Endothelial Glycocalyx as a Regulator of Fibrotic Processes

The endothelial glycocalyx, the gel layer covering the endothelium, is composed of glycosaminoglycans, proteoglycans, and adsorbed plasma proteins. This structure modulates vessels’ mechanotransduction, vascular permeability, and leukocyte adhesion. Thus, it regulates several physiological and pathological events. In the present review, we described the mechanisms that disturb glycocalyx stability such as reactive oxygen species, matrix metalloproteinases, and heparanase. We then focused our attention on the role of glycocalyx degradation in the induction of profibrotic events and on the possible pharmacological strategies to preserve this delicate structure.     

Investigation of the changes in physical properties of PES/PVC fabrics after aging

The aim of this work was to investigate the physical and mechanical performance of architectural polyester (PES)–poly(vinyl chloride) (PVC) membranes exposed to different artificial aging conditions. Two commercially available architectural membranes were chosen as research objects. The durability of the PES/PVC fabrics was evaluated by the loss in mechanical performance, scanning electron microscopy, and X-ray diffraction analysis in order to understand the effect of the degradation agents on the surface of the membranes. The mechanical performance of the PES/PVC membranes was unchanged. Scanning electron microscopy images of the tested materials showed initial cracks after aging. The X-ray fluorescence analysis showed that at the time of aging, the amount of Cl and Si decreased slightly, while Ti decreased by half, and Ca by volume increased twice. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47523.     

Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action,Pharmacology, Safety,and Efficacy

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.     

Current advances concerning the most cited metal ions doped bioceramics and silicate-based bioactive glasses for bone tissue engineering

Studies related to biomaterials that stimulate the repair of living tissue have increased considerably, improving the quality of many people's lives that require surgery due to traumatic accidents, bone diseases, bone defects, and reconstructions. Among these biomaterials, bioceramics and bioactive glasses (BGs) have proved to be suitable for coating materials, cement, scaffolds, and nanoparticles, once they present good biocompatibility and degradability, able to generate osteoconduction on the surrounding tissue. However, the role of biomaterials in hard tissue engineering is not restricted to a structural replacement or for guiding tissue regeneration. Nowadays, it is expected that biomaterials develop a multifunctional role when implanted, orchestrating the process of tissue regeneration and providing to the body the capacity to heal itself. In this way, the incorporation of specific metal ions in bioceramics and BGs structure, including magnesium, silver, strontium, lithium, copper, iron, zinc, cobalt, and manganese are currently receiving enhanced interest as biomaterials for biomedical applications. When an ion is incorporated into the bioceramic structure, a new category of material is created, which has several unique properties that overcome the disadvantages of primitive material and favors its use in different biomedical applications. The doping can enhance handling properties, angiogenic and osteogenic performance, and antimicrobial activity. Therefore, this review aims to summarize the effect of selected metal ion dopants into bioceramics and silicate-based BGs in bone tissue engineering. Furthermore, new applications for doped bioceramics and BGs are highlighted, including cancer treatment and drug delivery.     

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete’s heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.     

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

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.