Renal Amyloidosis

Modern amyloid nomenclature, based on the amyloid fibril proteins, includes 31 types of amyloidosis. Renal involvement is commonly seen in AA, AL, and several other hereditary and acquired amyloidoses. AA amyloidosis, constituting up to 45% of all systemic amyloidosis cases, is associated with wide variety of chronic inflammatory conditions. The precursor protein of the fibrils in AA amyloidosis is an apolipoprotein, called serum amyloid A, and produced in the liver in response to proinflammatory cytokines. AL amyloidosis is actually known to be the most common form of systemic amyloidosis in the Western countries. In this type of amyloidosis the precursor proteins are monoclonal immunoglobulin light chains, produced by plasma cell clone. Clinical diagnosis of AA and AL systemic amyloidosis is based on the presence of proteinuria or nephrotic syndrome and impaired kidney function in patients with extrarenal manifestations. Kidney biopsy is crucial for the diagnostics, and while Congo red staining with examination of Congo-positive material in the polarized light is confirmative for amyloidosis as such, immune staining, helpful to distinguish AA and AL types, guides treatment strategies. In cases when neither AA nor AL amyloidosis are confirmed, one should consider rare types of amyloidosis—ALECT2, AapolA, AFib or ALys

Sustainable plastics derived from renewable resources

In this century, the major use of synthetic polymers have been as replacements for more traditional materials, particulary in packaging. Today the packaging industry is by far the major user of plastics. Another interesting application of these materials is drug delivery systems. Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage and tunable release of both hydrophilic and hydrophobic drugs. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. Aliphatic polyesters such as poly(L-lactic acid), poly(butylene succinate), and polyhydroxyalkanoates among others, constitute primary examples of bio-based polymers that distinguish by being fully renewable and displaying partial or total biodegradability. This Ph.D. Thesis is devoted to the synthesis of aliphatic random and block polyesters from renewable resources with application for packaging and drug delivery. The main goal of this project is to develop new bio-based polymers with similar or even improved properties compared to those of conventional plastics obtained from non-renewable sources. The two cyclic acetals, 2,3-di-O-methylene-L-threitol and dimethyl 2,3-di-O-methylene-L-threarate, were used for the synthesis of two series of PBS copolyesters differing in which unit, butylene or succinate, was replaced, in addition of the corresponding parent homopolyesters. 2,4:3,5-di-O-methylene-D-glucitol was used for the synthesis of PBS copolyesters by melt polycondensation. Three series of polyalkanoates (adipates, suberates and sebacates) were synthesized using as monomers three sugar-based bicyclic diols derived from D-glucose and D-mannose. ABA triblock copolyesters were synthesized by ROP of L-lactide in solution initiated by telechelic D-glucose- and L-tartaric-based polyester macroinitiators. The synthesized polyesters were characterized by nuclear magnetic resonance (NMR) spectroscopy, gel permeation chromatography (GPC) and viscosimetry. Thermal properties were analyzed by differential scanning calorimetry (DCS) and thermogravimetry (TGA). Crystalline structure of polyesters was studied by X-ray and its mechanical properties were evaluated as well. Hydrolytic degradation and biodegradation assays were followed by GPC and NMR. Nanoparticles made from triblock copolyesters were characterized by scanning electron microscopy (SEM) and dynamic light-scattering (DLS).En este siglo, el mayor empleo que se les ha dado a los polímeros sintéticos ha sido como sustitutos de materiales más tradicionales, en particular, materiales para envase y embalaje. Hoy en día la industria de envasado es, por mucho, la mayor consumidora de plásticos. Otra aplicación interesante de estos materiales son los sistemas de administración de fármacos. Los polímeros han jugado un papel fundamental la tecnología de administración de fármacos al proporcionar un medio de liberación controlada de agentes terapéuticos en dosis constantes durante largos periodos; la dosificación cíclica y la liberación sintonizable de fármacos hidrofílicos e hidrofóbicos. Actualmente, los avances modernos en la administración de fármacos se basan en el diseño racional de polímeros para la liberación de dosis controladas que modifican distintas funciones biológicas de forma específica. Los poliésteres alifáticos tales como el poli(ácido L-láctico), el poli(succinato de butileno) y los polihidroxialcanoatos, entre otros, constituyen ejemplos primarios de polímeros de base biológica que se distinguen por ser completamente renovables y presentar biodegradabilidad parcial o total. Este trabajo de doctorado está dedicado a la síntesis de poliésteres alifáticos al azar y de bloques a partir de recursos renovables con aplicación para el envasado y la administración de fármacos. El objetivo principal de este proyecto es desarrollar nuevos polímeros biológicos con propiedades similares o incluso mejores en comparación a los plásticos convencionales obtenidos a partir de fuentes norenovables. Los dos acetales cíclicos, 2,3-di-O-metileno-L-treitol y dimetil 2,3-di-O-metileno-L-trearato, se usaron para la síntesis de dos series de copoliésteres de PBS que difieren en qué unidad, butileno o succinato, se reemplazó, además de los homopoliésteres originales correspondientes. Se usó 2,4:3,5-di-O-metileno-D-glucitol para la síntesis de copoliésteres de PBS mediante policondensación en estado fundido. Se sintetizaron tres series de polialcanoatos (adipatos, suberatos y sebacatos) usando como monómeros tres dioles bicíclicos base azúcar derivados de D-glucosa y D-manosa. Los copoliésteres tribloques ABA se sintetizaron mediante ROP de L-láctido en solución iniciada por macroiniciadores de poliester telequelico basados en D-glucosa y L-tartárico. Los poliésteres sintetizados se caracterizaron por espectroscopia de resonancia magnética nuclear (RMN), cromatografía de permeación en gel (GPC) y viscosimetría. Las propiedades térmicas se analizaron mediante calorimetría de barrido diferencial (DCS) y termogravimetría (TGA). La estructura cristalina de los poliésteres se estudió mediante rayos X y sus propiedades mecánicas también se evaluaron. La degradación hidrolítica y los ensayos de biodegradación fueron seguidos por GPC y NMR. Las nanopartículas hechas de copoliésteres tribloque se caracterizaron por microscopía electrónica de barrido (SEM) y dispersión de luz dinámica (DLS)

Sustainable plastics derived from renewable resources

In this century, the major use of synthetic polymers have been as replacements for more traditional materials, particulary in packaging. Today the packaging industry is by far the major user of plastics. Another interesting application of these materials is drug delivery systems. Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage and tunable release of both hydrophilic and hydrophobic drugs. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. Aliphatic polyesters such as poly(L-lactic acid), poly(butylene succinate), and polyhydroxyalkanoates among others, constitute primary examples of bio-based polymers that distinguish by being fully renewable and displaying partial or total biodegradability. This Ph.D. Thesis is devoted to the synthesis of aliphatic random and block polyesters from renewable resources with application for packaging and drug delivery. The main goal of this project is to develop new bio-based polymers with similar or even improved properties compared to those of conventional plastics obtained from non-renewable sources. The two cyclic acetals, 2,3-di-O-methylene-L-threitol and dimethyl 2,3-di-O-methylene-L-threarate, were used for the synthesis of two series of PBS copolyesters differing in which unit, butylene or succinate, was replaced, in addition of the corresponding parent homopolyesters. 2,4:3,5-di-O-methylene-D-glucitol was used for the synthesis of PBS copolyesters by melt polycondensation. Three series of polyalkanoates (adipates, suberates and sebacates) were synthesized using as monomers three sugar-based bicyclic diols derived from D-glucose and D-mannose. ABA triblock copolyesters were synthesized by ROP of L-lactide in solution initiated by telechelic D-glucose- and L-tartaric-based polyester macroinitiators. The synthesized polyesters were characterized by nuclear magnetic resonance (NMR) spectroscopy, gel permeation chromatography (GPC) and viscosimetry. Thermal properties were analyzed by differential scanning calorimetry (DCS) and thermogravimetry (TGA). Crystalline structure of polyesters was studied by X-ray and its mechanical properties were evaluated as well. Hydrolytic degradation and biodegradation assays were followed by GPC and NMR. Nanoparticles made from triblock copolyesters were characterized by scanning electron microscopy (SEM) and dynamic light-scattering (DLS).En este siglo, el mayor empleo que se les ha dado a los polímeros sintéticos ha sido como sustitutos de materiales más tradicionales, en particular, materiales para envase y embalaje. Hoy en día la industria de envasado es, por mucho, la mayor consumidora de plásticos. Otra aplicación interesante de estos materiales son los sistemas de administración de fármacos. Los polímeros han jugado un papel fundamental la tecnología de administración de fármacos al proporcionar un medio de liberación controlada de agentes terapéuticos en dosis constantes durante largos periodos; la dosificación cíclica y la liberación sintonizable de fármacos hidrofílicos e hidrofóbicos. Actualmente, los avances modernos en la administración de fármacos se basan en el diseño racional de polímeros para la liberación de dosis controladas que modifican distintas funciones biológicas de forma específica. Los poliésteres alifáticos tales como el poli(ácido L-láctico), el poli(succinato de butileno) y los polihidroxialcanoatos, entre otros, constituyen ejemplos primarios de polímeros de base biológica que se distinguen por ser completamente renovables y presentar biodegradabilidad parcial o total. Este trabajo de doctorado está dedicado a la síntesis de poliésteres alifáticos al azar y de bloques a partir de recursos renovables con aplicación para el envasado y la administración de fármacos. El objetivo principal de este proyecto es desarrollar nuevos polímeros biológicos con propiedades similares o incluso mejores en comparación a los plásticos convencionales obtenidos a partir de fuentes norenovables. Los dos acetales cíclicos, 2,3-di-O-metileno-L-treitol y dimetil 2,3-di-O-metileno-L-trearato, se usaron para la síntesis de dos series de copoliésteres de PBS que difieren en qué unidad, butileno o succinato, se reemplazó, además de los homopoliésteres originales correspondientes. Se usó 2,4:3,5-di-O-metileno-D-glucitol para la síntesis de copoliésteres de PBS mediante policondensación en estado fundido. Se sintetizaron tres series de polialcanoatos (adipatos, suberatos y sebacatos) usando como monómeros tres dioles bicíclicos base azúcar derivados de D-glucosa y D-manosa. Los copoliésteres tribloques ABA se sintetizaron mediante ROP de L-láctido en solución iniciada por macroiniciadores de poliester telequelico basados en D-glucosa y L-tartárico. Los poliésteres sintetizados se caracterizaron por espectroscopia de resonancia magnética nuclear (RMN), cromatografía de permeación en gel (GPC) y viscosimetría. Las propiedades térmicas se analizaron mediante calorimetría de barrido diferencial (DCS) y termogravimetría (TGA). La estructura cristalina de los poliésteres se estudió mediante rayos X y sus propiedades mecánicas también se evaluaron. La degradación hidrolítica y los ensayos de biodegradación fueron seguidos por GPC y NMR. Las nanopartículas hechas de copoliésteres tribloque se caracterizaron por microscopía electrónica de barrido (SEM) y dispersión de luz dinámica (DLS).Postprint (published version

Peptides and Peptide Dendrimers as Drug Delivery and Anticancer Agents

Peptides are compounds, that are involved in a wide range of biological applications. Use of peptides in cancer therapy can become an alternative strategy to conventional chemotherapy, which is often complicated by increased resistance and detrimental side effects. In the beginning of this thesis, a general introduction gives short overview of current problems of cancer treatment (Chapter 1). The experimental work is divided into two parts. In the first part, we investigated peptides and peptide dendrimers as possible delivery vectors for chemotherapy drugs such as doxorubicin and 1,2-diaminocyclohexane-Platinum(II) (Chapters 2 and 3). We designed suitable drug delivery strategies and assessed the anticancer activity of conjugates. In the second part, we aimed to develop different peptidic molecules, which can directly act as anticancer agents. By using machine learning approaches, we generated linear, non-hemolytic anticancer peptides (Chapter 4). Further biological evaluations revealed membranolytic and mitochondria targeting properties of selected anticancer peptides. In the Chapter 5 we reported for the first time anticancer properties of peptide dendrimers and presented our attempts to build peptide dendrimers with so-called “isopeptide bonds”

Poly(butylene succinate) copolyesters containing cyclic acetalized tartrate units

Utilization of carbohydrate derivatives for polymer synthesis has been paid much attention not only because of the huge abundance of resources but also because of the promising biodegradability and biocompatibility of the polymers obtained from them. Of the different natural resources, carbohydrates stand out as highly convenient raw materials because they are inexpensive, readily available, and provide great functional diversity. Poly(butylene succinate) (PBS) and its copolymers are a family of biodegradable polymers with excellent biodegradability, thermoplastic processability and balanced mechanical properties. In this work, copolyesters of PBS were synthesized by taking different feed molar ratio of 2,3-di-O-methylene-L-threitol to 1,4-butanediol with dimethyl succinate, and 2,3-di-O-methylene dimethyl tartrate to dimethyl succinate with 1,4-butanediol. Chemical characterization of copolymers was carried out by NMR, FT-IR, viscosimetry and GPC. The number average molecular weights (Mn) of the polymers were found to vary in the range of 615 × 103 g∙mol-1. The physical properties of PBS materials varied in a wide range depending on their composition. The thermal behavior and the mechanical properties of these polyesters were evaluated and compared with PBS. The PBS copolyesters showed higher glass transition (Tg) and low melt temperatures (Tm) as compared to the parent polyester. Tg varies from -37 to 13 °C depending on the feed ratio of the comonomers. Regarding the mechanical properties, the introduction of cyclic acetal groups caused an increase in the elongation at break of the polyesters, and produced a reduction in the elastic modulus and tensile strength at the same time

Aperfeiçoamento de Abordagens para o Recrutamento de Pessoal na Indústria Hoteleira

The purpose of the article is to develop a recommendation system for hospitality enterprises using non-traditional forms of recruitment. The dynamism of changes in the environment is found to necessitate the use of innovative approaches based on the real needs and opportunities of modern hospitality industry enterprises. It is confirmed that the effectiveness of personnel recruitment depends on the mastery of up-to-date methods. It is established that implementing the totality of the proposed modern human resource management technologies will contribute to increased personnel productivity and efficiency of hotel enterprises. The introduction and implementation of innovative technologies of personnel management are found to bring changes to other resource areas – in the nature of the hotel product, in the way relationships with the key customers are constructed, and in the economy of the hotel enterprise as a whole in a digitalized environment.El objetivo del artículo es desarrollar un sistema de recomendación para empresas de hostelería que utilicen formas de contratación no tradicionales. Se considera que el dinamismo de los cambios en el entorno requiere el uso de enfoques innovadores basados en las necesidades y oportunidades reales de las empresas modernas de la industria hotelera. Se confirma que la eficacia de la contratación de personal depende del dominio de los métodos actualizados. Se establece que la implementación de la totalidad de las tecnologías modernas de gestión de recursos humanos propuestas contribuirá a aumentar la productividad del personal y la eficiencia de las empresas hoteleras. Se encuentra que la introducción e implementación de tecnologías innovadoras de gestión de personal trae cambios a otras áreas de recursos: en la naturaleza del producto hotelero, en la forma en que se construyen las relaciones con los clientes clave y en la economía de la empresa hotelera en su conjunto. en un entorno digitalizado.O objetivo do artigo é desenvolver um sistema de recomendação para empresas de hospitalidade usando formas não tradicionais de recrutamento. O dinamismo das mudanças no ambiente exige o uso de abordagens inovadoras baseadas nas reais necessidades e oportunidades das empresas modernas da indústria hoteleira. Confirma-se que a eficácia do recrutamento de pessoal depende do domínio de métodos atualizados. Fica estabelecido que a implementação da totalidade das modernas tecnologias de gestão de recursos humanos propostas contribuirá para o aumento da produtividade do pessoal e da eficiência das empresas hoteleiras. A introdução e implementação de tecnologias inovadoras de gestão de pessoal trazem mudanças para outras áreas de recursos – na natureza do produto hoteleiro, na forma como os relacionamentos com os principais clientes são construídos e na economia da empresa hoteleira como um todo em um ambiente digitalizado

Triblock copolyesters derived from lactic acid and glucose: synthesis, nanoparticle formation and simulation

ABA triblock copolyesters were synthesized by ring-opening polymerization (ROP) of l-lactide in solution initiated by a telechelic d-glucose-based polyester macroinitiator. The macroinitiator with a number-average molecular weight about 2500 g mol-1 was synthesized by non-stoichiometric polycondensation in the melt of 2,4:3,5-di-O-methylene-d-glucitol and dimethyl succinate. Two triblock copolyesters of Mn ranging between ~6000 and ~9000 g mol-1, and differing in the length of the polylactide blocks were prepared. These copolyesters started to decompose when heated at ~220 °C and degraded slowly upon aqueous incubation under physiological conditions. They did not display any perceivable crystallinity and showed a single glass transition temperature (Tg) around 60 °C with the higher value corresponding to the larger content in glucitol units. The copolyesters were able to form nanoparticles with average diameters of ~100–130 nm and satisfactory dispersity. The effect of the block lengths on size, ¿-potential values and physical stability of the nanoparticles was evaluated. A molecular dynamics simulation study allowed modelling the two-phase structure of the nanoparticles and evidenced the preference of the glucose-based block to be peripherally located.Peer ReviewedPostprint (author's final draft

Sugar-based bicyclic monomers for aliphatic polyesters: a comparative appraisal of acetalized alditols and isosorbide

Three series of polyalkanoates (adipates, suberates and sebacates) were synthesized using as monomers three sugar-based bicyclic diols derived from D-glucose (Glux-diol and isosorbide) and D-mannose (Manx-diol). Polycondensations were conducted in the melt applying similar reaction conditions for all cases. The aim was to compare the three bicyclic diols regarding their suitability to render aliphatic polyesters with enhanced thermal and mechanical properties. The ensuing polyesters had molecular weights (Mw) in the 25,000–50,000 g mol-1 range with highest values being attained for Glux-diol. All the polyesters started to decompose above 300 °C and most of them did not display perceivable crystallinity. On the contrary, they had glass transition temperatures much higher than usually found in homologous polyesters made of alkanediols, and showed a stress– strain behavior consistent with their Tg values. Glux-diol was particularly effective in increasing the Tg and to render therefore polyesters with high elastic modulus and considerable mechanical strength.Peer ReviewedPostprint (published version

Forecasting risk of bankruptcy for machine-building plants

The paper presents an overview of well-known bankruptcy risk forecasting models, elaborated as by Russian so by foreign authors, on the basis of the data about financial and business activities of the biggest machine-building Russian plants. The authors substantiate and confirm appropriateness of a fuzzy set model to the problem of bankruptcy risk forecasting. This model is worked out on the basis of 10 most important factors, which have the greatest influence on sales proceeds as the main financial source for a production plant