Preparation of 4-aryl-2-trifluoromethylbenzonitrile derivatives as androgen receptor antagonists for topical suppression of sebum production

A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).     

Steneosaurus edwardsi (Thalattosuchia: Teleosauridae), the largest known crocodylomorph of the Middle Jurassic

Teleosaurids were a clade of marine crocodylomorphs that were globally distributed during the Jurassic Period. They evolved a wide range of body sizes, from small (～2–3 m) to very large (> 9 m). Until now, the largest known Middle Jurassic teleosaurid was ‘Steneosaurus’ obtusidens, from the Oxford Clay Formation of the UK. Here, we re‐examine a very large Oxford Clay specimen (ilium, ischium, and femur) that had been tentatively attributed to ‘S.’ obtusidens. Based on comparative anatomical study with the ‘S.’ obtusidens holotype and referred specimens of Steneosaurus edwardsi and Steneosaurus leedsi, we conclude that this very large individual actually pertains to S. edwardsi. Based on comparisons with the Machimosaurus mosae neotype (which has a complete femur and skeleton), we estimate a total length in excess of 7 m for this large S. edwardsi individual, making it the largest known Middle Jurassic teleosaurid. Therefore, along with the closely related genus Machimosaurus, this clade of large‐bodied Middle–Late Jurassic teleosaurids were the largest species during the first 100 million years of crocodylomorph evolution. © 2015 The Linnean Society of London, Biological Journal of the Linnean Society, 2015, ●● , ●●–●●.     

Type III neuregulin 1 regulates pathfinding of sensory axons in the developing spinal cord and periphery

Sensory axons must develop appropriate connections with both central and peripheral targets. Whereas the peripheral cues have provided a classic model for neuron survival and guidance, less is known about the central cues or the coordination of central and peripheral connectivity. Here we find that type III Nrg1, in addition to its known effect on neuron survival, regulates axon pathfinding. In type III Nrg1(-/-) mice, death of TrkA(+) nociceptive/thermoreceptive neurons was increased, and could be rescued by Bax elimination. In the Bax and type III Nrg1 double mutants, axon pathfinding abnormalities were seen for TrkA(+) neurons both in cutaneous peripheral targets and in spinal cord central targets. Axon guidance phenotypes in the spinal cord included penetration of axons into ventral regions from which they would normally be repelled by Sema3A. Accordingly, sensory neurons from type III Nrg1(-/-) mice were unresponsive to the repellent effects of Sema3A in vitro, which might account, at least in part, for the central projection phenotype, and demonstrates an effect of type III Nrg1 on guidance cue responsiveness in neurons. Moreover, stimulation of type III Nrg1 back-signaling in cultured sensory neurons was found to regulate axonal levels of the Sema3A receptor neuropilin 1. These results reveal a molecular mechanism whereby type III Nrg1 signaling can regulate the responsiveness of neurons to a guidance cue, and show that type III Nrg1 is required for normal sensory neuron survival and axon pathfinding in both central and peripheral targets.     

A QbD Case Study: Bayesian Prediction of Lyophilization Cycle Parameters

As stipulated by ICH Q8 R2 (1), prediction of critical process parameters based on process modeling is a part of enhanced, quality by design approach to product development. In this work, we discuss a Bayesian model for the prediction of primary drying phase duration. The model is based on the premise that resistance to dry layer mass transfer is product specific, and is a function of nucleation temperature. The predicted duration of primary drying was experimentally verified on the lab scale lyophilizer. It is suggested that the model be used during scale-up activities in order to minimize trial and error and reduce costs associated with expensive large scale experiments. The proposed approach extends the work of Searles et al. (2) by adding a Bayesian treatment to primary drying modeling.     

Effect of Soy Protein Subunit Composition on the Rheological Properties of Soymilk during Acidification

The effect of soy protein subunit composition on the acid-induced aggregation of soymilk was investigated by preparing soymilk from different soybean lines lacking specific glycinin and β-conglycinin subunits. Acid gelation was induced by glucono-δ-lactone (GDL) and analysis was done using diffusing wave spectroscopy and rheology. Aggregation occurred near pH 5.8 and the increase in radius corresponded to an increase in the elastic modulus measured by small deformation rheology. Diffusing wave spectroscopy was also employed to follow acid gelation, and data indicated that particle interactions start to occur at a higher pH than the pH of onset of gelation (corresponding to the start of the rapid increase in elastic modulus). The protein subunit composition significantly affected the development of structure during acidification. The onset of aggregation occurred at a higher pH for soymilk samples containing group IIb (the acidic subunit A₃) of glycinin, than for samples prepared from Harovinton (a commercial variety containing all subunits) or from genotypes null in glycinin. The gels made from lines containing group I (A₁, A₂) and group IIb (A₃) of glycinin resulted in stiffer acid gels compared to the lines containing only β-conglycinin. These results confirmed that the ratio of glycinin/β-conglycinin has a significant effect on gel structure, with an increase in glycinin causing an increase in gel stiffness. The type of glycinin subunits also affected the aggregation behavior of soymilk.     

A trade-off between nitrogen uptake and use increases responsiveness to elevated CO2 in infrequently cut mixed C3 grasses

The aim of this study was to evaluate whether the responsiveness of mixed C3 grass species to elevated CO2 is related more to nitrogen uptake or to N-use efficiency. Nitrogen uptake and whole-plant N-use efficiency were investigated with two binary mixtures: Lolium perenne was mixed either with Festuca arundinacea or with Holcus lanatus. The swards were grown on sand with or without CO2 doubling, and subjected to two cutting frequencies. A C20 alcohol was used as a marker to determine species proportion in the total root mass of the mixtures. The mean residence time of N was calculated from that of 15N-labelled fertilizer. Lolium perenne took up significantly more N per unit root mass than its grass competitors, but its N-use efficiency was lower. Elevated CO2 significantly reduced the N uptake of the three grass species. A trade-off between N capture and use was found, as N-use efficiency and N-uptake rate were negatively correlated. A high N-use efficiency, and conversely low N uptake appeared to favour the responsiveness to elevated CO2 of the infrequently cut grasses.     

Surgical issues surrounding use of aromatase inhibitors

There are important surgical issues related to the use of the third generation aromatase inhibitors in both the neoadjuvant and adjuvant settings. Neoadjuvant hormone therapy is effective at downstaging tumours, particularly large tumours initially thought to be inoperable or requiring mastectomy. Randomised trials have shown that the newer aromatase inhibitors letrozole and anastrozole increase the numbers of women who are suitable for breast-conservation compared with tamoxifen, and that letrozole is superior to tamoxifen in terms of clinical response.

Aromatase inhibitors are most effective in ER-rich tumours and are clinically and biologically effective in both HER2 positive and negative tumours, whereas HER2 positive tumours show a level of resistance to tamoxifen.

In neoadjuvant studies comparing aromatase inhibitors with tamoxifen, the duration of use has been 3–4 months, by which time any response is usually evident but longer treatment periods produce continued shrinkage and response. The re-excision rate following breast conservation surgery after neoadjuvant hormone therapy is favourable compared with the rates following immediate wide local excision. Local recurrence rates are acceptable in patients undergoing neoadjuvant therapy and breast-conserving surgery providing post-operative radiotherapy is given.

Adjuvant aromatase inhibitors, as well as having an effect on metastatic disease and survival, reduce local and regional recurrence.     

1-Aryl-3,4-dihydro-1H-quinolin-2-one derivatives, novel and selective norepinephrine reuptake inhibitors

A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and advanced intermediates for SAR expansion.     

Exploring the effect of xenon on biomembranes

We report the initial findings of 100 ns molecular dynamics simulations of the role of cellular membranes in general anaesthesia. The effect of xenon on hydrated dipalmitoylphosphatidylcholine bilayers is described. The xenon atoms were found to prefer the interfacial and central regions of the bilayer. The presence of xenon was observed to lead to a small increase in the surface area, membrane thickness, and order of the acyl chains.