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Herein, we present the synthesis of three new neutral aryl-BIAN ZnCl2 complexes (where aryl-BIAN = bis(aryl-imino)acenaphthene) with formulations [Zn(4-iPrC6H4-BIAN)Cl2] (1), [Zn(2-iPrC6H4-BIAN)Cl2] (2) and [Zn(4-NO2C6H4-BIAN)Cl2] (3) obtained through a green synthesis methodology. Compounds 1 and 2 were fully characterized by elemental analysis, ESI-LS mass spectrometry, FT-IR ATR mode, and multinuclear NMR spectroscopic techniques. Compound 3 was characterized by elemental analysis, ESI-LS mass spectrometry and FT-IR, ATR mode. The solid-state molecular structures of compounds 1 and 2 were determined by single crystal X-ray diffraction. The new complexes 1, 2 and 3, and the known complexes of formulations [Zn(2,6-iPr2C6H3-BIAN)Cl2] (4) and [Zn(2,4,6-Me3C6H2-BIAN)Cl2] (5) were tested as catalysts in the cycloaddition reaction of CO2 and epoxides using the tetrabutylammonium bromide salt as a co-catalyst. Primary studies revealed that complex 4 presented the highest catalytic activity among all synthetized complexes. Good reaction TOFs were obtained for the conversion of propylene oxide (112 h−1) after 3 hours and for the conversion of styrene oxide (23 h−1) after 8 hours, at 4 MPa and 333 K. For more sterically hindered cyclohexene oxide, no cyclic carbonate formation was observed, under the same operational conditions. Furthermore, the effect of reaction time (1–40 h), pressure (0.5–40 MPa) and nucleophile to metal ratio (0.5–100) on final cyclic carbonate formation was investigated. [ABSTRACT FROM AUTHOR]

Accurate measurement and prediction of the phase behaviour of mixtures involved in a chemical process are crucial for its optimisation. Given the importance of CO 2 conversion technologies and considering possible benefits of CO 2 -ionic liquid biphasic systems, i.e., facilitating a product separation, we investigated the high-pressure behaviour of components of interest in a recently developed process of cyclic carbonate synthesis directly from CO 2 and potentially bio-based alcohols. The solubility of 1,2-butanediol and 1,2-butylene carbonate in a dense carbon dioxide phase was determined experimentally at the temperature of 313.2 K and pressures between 6 and 18 MPa. The influence of 1-hexyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ionic liquid, [hmim][FAP], as a solvent, on the solubility of these compounds in CO 2 -rich phase, in ternary (CO 2 + 1,2-butanediol + [hmim][FAP]), CO 2 + butylene carbonate + [hmim][FAP]) and quaternary (CO 2 + 1,2-butanediol + butylene carbonate + [hmim][FAP]) mixtures was investigated. The experimental results of the two binary systems were correlated using the density-based Chrastil equation. The knowledge of phase equilibria behaviours reported in this work will be useful for designing chemical conversions of carbon dioxide using [hmim][FAP] ionic liquid as reaction solvents. [Display omitted] • solubility of 1,2-butanediol and butylene carbonate in dense CO 2. • phase behaviour of ternary and quaternary CO 2 -IL biphasic mixtures. • 1-hexyl-3-methylimidazolium tris(pentafluoroalkyl)trifluorophosphate ionic liquid as solubility modifier. [ABSTRACT FROM AUTHOR]

Large quantities of apple pomace remain as waste material after apple juice production. The idea of the study assumed that, due to the large share of seeds, apple pomace could serve as a source of edible oil. The aim of the study was to assess the oil content and fatty acids composition of oil extracted from seeds separated from dried apple pomace, and to compare its composition to the canola and grape seed oils. The oil yield from apple pomace seeds was approximately 159 g·kg-1. The oil contained a high level of unsaturated fatty acids, predominantly linoleic acid. Polyunsaturated fatty acids were more abundant in apple seed oil than in canola oil, but less abundant than in grape seed oils. The level of monounsaturated acids was lower than in canola oil but higher than in grape seed oil. The obtained results suggest that apple pomace might serve as a material for new edible oil production of high nutritional value. Hereby, the large quantities of wastes remaining after industrial apple processing could be utilized in an innovative and profitable way. [ABSTRACT FROM AUTHOR]

The solubility of high-pressure carbon dioxide in mixtures of ionic liquid and water was determined experimentally for 1-ethyl-3-methylimidazolium trifluoromethanesulfonate and 1-alkyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ionic liquids (where alkyl is ethyl, butyl, or hexyl). Experiments were performed at 313.15 K and/or 318.15 K, at pressures up to 10 MPa, and for various compositions (dry ionic liquids, 0.1 or 10 wt % of water), depending on the ionic liquid under investigation. It was found that the solubility of carbon dioxide in tris(pentafluoroethyl)trifluorophosphate-based ionic liquids is not affected by the water content, whereas for 1-ethyl-3-methylimidazolium trifluoromethanesulfonate, the carbon dioxide sorption capacity is reduced by up to 10%, when 10 wt % of water is present in the system, at the same temperature and pressure. [ABSTRACT FROM AUTHOR]

Nowadays, the concept of good governance plays a central role in debates in the area of social sciences in general and in the field of public administration in particular. The concept has been used frequently but often with quite different meanings and implications, moreover, one should underline the significant role of social participation in this concept as it involves citizens assessing their own needs and participating in local projects. Therefore, for social participation, transparency of government information is needed, as well as the inclusion of members in the decision-making process. Excluding the weak and powerless from decisionmaking is a cause of poverty because it denies them rights and creates unequal power relationships. This paper discusses a variety of meanings and different approaches to the role of social participation in the concept of good governance but its main focus is on the capacity of government to make and implement social participation policies and, thereby, develop knowledge based economies based on active participation of citizens and their well-developed bridging social capital. [ABSTRACT FROM AUTHOR]

The high-pressure solubility of carbon dioxide in ionic liquids based on tetracyanoborate anion, 1-ethyl-3-methylimidazolium tetracyanoborate ([emim][B(CN) 4 ]) and 1-hexyl-3-methylimidazolium tetracyanoborate ([hmim][B(CN) 4 ]), was determined experimentally at the temperature of 313.15 K and pressures up to 19 MPa. Additionally, measurements of volume expansion of a liquid phase, based on a change in total or molar volume of a liquid upon carbon dioxide addition, are reported. The obtained results show that CO 2 has a high solubility in tetracyanoborate-based ionic liquids, comparable, or even slightly higher, to the CO 2 solubility in fluorinated CO 2 -philic ionic liquids. Approximately 60% CO 2 -induced volume expansion of the liquid was observed at the highest pressures, an unprecedented result for ionic liquid+ CO 2 systems. [ABSTRACT FROM AUTHOR]

Abstract: The solubility of carbon dioxide in ionic liquids was measured in a new apparatus. The ionic liquids chosen have ammonium-based cations and show melting temperature decreases under CO2 pressure that range from low (25K) to extremely high (120K). The main purpose of this study was to check whether the solubility of the gas in each liquid could explain the previously reported wide differences in melting point depression (MPD). The results show there is no correlation between solubility and MPD. [Copyright &y& Elsevier]

Highlights: [•] Solubilities of salts were enhanced by temperature increase. [•] For all studied systems activity coefficients lower then unity were observed. [•] Melting point depression of 20K was observed for [bmim]3[GdCl6]. [ABSTRACT FROM AUTHOR]

Structure, and consequently properties, of ionic liquids can be easily tailored by changing cation/anion combinations and/or attaching functional groups. By grafting enantiopure moieties to the framework of ionic liquid it is possible to prepare bioinspired chiral molecules that can serve as a reaction medium, additive or even asymmetric catalyst. In this context, new chiral ionic liquids (CILs), based on biomolecules, such as aminoacids (l-Cysteine derivatives), have been synthesised and tested in asymmetric aldol condensation of aldehydes and ketones. The best results were obtained for CILs composed of S-methyl-l-cysteine cation and bis(trifluoromethane)sulfonimide anion, in the reaction of 2- or 4-nitrobenzaldehyde with acetone or cyclohexanone, giving the aldol product in moderate yields 70–76% and high ee values (up to 96%). [ABSTRACT FROM AUTHOR]

Abstract: Mutual miscibility in mixtures containing ethyl lactate and various hydrocarbons (alkanes, alkenes, cyclohexane, alkyl cyclohexanes and terpenes) were explored in a range of temperatures from (273.2 to 320.9)K and at atmospheric pressure. Thus, the respective temperature–composition phase diagrams were constructed. The influence of temperature, aliphatic chain length and of double bond presence on liquid phase behavior was discussed. The obtained liquid–liquid solubility data were represented using the UNIQUAC-based model which showed to be an appropriate tool for representing the liquid–liquid behavior of (hydrocarbon+ethyl lactate) mixtures. [Copyright &y& Elsevier]

The article discusses nonedible lignocelluose biomass as alternative fuel source. The green fuel source is composed of cellulose, hemicellulose, and lignin which are from the non-edible parts of plants. Several methods are applied for fuel extraction from a biomass such as acid hydrolysis, organosolv, or ionic liquids. One building block chemical that can be obtained from biomass is 5-hydroxymethylfurfural (5-HMF) which can be used to synthesize beneficial compounds extracted from petroleum.

Fibroblast growth factors (FGFs) are involved in diverse cellular processes such as cell migration, angiogenesis, osteogenesis, wound healing and embryonic and foetal development. Human acidic fibroblast growth factor (FGF-1) is the only member of the FGF family that binds with high affinity to all four FGF receptors and thus is considered to be the human mitogen with the broadest specificity. However, pharmacological applications of FGF-1 are limited owing to its low stability. It has previously been reported that the introduction of single mutations can significantly improve the stability of FGF-1 and its resistance to proteolytic degradation. Here, the structure of the Q40P/S47I/H93G triple mutant of FGF-1, which exhibits much higher stability, a prolonged half-life and enhanced mitogenic activity, is presented. Compared with the wild-type structure, three localized conformational changes in the stable triple mutant were observed, which is in agreement wit h the perfect energetic additivity of the single mutations described in a previous study. The huge change in FGF-1 stability (the denaturation temperature increased by 21.5 K, equivalent to Δ ΔGden = 24.3 kJ mol-1) seems to result from the formation of a short 310-helix (position 40), an improvement in the propensity of amino acids to form β-sheets (position 47) and the rearrangement of a local hydrogen-bond network (positions 47 and 93). [ABSTRACT FROM AUTHOR]

Ethyl lactate is a hydrophilic solvent produced from bio-renewable sources (bioethanol and lactic acid produced from corn fermentation) that is considered as a "green" solvent due to its extremely low toxicity, biodegradability and negligible eco-toxicity. This work focuses on the utilization of ethyl lactate to form aqueous two-phase systems (ATPS) in the presence of inorganic salts for the extraction of antibiotics from aqueous solutions. The performance of three thiosulfate salts (Na 2 S 2 O 3 , K 2 S 2 O 3 and (NH 4) 2 S 2 O 3) as salting-out media for the extraction of chloramphenicol and tetracycline from their aqueous solutions was examined. In this respect, cloud points for the ternary solutions composed of ethyl lactate, water and salt were determined at atmospheric pressure (0.1 MPa) and 298.2 K. Partition coefficients of chloramphenicol and tetracycline between the two phases were determined by chemical analysis of phases in equilibrium for different initial compositions at 298.2 K. This paper is the first report to demonstrate the ability of the ATPS based on ethyl lactate to efficiently separate antibiotics. Thus, ATPS based on ethyl lactate represents a new and green platform for the extraction of antibiotics from aqueous solutions which can facilitate their detection, identification and quantification in surface waters as well as their extraction from fermentation broths. [ABSTRACT FROM AUTHOR]

Galectins constitute a class of lectins that specifically interact with β-galactoside sugars in glycoconjugates and are implicated in diverse cellular processes, including transport, autophagy or signaling. Since most of the activity of galectins depends on their ability to bind sugar chains, galectins exert their functions mainly in the extracellular space or at the cell surface, which are microenvironments highly enriched in glycoconjugates. Galectins are also abundant inside cells, but their specific intracellular functions are largely unknown. Here we report that galectin-1, -3, -7 and -8 directly interact with the proteinaceous core of fibroblast growth factor 12 (FGF12) in the cytosol and in nucleus. We demonstrate that binding of galectin-1 to FGF12 in the cytosol blocks FGF12 secretion. Furthermore, we show that intracellular galectin-1 affects the assembly of FGF12-containing nuclear/nucleolar ribosome biogenesis complexes consisting of NOLC1 and TCOF1. Our data provide a new link between galectins and FGF proteins, revealing an unexpected glycosylation-independent intracellular interplay between these groups of proteins. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor 1 (FGFR1) is a heavily N-glycosylated cell surface receptor tyrosine kinase that transmits signals across the plasma membrane, in response to fibroblast growth factors (FGFs). Balanced FGF/FGFR1 signaling is crucial for the development and homeostasis of the human body, and aberrant FGFR1 is frequently observed in various cancers. In addition to its predominant localization to the plasma membrane, FGFR1 has also been detected inside cells, mainly in the nuclear lumen, where it modulates gene expression. However, the exact mechanism of FGFR1 nuclear transport is still unknown. In this study, we generated a glycosylation-free mutant of FGFR1, FGFR1.GF, and demonstrated that it is localized primarily to the nuclear envelope. We show that reintroducing N-glycans into the D3 domain cannot redirect FGFR1 to the plasma membrane or exclude the receptor from the nuclear envelope. Reestablishment of D2 domain N-glycans largely inhibits FGFR1 accumulation in the nuclear envelope, but the receptor continues to accumulate inside the cell, mainly in the ER. Only the simultaneous presence of N-glycans of the D2 and D3 domains of FGFR1 promotes efficient transport of FGFR1 to the plasma membrane. We demonstrate that while disturbed FGFR1 folding results in partial FGFR1 accumulation in the ER, impaired FGFR1 secretion drives FGFR1 trafficking to the nuclear envelope. Intracellular FGFR1.GF displays a high level of autoactivation, suggesting the presence of nuclear FGFR1 signaling, which is independent of FGF. Using mass spectrometry and proximity ligation assay, we identified novel binding partners of the nuclear envelope-localized FGFR1, providing insights into its cellular functions. Collectively, our data define N-glycosylation of FGFR1 as an important regulator of FGFR1 kinase activity and, most importantly, as a switchable signal for FGFR1 trafficking between the nuclear envelope and plasma membrane, which, due to spatial restrictions, shapes FGFR1 interactome and cellular function. EsPakJEGK2gtBioMMpFVm_ Video Abstract [ABSTRACT FROM AUTHOR]

Different Chiral Ionic Liquids (CIL) based on L-proline have been developed. Simple and efficient synthetic methodologies are used, allowing preparation in good yields for twelve novel CILs using L-proline as a cation or anion combined with suitable counter-ions. A detailed physical and chemical characterization of the CILs was performed to evaluate the influence of counter-ions on the final properties. The most promissory CILs were tested as efficient chiral catalysts in IL media for asymmetric Michael addition reactions of ketones and aldehydes to nitro-olefins. Similar or even better conversions and enantioselectivities (ee up to 95%) compared to the original L-proline were achieved. Additionally, a good product extraction performance using supercritical CO2 processes was obtained. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to detect trends in human resource management (HRM) research presented in journals during the 2000–2020 timeframe. The research question is: How are the interests of researchers changing in the field of HRM and which topics have gained popularity in recent years? Design/methodology/approach: The approach adopted in this study was designed to overcome all the limitations specific to the systematic literature reviews and bibliometric studies presented in the Introduction. The full texts of papers were analyzed. The text-mining tools detected first clusters and then trends, moreover, which limited the impact of a researcher's bias. The approach applied is consistent with the general rules of systematic literature reviews. Findings: The article makes a threefold contribution to academic knowledge. First, it uses modern methodology to gather and synthesize HRM research topics. The proposed approach was designed to allow early detection of nascent, non-obvious trends in research, which will help researchers address topics of high value for both theory and practice. Second, the results of our study highlight shifts in focus in HRM over the past 19 years. Third, the article suggests further directions of research. Research limitations/implications: In this study, the approach designed to overcome the limitations of using systematic literature review was presented. The analysis was done on the basis of the full text of the articles and the categories were discovered directly from the articles rather than predetermined. The study's findings may, however, potentially be limited by the following issues. First, the eligibility criteria included only papers indexed in the Scopus and WoS database and excluded conference proceedings, book chapters, and non-English papers. Second, only full-text articles were included in the study, which could narrow down the research area. As a consequence, important information regarding the research presented in the excluded documents is potentially lost. Third, most of the papers in our database were published in the International Journal of Human Resource Management, and therefore such trends as "challenges for international HRM" can be considered significant (long-lasting). Another – the fourth – limitation of the study is the lack of estimation of the proportion between searches in HRM journals and articles published in other journals. Future research may overcome the above-presented limitations. Although the authors used valuable techniques such as TF-IDF and HDBSCAN, the fifth limitation is that, after trends were discovered, it was necessary to evaluate and interpret them. That could have induced researchers' bias even if – as in this study – researchers from different areas of experience were involved. Finally, this study covers the 2000–2020 timeframe. Since HRM is a rapidly developing field, in a few years from now academics will probably begin to move into exciting new research areas. As a consequence, it might be worthwhile conducting similar analyses to those presented in this study and compare their results. Originality/value: The present study provides an analysis of HRM journals with the aim of establishing trends in HRM research. It makes contributions to the field by providing a more comprehensive and objective review than analyses resulting from systematic literature reviews. It fills the gap in literature studies on HRM with a novel research approach – a methodology based on full-text mining and a big data toolset. As a consequence, this study can be considered as providing an adequate reflection of all the articles published in journals strictly devoted to HRM issues and which may serve as an important source of reference for both researchers and practitioners. This study can help them identify the core journals focused on HRM research as well as topics which are of particular interest and importance. [ABSTRACT FROM AUTHOR]

Precise anticancer therapies employing cytotoxic conjugates constitute a side-effect-limited, highly attractive alternative to commonly used cancer treatment modalities, such as conventional chemotherapy, radiotherapy or surgical interventions. Receptor tyrosine kinases are a large family of N-glycoproteins intensively studied as molecular targets for cytotoxic conjugates in various cancers. At the cell surface, these receptors are embedded in a dense carbohydrate layer formed by numerous plasma membrane glycoproteins. The complexity of the cell surface architecture is further increased by galectins, secreted lectins capable of recognizing and clustering glycoconjugates, affecting their motility and activity. Cell surface N-glycosylation is intensively remodeled by cancer cells; however, the contribution of this phenomenon to the efficiency of treatment with cytotoxic conjugates is largely unknown. Here, we evaluated the significance of N-glycosylation for the internalization and toxicity of conjugates targeting two model receptor tyrosine kinases strongly implicated in cancer: HER2 and FGFR1. We employed three conjugates of distinct molecular architecture and specificity: AffibodyHER2-vcMMAE (targeting HER2), vcMMAE-KCK-FGF1.E and T-Fc-vcMMAE (recognizing different epitopes within FGFR1). We demonstrated that inhibition of N-glycosylation reduced the cellular uptake of all conjugates tested and provided evidence for a role of the galectin network in conjugate internalization. In vitro binding studies revealed that the reduced uptake of conjugates is not due to impaired HER2 and FGFR1 binding. Importantly, we demonstrated that alteration of N-glycosylation can affect the cytotoxic potential of conjugates. Our data implicate a key role for cell surface N-glycosylation in the delivery of cytotoxic conjugates into cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Solid–liquid, liquid–liquid and vapour–liquid equilibrium measurements for binary and ternary systems containing building blocks of biomass origin such as propionic acid, lactic acid and alternative solvents like carbon dioxide and 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid have been carried out at 313.15K. The binary solid–liquid and liquid–liquid equilibrium measurements were performed at ambient pressure. The vapour–liquid equilibrium was studied in the range of pressure from 3.54 to 12MPa while ternary systems were examined at 9, 10 and 12MPa. The samples from the coexisting phases were taken and the compositions of both liquid and vapour phases were determined experimentally. The three-phase system was observed for lactic acid+ionic liquid+CO2 as well. The achieved results were correlated using the Peng–Robinson equation of state with the Mathias–Klotz–Prausnitz mixing rule. The set of interaction parameters for the employed equations of state and the mixing rule for the investigated systems were obtained. [Copyright &y& Elsevier]

Background: Overexpression of FGFR1 is observed in numerous tumors and therefore this receptor constitutes an attractive molecular target for selective cancer treatment with cytotoxic conjugates. The success of cancer therapy with cytotoxic conjugates largely relies on the precise recognition of a cancer-specific marker by a targeting molecule within the conjugate and its subsequent cellular internalization by receptor mediated endocytosis. We have recently demonstrated that efficiency and mechanism of FGFR1 internalization are governed by spatial distribution of the receptor in the plasma membrane, where clustering of FGFR1 into larger oligomers stimulated fast and highly efficient uptake of the receptor by simultaneous engagement of multiple endocytic routes. Based on these findings we aimed to develop a modular, self-assembly system for generation of oligomeric cytotoxic conjugates, capable of FGFR1 clustering, for targeting FGFR1-overproducing cancer cells. Methods: Engineered FGF1 was used as FGFR1-recognition molecule and tailored for enhanced stability and site-specific attachment of the cytotoxic drug. Modified streptavidin, allowing for controlled oligomerization of FGF1 variant was used for self-assembly of well-defined FGF1 oligomers of different valency and oligomeric cytotoxic conjugate. Protein biochemistry methods were applied to obtain highly pure FGF1 oligomers and the oligomeric cytotoxic conjugate. Diverse biophysical, biochemical and cell biology tests were used to evaluate FGFR1 binding, internalization and the cytotoxicity of obtained oligomers. Results: Developed multivalent FGF1 complexes are characterized by well-defined architecture, enhanced FGFR1 binding and improved cellular uptake. This successful strategy was applied to construct tetrameric cytotoxic conjugate targeting FGFR1-producing cancer cells. We have shown that enhanced affinity for the receptor and improved internalization result in a superior cytotoxicity of the tetrameric conjugate compared to the monomeric one. Conclusions: Our data implicate that oligomerization of the targeting molecules constitutes an attractive strategy for improvement of the cytotoxicity of conjugates recognizing cancer-specific biomarkers. Importantly, the presented approach can be easily adapted for other tumor markers. [ABSTRACT FROM AUTHOR]

[Display omitted] • Receptor tyrosine kinases (RTKs) regulate pivotal cellular processes and are dysregulated in cancer. • RTKs are extensively glycosylated and this modification affects cellular functions of these receptors. • Galectins are carbohydrate binding proteins implicated in developmental processes and cancers. Galectins directly and indirectly affect RTKs, modulating RTKs activation, their cross-talk with other cell surface proteins and their cellular trafficking. • Galectins are responsible for oncogenic activation of RTKs. • RTK-galectin interplay constitutes an attractive target for development of anti-cancer therapies. Receptor tyrosine kinases (RTKs) constitute a large group of cell surface proteins that mediate communication of cells with extracellular environment. RTKs recognize external signals and transfer information to the cell interior, modulating key cellular activities, like metabolism, proliferation, motility, or death. To ensure balanced stream of signals the activity of RTKs is tightly regulated by numerous mechanisms, including receptor expression and degradation, ligand specificity and availability, engagement of co-receptors, cellular trafficking of the receptors or their post-translational modifications. One of the most widespread post-translational modifications of RTKs is glycosylation of their extracellular domains. The sugar chains attached to RTKs form a new layer of information, so called glyco-code that is read by galectins, carbohydrate binding proteins. Galectins are family of fifteen lectins implicated in immune response, inflammation, cell division, motility and death. The versatility of cellular activities attributed to galectins is a result of their high abundance and diversity of their cellular targets. A various sugar specificity of galectins and the differential ability of galectin family members to form oligomers affect the spatial distribution and the function of their cellular targets. Importantly, galectins and RTKs are tightly linked to the development, progression and metastasis of various cancers. A growing number of studies points on the close cooperation between RTKs and galectins in eliciting specific cellular responses. This review focuses on the identified complexes between galectins and RTK members and discusses their relevance for the cell physiology both in healthy tissues and in cancer. [ABSTRACT FROM AUTHOR]

Background: Antibody drug conjugates (ADCs) represent one of the most promising approaches in the current immuno-oncology research. The precise delivery of cytotoxic drugs to the cancer cells using ADCs specific for tumor-associated antigens enables sparing the healthy cells and thereby reduces unwanted side effects. Overexpression of fibroblast growth factor receptor 1 (FGFR1) has been demonstrated in numerous tumors and thereby constitutes a convenient molecular target for selective cancer treatment. We have recently engineered tetravalent anti-FGFR1 antibody, T-Fc, and have demonstrated that it displays extremely efficient internalization into FGFR1 producing cells, a feature highly desirable in the ADC approach. We have revealed that T-Fc mediates clustering of FGFR1, largely enhancing the uptake of FGFR1-T-Fc complexes by induction of clathrin-independent endocytic routes. The aim of this study was to obtain highly internalizing cytotoxic conjugate of the T-Fc for specific delivery of drugs into FGFR1-positive cancer cells. Methods: Conjugation of the T-Fc to a cytotoxic payload, vcMMAE, was carried out via maleimide chemistry, yielding the T-Fc-vcMMAE. The specific binding of the T-Fc-vcMMAE conjugate to FGFR1 was confirmed in vitro with BLI technique. Confocal microscopy and flow cytometry were applied to determine FGFR1-dependence of the T-Fc-vcMMAE internalization. Western blot analyses of FGFR1-dependent signaling were conducted to assess the impact of the T-Fc-vcMMAE on FGFR1 activation and initiation of downstream signaling cascades. Finally, using FGFR1-negative and FGFR1-possitive cell lines, the cytotoxic potential of the T-Fc-vcMMAE was evaluated. Results: We have performed the efficient conjugation of the tetravalent engineered antibody with a cytotoxic drug and generated FGFR1-specific ADC molecule, T-Fc-vcMMAE. We have demonstrated that T-Fc-vcMMAE conjugate exhibits high selectivity and affinity for FGFR1, similarly to T-Fc. Furthermore, we have shown that T-Fc constitutes an effective drug delivery vehicle as T-Fc-vcMMAE was efficiently and selectively internalized by FGFR1-producing cells leading to their death. Interestingly, we show that the efficiency of the uptake of T-Fc-vcMMAE corresponds well with the cytotoxicity of the conjugate, but doesn't correlate with the FGFR1expression level. Conclusion: Our results show that T-Fc-vcMMAE fulfills the key criteria for the successful cytotoxic drug carrier in a targeted approach against FGFR1-positive cancer cells. Furthermore, our data implicate that not solely expression level of the receptor, but rather its cellular trafficking should be taken into account for selection of suitable molecular targets and cancer models for successful ADC approach. [ABSTRACT FROM AUTHOR]

With almost 20 million new cases per year, cancer constitutes one of the most important challenges for public health systems. Unlike traditional chemotherapy, targeted anti-cancer strategies employ sophisticated therapeutics to precisely identify and attack cancer cells, limiting the impact of drugs on healthy cells and thereby minimizing the unwanted side effects of therapy. Protein drug conjugates (PDCs) are a rapidly growing group of targeted therapeutics, composed of a cancer-recognition factor covalently coupled to a cytotoxic drug. Several PDCs, mainly in the form of antibody-drug conjugates (ADCs) that employ monoclonal antibodies as cancer-recognition molecules, are used in the clinic and many PDCs are currently in clinical trials. Highly selective, strong and stable interaction of the PDC with the tumor marker, combined with efficient, rapid endocytosis of the receptor/PDC complex and its subsequent effective delivery to lysosomes, is critical for the efficacy of targeted cancer therapy with PDCs. However, the bivalent architecture of contemporary clinical PDCs is not optimal for tumor receptor recognition or PDCs internalization. In this review, we focus on multivalent PDCs, which represent a rapidly evolving and highly promising therapeutics that overcome most of the limitations of current bivalent PDCs, enhancing the precision and efficiency of drug delivery to cancer cells. We present an expanding set of protein scaffolds used to generate multivalent PDCs that, in addition to folding into well-defined multivalent molecular structures, enable site-specific conjugation of the cytotoxic drug to ensure PDC homogeneity. We provide an overview of the architectures of multivalent PDCs developed to date, emphasizing their efficacy in the targeted treatment of various cancers. • Protein-drug conjugates, PDCs, deliver a cytotoxic payload to cancer cells, leading to their death. • Multivalent PDCs are highly promising therapeutics characterized by increased precision and efficiency of drug delivery. • Protein scaffolds allow for the development of homogenous multivalent PDCs of diversified, well-defined architectures. • The modularity of protein scaffolds allows for rapid adaptation of PDCs to novel cancer-relevant targets. [ABSTRACT FROM AUTHOR]

A novel metalloprotein containing a unique [SMoSCuSMoS] cluster, designated as Orange Protein (ORP), was isolated for the first time from Desulfovibrio gigas, a sulphate reducer. The orp operon is conserved in almost all sequenced Desulfovibrio genomes and in other anaerobic bacteria, however, so far D. gigas ORP had been the only ORP characterized in the literature. In this work, the purification of another ORP isolated form Desulfovibrio alaskensis G20 is reported. The native protein is monomeric (12443.8 ± 0.1 Da by ESI-MS) and contains also a MoCu cluster with characteristic absorption bands at 337 and 480 nm, assigned to S-Mo charge transfer bands. Desulfovibrio alaskensis G20 recombinant protein was obtained in the apo-form from E. coli. Cluster reconstitution studies and UV-visible titrations with tetrathiomolybdate of the apo-ORP incubated with Cu ions indicate that the cluster is incorporated in a protein metal-assisted synthetic mode and the protein favors the 2Mo:1Cu stoichiometry. In Desulfovibrio alaskensis G20, the orp genes are encoded by a polycistronic unit composed of six genes whereas in Desulfovibrio vulgaris Hildenborough the same genes are organized into two divergent operons, although the composition in genes is similar. The gene expression of ORP ( Dde_3198) increased 6.6 ± 0.5 times when molybdate was added to the growth medium but was not affected by Cu(II) addition, suggesting an involvement in molybdenum metabolism directly or indirectly in these anaerobic bacteria. [ABSTRACT FROM AUTHOR]

The five-coordinate complex [RuCl(dppe)2]OTf ([2]OTf) is obtained in high yield by the sequential reduction of RuCl3 · nH2O to RuCl2(PPh3)3, subsequent phosphine substitution to give trans-RuCl2(dppe)2 (trans-1) and finally chloride abstraction (AgOTf, CH2Cl2). The use of [2]OTf as an entry point to mono-acetylide complexes trans-RuCl(C≡CC6H4R-4)(dppe)2 (3) is described, and represents an alternative route to the long-standing methods based on cis-RuCl2(dppe)2 (cis-1), which is always prepared as a mixture with the more thermodynamically stable trans isomer when prepared by phosphine substitution reactions of RuCl2(dmso)4. The molecular structures of [2]OTf, trans-RuCl(C≡CC6H4OMe-4)(dppe)2 (3b), trans-RuCl(C≡CC6H4Me-4)(dppe)2 (3c) and trans-RuCl(C≡CC6H4CO2Me-4)(dppe)2 (3e) are described. A facile and reproducible synthesis of cis-1 is also reported. [Copyright &y& Elsevier]

Fibroblast growth factor receptors (FGFRs) are integral membrane proteins that transmit signals through the plasma membrane. FGFRs signaling needs to be precisely adjusted as aberrant FGFRs function is associated with development of human cancers or severe metabolic diseases. The subcellular localization, trafficking and function of FGFRs rely on the formation of multiprotein complexes. In this study we revealed galectins, lectin family members implicated in cancer development and progression, as novel FGFR1 binding proteins. We demonstrated that galectin-1 and galectin-3 directly bind to the sugar chains of the glycosylated extracellular part of FGFR1. Although both galectins compete for the same binding sites on FGFR1, these proteins elicit different impact on FGFR1 function and cellular trafficking. Galectin-1 mimics fibroblast growth factor as it efficiently activates FGFR1 and receptor-downstream signaling pathways that result in cell proliferation and apoptotic evasion. In contrast, galectin-3 induces extensive clustering of FGFR1 on the cell surface that inhibits constitutive internalization of FGFR1. Our data point on the interplay between extracellular galectins and FGFRs in the regulation of cell fate. [ABSTRACT FROM AUTHOR]

Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute signaling circuits that transmit signals across the plasma membrane, regulating pivotal cellular processes like differentiation, migration, proliferation, and apoptosis. The malfunction of FGFs/FGFRs signaling axis is observed in numerous developmental and metabolic disorders, and in various tumors. The large diversity of FGFs/FGFRs functions is attributed to a great complexity in the regulation of FGFs/FGFRs-dependent signaling cascades. The function of FGFRs is modulated at several levels, including gene expression, alternative splicing, posttranslational modifications, and protein trafficking. One of the emerging ways to adjust FGFRs activity is through formation of complexes with other integral proteins of the cell membrane. These proteins may act as coreceptors, modulating binding of FGFs to FGFRs and defining specificity of elicited cellular response. FGFRs may interact with other cell surface receptors, like G-protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs). The cross-talk between various receptors modulates the strength and specificity of intracellular signaling and cell fate. At the cell surface FGFRs can assemble into large complexes involving various cell adhesion molecules (CAMs). The interplay between FGFRs and CAMs affects cell–cell interaction and motility and is especially important for development of the central nervous system. This review summarizes current stage of knowledge about the regulation of FGFRs by the plasma membrane-embedded partner proteins and highlights the importance of FGFRs-containing membrane complexes in pathological conditions, including cancer. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptors (FGFRs) in response to fibroblast growth factors (FGFs) transmit signals across the cell membrane, regulating important cellular processes, like differentiation, division, motility, and death. The aberrant activity of FGFRs is often observed in various diseases, especially in cancer. The uncontrolled FGFRs' function may result from their overproduction, activating mutations, or generation of FGFRs' fusion proteins. Besides their typical subcellular localization on the cell surface, FGFRs are often found inside the cells, in the nucleus and mitochondria. The intracellular pool of FGFRs utilizes different mechanisms to facilitate cancer cell survival and expansion. In this review, we summarize the current stage of knowledge about the role of FGFRs in oncogenic processes. We focused on the mechanisms of FGFRs' cellular trafficking—internalization, nuclear translocation, and mitochondrial targeting, as well as their role in carcinogenesis. The subcellular sorting of FGFRs constitutes an attractive target for anti-cancer therapies. The blocking of FGFRs' nuclear and mitochondrial translocation can lead to the inhibition of cancer invasion. Moreover, the endocytosis of FGFRs can serve as a tool for the efficient and highly selective delivery of drugs into cancer cells overproducing these receptors. Here, we provide up to date examples how the cellular sorting of FGFRs can be hijacked for selective cancer treatment. [ABSTRACT FROM AUTHOR]

In the rapidly developing field of targeted cancer therapy there is growing interest towards therapeutics combining two or more compounds to achieve synergistic action and minimize the chance of cancer resistance to treatment. We developed a fibroblast growth factor 2 (FGF2)-conjugate bearing two cytotoxic drugs with independent mode of action: α-amanitin and monomethyl auristatin E. Drugs are covalently attached to the targeting protein in a site-specific manner via maleimide-thiol conjugation and Cu(I)-catalyzed alkyne-azide cycloaddition. The dual warhead conjugate binds to FGF receptor 1 (FGFR1) and utilizes receptor-mediated endocytosis for selective internalization into cancer cells with FGFR1. The developed conjugate displays high cytotoxicity towards all tested FGFR1-positive cell lines. Most importantly, the improved cytotoxic effect of both drugs is observed for lung cancer cell line NCI-H446. The single drug-FGF2 conjugates have no impact on the viability of NCI-H446 cells, whereas the dual warhead-FGF2 conjugate selectively and efficiently kills these FGFR1 positive cancer cells. Due to the diversified mode of action the dual warhead-FGF2 conjugate may overcome the potential acquired resistance of FGFR1-overproducing cancer cells towards single cytotoxic drugs. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor 1 (FGFR1) is a plasma membrane protein that transmits signals from the extracellular environment, regulating cell homeostasis and function. Dysregulation of FGFR1 leads to the development of human cancers and noncancerous diseases. Numerous tumors overproduce FGFR1, making this receptor a perspective target for cancer therapies. Antibody-drug conjugates (ADCs) are highly potent and selective anticancer agents. ADCs are composed of antibodies (targeting factors) fused to highly cytotoxic drugs (warheads). The efficiency of ADC strategy largely depends on the internalization of cytotoxic conjugate into cancer cells. Here, we have studied an interplay between affinity of anti-FGFR1 antibodies and efficiency of their cellular uptake. We have developed a unique set of engineered anti-FGFR1 antibodies that bind the same epitope in the extracellular part of FGFR1, but with different affinities. We have demonstrated that these antibodies are effectively taken up by cancer cells in the FGFR1-dependent manner. Interestingly, we have found that efficiency, defined as rate and level of antibody internalization, largely depends on the affinity of engineered antibodies towards FGFR1, as high affinity antibody displays fastest internalization kinetics. Our data may facilitate design of therapeutically relevant targeting molecules for selective treatment of FGFR1 overproducing cancers. [ABSTRACT FROM AUTHOR]