Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development,Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.     

The kinetics of homogeneous nucleation of silver nanoparticles stabilized by polymers

The formation of Ag nanoparticles synthesized by homogeneous nucleation, stabilized by polymers (PVA and PVP) was monitored by UV–Vis spectrophotometry and transmission electron microscopy. Our aim was to differentiate between the two main phases of particle formation, i.e. nucleation and growth and to characterize their rates with the help of appropriate kinetic equations. Time resolved spectrophotometric measurements revealed that particle formation is an autocatalytic process: a slow, continuous nucleation phase (3–5 min) is followed by a rapid, autocatalytic growth phase where the maximal particle size is 5–7 nm. By freezing the reaction mixture, the process of particle growth can be followed from 5 to 40 min on TEM pictures. The first order rate constants were calculated and they are strongly depend on the polymer concentration. If the growing particles are attached by PEI to the surface of a solid support, the formation of silver nanoparticles can also be followed by atomic force microscopy (AFM) and we can control the particle growth on mica surface. The cross section analysis of the pictures show, that the particle growing process can be also monitored at solid–liquid interface.     

Direct evidence for As as a Zn-site impurity in ZnO

Arsenic has been reported in the literature as one of the few p-type dopants in the technologically promising II-VI semiconductor ZnO. However, there is an ongoing debate whether the p-type character is due to As simply replacing O atoms or to the formation of more complicated defect complexes, possibly involving As on Zn sites. We have determined the lattice location of implanted As in ZnO by means of conversion-electron emission channeling from radioactive (73)As. In contrast to what one might expect from its nature as a group V element, we find that As does not occupy substitutional O sites but in its large majority substitutional Zn sites. Arsenic in ZnO (and probably also in GaN) is thus an interesting example for an impurity in a semiconductor where the major impurity lattice site is determined by atomic size and electronegativity rather than its position in the periodic system.     

New convolutions and their applicability to integral equations of Wiener-Hopf plus Hankel type

We propose four new convolutions exhibiting convenient factorization properties associated with two finite interval integral transformations of Fourier-type together with their norm inequalities. Moreover, we study the solvability of a class of integral equations of Wiener-Hopf plus Hankel type (on finite intervals) with the help of the factorization identities of such convolutions. Fourier-type series are used to produce the solution formula of such equations, and a Shannon-type sampling formula is also obtained.     

Addendum to: Comparison between different types of abstract integrals in riesz spaces

In [3] we did not give explicitly the definition of measurability for realvalued functions, with respect to finitely additive measures with values in a Dedekind complete Riesz space. We note that, in [3], all involved functions are intended to be measurable. We now report the definition of measurability, which we gave in [2] (Definition 3.2).     

Interpreting technical evidence from spectral imaging of paintings by Édouard Manet in the Courtauld Gallery

The paintings by Édouard Manet in The Courtauld Gallery Déjeuner sur l'herbe (1863–68), Marguerite de Conflans en Toilette de Bal (1870–1880), Banks of the Seine at Argenteuil (1874), and A Bar at the Folies–Bergère (1882) were investigated for the first time using a range of non-invasive in situ analyses. The aims of the study were to investigate the painting techniques and materials used for this group of works and to critically evaluate the technical evidence derived from the integrated use of imaging techniques and portable spectroscopic methods in this context. The paintings were investigated by means of macro X-ray fluorescence (MA-XRF), reflection spectral imaging, portable UV–Vis–NIR spectroscopy, portable Raman spectroscopy, and reflection FTIR. MA-XRF and reflection spectral imaging allowed visualising elements in the compositions that were not visible using traditional methods of technical study. For example, MA-XRF analysis of Déjeuner sur l'herbe revealed elements of the development of the composition that provided new evidence to consider its relationship to other versions of the composition. The study also highlighted questions about the interpretation of elemental distribution maps and spectral images that did not correspond to the reworking visible in X-radiographs. For example, in A Bar at the Folies–Bergère Manet made numerous changes during painting, which were not clearly visualised with any of the techniques used. The research has wider implications for the study of Impressionist paintings, as the results will support technical studies of works by other artists of the period who used similar materials and painting methods.     

A DFT study of the conformational and electronic properties of echinatin,a retrochalcone,and its anion in the gas phase and aqueous solution

Structural Chemistry - Echinatin (Ech), a characteristic retrochalcone isolated from liquorice, a widely used herbal medicine, has been investigated in detail in terms of its conformational and...     

Asymptotic results for weighted means of linear combinations of independent Poisson random variables

ABSTRACT

In this paper we prove the large deviation principle for a class of weighted means of linear combinations of independent Poisson distributed random variables, which converge weakly to a normal distribution. The interest in these linear combinations is motivated by the diffusion approximation in Lansky [On approximations of Stein's neuronal model, J. Theoret. Biol. 107 (1984), pp. 631–647] of the Stein's neuronal model (see Stein [A theoretical analysis of neuronal variability, Biophys. J. 5 (1965), pp. 173–194]). We also prove an analogue result for sequences of multivariate random variables based on the diffusion approximation in Tamborrino, Sacerdote, and Jacobsen [Weak convergence of marked point processes generated by crossings of multivariate jump processes. Applications to neural network modeling, Phys. D 288 (2014), pp. 45–52]. The weighted means studied in this paper generalize the logarithmic means. We also investigate moderate deviations.     

Multiplexed therapeutic drug monitoring of antipsychotics in dried plasma spots by LC‐MS/MS

In this work, a convenient method for the therapeutic monitoring of seven common antipsychotic drugs in “dried plasma spot” samples has been developed. It is based on the liquid chromatography tandem mass spectrometry technique, operating in multiple reaction monitoring mode, and a straightforward procedure for the simultaneous extraction of all antipsychotics in a single step, with high extraction yield. The method was fully validated with proper accuracy, precision, selectivity and sensitivity, for all the drugs. Limits of quantification were 0.12, 1.09, 1.46, 1.47, 5.70, 1.32, 1.33 µg/L for haloperidol, aripiprazole, olanzapine, quetiapine, clozapine, risperidone, and paliperidone, respectively. Accuracy, intra‐ and interday precision values were <10% for all drugs at all concentration levels examined. The method was tested in the analysis of 30 plasma samples from real patients for each drug. The proposed analytical approach, by combining practical and logistical advantages of microsampling with liquid chromatography tandem mass spectrometry analytical performance, could offer an ideal strategy for accurate and timely therapeutic drug monitoring of antipsychotic drugs in most clinical settings, even in remote centers and/or in out‐patient settings, bringing so many potential improvements in psychiatric patient care.