The Reprimo-Like Gene Is an Epigenetic-Mediated Tumor Suppressor and a Candidate Biomarker for the Non-Invasive Detection of Gastric Cancer

Reprimo-like (RPRML) is an uncharacterized member of the Reprimo gene family. Here, we evaluated the role of RPRML and whether its regulation by DNA methylation is a potential non-invasive biomarker of gastric cancer. RPRML expression was evaluated by immunohistochemistry in 90 patients with gastric cancer and associated with clinicopathologic characteristics and outcomes. The role of RPRML in cancer biology was investigated in vitro, through RPRML ectopic overexpression. Functional experiments included colony formation, soft agar, MTS, and Ki67 immunofluorescence assays. DNA methylation-mediated silencing was evaluated by the 5-azacytidine assay and direct bisulfite sequencing. Non-invasive detection of circulating methylated RPRML DNA was assessed in 25 gastric cancer cases and 25 age- and sex-balanced cancer-free controls by the MethyLight assay. Downregulation of RPRML protein expression was associated with poor overall survival in advanced gastric cancer. RPRML overexpression significantly inhibited clonogenic capacity, anchorage-independent growth, and proliferation in vitro. Circulating methylated RPRML DNA distinguished patients with gastric cancer from controls with an area under the curve of 0.726. The in vitro overexpression results and the poor patient survival associated with lower RPRML levels suggest that RPRML plays a tumor-suppressive role in the stomach. Circulating methylated RPRML DNA may serve as a biomarker for the non-invasive detection of gastric cancer.     

Intracellular Redox-Modulated Pathways as Targets for Effective Approaches in the Treatment of Viral Infection

Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-kB, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-kB, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.     

Bounds on the effective response for gradient crystal inelasticity based on homogenization and virtual testing

This paper presents the application of variationally consistent selective homogenization applied to a polycrystal with a subscale model of gradient-enhanced crystal inelasticity. Although the full gradient problem is solved on Statistical Volume Elements (SVEs), the resulting macroscale problem has the formal character of a standard local continuum. A semi-dual format of gradient inelasticity is exploited, whereby the unknown global variables are the displacements and the energetic micro-stresses on each slip-system. The corresponding time-discrete variational formulation of the SVE-problem defines a saddle point of an associated incremental potential. Focus is placed on the computation of statistical bounds on the effective energy, based on virtual testing on SVEs and an argument of ergodicity. As it turns out, suitable combinations of Dirichlet and Neumann conditions pertinent to the standard equilibrium and the micro-force balance, respectively, will have to be imposed. Whereas arguments leading to the upper bound are quite straightforward, those leading to the lower bound are significantly more involved; hence, a viable approximation of the lower bound is computed in this paper. Numerical evaluations of the effective strain energy confirm the theoretical predictions. Furthermore, heuristic arguments for the resulting macroscale stress-strain relations are numerically confirmed.     

Poly(propylene)-based Films Modified with a Tetracationic Phthalocyanine with Applications in Photodynamic Inactivation of Candida albicans

Photoactive films based on polymer-like poly(propylene) were generated and utilized as support of zinc(II)tetramethyltetrapyridino[2,3-b:2′,3′-g:2″,3″-l:2″′,3″′-q]porphyrazinium salt (ZnTM2,3PyPz). Using a photograft polymerization of acrylic acid, the poly(propylene) film was functionalized with carboxyl groups (PP-g-PAAc), which attached ZnTM2,3PyPz by electrostatic bond to form PP-g-PAAc-Pc films. In vitro investigations indicated that PP-g-PAAc-Pc films produced photodynamic inactivation of Candida albicans cells, mainly mediated by a contribution of type II process. According to the results, the photodynamic activity produced by the PP-g-PAAc-Pc film and visible light irradiation can successfully inactivate C. albicans deposited on the surface of the films.     

Phase field simulations of ferroelastic toughening: The influence of phase boundaries and domain structures

Limited reliability of ferroelectric-based actuators restricts their use in high-performance applications, where stress-induced cracking of ferroelectric ceramics often leads to fatal failure. The main limiting factors are the relatively small fracture toughness and the brittle nature of ferroelectrics. However, ferroelectrics naturally exhibit fracture toughening (so called ferroelastic toughening) due to stress induced reorientation of non-180° domains that inhibits crack propagation. Here we present a phase-field study of ferroelastic toughening based on Landau–Ginzburg–Devonshire theory. The primary qualitative factors that control the magnitude of ferroelastic toughening are identified and discussed.     

A pattern based, robust approach to cyclic master surgery scheduling

The Master Surgery Scheduling problem consists of finding a suitable allocation of operating resources to surgical groups. A?myriad of variants of the problem has been addressed in literature. Here we focus on two major variants, arising during a cooperation with Sykehuset Asker og B?rum HF, a large hospital in the city of Oslo. The first variant asks for balancing patient queue lengths among different specialties, whereas the second for minimizing resort to overtime. To cope with these problems we introduce a new mixed integer linear formulation and show its beneficial properties. Both problems require the estimation of demand levels. As such estimation is affected by uncertainty, we also develop a light robustness approach to the second variant. Finally we present computational results on a number of real-world instances provided by our reference hospital.     

On the usability of different optical measuring techniques for joint roughness evaluation

Bulletin of Engineering Geology and the Environment - The roughness of rock discontinuities is an important input parameter for mechanical models of rock masses. To reliably calculate roughness...