Among the artists' materials of the nineteenth century, pastel crayons merit scientific interest since their early commercial formulations are mostly unknown and, until now, have been considerably ...less studied with respect to other contemporary painting materials. In this framework, research herein reports the results of a comprehensive multi-analytical study of 44 pastel crayons of two recognized brands (LeFranc and Dr. F. Schoenfeld) from the Munch museum collection of original materials belonging to Edvard Munch. The integrated use of complementary spectroscopic and hyphenated mass-spectrometry techniques allowed the compositional profiles of the crayons to be traced providing the identification of the inorganic and organic pigments, the fillers/extenders and the binders. All crayons resulted to be oil- based and the binder was identified to be a mixture of a drying oil (safflower or linseed oil), palm oil or Japan wax and beeswax. Among others, pigments such as ultramarine, chrome yellows, Prussian blue, manganese violet, viridian and madder lake have been identified. A significant alignment in formulations of the brands was observed with the only exception of the greens which showed distinctive pigment and filler compositions. The analytical information provided for these commercial artists' materials will be of great interest for academia, museum and other institutions hosting art collections dating from the same period and it will be used by the Munch museum to draw proper conservation strategies of its own artwork collections.
Triarylmethine dyes, such as Methyl and Crystal Violets, Diamond green and Magentas, produced since the late nineteenth century, consist of complex mixtures of homologous compounds, often differing ...only for the presence or position of the same substituent on the aromatic rings. In this paper, Liquid Chromatography-High Resolution Mass Spectrometry (HPLC-HRMS) was used for the characterization of the profile of three dyes: Methyl Blue, Methyl Violet and Fuchsine. The comprehension of dye synthesis and production strategies was often achieved by analyzing the single components by diode array detector. Nevertheless, the nature of the individual components needs to be confirmed by tandem mass spectrometric techniques through the solving of the structural issues.
The analysis of standards and reference materials by tandem high resolution mass spectrometry allowed us to identify peculiar fragmentation pathways for the components of magentas and methyl violet dyes.
The results highlighted the importance to undertake the measurements both in negative and positive ionization mode. The elucidation of specific fragmentation patterns allows the discrimination between different classes of compounds, while the identification of specific fragment ions allows one to distinguish isomers belonging to the same series.
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•We fully characterized the composition of three triarylmethine dyes by LC-ESI-Q-ToF.•We studied the positive and negative tandem mass spectra of methyl blue.•We rationalized the MS/MS fragmentation of crystal violet and fuchsine components.
Despite development of novel agents targeting oncogenic pathways, matching targeted therapies to the genetic status of individual tumors is proving to be a daunting task for clinicians. To improve ...the clinical efficacy and to reduce the toxic side effects of treatments, a deep characterization of genetic alterations in different tumors is required. The mutational profile often evidences a gain of function or hyperactivity of phosphoinositide 3-kinases (PI3Ks) in tumors. These enzymes are activated downstream tyrosine kinase receptors (RTKs) and/or G proteins coupled receptors (GPCRs) and, via AKT, are able to induce mammalian target of rapamycin (mTOR) stimulation. Here, we elucidate the impact of class I (p110α, β, γ, and δ) catalytic subunit mutations on AKT-mediated cellular processes that control crucial mechanisms in tumor development. Moreover, the interrelation of PI3K signaling with mTOR, ERK, and RAS pathways will be discussed, exploiting the potential benefits of PI3K signaling inhibitors in clinical use.
Ovarian cancer (OC) grows and interacts constantly with a complex microenvironment, in which immune cells, fibroblasts, blood vessels, signal molecules and the extracellular matrix (ECM) coexist. ...This heterogeneous environment provides structural and biochemical support to the surrounding cells and undergoes constant and dynamic remodeling that actively promotes tumor initiation, progression, and metastasis. Despite the fact that traditional 2D cell culture systems have led to relevant medical advances in cancer research, 3D cell culture models could open new possibilities for the development of an in vitro tumor microenvironment more closely reproducing that observed in vivo. The implementation of materials science and technology into cancer research has enabled significant progress in the study of cancer progression and drug screening, through the development of polymeric scaffold-based 3D models closely recapitulating the physiopathological features of native tumor tissue. This article provides an overview of state-of-the-art in vitro tumor models with a particular focus on 3D OC cell culture in pre-clinical studies. The most representative OC models described in the literature are presented with a focus on hydrogel-based scaffolds, which guarantee soft tissue-like physical properties as well as a suitable 3D microenvironment for cell growth. Hydrogel-forming polymers of either natural or synthetic origin investigated in this context are described by highlighting their source of extraction, physical-chemical properties, and application for 3D ovarian cancer cell culture.
Photoactivatable Pt(IV) prodrugs represent nowadays an intriguing class of potential metal-based drugs, endowed with more chemical inertness in their oxidized form and better selectivity for the ...target with respect to the clinically established Pt(II) compounds. In fact, they have the possibility to be reduced by light irradiation directly at the site of interest. For this reason, we synthesized a new Pt(IV) complex, Pt(OCOCH
)
(4'-phenyl-2,2':6',2''-terpyridine)CF
SO
(
), that is well soluble in aqueous medium and totally unreactive towards selected model biomolecules until its reduction. The highlight of this work is the rapid and efficient photoreduction of
with visible light (460 nm), which leads to its reactive Pt(II) analogue. This behavior was made possible by taking advantage of an efficient catalytic system based on flavin and NADH, which is naturally present in the cellular environment. As a comparison, the reduction of
was also studied with simple UV irradiation, but both UV-Vis spectrophotometry and
H-NMR spectrometry showed that the flavin-catalyzed reduction with visible light was faster. Lastly, the reactivity against two representative biological targets, i.e., human serum albumin and one monofilament oligonucleotide fragment, was evaluated by high-resolution mass spectrometry. The results clearly pointed out that the prodrug
did not interact with these targets until its photoreduction to the Pt(II) analogue.
44Sc is a promising radionuclide for positron emission tomography (PET) in nuclear medicine. As a part of the implementation of a production site for 44Sc, precise knowledge of the activity of the ...product is necessary. At the Paul Scherrer Institute (PSI) and the University of Bern (UniBE), 44Sc is produced by enriched 44CaO-target irradiation with a cyclotron. The two sites use different techniques for activity measurement, namely a dose calibrator at the PSI and a gamma-ray spectrometry system at UniBE and PSI. In this work, the 44Sc was produced at the PSI, and samples of the product were prepared in dedicated containers for onsite measurements at PSI, UniBE, and the Institute of Radiation Physics (IRA) in Lausanne for precise activity measurement using primary techniques and for the calibration of the reference ionization chambers. An accuracy of 1% was obtained for the activity measurement, allowing for a precise calibration of the dose calibrator and gamma-ray spectrometry of the two production sites. Each production site now has the capability of measuring 44Sc activity with an accuracy of 2%.
Objectives. To investigate the ability of bone marrow (BM)-derived mesenchymal stromal cells (BM-MSCs) in suppressing the proliferation of stimulated lymphocytes across a range of conditions ...including autologous BM-MSCs derived from autoimmune disease (AD) patients.
Methods.
In vitro cultures of BM-MSCs from healthy donors and AD patients were established and characterized by their differentiation potential into adipocytes and osteoblasts, and their fibroblast-colony-forming unit (CFU-F) ability and phenotype by flow cytometry.
BM-MSCs (irradiated and non-irradiated) from healthy and AD patients were tested for their ability to suppress the in vitro proliferation of autologous and allogeneic peripheral blood mononuclear cells (PBMC) (from healthy donors and patients suffering from various ADs) stimulated with anti-CD3ε antibody alone or in combination with anti-CD28 antibody. The anti-proliferative effect of the BM-MSCs from healthy donors was tested also on transformed B-cell lines as a model of non-antigen-stimulated lymphocytes.
Results. BM-MSCs from healthy donors and AD patients reduced the proliferation of autologous and allogeneic PBMCs by up to 90% in a cell dose-dependent fashion. The immunosuppression was independent of the proliferation of the BM-MSCs and was also effective on already proliferating cells. It was independent also of the clinical activity of AD.
An MSC dose-dependent pattern of suppression of proliferation was observed also with transformed B-cell lines, similar to that observed with proliferating PBMC.
Conclusions.The BM-MSCs exhibit extensive anti-proliferative properties against lymphocytes under different conditions. This property might offer a form of immunomodulatory cellular therapy for AD patients if further confirmed in animal models.
44Sc has favorable properties for cancer diagnosis using Positron Emission Tomography (PET) making it a promising candidate for application in nuclear medicine. The implementation of its production ...with existing compact medical cyclotrons would mean the next essential milestone in the development of this radionuclide. While the production and application of 44Sc has been comprehensively investigated, the development of specific targetry and irradiation methods is of paramount importance. As a result, the target was optimized for the 44Ca(p,n)44Sc nuclear reaction using CaO instead of CaCO3, ensuring decrease in target radioactive degassing during irradiation and increased radionuclidic yield. Irradiations were performed at the research cyclotron at the Paul Scherrer Institute (~11 MeV, 50 µA, 90 min) and the medical cyclotron at the University of Bern (~13 MeV, 10 µA, 240 min), with yields varying from 200 MBq to 16 GBq. The development of targetry, chemical separation as well as the practical issues and implications of irradiations, are analyzed and discussed. As a proof-of-concept study, the 44Sc produced at the medical cyclotron was used for a preclinical study using a previously developed albumin-binding prostate-specific membrane antigen (PSMA) ligand. This work demonstrates the feasibility to produce 44Sc with high yields and radionuclidic purity using a medical cyclotron, equipped with a commercial solid target station.
In the last two decades, the use of phthalates has been restricted worldwide due to their well-known toxicity. Nonetheless, phthalates are still widely used for their versatility, high plasticization ...effect, low cost, and lack of valuable alternatives. This study presents the fully bio-based and versatile glycerol trilevulinate plasticizer (GT) that was obtained by the valorization of glycerol and levulinic acid. The mild-conditions and solvent-free esterification used to synthesize GT was optimized by investigating the product by Fourier transform infrared and NMR spectroscopy. An increasing content of GT, from 10 to 40 parts by weight per hundred parts of resin (phr), was tested with poly(vinyl chloride), poly(3-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(lactic acid), and poly(caprolactone), which typically present complicated processability and/or mechanical properties. GT produced a significant plasticization effect on both amorphous and semicrystalline polymers, reducing their glass-transition temperature and stiffness, as observed by differential scanning calorimetry measurements and tensile tests. Remarkably, GT also decreased both the melting temperature and crystallinity degree of semicrystalline polymers. Furthermore, GT underwent enzyme-mediated hydrolysis to its initial constituents, envisioning a promising prospective for environmental safety and upcycling. Furthermore, 50% inhibitory concentration (IC50) tests, using mouse embryo fibroblasts, proved that GT is an unharmful alternative plasticizer, which makes it potentially applicable in the biomedical field.
The use of Pt(iv) complexes as potential anticancer drugs is attractive, because they have higher stability and less side effects than Pt(ii) compounds. Moreover, some Pt(iv) complexes can also be ...activated with light, opening an avenue to photochemotherapy. Our purpose is to widen the library of photoactivatable Pt(iv)-based prodrugs and here we report on the oxidation of the Pt(ii) compound PtCl(4'-phenyl-2,2':6',2''-terpyridine)CF
SO
(1) with PhICl
or H
O
. The synthetic procedure avoids the formation of multiple species: the treatment with PhICl
produces the Pt(iv) complex with axial chlorides, PtCl
(4'-phenyl-2,2':6',2''-terpyridine)CF
SO
(2), while H
O
oxidation and post-synthesis carboxylation produce Pt(OCOCH
)
Cl(4'-phenyl-2,2':6',2''-terpyridine)CF
SO
(3), bearing acetates in the axial positions. 2 and 3 are stable in physiological-like buffers and in DMSO in the dark, but undergo photoreduction to 1 upon irradiation at 365 nm. Their stability toward reduction is a fundamental parameter to consider: cyclic voltammetry experiments show that the 2 electron reduction Pt(iv) → Pt(ii) occurs at a more negative potential for 3, because of the greater stabilization provided by the acetate axial groups; noteworthily, 3 is stable for hours also in the presence of mM concentration of glutathione. The cytotoxicity of 2 and 3 toward A2780 and A2780cis cell lines reveals that 3 is the least toxic in the dark, but is able to produce cytotoxic effects far higher than cisplatin when irradiated. To shed light on the mechanistic aspects, the interaction with protein and DNA models has been explored through high-resolution mass spectrometry revealing that 2 and 3 behave as prodrugs, but are able to bind to biological targets only after irradiation.
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