Simultaneous quantitative analysis of letrozole, its carbinol metabolite, and carbinol glucuronide in human plasma by LC-MS/MS

Letrozole is an efficient endocrine treatment of postmenopausal breast cancer, however, not all patients benefit from this treatment, and moreover, severe side-effects like arthralgia frequently lead to discontinuation. To better understand inter-individual variability in drug response and side-effects, plasma analysis of steady-state concentrations of letrozole and its major metabolites is crucial. We developed a rapid, sensitive, and specific method for the simultaneous quantification of letrozole and its metabolites 4,4′-(hydroxymethylene)dibenzonitrile (carbinol) and bis(4-cyanophenyl)methyl hexopyranosiduronic acid (carbinol-gluc) by UHPLC-ESI-MS/MS using in-house synthesized, stable isotope-labeled internal standards. Following solid-phase extraction in BondElut C18 96-well plates, the analytes were separated on a ZORBAX Eclipse XDB-C18 column (1.8 μm, 4.6 × 50 mm) with a gradient of acetonitrile in 0.1% acetic acid in water and detected on a triple quadrupole mass spectrometer with electrospray ionization in the multiple reaction monitoring mode. Lower limits of quantification were 20, 0.2, and 2 nM for letrozole, carbinol, and carbinol-gluc, respectively. The assay has been validated according to FDA guidance and applied to the analysis of 20 plasma samples of postmenopausal breast cancer patients treated with 2.5 mg of letrozole per day. Mean plasma levels (±SD) were 366 ± 173, 0.38 ± 0.09, and 34 ± 12 nM for letrozole, carbinol, and carbinol-gluc, respectively. Our rapid and sensitive mass spectrometry based method enables future pharmacokinetic investigations of letrozole outcome.     

Optical parametric generation in CdSiP2 at 6.125 μm pumped by 8 ns long pulses at 1064 nm

A 21.4 mm long noncritically cut CdSiP2 crystal, pumped by 8 ns pulses at 1064 nm in a double-pass configuration for pump, signal, and idler, generated 523 μJ, 5.8 ns idler pulses at 6.125 μm. The average power of 52.3 mW at the repetition rate of 100 Hz is the highest ever achieved at such wavelengths with direct down conversion from the 1 μm spectral range.     

A superoleophobic textile repellent towards impacting drops of alkanes

A commercially available polyester fabric has been rendered superoleophobic by coating with silicone nanofilaments and subsequent plasma fluorination. The treated samples show outstanding oil-repellency. They achieve the highest possible oil-repellency grade of 8, repel impacting drops of alkanes and show a plastron layer in hexadecane. The oil repellency is shown to depend on the topography of the silicone nanofilament coating.     

Types of self-motions of planar Stewart Gough platforms

We show that the self-motions of general planar Stewart Gough platforms can be characterized in the complex extension of the Euclidean 3-space by the movement of three platform points in planes orthogonal to the planar base (3-point Darboux motion) and a simultaneous sliding of three planes orthogonal to the planar platform through points of the base (3-plane Mannheim motion). Based on this consideration, we prove that all one-parametric self-motions of a general planar Stewart Gough platform can be classified into two types (type I DM and type II DM, where DM abbreviates Darboux Mannheim). We also succeed in presenting a set of 24 equations yielding a type II DM self-motion that can be computed explicitly and that is of great simplicity seen in the context of self-motions. These 24 conditions are the key for the complete classification of general planar Stewart Gough platforms with type II DM self-motions, which is an important step in solving the famous Borel Bricard problem.     

Ultraviolet resonance Raman spectroscopy of locked single‐stranded oligo(dA) reveals conformational implications of the locked ribose in LNA

We report here the first UV resonance Raman spectroscopic (UVRRS) study on locked nucleic acid (LNA) oligomers. Locking a base in nucleic acid (NA) oligomers produces a conformational change in the glycosyl bond between backbone and base. We present evidence of this change in LNAs when compared to their natural analogs using UVRRS. Wavenumber downshifts and peak amplitude increases, especially of the ∼1481 cm⁻¹ peak that is a spectral marker for part of the glycosyl bond, correlate with the fraction of locked bases when single‐stranded oligomers incorporating up to three locked bases were examined. By varying the position of the locked base within a fixed length sequence, we conclude that one, or at most two bases, on either side of the lock is affected. We further conclude from these data, and previously published reports, that the conformation of LNA is determined by imidazole–imidazole and pyrimidine–pyrimidine repulsion and imidazole–pyrimidine attraction in contrast to dispersion attraction‐dependent aggregation in the B conformation of DNA. Copyright © 2009 John Wiley & Sons, Ltd.     

Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer

Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960’s. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes—as well complexes with other metals (osmium, iron, platinum)—can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.     

Revealing the Distribution of Metal Carboxylates in Oil Paint from the Micro‐ to Nanoscale

Oil paints comprise pigments, drying oils, and additives that together confer desirable properties, but can react to form metal carboxylates (soaps) that may damage artworks over time. To obtain information on soap formation and aggregation, we introduce a new tapping‐mode measurement paradigm for the photothermal induced resonance (PTIR) technique that enables nanoscale IR spectroscopy and imaging on highly heterogenous and rough paint thin sections. PTIR is used in combination with μ‐computed tomography and IR microscopy to determine the distribution of metal carboxylates in a 23‐year old oil paint of known formulation. Results show that heterogeneous agglomerates of Al‐stearate and a Zn‐carboxylate complex with Zn‐stearate nano‐aggregates in proximity are distributed randomly in the paint. The gradients of zinc carboxylates are unrelated to the Al‐stearate distribution. These measurements open a new chemically sensitive nanoscale observation window on the distribution of metal soaps that can bring insights for understanding soap formation in oil paint.