thyroid axis activity. During active Cushing’s syndrome, the “immunological tolerance” guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing’s syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing’s syndrome patients, both during the active disease and after its remission.     

Preparation and flame resistance properties of revolutionary self-extinguishing epoxy nanocomposites based on layered double hydroxides

Layered double hydroxides/epoxy (LDHs/EP) nanocomposites were prepared from organo-modified LDHs, a diglycidyl ether of bisphenol A monomer (DGEBA) and amine curing agents. The organo-modified LDHs were obtained by ionic exchange of a magnesium-aluminum carbonate LDH in an acid medium. X-ray diffraction and transmission electron microscopy showed a dispersion of the layers at a nanometer scale, indicating the formation of LDH/EP nanocomposites. The thermal degradation and flame resistance properties of LDH/EP nanocomposites, montmorillonite-epoxy (MMT/EP) nanocomposites, LDH/EP microcomposites and aluminum hydroxide-epoxy microcomposites were compared by thermogravimetrical analyses, simultaneous thermal analyses, UL94 and cone calorimeter tests. Only LDH/EP nanocomposites showed self-extinguishing behavior in the horizontal UL94 test; LDH/EP microcomposites and MMT/EP nanocomposites samples burned completely showing that the unique flame resistance of LDH/EP nanocomposites is related to both the level of dispersion and the intrinsic properties of LDH clay. Furthermore, cone calorimeter revealed intumescent behavior for LDH/EP nanocomposites and a higher reduction in the peak heat release rate compared to MMT/EP nanocomposites.