Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo

Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib’s potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib’s drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations.     

Cornet‐Like Phosphotriazine/Diamine Polymers as Reductant and Matrix for the Synthesis of Silver Nanocomposites with Antimicrobial Activity

The synthesis of silver nanoparticles attached on the surface of a hollow cornet‐like polymer matrix which served as a reductant and host matrix is described. This hybrid organic/inorganic macromolecular matrix is exhibiting anion‐exchange properties, porous structure and hollow morphologies, and absorptions in the visible light region. Due to the anion‐exchange property and the 3D orientation of the macromolecular chains the material is defining a new functional organic/inorganic hybrid. For the synthesis of nanoparticles, no other reducing agents were used and silver nanoparticles with a mean diameter of less than 20 nm were attached on the surface of the polymer, thus inheriting the composite with high antibacterial activity tested in bacterial strains and yeasts.

     

Systemic Inflammation and the Breakdown of Intestinal Homeostasis Are Key Events in Chronic Spinal Cord Injury Patients

Our aim was to investigate the subset distribution and function of circulating monocytes, proinflammatory cytokine levels, gut barrier damage, and bacterial translocation in chronic spinal cord injury (SCI) patients. Thus, 56 SCI patients and 28 healthy donors were studied. The levels of circulating CD14^+highCD16⁻, CD14^+highCD16⁺, and CD14^+lowCD16⁺ monocytes, membrane TLR2, TLR4, and TLR9, phagocytic activity, ROS generation, and intracytoplasmic TNF-α, IL-1, IL-6, and IL-10 after lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. Serum TNF-α, IL-1, IL-6 and IL-10 levels were measured by Luminex and LPS-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP) and zonulin by ELISA. SCI patients had normal monocyte counts and subset distribution. CD14^+highCD16⁻ and CD14^+highCD16⁺ monocytes exhibited decreased TLR4, normal TLR2 and increased TLR9 expression. CD14^+highCD16⁻ monocytes had increased LPS-induced TNF-α but normal IL-1, IL-6, and IL-10 production. Monocytes exhibited defective phagocytosis but normal ROS production. Patients had enhanced serum TNF-α and IL-6 levels, normal IL-1 and IL-10 levels, and increased circulating LBP, I-FABP, and zonulin levels. Chronic SCI patients displayed impaired circulating monocyte function. These patients exhibited a systemic proinflammatory state characterized by enhanced serum TNF-α and IL-6 levels. These patients also had increased bacterial translocation and gut barrier damage.     

Interlayer bonding between thermoplastic composites and metals by in-situ polymerization technique

Fiber-metal laminates (FMLs) offer the superior characteristics of polymer composites (i.e., light weight, high strength and stiffness) with the ductility and fracture strength of metals. The bond strength between the two dissimilar materials, composite and metal, dictates the properties and performance of the FMLs. The bonding becomes more critical when the polymer matrix is thermoplastic and hydrophobic in nature. This work employed a novel bonding technique between thermoplastic composites and a metal layer using six different combinations of organic coatings. The flexural, and interlaminar shear strength of the thermoplastic fiber metal laminates (TP-FMLs) were examined to investigate the bond strengths in the different cases along with fracture characteristics revealed from the tested samples using scanning electron microscopy. The viscoelastic performance of the fabricated TP-FMLs were also investigated using the dynamic mechanical thermal analysis method.     

The Neglected Water Rebound Effect of Income and Employment Growth

Water Resources Management - The water footprint assessment, particularly for the agricultural sector, is often a valuable input to water policy formation globally. Efforts on reducing it focus on...     

Simulating Future Groundwater Recharge in Coastal and Inland Catchments

Groundwater is a primary source of drinking water in the Mediterranean, however, climate variability in conjunction with mismanagement renders it vulnerable to depletion. Spatiotemporal studies of groundwater recharge are the basis to develop strategies against this phenomenon. In this study, groundwater recharge was spatiotemporally quantified using the Soil and Water Assessment Tool (SWAT) in one coastal and one inland hydrological basin in Greece. A double calibration/validation (CV) procedure using streamflow data and MODIS ET was conducted for the inland basin of Mouriki, whereas only ET values were used in the coastal basin of Anthemountas. Calibration and simulation recharge were accurate in both sites according to statistical indicators and previous studies. In Mouriki basin, mean recharge and runoff were estimated as 16% and 9%, respectively. In Anthemountas basin recharge to the shallow aquifer and surface runoff were estimated as 12% and 16%, respectively. According to the predicted RCP 4.5 and 8.5 scenarios, significant variations in groundwater recharge are predicted in the coastal zone for the period 2020–2040 with average annual recharges decreasing by 30% (RCP 4.5) and 25% (RCP 8.5). Variations in groundwater recharge in the inland catchment of Mouriki were insignificant for the simulated period. Anthemountas basin was characterized by higher runoff rates. Groundwater management in coastal aquifers should include detailed monitoring of hydrological parameters, reinforced groundwater recharge during winter and reduced groundwater abstraction during summer depending on the spatiotemporal distribution of groundwater recharge.

     

Antioxidant capacity and phenolic compounds in commercially grown native Australian herbs and spices

The antioxidant capacities and phenolic composition in six native, commercially grown, Australian herbs and spices were investigated. Tasmannia pepper leaf, followed by anise myrtle and lemon myrtle contained the highest levels of total phenolics (TP; 102.1; 55.9 and 31.4 mg gallic acid equivalents (GAE)/g dry weight (DW), respectively). Tasmannia pepper leaf exhibited the highest oxygen radical absorbance capacity (ORAC assay) followed by lemon myrtle and anise myrtle. Anise myrtle exhibited the highest total reducing capacity [TRC; Ferric Reducing Antioxidant Power (FRAP) assay], followed by Tasmannia pepper leaf and lemon myrtle. Australian bush tomato, with TP content of 12.4 ± 0.9 mg GAE/gDW and TRC of 206.2 μMol Fe⁺²/gDW, resembled the Chinese Barbary Wolfberry fruit. The TP content of Tasmannia pepper berry (16.86 mg GAE/gDW) was similar to that of black pepper, but it’s TRC was 25% lower. Cinnamic acids and flavonoids, tentatively identified by mass spectrometry, were identified as the main sources of antioxidant activities.     

Turbulent Sprays Evaporating Under “Stabilized Cool Flame” Conditions: Assessment of two CFD Approaches

An “in-house” computational fluid dynamics code implementing a Euler-Lagrange approach is extended by incorporating the Euler-Euler (two-fluid model) approach, to improve prediction capabilities of flow and thermal characteristics of turbulent evaporating sprays. The performance of both approaches is assessed by comparing predictions with experimental data for a variety of evaporating-spray test cases. The applicability of the Euler-Lagrange and Euler-Euler approach is established in an isopropyl alcohol–air turbulent flow, in which characteristic droplet quantity predictions are in satisfactory overall agreement with measurements. The evaporating spray characteristics are then predicted under “stabilized cool flame” conditions and the computational results are compared to experimental data for a nonreactive case and a reactive case. In both cases, the velocity and thermal fields are successfully captured by both approaches. Overall, the article demonstrates an approach toward the development of performance-based computational tools.     

Moisture sorption isotherms and isosteric heat of sorption of leaves and stems of lemon balm (Melissa officinalis L.) established by dynamic vapor sorption

The equilibrium moisture contents (MC) of leaves and stems of lemon balm (Melissa officinalis L.) were determined separately at temperatures of 25, 35 and 45 °C over a stepwise increase of relative humidity (RH) ranging from 3 to 90% by an automatic, gravimetric analyzer (DVS system). Equilibrium was achieved within 6 h for most of the target values of relative humidity. The equilibrium moisture content of leaves was significantly higher than that of stems (p < 0.05). Differences in moisture sorption capacity between the leaves and stems can be attributed to chemical composition and structure of the tissues. Five three-parameter moisture sorption models (modifications of Chung–Pfost, GAB, Halsey, Henderson and Oswin) were tested for their effectiveness to fit the experimental sorption data. The modified Oswin equation was found to be the best model to describe the adsorption isotherms of both leaves and stems of lemon balm. The recommended MC values of leaves and stems for microbial safe storage at 25 °C were 0.124 and 0.113 kg water per kg dry solids, respectively. The net isosteric heat of sorption was computed from the predicted sorption data by applying the integrated form of the Clausius–Clapeyron equation.     

Inhibitory effect of organic acid salts on spoilage flora in culture medium and cured cooked meat products under commercial manufacturing conditions

Lactobacillus curvatus, isolated from a spoiled vacuum-packaged 'pariza' type meat product, was used to inoculate modified MRS broth containing sodium lactate, sodium acetate and potassium sorbate in different concentrations, alone or in inter se combinations. Two commercial preparations (MIX 1 and MIX 2) were also used containing combinations of the above antimicrobials. Results from the preservatives addition to the culture medium showed highest antimicrobial activity in the case of the sodium lactate (2%, 3% or 4%), sodium acetate (0.5%) and potassium sorbate (0.15%) combination. Results from the preservatives addition to two types of thermally processed meats showed that sodium lactate and the combination of sodium lactate, sodium acetate and potassium sorbate were the most effective; extending the products shelf life an additional 10 days. Finally, MIX 1 and MIX 2 suppressed the lactic acid bacteria (LAB) growth in the culture medium but not in the final product.