Combined Treatment with PI3K Inhibitors BYL-719 and CAL-101 Is a Promising Antiproliferative Strategy in Human Rhabdomyosarcoma Cells

Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer arising from skeletal muscle myogenic progenitors. Recent studies have shown an important role for AKT signaling in RMS progression. Aberrant activation of the PI3K/AKT axis is one of the most frequent events occurring in human cancers and serves to disconnect the control of cell growth, survival, and metabolism from exogenous growth stimuli. In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, {"type":"entrez-protein","attrs":{"text":"CZC24832","term_id":"994587862","term_text":"CZC24832"}}CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. Cytotoxicity, cell cycle, apoptosis, and the activation of downstream targets were analyzed. Of the individual inhibitors, BYL-719 demonstrated the most anti-tumorgenic properties. BYL-719 treatment resulted in G1/G0 phase cell cycle arrest and apoptosis. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.     

Studies on the synthesis of heterocyclic compounds. XIV. Cleavage of 1,3-benzoxathioles by magnesium bromide-acetic anhydride

The cleavage reaction of some 1,3-benzoxathioles with magnesium bromide and acetic anhydride has been studied. In all the 1,3-benzoxathioles studied, the opening of the heterocyclic ring occurs first with cleavage of the C O bond and formation of bromides and their corresponding products of hydrolysis. Successively also the cleavage of the C S bond can occur. The competitive electrophilic substitution on the benzene ring becomes appreciable only in the 1,3-benzoxathioles-2,2-disubstituted with sterically demanding groups. The structure of newly prepared compounds has been determined by analytical and spectroscopic data and when possible by comparison with authentic samples.     

Development of an integrated chromatographic system for on-line digestion and characterization of phosphorylated proteins

The development of an integrated chromatographic system for complete phosphoprotein analysis is described. The digestion of phosphoproteins with trypsin- or pronase-based monolithic bioreactors is carried out on-line with selective enrichment on a TiO(2) trap and separation of the produced phosphopeptides by reversed-phase liquid chromatography-multiple mass spectrometry (RPLC/MS(n)). A detailed study on the selective extraction of peptides with different degrees of phosphorylation on TiO(2) cartridges is discussed. This analytical strategy has been optimized using beta-casein as a standard phosphoprotein, and then applied to the identification of phosphorylation sites in insulin-like grow factor-binding protein 1 (IGFBP-1) isolated from amniotic fluid.     

HPTLC‐MALDI MS for (glyco)sphingolipid multiplexing in tissues and blood: A promising strategy for biomarker discovery and clinical applications

Sphingolipids have hydrophilic and hydrophobic properties, different saturation and combination of the oligosaccharide chains and mass homology of species located in a narrow m/z region hampering their recognition. To target sphingolipids for diagnostic purposes, standardized methods for lipid extraction, quali‐ and quantitative assessments are required. In this study, HPTLC‐MALDI MS was adopted to establish sphingolipid and glycosphingolipid profiles in muscle, brain and serum to create a database of molecules to be searched in the preclinical and clinical investigations. Specific protocols for lipid extraction were set up based on the characteristics of the tissue or/and fluids; this approach maximizes the HPTLC‐MALDI MS analytical throughput both for lipids extracted in organic and aqueous phase. This study indicates that alkaline hydrolysis is necessary for the detection of low abundant species such as Gb3Cer and ceramides in serum and Gb4Cer, CerP and HexCer in muscle tissue. The high hydrophobicity of ceramides has been overcome by the development of HPTLC plate in chloroform:methanol/50:3.5, which increases the number and the intensity of low abundant Cer species. MS/MS analysis has been conducted directly on HPTLC plate allowing the molecular recognition; furthermore a dataset of spectra was acquired to create a database for future profiling of these molecules.     

Asymptotic Results for First-Passage Times of Some Exponential Processes

Methodology and Computing in Applied Probability - We consider the process {V (t) : t ≥ 0} defined by V (t) = v0eX(t) (for all t ≥ 0), where v0 > 0 and {X(t) :...     

Membrane distillation operated at high seawater concentration factors: Role of the membrane on CaCO3 scaling in presence of humic acid

This study aims at investigating the kinetics of calcium carbonate precipitation (scaling), that occurs in the form of vaterite, when treating seawater by direct contact membrane distillation (DCMD) operated at high concentration factors (from 4 to 6). Induction time measurements carried out by dynamic light scattering (DLS) allowed to identify the shifting between homogeneous and heterogeneous nucleation mechanisms as a function of supersaturation. CaCO₃ interfacial energy, evaluated for concentrated seawater solutions as 45 mJ/m², increased by 7% as a consequence of the inhibition effect of humic acid, and it was reduced to 32 mJ/m² in correspondence of heterogeneous nucleation occurring on microporous polypropylene membranes. Gibbs free energy barrier to the formation of critical nuclei was predicted with good accuracy as a function of physico-chemical properties of the membrane (porosity: 0.70, contact angle: 115 ± 2°).     

Control of the vortex flow in microchannel arrays produced in YBCO films by heavy-ion lithography

High-energy heavy-ion lithography is a powerful tool for tuning both structural and electromagnetic properties of high temperature superconductors by inducing nanometer scale defects confined in micron scale patterns. We show how the vortex dynamics in YBCO thin films patterned by heavy-ion lithography can be controlled and potentially exploited for device applications. Both local critical temperature and local critical currents are effectively tailored by the imposed irradiation geometry. The direct visualization of the real-time dynamics of the magnetic pattern is achieved by the magneto-optical imaging technique, while confined vortex flow is revealed by the simultaneous measurement of the electrical resistance both along and perpendicular (Hall resistance) to the direction of the applied current. It is shown that, for microchannel arrays inclined with respect to the transport current flow, the direction of vortex motion is solely determined by the imposed irradiation pattern geometry, in a well-defined temperature range, for a given applied current.     

Bright photoluminescent hybrid mesostructured silica nanoparticles

Bright photoluminescent mesostructured silica nanoparticles were synthesized by the incorporation of fluorescent cyanine dyes into the channels of MCM-41 mesoporous silica. Cyanine molecules were introduced into MCM-41 nanoparticles by physical adsorption and covalent grafting. Several photoluminescent nanoparticles with different organic loadings have been synthesized and characterized by X-ray powder diffraction, high resolution transmission electron microscopy and nitrogen physisorption porosimetry. A detailed photoluminescence study with the analysis of fluorescence lifetimes was carried out to elucidate the cyanine molecules distribution within the pores of MCM-41 nanoparticles and the influence of the encapsulation on the photoemission properties of the guests. The results show that highly stable photoluminescent hybrid materials with interesting potential applications as photoluminescent probes for diagnostics and imaging can be prepared by both methods.