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.     

To treat or not to treat: comparison of different criteria used to determine whether weight loss is to be recommended

Background  

Excess body fat is a major risk factor for disease primarily due to its endocrine activity. In recent years several criteria have been introduced to evaluate this factor. Nevertheless, treatment need is currently assessed only on the basis of an individual's Body Mass Index (BMI), calculated as body weight (in kg) divided by height in m². The aim of our study was to determine whether application of the BMI, compared to adiposity-based criteria, results in underestimation of the number of subjects needing lifestyle intervention.     

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     

A self-resonant frequency-modulated micromachined passive pressure transensor

In this paper, we report on the design, fabrication, and test of a passive pressure transensor. The sensor uses the self-resonant frequency modulation of an integrated coil to detect the pressure variations. This modulation is generated by the relative displacement of a ferrite core attached to a silicone rubber membrane. This scheme simplifies the packaging of the passive transensor by removing the requirement for a separate capacitor to form the resonator. A 30-turn 1.7-/spl mu/H coil having dimensions of 3/spl times/3 mm/sup 2/ is used in a prototype design yielding a sensitivity of 9.6 kHz/kPa with a cylindrical ferrite core of 0.95-mm diameter and 0.5-mm height. We also present a theoretical model of the sensor that shows good agreement with the experimental data. This model can be a useful tool for further optimization of the senors.     

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.     

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.