Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells

Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.     

Heterogeneity of Mismatch Repair Status and Microsatellite Instability between Primary Tumour and Metastasis and Its Implications for Immunotherapy in Colorectal Cancers

Deficient mismatch repair system (dMMR)/microsatellite instability (MSI) is found in about 5% of metastatic colorectal cancers (mCRCs) with a major therapeutic impact for immune checkpoint inhibitor (ICI) use. We conducted a multicentre study including all consecutive patients with a dMMR/MSI mCRC. MSI status was determined using the Pentaplex panel and expression of the four MMR proteins was evaluated by immunohistochemistry (IHC). The primary endpoint was the rate of discordance of dMMR/MSI status between primary tumours and paired metastases. We included 99 patients with a dMMR/MSI primary CRC and 117 paired metastases. Only four discrepancies (3.4%) with a dMMR/MSI primary CRC and a pMMR/MSS metastasis were initially identified and reviewed by expert pathologists and molecular biologists. Two cases were false discrepancies due to human or technical errors. One discordant case could not be confirmed due to the low level of tumour cells. The last case had a confirmed discrepancy with a dMMR/MSI primary CRC and a pMMR/MSS peritoneal metastasis. Our study demonstrated a high concordance rate of dMMR/MSI status between primary CRCs and their metastases. The analysis of one sample, either from the primary tumour or metastasis, with consistent dMMR and MSI status seems to be sufficient prior to treatment with ICI.     

Three-Dimensional Simulation of Porosity in Plasma-Sprayed Alumina Using Microtomography and Electrochemical Impedance Spectrometry for Finite Element Modeling of Properties

Moving from a 2-dimensional to a 3-dimensional (3D) approach to microstructure and properties has been expected eagerly for a long while to result in a dramatic increase in the knowledge of thermally sprayed coatings. To meet these expectations, in the present study, microtomography and electrochemical impedance spectroscopy (EIS) were carried out to simulate the microstructure of plasma-sprayed alumina. As-sprayed and excimer laser-processed deposits were studied. Some unexpected but relevant results, e.g., regarding pore orientation in the coatings, could be obtained. EIS led to the establishment of an equivalent electrical circuit representation of the microstructure which enabled modeling of the insulating properties as a function of interfaces and pore interconnection. The pore interconnection was studied by microtomography. From this 3D simulation, a finite element analysis of Young’s modulus properties was developed and compared to experiments. Using this approach, excimer laser surface processing was shown to be an innovative process to modify insulating characteristics of plasma-sprayed alumina.     

Detection and Modulation of Olfactory Sensing Receptors in Carnivorous Rainbow Trout (Oncorhynchus mykiss) Fed from First Feeding with Plant-Based Diet

Sense of smell is mediated by diverse families of olfactory sensing receptors, conveying important dietary information, fundamental for growth and survival. The aim of this study was to elucidate the role of the sensory olfactory pathways in the regulation of feeding behavior of carnivorous rainbow trout (RT, Oncorhynchus mykiss), from first feeding until 8 months. Compared to a commercial diet, RT fed with a total plant-based diet showed drastically altered growth performance associated with feed intake from an early stage. Exhaustive examination of an RT genome database identified three vomeronasal type 1 receptor-like (ORA), 10 vomeronasal type 2 receptor-like (OLFC) and 14 main olfactory receptor (MOR) genes, all highly expressed in sensory organs, indicating their potential functionality. Gene expression after feeding demonstrated the importance in olfactory sensing perception of some OLFC (olfcg6) and MOR (mor103, -107, -112, -113, -133) receptor family genes in RT. The gene ora1a showed evidence of involvement in olfactory sensing perception for fish fed with a commercial-like diet, while ora5b, mor118, mor124 and olfch1 showed evidence of involvement in fish fed with a plant-based diet. Results indicated an impact of a plant-based diet on the regulation of olfactory sensing pathways as well as influence on monoaminergic neurotransmission in brain areas related to olfactory-driven behaviors. The overall findings suggest that feeding behavior is mediated through olfactory sensing detection and olfactory-driven behavior pathways in RT.     

Effect of sub-micron silica fillers on the mechanical performances of epoxy-based composites

Solid state thermo-mechanical properties, as well as low and large strain mechanical behaviour, of epoxy composites filled with sub-micron pyrogenic silica are discussed in this paper. The reinforcement mechanisms involved are investigated. Two distinct series of pyrogenic silica were used: hydrophilic silica with various specific surface areas and silica grafted with various organo-modifications. Furthermore, two series of networks, having either a high or low crosslink density, and resulting thus either in glassy or rubbery materials at room temperature, were considered. Dynamic mechanical analysis, uniaxial tensile tests and fracture mechanic tests were performed.All our results showed that pyrogenic silica leads to an improvement of network mechanical properties both in the glassy and rubbery states. The simultaneous increase of stiffness and toughness was observed, demonstrating the great potential of pyrogenic silica for the reinforcement of thermosetting systems. This exceptional behaviour has been interpreted in terms of the interactions and morphology developed.     

Influence of Low Fractions of Styrene/Butyl Acrylate Polymer Latexes on Some Properties of Ordinary Portland Cement Mortars

The influence of the chemical structure of styrene/butyl acrylate latexes on some properties of ordinary Portland cement mortars has been investigated for low fractions of polymer with respect to the amount of cement. The structural parameters that were varied included the presence of carboxylic surface charges, the nature of the surfactant system, the molecular weight of the non‐ionic emulsifier, and the particle surface coverage. The first part of the study showed that sterically stabilised latexes remain colloidally and chemically stable for several hours in the cement interstitial medium. Moreover, no interaction could be shown between cement and latex components. Then, for a fraction of about 5wt.‐% of polymer, no significant influence of the presence of the latex was observed on the end‐use properties of the mortars. However, it clearly appears that the use of a fraction of anionic stabiliser is highly detrimental to the paste workability, whereas this latter property is improved by the presence of non‐ionic surfactant due to steric repulsion forces. Finally, the microstructure analysis confirms that the particles are homogenously dispersed in the mineral matrix and that they remain smooth and spherical.

     

Analytical electron microscopy and focused ion beam: complementary tool for the imaging of copper sorption onto iron oxide aggregates

Nanometre‐scale electron spectroscopic imaging has been applied to characterize the operation of a copper filtration plant in environmental science. Copper washed off from roofs and roads is considered to be a major contributor to diffuse copper pollution of urban environments. A special adsorber system has been suggested to control the diffusion of copper fluxes by retaining Cu with a granulated iron hydroxide. The adsorber was tested over an 18‐month period on facade runoff. The concentrations range of Cu in the runoff water was measured between 10 and 1000 p.p.m. and could be reduced by between 96% and 99% in the adsorption ditch. Before the analysis of the adsorber, the suspended material from the inflow was ultracentrifuged onto TEM grids and analysed by energy‐filtered transmission electron microscopy (EFTEM). Copper was found either as small precipitates 5–20 nm in size or adsorbed onto organic and inorganic particles. This Cu represents approximately 30% of the total dissolved Cu, measured by atomic emission spectrometry. To locate where the copper sorption takes place within the adsorber, the granulated iron oxide was analysed by analytical electron microscopy after exposure to the roof run‐off water. A section of the granulated iron hydroxide was prepared by focused ion beam milling. The thickness of the lamina was reduced to 100 nm and analysed by EFTEM. The combination of these two techniques allowed us to observe the diffusion of Cu into the aggregate of Fe. Elemental maps of Fe and Cu revealed that copper was not only present at the surface of the granules but was also sorbed onto the fine particles inside the adsorber.     

Interplay of different NOM fouling mechanisms during ultrafiltration for drinking water production

Ultrafiltration is an emerging technology for drinking water production, but a main challenge remains the lack of understanding about fouling. This paper investigates the impact of molecular interactions between different natural organic matter (NOM) compounds on ultrafiltration fouling mechanisms. We performed dead-end filtration experiments with individual and mixed humic acid and alginate (polysaccharide). Alginate showed detrimental, but mostly reversible, flux decline and high solute retention. Our results indicate that this was caused by pore blocking transformed into cake building and weak molecular foulant-membrane and foulant-foulant interactions. In the presence of calcium, aggravated fouling was observed, related to complexation of alginate and its subsequently induced gel formation. With humic acid, more severe irreversible fouling occurred due to humic acid adsorption. Minor adsorption of alginate onto the membrane was also observed, which probably caused the substantial irreversible flux decline. The fouling characteristics in the mixtures reflected a combination of the individual humic acid and alginate experiments and we conclude, that the individual fouling mechanisms mutually influence each other. A model elucidates this interplay of the individual fouling mechanisms via hydrophobic and electrostatic interactions. In our study such an interplay resulted in an alginate cake, or gel in the presence of calcium, which is relatively irreversibly adsorbed onto the membrane by humic acid associations. This study shows the importance of mutual influences between various foulants for improved understanding of fouling phenomena. Furthermore it shows that substances with a minor individual influence might have a large impact in mixed systems such as natural water.     

Parametric Drug Release Optimization of Anti-Inflammatory Drugs by Gold Nanoparticles for Topically Applied Ocular Therapy

Eye drops represent 90% of all currently used ophthalmic treatments. Only 0.02% of therapeutic molecules contained in eye drops reach the eye anterior chamber despite their high concentration. The tear film efficiently protects the cornea, reducing access to the target. Thereby, the increase in the drug bioavailability and efficiency must come from the mucoadhesion optimization of the drug delivery system. The gold nanoparticles, used as a drug delivery system in this study, already showcased ultrastable and mucoadhesive properties. The goal was to study the gold nanoparticles’ ability to release two specific ophthalmic drugs, flurbiprofen and ketorolac. The parameters of interest were those involving the loading conditions, the gold nanoparticles properties, and the release experimental conditions. The drug release was measured using an in vitro model based on dialysis bags coupled with UV–visible spectroscopy. Gold nanoparticles showed an ability to release different molecules, whether hydrophobic or hydrophilic, in passive or active drug release environments. Based on these preliminary results, gold nanoparticles could represent a promising drug delivery system for ketorolac and flurbiprofen when topically applied through eye drops.