LC–MS–MS Study of the Pharmacokinetics of a 9-β-Dihydro-9,10-O-acetal Derivative of Docetaxel in Rats and Beagle Dogs

SHR110008 is a representative 9-β-dihydro-9,10-O-acetal taxane with greater anticancer activity and less toxicity than docetaxel. To support a preclinical study of its pharmacokinetics and to predict the effect of 9-β-dihydro-9,10-O-acetal modification on its pharmacokinetic properties, we have developed a sensitive and rapid liquid chromatographic–tandem mass spectrometric method for quantitative analysis of SHR110008 in rat and dog plasma. Plasma was extracted with ethyl acetate. The analytes were separated on a 150 × 4.6 mm i.d., 5 μm particle, reversed-phase C₁₈ column with 90:10 (v/v) methanol–0.1% formic acid as mobile phase at a flow rate of 0.3 mL min^?1. Detection was performed by triple-quadrupole tandem mass spectrometry in selected reaction monitoring (SRM) mode with an electrospray ionization source. The precursor-to-product ion transition m/z 933 → 142 was used. The method was validated for accuracy and precision, and linearity in the two matrices was good. Lower limits of quantification (LLOQ) in rat and dog plasma were 5 and 2 ng mL^?1, respectively. There were no stability-related problems in the procedure for analysis of SHR110008. The method was successfully used in a preclinical study of the pharmacokinetics of SHR110008 in rats and beagle dogs. The pharmacokinetics of SHR110008 were non-linear in rats and dogs. The elimination half-life ranged from 5.18 to 7.32 h for the rats and from 6.42 to 8.42 h for the dogs.     

Clifford Theory for Glider Representations

Classical Clifford theory studies the decomposition of simple G-modules into simple H-modules for some normal subgroup H ? G. In this paper we deal with chains of normal subgroups 1?G ₁?· · ·?G _d = G, which allow to consider fragments and in particular glider representations. These are given by a descending chain of vector spaces over some field K and relate different representations of the groups appearing in the chain. Picking some normal subgroup H ? G one obtains a normal subchain and one can construct an induced fragment structure. Moreover, a notion of irreducibility of fragments is introduced, which completes the list of ingredients to perform a Clifford theory.     

Improved determination of isolated trans isomers in edible oils by Fourier transform infrared spectroscopy using spectral reconstitution

A substantially more sensitive and accurate alternative to the single-bounce attenuated total reflectance (SB-ATR) Fourier transform infrared spectroscopic method of AOAC/American Oil Chemists' Society (AOCS) was developed for determination of isolated trans isomers, based on transmission measurements using a technique called spectral reconstitution (SR). The method involves the 1:1.5 dilution of an oil with odorless mineral spirits (OMS) containing a spectral marker. The resulting reduction in sample viscosity facilitates the use of a transmission flow cell, with the spectral marker serving to determine the precise dilution ratio. This allows the spectral contributions of the OMS to be eliminated and a facsimile of the neat oil spectrum to be mathematically reconstituted. The transmission-SR (T-SR) procedure was initially evaluated relative to SB-ATR to track changes in the trans content of mixtures of unhydrogenated canola and a highly hydrogenated sunflower oil (0-30% trans). The results indicated that the T-SR procedure had the potential to serve as the basis of an accurate quantitative method. A subsequent T-SR calibration based on the spectral ratioing principle of the SB-ATR AOACIAOCS method was developed by gravimetrically adding trielaidin (0-4%) to extra virgin olive oil (EVO), producing an excellent linear response with a standard deviation (SD) of < 0.04% trans. Subsequent comparison of SB-ATR and T-SR calibrations developed for 5 oils of different types, each spiked with low levels of trielaidin (0-1.2% trans), clearly indicated that SB-ATR was signal-limited, whereas the T-SR procedure performed well. The EVO calibration was subsequently used to predict the added trans content of these spiked oils, after the spectrum of the corresponding unspiked oil had been ratioed out. The resulting plot of predicted versus added trans was linear, with a slope of 1.02 and an overall SD of <0.05% trans. When the spectra of these oils were ratioed against the spectrum of EVO, the trans predictions for some of the oils were offset by 2-3 percentage points, emphasizing the need for the appropriate trans-free reference oil to perform accurate analyses. If the latter condition is met, then T-SR provides a very simple technique, with the potential for automation, for analysis of oils by transmission spectroscopy, with approximately 20x the sensitivity of the AOAC/AOCS SB-ATR method.     

Stroboscopic XMCD-PEEM imaging of standing and propagating spinwave modes in permalloy thin-film structures

Using synchrotron-based stroboscopic photoemission electron microscopy with X-ray circular dichroism as contrast method, we have investigated the high-frequency response of permalloy thin-film structures. Standing precessional modes have been studied in rectangular elements (16 × 32 μm², 10 nm thick) with a high time resolution of about 15 ps in the low-α mode of BESSY. With increasing amplitude of the applied magnetic AC field the particle is driven from an initial symmetric Landau flux-closure state into an asymmetric state and finally into a single-domain state magnetized perpendicular to the applied field H_AC. The electromagnetic microwave field thus can induces a net magnetization in a small particle. This behaviour is a result of the constant throughput of energy (open system) that allows for an increase of local order, contrary to the usual increase on entropy in closed systems. A propagating spinwave in an ultrathin elliptical particle (semi axes 6 × 12 μm², 3 nm thick) was observed in a snapshot series with 25 ps time increment. The phase front of the spinwave with large precessional angle (bright contrast) propagates with a velocity of 8100 m/s, i.e. much faster than typical domain wall velocities in permalloy.     

Plumbonacrite Identified by X‐ray Powder Diffraction Tomography as a Missing Link during Degradation of Red Lead in a Van Gogh Painting

Red lead, a semiconductor pigment used by artists since antiquity, is known to undergo several discoloration phenomena. These transformations are either described as darkening of the pigment caused by the formation of either plattnerite (β‐PbO₂) or galena (PbS) or as whitening by which red lead is converted into anglesite (PbSO₄) or (hydro)cerussite (2 PbCO₃?Pb(OH)₂; PbCO₃). X‐ray powder diffraction tomography, a powerful analytical method that allows visualization of the internal distribution of different crystalline compounds in complex samples, was used to investigate a microscopic paint sample from a Van Gogh painting. A very rare lead mineral, plumbonacrite (3 PbCO₃? Pb(OH)₂?PbO), was revealed to be present. This is the first reported occurrence of this compound in a painting dating from before the mid 20th century. It constitutes the missing link between on the one hand the photoinduced reduction of red lead and on the other hand (hydro)cerussite, and thus sheds new light on the whitening of red lead.     

Poly(phosphoester)s: A New Platform for Degradable Polymers

Poly(phosphoester)s (PPEs) play an important role in nature. They structure and determine life in the form of deoxy‐ and ribonucleic acid (DNA and RNA), and, as pyrophosphates, they store up chemical energy in organisms. Polymer chemistry, however, is dominated by the nondegradable polyolefins and degradable poly(carboxylic ester)s (PCEs) that are produced on a large scale today. Recent studies have illustrated the potential of PPEs for future applications beyond flame retardancy, and provided a coherent vision to implement this classic biopolymer in modern applications that demand biocompatibility and degradability as well as the possibility to adjust the properties to individual needs.     

Molecular,Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of only a few prodrug molecules created a concentration of MMAE sufficient enough for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor-targeted glucuronides attractive for translational medicine.     

Catalytic Oxidation of CO on a Curved Pt(111) Surface: Simultaneous Ignition at All Facets through a Transient CO-O Complex**

The catalytic oxidation of CO on transition metals, such as Pt, is commonly viewed as a sharp transition from the CO-inhibited surface to the active metal, covered with O. However, we find that minor amounts of O are present in the CO-poisoned layer that explain why, surprisingly, CO desorbs at stepped and flat Pt crystal planes at once, regardless of the reaction conditions. Using near-ambient pressure X-ray photoemission and a curved Pt(111) crystal we probe the chemical composition at surfaces with variable step density during the CO oxidation reaction. Analysis of C and O core levels across the curved crystal reveals that, right before light-off, subsurface O builds up within (111) terraces. This is key to trigger the simultaneous ignition of the catalytic reaction at different Pt surfaces: a CO-Pt-O complex is formed that equals the CO chemisorption energy at terraces and steps, leading to the abrupt desorption of poisoning CO from all crystal facets at the same temperature.     

Toward an optimal distribution of b values for intravoxel incoherent motion imaging

The intravoxel incoherent motion (IVIM) theory provides a framework for the separation of perfusion and diffusion effects in diffusion-weighted imaging (DWI). To measure the three free IVIM parameters, DWIs with several diffusion weightings b must be acquired. To date, the used b value distributions are chosen heuristically and vary greatly among researchers. In this work, optimal b value distributions for the three parameter fit are determined using Monte-Carlo simulations for the measurement of a low, medium and high IVIM perfusion regime. The first 16 b values of a b value distribution, which was optimized to be appropriate for all three regimes, are {0, 40, 1000, 240, 10, 750, 90, 390, 170, 10, 620, 210, 100, 0, 530 and 970} in units of seconds per square meter. This distribution performed well for all organs and outperformed a distribution frequently used in the literature. In case of limited acquisition time, the b values should be chosen in the given order, but at least 10 b values should be used for current clinical settings. The overall parameter estimation quality depends strongly and nonlinearly on the signal-to-noise ratio (SNR): it is essential that the SNR is considerably higher than a critical SNR. This critical SNR is about 8 for medium and high IVIM perfusion and 50 for the low IVIM perfusion regime. Initial in vivo IVIM measurements were performed in the abdomen and were in keeping with the numerically simulated results.