Encapsulation of a small-molecule drug based on substituted 2-aminothiophenes in calcium carbonate carriers for therapy of melanoma.

Although small molecule drugs are widely used in chemotherapy, their low bioavailability, low-concentrated dose in the tumor zone, systemic toxicity, and chemoresistance can significantly limit the therapeutic outcome. These drawbacks can be overcome by two main strategies: (i) development of novel therapeutic molecules with more significant antitumor activity than currently available drugs and (ii) loading chemotherapeutic agents into drug delivery systems. In this study, we aimed to encapsulate a highly prospective small molecule drug based on substituted 2-aminothiophene (2-AT) into calcium carbonate (CaCO3) microparticles (MPs) for the treatment of melanoma tumors. In particular, we have optimized the encapsulation of 2-AT into MPs (2-AT@MPs), studied drug release efficiency, investigated cellular uptake, and evaluated in vivo biodistribution and tumor inhibition efficiency. In vitro results revealed that 2-AT@MPs were able to penetrate into tumor spheroids, leading to prolonged release of 2-AT. By performing intratumoral injection of 2-AT@MPs we observed significant melanoma suppressions in murine models: ∼0.084 cm3 for 2-AT@MPs at a dose of 0.4 g kg-1versus ∼1.370 cm3 for untreated mice. In addition, the 2-AT@MPs showed negligible in vivo toxicity towards major organs such as heart, lung, liver, kidney, and spleen. Thus, this work provided an efficient strategy for the improved chemotherapy of solid tumors by using an encapsulated form of small molecule drugs.

Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies.

A new efficient and versatile one-pot three-component synthesis of substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives has been developed. It is based on a multistep cascade reaction from 2-aminothiophenes and 2-hydroxy-4-oxobut-2-enoic acids, and derivatives of cyanoacetic acid catalyzed by diisopropylethylamine. As a result, novel pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives (21 compounds) were synthesized in a mild reaction conditions with a high yield. The structures of the developed compounds were confirmed by NMR and elemental analysis. The influence of electron-withdrawing or electron-donor substituents on the antitumor activity of the developed compounds has been identified. In vitro screening analysis of 21 compounds revealed six lead candidates (12aa, 12dc, 12hc, 12ic, 12lb, and 12mb) that demonstrated the most significant antitumor activity against B16-F10, 4T1 and CT26 cells. Necrosis/apoptosis assay showed that apoptosis was the predominant mechanism of cell death. Molecular docking analysis revealed several potential targets for tested compounds, i.e. phosphatidylinositol 5-phosphate 4-kinase (PI5P4K2C), proto-oncogene serine/threonine-protein kinase (Pim-1), nicotinamide phosphoribosyltransferase (NAMPT) and dihydrofolate reductase (DHFR). The lead compound (12aa) can effectively induce cell apoptosis, possesses a high yield (98 %) and requires low-cost starting chemicals for its synthesis. In vivo experiments with melanoma-bearing mice confirmed that 12aa compound resulted in the significant tumor inhibition on 15 d after the therapy. In particular, tumor volume was ∼0.19 cm3 for 50 mg/kg versus ∼2.39 cm3 in case of untreated mice and tumor weight was ∼71.6 mg for 50 mg/kg versus ∼452.4 mg when considered untreated mice. Thus, our results demonstrated the high potential of the 12aa compound in the treatment of melanoma and can be recommended for further preclinical studies.

The Kinetic Study of the Influence of Common Modifiers on the Curing Process of Epoxy Vitrimers.

An analysis of the influence of common modifiers on the kinetics of the curing process of epoxy-anhydride vitrimers was carried out. As common modifiers to enhance the "vitrimeric" nature of the material, zinc acetylacetonate as a transesterification catalyst and glycerol as a modifier of hydroxyl group content were chosen. The curing process of all obtained compositions was studied by differential scanning calorimetry (DSC) followed by the application of the isoconversional approach. It was shown that additives significantly affect the curing process. The resulting cured polymers were shown to be chemically recyclable by dissolution in the mixture of ethylene glycol and N-methylpirrolidone in a volume ratio of nine to one. The introduction of both zinc acethylacetonate and glycerol to the neat formulation led to a decrease in the dissolution time by 85.7% (from 35 h for the neat epoxy-anhydride formulation to 5 h for the modified formulation). In order to show the opportunity of the secondary use of recyclates, the mixtures based on the basic composition containing 10 wt. % of secondary polymers were also studied. The introduction of a recycled material to neat composition led to the same curing behavior as glycerol-containing systems.

Self-Lubricating and Shape-Stable Phase-Change Materials Based on Epoxy Resin and Vegetable Oils.

Palm or coconut oil is capable of dissolving in a mixture of bisphenol A-based epoxy resin and a high-temperature hardener (4,4'-diaminodiphenyl sulfone) when heated and then forms a dispersed phase as a result of cross-linking and molecular weight growth of the epoxy medium. Achieving the temporary miscibility between the curing epoxy matrix and the vegetable oil allows a uniform distribution of vegetable oil droplets in the epoxy medium. This novel approach to creating a dispersed phase-change material made a cured epoxy polymer containing up to 20% oil. The miscibility of epoxy resin and oil was studied by laser interferometry, and phase state diagrams of binary mixtures were calculated according to theory and experiments. A weak effect of oil on the viscosity and kinetics of the epoxy resin curing was demonstrated by rotational rheometry. According to differential scanning calorimetry and dynamic mechanical analysis, the oil plasticizes the epoxy matrix slightly, expanding its glass transition region towards low temperatures and reducing its elastic modulus. In the cured epoxy matrix, oil droplets have a diameter of 3-14 µm and are incapable of complete crystallization due to their multi-component chemical composition and non-disappeared limited miscibility. The obtained phase-change materials have relatively low specific energy capacity but can be used alternatively as self-lubricating low-noise materials due to dispersed oil, high stiffness, and reduced friction coefficient. Palm oil crystallizes more readily, better matching the creation of phase-change materials, whereas coconut oil crystallization is more suppressed, making it better for reducing the friction coefficient of the oil-containing material.

Epoxy Phase-Change Materials Based on Paraffin Wax Stabilized by Asphaltenes.

The usual problem of meltable phase-change agents is the instability in their form upon heating, which can be solved by placing them into a continuous polymer matrix. Epoxy resin is a suitable medium for dispersing molten agents, but it is necessary to make the obtained droplets stable during the curing of the formed phase-change material. This work shows that molten paraffin wax forms a Pickering emulsion in an epoxy medium and in the presence of asphaltenes extracted from heavy crude oil. Theoretical calculations revealed the complex equilibrium in the epoxy/wax/asphaltene triple system due to their low mutual solubility. Rheological studies showed the viscoplastic behavior of the obtained dispersions at 25 °C, which disappears upon the heating and melting of the paraffin phase. Wax and asphaltenes increased the viscosity of the epoxy medium during its curing but did not inhibit cross-linking or reduce the glass transition temperature of the cured polymer. As a result of curing, it is possible to obtain phase-change materials containing up to 45% paraffin wax that forms a dispersed phase with a size of 0.2-6.5 µm. The small size of dispersed wax can decrease its degree of crystallinity to 13-29% of its original value, reducing the efficiency of the phase-change material.

Synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives and their precursors containing 2-aminothiophenes fragments as anticancer agents for therapy of pulmonary metastatic melanoma.

The design and synthesis of new promising compounds based on thienopyrimidine scaffold containing 2-aminothiophene fragments with good safety and favorable drug-like properties are highly relevant for chemotherapy. In this study, a series of 14 variants of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives (11aa-oa) and their precursors (31 compounds) containing 2-aminothiophenes fragments (9aa-mb, 10aa-oa) were synthesized and screened for their cytotoxicity against B16-F10 melanoma cells. The selectivity of the developed compounds was assessed by determining the cytotoxicity using normal mouse embryonic fibroblasts (MEF NF2 cells). The lead compounds 9cb, 10ic and 11jc with the most significant antitumor activity and minimum cytotoxicity on normal non-cancerous cells were chosen for further in vivo experiments. Additional in vitro experiments with compounds 9cb, 10ic and 11jc showed that apoptosis was the predominant mechanism of death in B16-F10 melanoma cells. With support from in vivo studies, compounds 9cb, 10ic and 11jc demonstrated the biosafety to healthy mice and significant inhibition of the metastatic nodules in pulmonary metastatic melanoma mouse model. Histological analysis detected no abnormal changes in the main organs (the liver, spleen, kidneys, and heart) after the therapy. Thus, the developed compounds 9cb, 10ic and 11jc demonstrate high efficiency in the treatment of pulmonary metastatic melanoma and can be recommended for further preclinical investigation of the melanoma treatment.

The fungal literature-based occurrence database for southern West Siberia (Russia).

BACKGROUND: The paper presents the initiative on literature-based occurrence data mobilisation of fungi and fungi-related organisms (literature-based occurrences, Darwin Core MaterialCitation) to develop the Fungal literature-based occurrence database for the southern West Siberia (FuSWS). The initiative on mobilisation of literature-based occurrence data started in the northern part of West Siberia in 2016. The present project extends the initiative to the southern regions and includes ten administrative territories (Tyumen Region, Sverdlovsk Region, Chelyabinsk Region, Omsk Region, Kurgan Region, Tomsk Region, Novosibirsk Region, Kemerovo Region, Altai Territory and Republic of Altai). The area occupies the central to southern part of the West Siberian Plain and extends for about 1.5 K km from the west to the east from the eastern slopes of the Ural Mountains to Yenisey River and from north to south-about 1.3 K km. The total area equals about 1.4 million km2.The initiative is actively growing in spatial, collaboration and data accumulation terms. The working group of about 30 mycologists from eight organisations dedicated to the data mobilisation was created as part of the Siberian Mycological Society (informal organisation since 2019). They have compiled the almost complete bibliographic list of mycology-related papers for the southern West Siberia, including over 900 publications for the last two centuries (the earliest dated 1800). All literature sources were digitised and an online library was created to integrate bibliography metadata and digitised papers using Zotero bibliography manager. The analysis of published sources showed that about two-thirds of works contain occurrences of fungi for the scope of mobilisation.At the time of the paper submission, the database had been populated with a total of about 8 K records from 93 sources. The dataset is uploaded to GBIF, where it is available for online search of species occurrences and/or download. The project's page with the introduction, templates, bibliography list, video-presentations and written instructions is available (in Russian) at the web site of the Siberian Mycological Society. The initiative will be continued in the following years to extract the records from all published sources. NEW INFORMATION: The paper presents the first project with the aim of literature-based occurrence data mobilisation of fungi and fungi-related organisms in the southern West Siberia. The full bibliography and a digital library of all regional mycological publications created for the first time includes about 900 published works. By the time of paper submission, nearly 8 K occurrence records were extracted from about 90 literature sources and integrated into the FuSWS database published in GBIF.

The Influence of Substituents in Phosphazene Catalyst-Flame Retardant on the Thermochemistry of Benzoxazine Curing.

This work is devoted to the influence of phosphazene modifiers with different substituents on the curing process, thermal properties and flammability of benzoxazine resin. Novel catalysts with m-toluidine substituents were introduced. The catalytic activity of studied phosphazene compounds decreased in the row: hexachlorocyclotriphosphazene (HCP) > tetra m-toluidine substituted phosphazene PN-mt (4) > hexa m-toluidine substituted phosphazene PN-mt (6) > hexaphenoxycyclotriphosphazene (HPP), where HPP is totally inactive. Two types of catalysis: basic and acid were proposed. A brief study of resulting properties of polybenzoxazines was presented. The addition of any studied modifier caused the decrease of glass transition temperature and thermal stability of polymers. The morphology of cured compositions was characterized by matrix-dispersion phase structure. All phosphazene containing polybenzoxazines demonstrated the improved flame resistance.

Isothermal Kinetics of Epoxyphosphazene Cure.

The influence of epoxycyclophosphazene modifier on the process of epoxy-amine curing was studied by differential scanning calorimetry (DSC). The study revealed that the curing process of epoxyphosphazene binders with 4'4'diaminodiphenylsulfone (DDS) provides more complete curing of the formulations in comparison with ones applying low molecular-weight polyamide curing agent (L-20). The isothermal kinetics of curing was described by means of model fitting and the isoconversional approach (Friedman method). Accurate n-order approximation was obtained for all systems under study. In particular, the 2-order equation fits well with the main part of curing excluding high degrees of conversion. The process of curing could be distinguished into three zones. The transition from zone 2 to zone 3 correlates with gelation. According to the isoconversional analysis by Friedman method, the diffusion-controlled mechanism is found at final stage of curing.

Synthesis and Application of Arylaminophosphazene as a Flame Retardant and Catalyst for the Polymerization of Benzoxazines.

A novel type of phosphazene containing an additive that acts both as a catalyst and as a flame retardant for benzoxazine binders is presented in this study. The synthesis of a derivative of hexachlorocyclotriphosphazene (HCP) and meta-toluidine was carried out in the medium of the latter, which made it possible to achieve the complete substitution of chlorine atoms in the initial HCP. Thermal and flammability characteristics of modified compositions were investigated. The modifier catalyzes the process of curing and shifts the beginning of reaction from 222.0 °C for pure benzoxazine to 205.9 °C for composition with 10 phr of modifier. The additive decreases the glass transition temperature of compositions. Achievement of the highest category of flame resistance (V-0 in accordance with UL-94) is ensured both by increasing the content of phenyl residues in the composition and by the synergistic effect of phosphorus and nitrogen. A brief study of the curing kinetics disclosed the complex nature of the reaction. An accurate two-step model is obtained using the extended Prout-Tompkins equation for both steps.

The Curing Rheokinetics of Epoxyphosphazene Binders.

The influence of epoxyphosphazene-modifying additives on the features of the hot curing process of epoxy-amine composition was studied by the rotational viscometry method. The modification caused an acceleration of the curing process, changed rheokinetics of viscosity increase, especially the stage molecular mass growth of linear chains became almost twice shorter for composition with 30% modifier than for unmodified one. We suggest the reason for these changes is the polyfunctionality of epoxyphosphazene, which finally results in high-density network formation. In cold curing process the bulkiness of epoxyphosphazene molecule and the lack of heat for its motion results in incomplete cure. Thus, in order to cope with these difficulties hot curing systems were proposed and studied.

Quality of evidence in a post-Soviet country: evaluation of methodological quality of controlled clinical trials published in national journals from Uzbekistan.

BACKGROUND: Most researchers in Uzbekistan prefer to publish their reports in journals of their home country. Moreover, the proportion of healthcare practitioners who prefer to use these national sources of information also remains high. However, the quality of publications from national journals, in post-Soviet countries, has not been systematically evaluated until now. The primary objective of this study was to evaluate the quality of randomized controlled trials' (RCTs) reports published in medical journals from Uzbekistan. We supposed that reports had at least minimal quality to contribute to the higher quality of healthcare. METHODS: To evaluate the quality of RCTs, we selected two journals from the list of national medical journals for which background information was provided. We decided to select articles from journals that had the highest subscription rate and were likely to have the highest impact on clinical decisions. The journals were Medical Journal of Uzbekistan and Paediatrics. Only issues published in 2007-2017 were considered for evaluation. Two evaluators independently scored RCTs and controlled clinical trials (CCTs) reported in the journals. The 5-point scale developed by Jadad et al. was used to evaluate the quality of reports. Consensus-based decision was made about the final score of each report. RESULTS: We reviewed 1311 studies in the two journals and found 380 clinical trials reports for the final evaluation. Our main finding was that none of the reports received a final score of more than 1, with an absolute agreement between evaluators. A median score of the studied reports was equal to 0, predicting a very low quality of controlled trials reported in the national journals (Wilcoxon signed-rank test p = 1.0; 95% CI = 0-0). CONCLUSIONS: We believe that quality of reports about controlled trials, in Uzbekistan, can be considered insufficient to contribute to the higher quality of care and patients' safety. In the worst case, such condition can cause serious damage to the public health and lead to ineffective use of resources in the country. Therefore, the better reporting and organization of RCTs and CCTs should become a main goal of all stakeholders interested in the effective and safe healthcare in the country.

Synthesis of Phosphazene-Containing, Bisphenol A-Based Benzoxazines and Properties of Corresponding Polybenzoxazines.

With the aim of obtaining halogen-free polybenzoxazazines with reduced flammability, phosphazene-containing benzoxazines (PhBZ) were synthesized in a two-stage method. In the first stage of the reaction of hexachlorocycotriphosphazene with bisphenol A at molar ratios of 1:12, 1:16, and 1:24, respectively, mixtures of bisphenol and hydroxyaryloxycyclotriphosphazenes were obtained, which mainly contained P3N3[OC6H4C(CH3)3C6H4OH]6. In the second stage, when these mixtures interacted with aniline and an excess of paraformaldehyde in toluene at 80-90 °C, PhBZ containing 20-50% of the phosphazene component with Mw 1200-5800 were formed. According to 1H and 13C NMR spectroscopy, PhBZ contain a small amount of oligomeric compounds with Mannich aminomethylene bridges. With an increase of the content of the phosphazene component, the curing temperature of PhBZ decreases from 242 °C to 215 °C. Cured PhBZ samples with a phosphorus content of more than 1.5% have increased flammability resistance according to UL-94.

Preparation and Structural Characterization of Complex Oxide Eutectic Precursors from Polymer-Salt Xerogels Obtained by Microwave-Assisted Drying.

Sol-gel synthesis is an acknowledged method for obtaining fine inorganic powders of a different nature. Implementation of water-soluble polymers as gel-forming media makes this technique even more readily available, especially in cases where conventional gel formation is suppressed. In polymer-salt solutions, polymers serve as scaffolds for salt constituents' bulk crystallization. When dried, solid salt particles are deposited on the polymer surface or in polymer matrix pores, which leads to higher grain size uniformity. The present work discusses the effect of drying conditions on phase composition and structure characteristics of complex oxide eutectics in ternary systems, CaO-Al2O3-Y2O3 (CAY) and MgO-Al2O3-Y2O3 (MAY), obtained from polymer-salt compositions based on polyvinyl alcohol (PVA), Na-salt of carboxymethylcellulose (Na-CMC) or polyvinylpyrrolidone (PVP). Microwave-assisted drying proved to be more efficient compared to convective process; however such technique requires careful selection of gel-forming polymer.

The impact of neighborhood to industrial areas on health in Uzbekistan: an ecological analysis of congenital diseases, infant mortality, and lung cancer.

After political sovereignty, Uzbekistan's industry is growing fast. However, no investigation was performed so far, to evaluate whether an environmental risk, associated with the industry, is also increasing. Our aim was to investigate whether the distance from factories, as a surrogate measurement for environmental exposure to community, has any influence on some health outcomes in communities of Uzbekistan. For this first investigation, we analyzed prevalence of congenital diseases, infant mortality, and incidence rates of lung cancer, as examples for diseases associated with environmental factors. As crude measurement for the association, we used correlation and regression analysis with the distance to the next factory or plant as explanatory variable. A regression analysis demonstrated an association between the three outcome variables, with the strongest negative correlation (r = - 0.48) and the highest determination power (r2 = 0.23) for congenital diseases' prevalence. For infant mortality and lung cancer incidence, descriptions and analyses demonstrated lower negative correlation of them with the distance and a lower predictive power of linear models. So, closer distance of the community to specific industrial plants can be considered an indirect factor of higher prevalence of congenital diseases in those communities. Prospective research is needed to further investigate whether the association between birth defects in a neighborhood of industrial plants is causal or due to confounding factors. A policy should consider a degree of known factors distribution in an environment and perform effective prevention of congenital diseases, in close communities.

Psiloboletinus is an independent genus sister to Suillus.

The genus Psiloboletinus was proposed by Rolf Singer in 1945 based on Phylloporus lariceti, a species that associates with Larix in the Altai Mountains of central and eastern Asia. However, this classification has been controversial due to the morphological similarity to known genera Boletinus and Fuscoboletinus. Because of the lack of fresh material to study, the phylogenetic position of Psiloboletinus has remained unknown since its publication. However, the recently described species Suillus foetidus reported from northeast China allows this issue to be reexamined and resolved. Through morphological observations and comparison, we find that S. foetidus is a heterotypic synonym of Ps. lariceti. Furthermore, Psiloboletinus should be retained as an independent genus sister to Suillus based on molecular phylogenetic evidence and morphological features.