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.     

Role of Extracellular Vesicles in Epithelial Ovarian Cancer: A Systematic Review

Extracellular vesicles (EVs) are a heterogeneous group of cell-derived submicron vesicles released under physiological or pathological conditions. EVs mediate the cellular crosstalk, thus contributing to defining the tumor microenvironment, including in epithelial ovarian cancer (EOC). The available literature investigating the role of EVs in EOC has been reviewed following PRISMA guidelines, focusing on the role of EVs in early disease diagnosis, metastatic spread, and the development of chemoresistance in EOC. Data were identified from searches of Medline, Current Contents, PubMed, and from references in relevant articles from 2010 to 1 April 2020. The research yielded 194 results. Of these, a total of 36 papers, 9 reviews, and 27 original types of research were retained and analyzed. The literature findings demonstrate that a panel of EV-derived circulating miRNAs may be useful for early diagnosis of EOC. Furthermore, it appears clear that EVs are involved in mediating two crucial processes for metastatic and chemoresistance development: the epithelial–mesenchymal transition, and tumor escape from the immune system response. Further studies, more focused on in vivo evidence, are urgently needed to clarify the role of EV assessment in the clinical management of EOC patients.     

A “Golden Age” for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system

Leishmaniasis is one of the most neglected diseases worldwide and is considered a serious public health issue. The current therapeutic options have several disadvantages that make the search for new therapeutics urgent. Gold compounds are emerging as promising candidates based on encouraging in vitro and limited in vivo results for several Au^I and Au^III complexes. The antiparasitic mechanisms of these molecules remain only partially understood. However, a few studies have proposed the trypanothione redox system as a target, similar to the mammalian thioredoxin system, pointed out as the main target for several gold compounds with significant antitumor activity. In this review, we present the current status of the investigation and design of gold compounds directed at treating leishmaniasis. In addition, we explore potential targets in Leishmania parasites beyond the trypanothione system, taking into account previous studies and structure modulation performed for gold-based compounds.     

The properties of electroactive ruthenium oxide coatings supported by titanium-based ternary carbides

Electroactive oxide coatings on titanium, known in industrial chlorine production as dimensionally stable anodes (DSA), are of limited service life owing to the dissolution of active oxide, but also due to low corrosion stability of titanium, at high anodic potentials and elevated temperatures. In order to improve the anode stability, ternary carbide, Ti₃SiC₂, could be a promising material for the coating support, since chemical corrosion stability of Ti₃SiC₂ is significantly higher if compared to Ti. In this work, the possibility of the sol-gel preparation of RuO₂-TiO₂ coating on Ti₃SiC₂ is investigated and comparison of the basic characteristics of sol-gel processed oxide coating, Ru_0.5Ti_0.5O₂, applied onto Ti₃SiC₂ and Ti, is reported. Microscopic investigation of the coating surface showed that considerably less cracked coating is formed onto the Ti₃SiC₂ support. Slightly higher voltammetric currents are registered for Ti₃SiC₂-supported coating in H₂SO₄ and NaCl solution. The activity for chlorine evolution is higher, while the currents of oxygen evolution reaction are lower for Ru_0.5Ti_0.5O₂/Ti₃SiC₂ anode in comparison to Ru_0.5Ti_0.5O₂/Ti anode. Even though these preliminary results on the basic electrochemical properties of Ru_0.5Ti_0.5O₂/Ti₃SiC₂ anode and chemical stability of Ti₃SiC₂ are promising, the accelerated stability test in NaCl solution showed that coated Ti₃SiC₂ is not anodically stable and lasts considerably shorter than Ru_0.5Ti_0.5O₂/Ti anode prepared and tested under the same conditions.     

A low-cost real time virtual system for postural stability assessment at home

Background and objective

The degeneration of the balance control system in the elderly and in many pathologies requires measuring the equilibrium conditions very often. In clinical practice, equilibrium control is commonly evaluated by using a force platform (stabilometric platform) in a clinical environment.In this paper, we demonstrate how a simple movement analysis system, based on a 3D video camera and a 3D real time model reconstruction of the human body, can be used to collect information usually recorded by a physical stabilometric platform.

Methods

The algorithm used to reconstruct the human body model as a set of spheres is described and discussed. Moreover, experimental measurements and comparisons with data collected by a physical stabilometric platform are also reported. The measurements were collected on a set of 6 healthy subjects to whom a change in equilibrium condition was stimulated by performing an equilibrium task.

Results

The experimental results showed that more than 95% of data collected by the proposed method were not significantly different from those collected by the classic platform, thus confirming the usefulness of the proposed system.

Conclusions

The proposed virtual balance assessment system can be implemented at low cost (about 500$) and, for this reason, can be considered a home use medical device. On the contrary, astabilometric platform has a cost of about 10,000$ and requires periodical calibration. The proposed system does not require periodical calibration, as is necessary for stabilometric force platforms, and it is easy to use. In future, the proposed system with little integration can be used, besides being an emulator of a stabilometric platform, also to recognize and track, in real time, head, legs, arms and trunk, that is to collect information actually obtained by sophisticated optoelectronic systems.     

Bond calibration method for Young’s modulus determination in the discrete element method framework

A new methodology for the calibration of bond microparameters in rocks represented by a package of joined random spherical particles in the discrete element method (DEM) framework is presented. Typically, calibration is achieved through a trial-and-error procedure using several DEM simulations of uniaxial compressive tests (UCTs). The bond calibration model (BCM) does not need a time-dependent UCT-DEM simulation to establish the relation between the microproperties of the bond and the macroproperties of the rock specimen. The BCM uses matrices to describe the interaction forces exerted by bonds and, by means of an assembly process similar to the finite element method, it can describe the complex network of bonds, enabling the model to capture small variations in particle size and bond distribution as demonstrated in this work. In this work, the BCM is presented and compared with UCT simulations performed using Esys Particle software. Multiple simulations are done with constant bond properties and different particle size ratios (\(D_{MAX}/D_{MIN})\) that cause small variations in the specimen’s Young’s modulus; these variations are well captured by the BCM with an error of <10%.     

Biocompatible nano-gallium/hydroxyapatite nanocomposite with antimicrobial activity

Intensive research in the area of medical nanotechnology, especially to cope with the bacterial resistance against conventional antibiotics, has shown strong antimicrobial action of metallic and metal-oxide nanomaterials towards a wide variety of bacteria. However, the important remaining problem is that nanomaterials with highest antibacterial activity generally express also a high level of cytotoxicity for mammalian cells. Here we present gallium nanoparticles as a new solution to this problem. We developed a nanocomposite from bioactive hydroxyapatite nanorods (84?wt %) and antibacterial nanospheres of elemental gallium (16?wt %) with mode diameter of 22?±?11?nm. In direct comparison, such nanocomposite with gallium nanoparticles exhibited better antibacterial properties against Pseudomonas aeruginosa and lower in-vitro cytotoxicity for human lung fibroblasts IMR-90 and mouse fibroblasts L929 (efficient antibacterial action and low toxicity from 0.1 to 1?g/L) than the nanocomposite of hydroxyapatite and silver nanoparticles (efficient antibacterial action and low toxicity from 0.2 to 0.25?g/L). This is the first report of a biomaterial composite with gallium nanoparticles. The observed strong antibacterial properties and low cytotoxicity make the investigated material promising for the prevention of implantation–induced infections that are frequently caused by P. aeruginosa.     

Polymorphic bytecode instrumentation

Bytecode instrumentation is a widely used technique to implement aspect weaving and dynamic analyses in virtual machines such as the Java virtual machine. Aspect weavers and other instrumentations are usually developed independently and combining them often requires significant engineering effort, if at all possible. In this article, we present polymorphic bytecode instrumentation(PBI), a simple but effective technique that allows dynamic dispatch amongst several, possibly independent instrumentations. PBI enables complete bytecode coverage, that is, any method with a bytecode representation can be instrumented. We illustrate further benefits of PBI with three case studies. First, we describe how PBI can be used to implement a comprehensive profiler of inter‐procedural and intra‐procedural control flow. Second, we provide an implementation of execution levels for AspectJ, which avoids infinite regression and unwanted interference between aspects. Third, we present a framework for adaptive dynamic analysis, where the analysis to be performed can be changed at runtime by the user. We assess the overhead introduced by PBI and provide thorough performance evaluations of PBI in all three case studies. We show that pure Java profilers like JP2 can, thanks to PBI, produce accurate execution profiles by covering all code, including the core Java libraries. We then demonstrate that PBI‐based execution levels are much faster than control flow pointcuts to avoid interference between aspects and that their efficient integration in a practical aspect language is possible. Finally, we report that PBI enables adaptive dynamic analysis tools that are more reactive to user inputs than existing tools that rely on dynamic aspect‐oriented programming with runtime weaving. These experiments position PBI as a widely applicable and practical approach for combining bytecode instrumentations. © 2015 The Authors. Software: Practice and Experience Published by John Wiley & Sons Ltd.     

Development of an auxiliary system for the execution of vascular catheter interventions with a reduced radiological risk; system description and first experimental results

Vascular catheterization is a common procedure in clinical medicine. It is normally performed by a specialist using an X-ray fluoroscopic guide and contrast-media. In the present paper, an image-guided navigation system which indicates a path providing guidance to the desired target inside the vascular tree is described with the aim of reducing the exposure of personnel and patients to X-rays during the catheterization procedure. A 3D model of the patient vascular tree, reconstructed with data collected by an angiography before starting the intervention, is used as a guide map instead of fluoroscopic scans. An accurate spatial correspondence between the body of the patient and the 3D reconstructed vascular model is established and, by means of a position indicator installed over the catheter tip, the real-time position/orientation of the tip is indicated correctly. This paper describes the system and the operational procedures necessary to use the proposed method efficiently during a catheter intervention. Preliminary experimental results on a phantom are also reported.