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.     

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.     

Fabrication of composites from different carbon content ferrous powders adopting thermomechanical processes

In this research, deep consolidation technique is utilized for processing of low and high carbon content ferrous powders to manufacture composite material. High carbon content ferrous powders were used as reinforcing material. The powder particles were allowed to mix with low carbon content ferrous powders in 50:50 weight percent for fabrication of composites. The composites were heat treated at three different temperatures (i.e., 800°C, 900°C, and 1000°C). The changes in microstructure, microhardness, the grain size, and bonding among powder particles were studied. Refinement of grains was observed and this led to improved hardness enabling the processed material to be used as a suitable composite. Abrasive wear tests were carried out using a laboratory tribometer in dry reciprocating sliding contact against Sic abrasive paper. The outcomes demonstrate that the abrasive wear resistance was notably affected by the treatment temperature and hardness of the composites.     

Giovan Battista Della Porta's construction of pneumatic phenomena and his use of recipes as heuristic tools

In this paper, I suggest that research results from the history and philosophy of modern science provide a valuable methodological contribution for investigating early modern experimental philosophy and employ them to reassess the contribution of Giovan Battista Della Porta to its development. In modern science, the production of experimental knowledge is dependent on a complex array of communication strategies involving verbal terminology, diagrams, standardized instruments, and measurement units. Historians and philosophers have investigated the constitutive connection between such strategies and the phenomena scientists study in laboratories, showing how the two often co-evolved during the 19th and 20th centuries. Della Porta took an important first step towards the development of such methods by transforming the traditional recipe format into a strategy for mutually connecting, conceptualizing, and sharing observations made in experiments involving similar, but not identical, instruments and procedures. I use as a case study the changing manner in which he used recipes for presenting and connecting a number of pneumatic experiences from the first edition of Natural Magic (1558) until his meteorology treatise On Transmutations of Air (1610). In modern terms, those experiences can be interpreted as demonstrating the air's expansion and contraction with heat or pressure. However, today's notions of air pressure, density, and volume did not exist around 1600 and the verbal, visual, and quantitative means of expressing them had yet to be created. Della Porta did not create the modern notions, but he contributed to their emergence in a substantial way with his discussions of those pneumatic experiences. Della Porta's innovation may be described as the creation of a new epistemic genre, but it was not of a purely literary character, since the recipes also shaped the instruments and procedures they described, transforming them into new means of knowledge production in experimental philosophy.     

A Phenylacetamide Resveratrol Derivative Exerts Inhibitory Effects on Breast Cancer Cell Growth

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.     

Indoor air quality and the associated health risk in primary school buildings in Central Europe – The InAirQ study

The indoor air quality (IAQ) was investigated in sixty-four primary school buildings in five Central European countries (Czech Republic, Hungary, Italy, Poland, and Slovenia). The concentration of volatile organic compounds, aldehydes, PM_2.5 mass, carbon dioxide, radon, as well as physical parameters were investigated during the heating period of 2017/2018. Significant differences were identified for the majority of the investigated IAQ parameters across the countries. The median indoor/outdoor ratios varied considerably. A comprehensive evaluation of IAQ in terms of potential health effects and comfort perception was performed. Hazard quotient values were below the threshold value of 1 with one exception. In contrast, 31% of the school buildings were characterized by hazard index values higher than 1. The maximum cumulative ratio approach highlighted that the concern for non-carcinogenic health effects was either low or the health risk was driven by more substances. The median excess lifetime cancer risk values exceeded the acceptable value of 1 × 10⁻⁶ in the case of radon and formaldehyde. PM_2.5 mass concentration values exceeded the 24 h and annual guideline values set by the World Health Organization in 56 and 85% of the cases, respectively. About 80% of the schools could not manage to comply with the recommended concentration value for carbon dioxide (1000 ppm).     

Computer Simulations Then and Now: an Introduction and Historical Reassessment

NTM Zeitschrift für Geschichte der Wissenschaften, Technik und Medizin -     

Carbon nanotubes play an important role in the spatial arrangement of calcium deposits in hydrogels for bone regeneration

Age related bone diseases such as osteoporosis are considered among the main causes of reduced bone mechanical stability and bone fractures. In order to restore both biological and mechanical function of diseased/fractured bones, novel bioactive scaffolds that mimic the bone structure are constantly under development in tissue engineering applications. Among the possible candidates, chitosan-based thermosensitive hydrogel scaffolds represent ideal systems due to their biocompatibility, biodegradability, enhanced antibacterial properties, promotion of osteoblast formation and ease of injection, which makes them suitable for less invasive surgical procedures. As a main drawback, these chitosan systems present poor mechanical performance that could not support load-bearing applications. In order to produce more mechanically-competent biomaterials, the combined addition of hydroxyapatite and carbon nanotubes (CNTs) is proposed in this study. Specifically, the aim of this work is to develop thermosensitive chitosan hydrogels containing stabilised single-walled and multi-walled CNTs, where their effect on the mechanical/physiochemical properties, calcium deposition patterns and ability to provide a platform for the controlled release of protein drugs was investigated. It was found that the addition of CNTs had a significant effect on the sol–gel transition time and significantly increased the resistance to compression for the hydrogels. Moreover, in vitro calcification studies revealed that CNTs played a major role in the spatial arrangements of newly formed calcium deposits in the composite materials studied, suggesting that they may have a role in the way the repair of fragile and/or fractured bones occurs in vivo.