Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution

The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients’ prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones’ survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host’s immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.     

Biological Implications of a Stroke Therapy Based in Neuroglobin Hyaluronate Nanoparticles. Neuroprotective Role and Molecular Bases

Exogenous neuroprotective protein neuroglobin (Ngb) cannot cross the blood–brain barrier. To overcome this difficulty, we synthesized hyaluronate nanoparticles (NPs), able to deliver Ngb into the brain in an animal model of stroke (MCAO). These NPs effectively reached neurons, and were microscopically identified after 24 h of reperfusion. Compared to MCAO non-treated animals, those treated with Ngb-NPs showed survival rates up to 50% higher, and better neurological scores. Tissue damage improved with the treatment, but no changes in the infarct volume or in the oxidative/nitrosative values were detected. A proteomics approach (p-value < 0.02; fold change = 0.05) in the infarcted areas showed a total of 219 proteins that significantly changed their expression after stroke and treatment with Ngb-NPs. Of special interest, are proteins such as FBXO7 and NTRK2, which were downexpressed in stroke, but overexpressed after treatment with Ngb-NPs; and ATX2L, which was overexpressed only under the effect of Ngb. Interestingly, the proteins affected by the treatment with Ngb were involved in mitochondrial function and cell death, endocytosis, protein metabolism, cytoskeletal remodeling, or synaptic function, and in regenerative processes, such as dendritogenesis, neuritogenesis, or sinaptogenesis. Consequently, our pharmaceutical preparation may open new therapeutic scopes for stroke and possibly for other neurodegenerative pathologies.     

Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl⁻ currents and intracellular Ca²⁺ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca²⁺ activated Cl⁻ channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca²⁺ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.     

Methylene blue adsorption by chemically activated waste pork bones

Bone is an inorganic template containing organic material inside which can be converted into hydroxyapatite‐rich material by pyrolysis. Nowadays, there is a growing research interest in the use of hydroxyapatite, the chemical formula of which is Ca₁₀(PO₄)₆(OH)₂. In the present work, pork bone, an abundant biomass source and food waste, has been converted into structured porous hydroxyapatite by a three‐step process including precharring under mild conditions, chemical activation, and thermal activation. The investigated activating agents were NaOH, KOH, K₂CO₃, H₂SO₄, and H₃PO₄. A thorough investigation of the influence of different activating protocols on the chemical and textural properties of the produced material was carried out by nitrogen adsorption–desorption at 77 K, potentiometric titrations, Fourier transform infrared, and X‐ray diffraction techniques. Chemical activation with NaOH, K₂CO₃, and H₂SO₄ increased the specific surface area up to 53%. H₃PO₄ reduced both surface area and pore volume, and KOH showed little influence on the pore structure. The produced materials were evaluated by methylene blue adsorption tests and showed significant improvement as a result of chemical activation. As a main effect, acid treatment increased methylene blue adsorption kinetics, probably owing to an increase in micropororosity, whereas alkali activation enhanced the adsorption capacity of the resultant biochar.     

How to Attain Ultralow Interfacial Tension and Three-Phase Behavior with Surfactant Formulation for Enhanced Oil Recovery: A Review. Part 4: Robustness of the Optimum Formulation Zone Through the Insensibility to Some Variables and the Occurrence of Complex Artifacts

In enhanced oil recovery, not only the low-tension performance, but also the robustness at optimum formulation is an important issue. The fourth part of our review series is dedicated to robustness, defined as the width of the zone exhibiting three-phase behavior around the optimum formulation, whatever the scanned variable. It is first corroborated from a screening of the available data in the literature that the tension minimum is inversely proportional to the square of the three-phase range in the HLD scale. However, since there is still an inaccuracy of about a factor 10 in the tension minimum, some significant improvement can be attained in some cases by increasing the three-phase behavior width in two ways. The first approach consists of finding systems that are insensitive to some formulation variable such as temperature, surfactant mixture composition or concentration, and water-to-oil ratio. The second way is to produce an artifact through which the optimum formulation is produced twice in a scan. If the distance between the two events in the scan is reduced down to be zero, their corresponding three-phase behavior zones merge and result in a wider WIII region with a low tension. Several cases of such events are reported: alkaline scans, anionic-nonionic and anionic-cationic mixture changes, linear change in composition in three-surfactant mixture, partial precipitation from a surfactant mixture in a salinity scan, and excessive partitioning of polyethoxylated nonionics. More complex transitions with three effects in a single scan or three concomitantly scanned variables show even more possibilities in practice.     

Effect of a novel soy fermented product enriched with isoflavones and calcium on bone tissue of rats

The objective was to evaluate the effect of soy fermented product intake on the corporal weight and bone tissue of ovariectomized mature rats. This product was fermented with Enterococcus faecium and Lactobacillus jugurti and enriched with isoflavones and calcium. The animals were divided in 5 groups: sham-ovariectomized; ovariectomized; ovariectomized treated with soy fermented product enriched with isoflavones and calcium; ovariectomized treated with soy fermented product enriched with calcium and ovariectomized treated with non-fermented product enriched only with calcium. In order to evaluate the effect of the tested product on bone tissue (femur and tibia), the following parameters were analyzed: length; mechanical assay of three points; density (Archimedes principle); mineral content; calcium content; measure of the trabecular widths. The corporal weight of group treated with soy fermented product containing isoflavones and calcium showed no statistical difference from sham-ovariectomized group and trabecular widths tended to have larger than ovariectomized group. However, there was no significant difference to the other evaluated parameters in result of the diverse treatments. Thus, soy fermented product enriched with isoflavones and calcium inhibited the increasing of corporal weight caused by ovariectomy and revealed a tendency to trabecular protection after castration.     

Active nano-CuPt3 electrocatalyst supported on graphene for enhancing reactions at the cathode in all-vanadium redox flow batteries

Graphene-supported monometallic (Pt) and bimetallic (CuPt₃) cubic nanocatalysts have been investigated as new positive electrode materials for improving the VO₂⁺/VO²⁺ redox process occurring in the vanadium redox flow batteries (VRB). High-resolution transmission electron microscopy (HRTEM) and scanning electron microscopy (SEM) have been employed to characterize the electrodes. The presence of the CuPt₃ nanocubes on graphene conferred higher electrocatalytic activity due to the much higher electroactive area compared to that obtained with the Pt nanoparticles. The electrochemical surface area of the nano-(CuPt₃)-decorated graphene electrode was 105% higher compared to non-decorated graphene, being then a promising alternative for improving the VRB.     

Multi‐element characterisation of carob,fig and almond liqueurs by MP‐AES

Carob pod, fig and almond liqueurs are produced in various Mediterranean regions. This work reports the mineral content of these traditional beverages and evaluates the influence of the raw material. Twenty‐five fruit liqueurs from 16 producers were analysed. A simple open‐vessel sample mineralization by wet digestion using nitric acid–hydrogen peroxide (1:1) was used before spectrometric analysis. Nine essential elements (Cu, Ca, Mg, Na, K, Fe, Zn, Mn and P) and two non‐essentials (Cd and Pb) were quantified by microwave plasma–atomic emission spectrometry (MP‐AES). Carob liqueur presented the broader profile of minerals and was the only fruit liqueur containing iron (72.7% of samples), phosphorous, manganese and low levels of lead (in two of the 11 samples). Conversely, almond liqueurs contained the lowest mineral content with only five elements detected. Fruit liqueurs showed variability in mineral content even within the same liqueur, presumably as a consequence of the different manufacturing processes. Despite this variability, application of principal component analysis to essential mineral concentrations (K, Na, Ca, Mg, Mn, Fe and Zn) resulted in satisfactory classification (PC1 and PC2 accounting for 78.5% of the total variance) of the Portuguese liqueurs evaluated. Copyright © 2018 The Institute of Brewing & Distilling