Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group

BACKGROUND: The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1-receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy. METHODS: In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 microg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 before cisplatin and placebo on days 2 to 5 (group 2), or placebo before cisplatin and placebo on days 2 to 5 (group 3). Additional medication was available at any time to treat occurrences of vomiting or nausea. RESULTS: In the acute-emesis phase, 93 percent of the patients in groups 1 and 2 combined and 67 percent of those in group 3 had no vomiting (P<0.001). In the delayed-emesis phase, 82 percent of the patients in group 1, 78 percent of those in group 2, and 33 percent of those in group 3 had no vomiting (P<0.001 for the comparison between group 1 or 2 and group 3). The median nausea score in the delayed-emesis phase was significantly lower in group 1 than in group 3 (P=0.003). No serious adverse events were attributed to L-754,030. CONCLUSIONS: The neurokinin-1-receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.     

>700W continuous-wave output power from single laser diode bar

>700 W continuous-wave output power has been demonstrated from a single 1 cm-wide laser bar (~940 nm) with 77% fill factor. Maximum power conversion efficiency (PCE) of 65% has been achieved. Facet power density of 170 mW/mum and maximum PCE of 69% have been measured for 10% fill-factor bars with 3 mm cavity length     

Delaminierungseigenschaften und Scherfestigkeiten von verklebten rotkernigen Buchenholzlamellen

The paper deals with investigations on dry shear strength and delamination behavior of gluelines between beech wood laminations showing no or distinct red heartwood. The investigations covered 36 parameter combinations comprising besides the red heartwood two widths of the laminations, two different adhesive families and two delamination procedures related to verification of adhesive type I or II. The tests revealed no influence of red heartwood on shear strength which for all parameter combinations exceeded almost throughout 10 N/mm². In contrary thereto the delamination tests revealed a distinct dependency of the glueline integrity on red heartwood and width of the adherents. No parameter combination conformed to the requirements of adhesive type I. In case of laminations without red heartwood the requirements of adhesive type II were met. Gluelines between two laminations with red heartwood showed throughout very pronounced delamination above 50%. The integrity of gluelines versus delamination represents one of the essential normative requirements for adhesives used in glued load bearing wooden elements. This proof was not possible for gluelines of beech wood laminations with red heartwood when applying today’s European delamination test procedures and performance requirements developed and established for gluelines of softwood laminations.     

Phenotype Diversity of Macrophages in Osteoarthritis: Implications for Development of Macrophage Modulating Therapies

Chronic inflammation is implicated in numerous human pathologies. In particular, low-grade inflammation is currently recognized as an important mechanism of osteoarthritis (OA), at least in some patients. Among the signs of the inflammatory process are elevated macrophage numbers detected in the OA synovium compared to healthy controls. High macrophage counts also correlate with clinical symptoms of the disease. Macrophages are central players in the development of chronic inflammation, pain, cartilage destruction, and bone remodeling. However, macrophages are also involved in tissue repair and remodeling, including cartilage. Therefore, reduction of macrophage content in the joints correlates with deleterious effects in OA models. Macrophage population is heterogeneous and dynamic, with phenotype transitions being induced by a variety of stimuli. In order to effectively use the macrophage inflammatory circuit for treatment of OA, it is important to understand macrophage heterogeneity and interactions with surrounding cells and tissues in the joint. In this review, we discuss functional phenotypes of macrophages and specific targeting approaches relevant for OA treatment development.     

Hydration Shells of DNA from the Point of View of Terahertz Time-Domain Spectroscopy

Hydration plays a fundamental role in DNA structure and functioning. However, the hydration shell has been studied only up to the scale of 10–20 water molecules per nucleotide. In the current work, hydration shells of DNA were studied in a solution by terahertz time-domain spectroscopy. The THz spectra of three DNA solutions (in water, 40 mm MgCl₂ and 150 mM KCl) were transformed using an effective medium model to obtain dielectric permittivities of the water phase of solutions. Then, the parameters of two relaxation bands related to bound and free water molecules, as well as to intermolecular oscillations, were calculated. The hydration shells of DNA differ from undisturbed water by the presence of strongly bound water molecules, a higher number of free molecules and an increased number of hydrogen bonds. The presence of 40 mM MgCl₂ in the solution almost does not alter the hydration shell parameters. At the same time, 150 mM KCl significantly attenuates all the found effects of hydration. Different effects of salts on hydration cannot be explained by the difference in ionic strength of solutions, they should be attributed to the specific action of Mg²⁺ and K⁺ ions. The obtained results significantly expand the existing knowledge about DNA hydration and demonstrate a high potential for using the THz time-domain spectroscopy method.     

Convective heat transfer of ferrofluid in a lid-driven cavity with a heat-conducting solid backward step under the effect of a variable magnetic field

The effect of variable magnetic field on the mixed convective flow of a ferrofluid within a lid-driven cavity has been analyzed numerically. A heat-conducting solid block is located in the bottom part of the cavity. Governing partial differential equations have been formulated taking into account that the magnetic source is a point source located over the moving lid. Analysis has been performed for a wide range of Hartmann number, nanoparticles volume fraction, and magnetic number. It has been found that the growth of the magnetic number leads to the heat transfer enhancement.     

Radikalabfang. I. ESR-spektroskopische Untersuchungen von Radikalreaktionen einiger 3-Nitrono-6-oxo-cyclohexadiene

Spin Trapping. I. Investigation of Radical Reactions of Some 3-Nitrono-6-oxocyclohexadienes by ESR-Spectroscopy The title compounds ( 3, 4 and 5 ) add O- and C-centered radicals to the nitrono group to yield spin adducts containing a 4-oxo-cyclohexadienyl group in the α-position ( 6, 7 and 8 ). These new nitroxylradicals undergo α- and ß-scission. The nitroxyl radicals and the paramagnetic decomposition products were detected by esr-spectroscopy. Further, a more general way of radical-induced decomposition was discussed.     

Comparative Analysis of Exo- and Endonuclease Activities of APE1-like Enzymes

Apurinic/apyrimidinic (AP)-endonucleases are multifunctional enzymes that are required for cell viability. AP-endonucleases incise DNA 5′ to an AP-site; can recognize and process some damaged nucleosides; and possess 3′-phosphodiesterase, 3′-phosphatase, and endoribonuclease activities. To elucidate the mechanism of substrate cleavage in detail, we analyzed the effect of mono- and divalent metal ions on the exo- and endonuclease activities of four homologous APE1-like endonucleases (from an insect (Rrp1), amphibian (xAPE1), fish (zAPE1), and from humans (hAPE1)). It was found that the enzymes had similar patterns of dependence on metal ions’ concentrations in terms of AP-endonuclease activity, suggesting that the main biological function (AP-site cleavage) was highly conserved among evolutionarily distant species. The efficiency of the 3′-5′ exonuclease activity was the highest in hAPE1 among these enzymes. In contrast, the endoribonuclease activity of the enzymes could be ranked as hAPE1 ≈ zAPE1 ≤ xAPE1 ≤ Rrp1. Taken together, the results revealed that the tested enzymes differed significantly in their capacity for substrate cleavage, even though the most important catalytic and substrate-binding amino acid residues were conserved. It can be concluded that substrate specificity and cleavage efficiency were controlled by factors external to the catalytic site, e.g., the N-terminal domain of these enzymes.     

Adaptation to Hypoxia May Promote Therapeutic Resistance to Androgen Receptor Inhibition in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) surpasses other BC subtypes as the most challenging to treat due to its lack of traditional BC biomarkers. Nearly 30% of TNBC patients express the androgen receptor (AR), and the blockade of androgen production and AR signaling have been the cornerstones of therapies for AR-positive TNBC. However, the majority of women are resistant to AR-targeted therapy, which is a major impediment to improving outcomes for the AR-positive TNBC subpopulation. The hypoxia signaling cascade is frequently activated in the tumor microenvironment in response to low oxygen levels; activation of the hypoxia signaling cascade allows tumors to survive despite hypoxia-mediated interference with cellular metabolism. The activation of hypoxia signaling networks in TNBC promotes resistance to most anticancer drugs including AR inhibitors. The activation of hypoxia network signaling occurs more frequently in TNBC compared to other BC subtypes. Herein, we examine the (1) interplay between hypoxia signaling networks and AR and (2) whether hypoxia and hypoxic stress adaptive pathways promote the emergence of resistance to therapies that target AR. We also pose the well-supported question, “Can the efficacy of androgen-/AR-targeted treatments be enhanced by co-targeting hypoxia?” By critically examining the evidence and the complex entwinement of these two oncogenic pathways, we argue that the simultaneous targeting of androgen biosynthesis/AR signaling and hypoxia may enhance the sensitivity of AR-positive TNBCs to AR-targeted treatments, derail the emergence of therapy resistance, and improve patient outcomes.