Phosphate Coordination to Metal-Organic Layer Secondary Building Units Prolongs Drug Retention for Synergistic Chemoradiotherapy

Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy. In the meantime, the MOL sensitizes cancer cells to X-ray irradiation and provides potent radiotherapeutic effects. GMP-loaded MOL (GMP/MOL) enhances cytotoxicity by 2-fold and improves radiotherapeutic effects over free GMP in vitro. In a colon cancer model, GMP/MOL retains GMP in tumors for more than four days and, when combined with low-dose radiotherapy, inhibits tumor growth by 98 %. The synergistic chemoradiotherapy enabled by GMP/MOL shows a cure rate of 50 %, improves survival, and ameliorates cancer-proliferation histological biomarkers.     

Enzyme-Mediated Preparation of (+)- and (–)-cis-α-Irone and (+)- and (–)-trans-α-Irone

The preparation of (−)- and (+)-trans-α-irone ( 1a and 1b , resp.) and of (+)- and (−)-cis-α-irone ( 1c and 1d , resp.) from commercially available Irone alpha ^® is reported. The relevant step in the synthetic sequence is the initial chromatographic separation of crystalline (±)-4,5-epoxy-4,5-dihydro-cis-α-irone ((±)- 5 ) from oily (±)-4,5-epoxy-4,5-dihydro-trans-α-irone ((±)- 4 ). The latter was subsequently converted, after NaBH₄ reduction, into the crystalline 3,5-dinitrobenzoate ester (±)- 8 , thus allowing a complete separation of the two corresponding diastereoisomeric alcohol derivatives. Suitable enantiomerically pure precursors of the desired products 1a – d were obtained by kinetic resolution of the racemic allylic alcohols derived from (±)- 5 and (±)- 8 , mediated by lipase PS (Amano). The last steps consisted of MnO₂ oxidation and removal of the epoxy moiety with Me₃SiCl/NaI in MeCN. External panel olfactory evaluation showed that (−)-cis-α-irone ( 1d ) has the finest and most distinct `orris butter' character.     

Spectral properties of (5-phenyl-1,3,4-oxadiazol-2-yl)-7-hydroxycoumarin (POHC)

The electronic absorption, emission and excitation spectra of POHC were measured in different solvents and are affected by solvent polarity. The fluorescence quantum yield of POHC decreases with increasing Richardt and Dimorth solvent parameter (E(T)) value of the solvent. In dilute solutions POHC is almost totally present in its protonated nitrogen tautomer form. The deprotonation is a reversible process. A shoulder in the absorption spectra at approximately 473 nm indicates the presence of a portion of the tautomer (s) that disappears on lowering the temperature. Molecular oxygen acts as a quencher with quenching rate constant of 1.8 x 10(10) M(-1) s(-1) in DMF. Energy transfer from POHC to rhodamine 6G in ethanol was also studied. POHC is relatively photostable in ethanol (phic approximately 1.7 x 10(-4)). Quantum chemical calculations were carried out and correlated to experimental observations.     

Bayesian Copulae Distributions, with Application to Operational Risk Management

The aim of this paper is to introduce a new methodology for operational risk management, based on Bayesian copulae. One of the main problems related to operational risk management is understanding the complex dependence structure of the associated variables. In order to model this structure in a flexible way, we construct a method based on copulae. This allows us to split the joint multivariate probability distribution of a random vector of losses into individual components characterized by univariate marginals. Thus, copula functions embody all the information about the correlation between variables and provide a useful technique for modelling the dependency of a high number of marginals. Another important problem in operational risk modelling is the lack of loss data. This suggests the use of Bayesian models, computed via simulation methods and, in particular, Markov chain Monte Carlo. We propose a new methodology for modelling operational risk and for estimating the required capital. This methodology combines the use of copulae and Bayesian models.      

Apoptosis induction and mitochondria alteration in human HeLa tumour cells by photoproducts of Rose Bengal acetate

The aim of this work was to investigate the apoptosis induction and mitochondria alteration after photodamage exerted by incubation of HeLa cells with Rose Bengal acetate-derivative (RBAc) followed by irradiation for a total dose of 1.6 J/cm2. This treatment was previously demonstrated to reduce cell viability under mild treatment conditions, suggesting the restoration of the photoactive molecule in particularly sensitive cell sites. Indeed, Rose Bengal (RB) is a very efficient photosensitizer, whose photophysical properties are inactivated by addition of the quencher group acetate. The RBAc behaves as a fluorogenic substrate by entering easily the cells where the original, photoactive molecule is restored by specific esterases. Different intracellular sites of photodamage of RB are present. In particular, fluorescence imaging of Rodamine 123 and JC-1 labelled cells showed altered morphology and loss of potential membrane of mitochondria. MTT and NR assays gave indications of alteration of mitochondrial and lysosomal enzyme activities. These damaged sites were likely responsible for triggering apoptosis. Significant amount of apoptotic cell death (about 40%) was induced after light irradiation followed RBAc incubation as revealed by morphological (modification of cell shape and blebs formation), cytochemical (FITC-Annexin-V positive cells) and nuclear fragmentation assays.     

Montmorillonite as an adsorbent for extraction and concentration of atrazine, propazine, deethylatrazine, deisopropylatrazine and hydroxyatrazine

Adsorption properties of the clay mineral montmorillonite in the potassium homoionic form (KMT) was investigated to achieve the extraction and concentration of the herbicides atrazine (AT) and propazine (PROP), as well as the main degradation products of atrazine, namely deethylatrazine (DEA), deisopropylatrazine (DIA) and hydroxyatrazine (ATOH). A batch approach was proposed, with recovery percentages for AT, PROP and DIA higher than 90% at concentrations of 0.50 and 2.50 μg L⁻¹. For DEA and ATOH, however, low recoveries were obtained. For DEA, this fact can be explained by its low K_d with KMT, contrary to ATOH, which interacts strongly with the mineral surface, hindering the complete desorption and hence, generating low recovery percentages. The influence of pH, ionic strength and humic acid was studied, and a comparison with the C₁₈ phase as SPE cartridges was carried out. Montmorillonite showed a similar performance to commercial cartridge for concentrations of AT, DEA and PROP, but better recoveries for DIA was obtained using the clay mineral. For ATOH the recovery was also higher on the clay mineral, although for this compound the most suitable SPE cartridge is constituted by cation exchange resin. After the concentration and elution steps, the 0.50 and 2.50 μg L⁻¹ gave chromatographic peak areas that could be easily quantified with an analytical curve obtained in the concentration range between 7.5 and 100 μg L⁻¹. The obtained concentration factors are suitable to allow the application of the method to the monitoring of triazine residues in drinking water.     

A liquid chromatography‐atmospheric pressure photoionization tandem mass spectrometric (LC‐APPI‐MS/MS) method for the determination of triterpenoids in medicinal plant extracts

An analytical method using liquid chromatography‐atmospheric pressure photoionization tandem mass spectrometry with toluene as a dopant was developed for the determination of triterpenes in medicinal plant extracts. The 12 compounds determined have been shown to exhibit biological activity, such as gastroprotective, hepatoprotective, anti‐inflammatory, antiviral and anti‐tumor effects. The parameters of the atmospheric pressure photoionization interface were optimized to obtain the highest possible sensitivity for all of the compounds. The limits of detection and quantification ranged from 0.4 to 157.9 µg l^?1 and 1.3 to 526.4 µg l^?1, respectively. The method was validated and applied to extracts of five medicinal plants species (Mansoa alliacea (Lam.) A.H.Gentry, Bauhinia variegata var variegata, Bauhinia variegata var alboflava, Cecropia obtuse Trécul and Cecropia palmate Willd) from the Amazonian region. The concentrations of the six triterpenes quantified in the samples ranged from 0.424 mg kg^?1 for ursolic acid to 371.96 mg kg^?1 for β‐amyrin, which were quantified by using the standard addition method (n = 3). Copyright © 2016 John Wiley & Sons, Ltd.     

Stable Peptides Instead of Stapled Peptides: Highly Potent αvβ6‐Selective Integrin Ligands

The αvβ6 integrin binds the RGD‐containing peptide of the foot and mouth disease virus with high selectivity. In this study, the long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub‐nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins. Computational studies were performed to disclose the molecular bases underlying the high binding affinity and receptor subtype selectivity of this peptide. Finally, the utility of the ligand for use in biomedical studies was also demonstrated here.     

Laboratory tests addressed to realize customized restoration procedures of underwater archaeological ceramic finds

The present contribution is part of a biennial research project funded by the Italian Ministry of Education, Universities and Research (MIUR). This study, currently in progress, deals with innovative experimental approaches applied to the chemical, mineralogical and physical transformations occurring during the prolonged permanence of archaeological ceramic finds in seawater environments as well as to restoration and conservation issues of the same underwater artifacts. The experimental approach used in this research consisted in the manufacture of ceramic test-pieces (briquettes) and their successive placing in underwater environment. This work aims at assessing how textural and compositional parameters along with firing temperatures of a ceramic paste could affect total porosity, pore size distribution and kinetics of capillary water absorption. A further purpose is concerned with the study of the potential modification of porosity and pore size distribution in the same ceramic bodies after immersion in seawater (3 and 6 months). The study was carried out using a multi-technique approach including investigations through polarized light microscopy (PLM), capillary water absorption test, mercury intrusion porosimetry (MIP) analyses and theoretical calculation of salt crystallization pressures. The obtained results show a different behavior of the six experimental pastes as a function of their compositional and textural features as well as pore size distribution and firing temperatures. These parameters, in various extents, have been found significantly influencing the kinetics of water absorption and the susceptibility of ceramic artifacts to salt crystallization processes, with important implications on conservation procedures needed before the musealization.