Sensitization of renal carcinoma cells to TRAIL-induced apoptosis by rocaglamide and analogs

Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells. Rocaglamide alone induced cell cycle arrest, but not apoptosis. Rocaglates averaged 4–5-fold higher potency as TRAIL sensitizers than as protein synthesis inhibitors suggesting a potential window for maximizing TRAIL sensitization while minimizing effects of general protein synthesis inhibition. A wide range of other rocaglate effects (e.g. on JNK or RAF-MEK-ERK signaling, death receptor levels, ROS, ER stress, eIF4E phosphorylation) were assessed, but did not contribute to TRAIL sensitization. Other than a rapid loss of MCL-1, rocaglates had minimal effects on mitochondrial apoptotic pathway proteins. The identification of structurally diverse/mechanistically similar TRAIL sensitizing rocaglates provides insights into both rocaglate structure and function and potential further development for use in RCC-directed combination therapy.This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research. Research performed at Boston University was supported in part by NIH R35 GM118173. Work at the BU-CMD is supported by R24 GM111625. (HHSN261200800001E - National Cancer Institute, National Institutes of Health; Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research; R35 GM118173 - NIH; R24 GM111625)Published versio

The discovery and dynamical evolution of an object at the outer edge of Saturn's A ring

This work was supported by the Science and Technology Facilities Council (Grant No. ST/F007566/1) and we are grateful to them for financial assistance. C.D.M. is also grateful to the Leverhulme Trust for the award of a Research Fellowshippublisher PDF not permitted, withdraw

Low-temperature, high-density magneto-optical trapping of potassium using the open 4S-5P transition at 405 nm

We report the laser cooling and trapping of neutral potassium on an open transition. Fermionic 40K is captured using a magneto-optical trap (MOT) on the closed 4S-4P transition at 767 nm and then transferred, with unit efficiency, to a MOT on the open 4S-5P transition at 405 nm. Because the 5P state has a smaller line width than the 4P state, the Doppler limit is reduced. We observe temperatures as low as 63(6) microkelvin, the coldest potassium MOT reported to date. The density of trapped atoms also increases, due to reduced temperature and reduced expulsive light forces. We measure a two-body loss coefficient of 2 x 10^-10 cm^3/s, and estimate an upper bound of 8x10^-18 cm^2 for the ionization cross section of the 5P state at 405 nm. The combined temperature and density improvement in the 405 nm MOT is a twenty-fold increase in phase space density over our 767 nm MOT, showing enhanced pre-cooling for quantum gas experiments. A qualitatively similar enhancement is observed in a 405 nm MOT of bosonic 41K.Comment: 8 pages, 8 figures, 1 tabl

Phase light curves for extrasolar Jupiters and Saturns

We predict how a remote observer would see the brightness variations of giant planets similar to Jupiter and Saturn as they orbit their central stars. We model the geometry of Jupiter, Saturn and Saturn's rings for varying orbital and viewing parameters. Scattering properties for the planets and rings at wavelenghts 0.6-0.7 microns follow Pioneer and Voyager observations, namely, planets are forward scattering and rings are backward scattering. Images of the planet with or without rings are simulated and used to calculate the disk-averaged luminosity varying along the orbit, that is, a light curve is generated. We find that the different scattering properties of Jupiter and Saturn (without rings) make a substantial difference in the shape of their light curves. Saturn-size rings increase the apparent luminosity of the planet by a factor of 2-3 for a wide range of geometries. Rings produce asymmetric light curves that are distinct from the light curve of the planet without rings. If radial velocity data are available for the planet, the effect of the ring on the light curve can be distinguished from effects due to orbital eccentricity. Non-ringed planets on eccentric orbits produce light curves with maxima shifted relative to the position of the maximum planet's phase. Given radial velocity data, the amount of the shift restricts the planet's unknown orbital inclination and therefore its mass. Combination of radial velocity data and a light curve for a non-ringed planet on an eccentric orbit can also be used to constrain the surface scattering properties of the planet. To summarize our results for the detectability of exoplanets in reflected light, we present a chart of light curve amplitudes of non-ringed planets for different eccentricities, inclinations, and the viewing azimuthal angles of the observer.Comment: 40 pages, 13 figures, submitted to Ap.

Unravelling Temporal Variability in Saturn's Spiral Density Waves: Results and Predictions

We describe a model that accounts for the complex morphology of spiral density waves raised in Saturn's rings by the co-orbital satellites, Janus and Epimetheus. Our model may be corroborated by future Cassini observations of these time-variable wave patterns

A survey of low-velocity collisional features in Saturn's F ring

Small (~50km scale), irregular features seen in Cassini images to be emanating from Saturn's F ring have been termed mini-jets by Attree et al. (2012). One particular mini-jet was tracked over half an orbital period, revealing its evolution with time and suggesting a collision with a local moonlet as its origin. In addition to these data we present here a much more detailed analysis of the full catalogue of over 800 F ring mini-jets, examining their distribution, morphology and lifetimes in order to place constraints on the underlying moonlet population. We find mini-jets randomly located in longitude around the ring, with little correlation to the moon Prometheus, and randomly distributed in time, over the full Cassini tour to date. They have a tendency to cluster together, forming complicated `multiple' structures, and have typical lifetimes of ~1d. Repeated observations of some features show significant evolution, including the creation of new mini-jets, implying repeated collisions by the same object. This suggests a population of <~1km radius objects with some internal strength and orbits spread over 100km in semi-major axis relative to the F ring but with the majority within 20km. These objects likely formed in the ring under, and were subsequently scattered onto differing orbits by, the perturbing action of Prometheus. This reinforces the idea of the F ring as a region with a complex balance between collisions, disruption and accretion.Comment: 21 pages, 12 figures. Accepted for publication in Icarus. Supplementary information available at http://www.maths.qmul.ac.uk/~attree/mini-jets

Cassini ISS mutual event astrometry of the mid-sized Saturnian satellites 2005-2012

Reproduced with permission from Astronomy & Astrophysics, © ES

Linear growth in preschool children treated with mass azithromycin distributions for trachoma: A cluster-randomized trial.

BackgroundMass azithromycin distributions have been shown to reduce mortality among pre-school children in sub-Saharan Africa. It is unclear what mediates this mortality reduction, but one possibility is that antibiotics function as growth promoters for young children.Methods and findings24 rural Ethiopian communities that had received biannual mass azithromycin distributions over the previous four years were enrolled in a parallel-group, cluster-randomized trial. Communities were randomized in a 1:1 ratio to either continuation of biannual oral azithromycin (20mg/kg for children, 1 g for adults) or to no programmatic antibiotics over the 36 months of the study period. All community members 6 months and older were eligible for the intervention. The primary outcome was ocular chlamydia; height and weight were measured as secondary outcomes on children less than 60 months of age at months 12 and 36. Study participants were not masked; anthropometrists were not informed of the treatment allocation. Anthropometric measurements were collected for 282 children aged 0-36 months at the month 12 assessment and 455 children aged 0-59 months at the month 36 assessment, including 207 children who had measurements at both time points. After adjusting for age and sex, children were slightly but not significantly taller in the biannually treated communities (84.0 cm, 95%CI 83.2-84.8, in the azithromycin-treated communities vs. 83.7 cm, 95%CI 82.9-84.5, in the untreated communities; mean difference 0.31 cm, 95%CI -0.85 to 1.47, P = 0.60). No adverse events were reported.ConclusionsPeriodic mass azithromycin distributions for trachoma did not demonstrate a strong impact on childhood growth.Trial registrationThe TANA II trial was registered on clinicaltrials.gov #NCT01202331