Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users

The original publication is available at www.springerlink.comPURPOSE 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. METHODS Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is the major challenge in compound design. RESULTS A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. CONCLUSIONS Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure

Solution-Processed Cu2_2S Nanostructures for Solar Hydrogen Production

Cu$_2$S is a promising solar energy conversion material due to its suitable optical properties, high elemental earth abundance, and nontoxicity. In addition to the challenge of multiple stable secondary phases, the short minority carrier diffusion length poses an obstacle to its practical application. This work addresses the issue by synthesizing nanostructured Cu$_2$S thin films, which enables increased charge carrier collection. A simple solution-processing method involving the preparation of CuCl and CuCl$_2$ molecular inks in a thiol-amine solvent mixture followed by spin coating and low-temperature annealing was used to obtain phase-pure nanostructured (nanoplate and nanoparticle) Cu$_2$S thin films. The photocathode based on the nanoplate Cu$_2$S (FTO/Au/Cu$_2$S/CdS/TiO$_2$/RuO$_x$) reveals enhanced charge carrier collection and improved photoelectrochemical water-splitting performance compared to the photocathode based on the non-nanostructured Cu$_2$S thin film reported previously. A photocurrent density of 3.0 mA cm$^{–2}$ at −0.2 versus a reversible hydrogen electrode (V$_{RHE}$) with only 100 nm thickness of a nanoplate Cu$_2$S layer and an onset potential of 0.43 V$_{RHE}$ were obtained. This work provides a simple, cost-effective, and high-throughput method to prepare phase-pure nanostructured Cu$_2$S thin films for scalable solar hydrogen production

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

The forfeiture rule and the law of succession A consultation paper

Also available via the InternetSIGLEAvailable from British Library Document Supply Centre- DSC:3423. 7764(no 172) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

A voyage to Vardø - A scientific account of an unscientific expedition

After the “Venus Transit Conference” that took place at the University of Tromsø from June 2 to June 3, 2012, participants were given the opportunity to either stay in Tromsø until the night of June 5–6, or to participate in a voyage to Finnmark, where the historical sites Vardø, Hammerfest, and the North Cape were to be visited. This voyage culminated in the observation of the 2012 transit of Venus at Vardø. This paper gives a detailed account of this voyage that lasted from June 3 to June 6, and emphasizes the historical, scientific, philosophical, educational and cultural involvement of the participants of the voyage and of the local population. The paper concludes with reflections on the prime condition for success of any of the Venus transit expeditions of the past: the weather must cooperate in the first place – not only during the quarter of a day of the transit, but also during the preceding weeks and months in order to allow the explorers to rightly determine their geographic positions and correctly set their clocks. The latter factor is no longer an issue nowadays, but the weather aspect remains today a limiting factor as much as it was 250 years ago. Despite the variable and partly clouded weather at Vardø during the time of the transit, the participants of this expedition were able to observe Venus in front of the Sun – with interruptions due to quickly moving clouds – between 4.30 a.m. and the fourth contact at 06:53:20 a.m. A large number of impressive, partly ‘dramatic’ photographs have been taken especially in this time interval.peerReviewe

A Voyage to Vardø. A Scientific Account of an Unscientific Expedition

After the “Venus Transit Conference” that took place at the University of Tromsø from June 2 to June 3, 2012, participants were given the opportunity to either stay in Tromsø until the night of June 5–6, or to participate in a voyage to Finnmark, where the historical sites Vardø, Hammerfest, and the North Cape were to be visited. This voyage culminated in the observation of the 2012 transit of Venus at Vardø. This paper gives a detailed account of this voyage that lasted from June 3 to June 6, and emphasizes the historical, scientific, philosophical, educational and cultural involvement of the participants of the voyage and of the local population. The paper concludes with reflections on the prime condition for success of any of the Venus transit expeditions of the past: the weather must cooperate in the first place – not only during the quarter of a day of the transit, but also during the preceding weeks and months in order to allow the explorers to rightly determine their geographic positions and correctly set their clocks. The latter factor is no longer an issue nowadays, but the weather aspect remains today a limiting factor as much as it was 250 years ago. Despite the variable and partly clouded weather at Vardø during the time of the transit, the participants of this expedition were able to observe Venus in front of the Sun – with interruptions due to quickly moving clouds – between 4.30 a.m. and the fourth contact at 06:53:20 a.m. A large number of impressive, partly ‘dramatic’ photographs have been taken especially in this time interval.Published versio

Molecular ink-derived chalcogenide thin films: Solution-phase mechanisms and solar energy conversion applications

The use of solution processing to fabricate metal chalcogenide thin films has gained considerable interest because of its low cost and scalability compared to vacuum deposition. Among the various types of solution processing, homogeneous molecular ink-based processes can lead to high-quality metal chalcogenide thin films, a prerequisite for high-efficiency solar energy conversion devices. In this review, we summarise studies on the fundamental understanding of the solution-phase mechanism of various types of molecular inks classified into three categories: hydrazine-, thiol-amine-, and organochalcogen-complex-based systems. The unique chemistry of each system is presented in conjunction with appropriate characterisation techniques to understand molecular interactions. Additionally, we also survey the recent solar energy conversion applications, such as solar cells and photoelectrodes for water splitting, with chalcogenide thin-film light absorbers prepared using each molecular ink technique. The strengths, limitations, and future possibilities of each system are discussed to provide insight into future advancements in molecular ink-derived chalcogenide thin films