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

EXAFS study of nickel tetracarbonyl and nickel clusters in zeolite Y

Adsorption and thermal decomposition of Ni(CO)4 in the cage system of zeolite Y have been studied with EXAFS, electron microscopy and IR spectroscopy , Ni(CO)4 is adsorbed as an intact molecule in both cation - free zeolite Y and NaY. Symmetry changes of the molecule in NaY are assigned to the formation of Na—OC-IMi bridges. Thermal treatment of the Ni(CO)4/NaY adduct leads to loss of CO concomitant with the formation of a binodal Ni phase. A major part of the forms clusters with diameter between 0.5 and about 1.5 nm, in addition to larger crystallites (5-30 nm), sticking at the outer surface of the zeolite matrix., The Ni-Ni scattering amplitude indicates increasing average particle size with increasing temperature

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

Explicit Formulae Showing the Effects of Texture on Acoustoelastic Coefficients

It is well known that crystallographic texture not only modifies the elastic constants of polycrystalline aggregates at (unstressed) natural states but also affects their acoustoelastic coefficients when the aggregates are stressed. While exact knowledge about the effects of texture on acoustoelastic coefficients has hitherto remained wanting, such effects are usually assumed to be negligible and are ignored in practical applications of acoustoelasticity (cf. [1] for example). Concerning this common practice, Thompson et al. [2] have urged caution: Care must be taken when [this] assumption is made since the influence of texture on acoustoelastic constants is stronger than its influence on elastic moduli or velocities

Submillimeter Follow-up of WISE-Selected Hyperluminous Galaxies

We have used the Caltech Submillimeter Observatory (CSO) to follow-up a sample of WISE-selected, hyperluminous galaxies, so called W1W2-dropout galaxies. This is a rare (~ 1000 all-sky) population of galaxies at high redshift (peaks at z=2-3), that are faint or undetected by WISE at 3.4 and 4.6 um, yet are clearly detected at 12 and 22 um. The optical spectra of most of these galaxies show significant AGN activity. We observed 14 high-redshift (z > 1.7) W1W2-dropout galaxies with SHARC-II at 350 to 850 um, with 9 detections; and observed 18 with Bolocam at 1.1 mm, with five detections. Warm Spitzer follow-up of 25 targets at 3.6 and 4.5 um, as well as optical spectra of 12 targets are also presented in the paper. Combining WISE data with observations from warm Spitzer and CSO, we constructed their mid-IR to millimeter spectral energy distributions (SEDs). These SEDs have a consistent shape, showing significantly higher mid-IR to submm ratios than other galaxy templates, suggesting a hotter dust temperature. We estimate their dust temperatures to be 60-120 K using a single-temperature model. Their infrared luminosities are well over 10^{13} Lsun. These SEDs are not well fitted with existing galaxy templates, suggesting they are a new population with very high luminosity and hot dust. They are likely among the most luminous galaxies in the Universe. We argue that they are extreme cases of luminous, hot dust-obscured galaxies (DOGs), possibly representing a short evolutionary phase during galaxy merging and evolution. A better understanding of their long-wavelength properties needs ALMA as well as Herschel data.Comment: Will be Published on Sep 1, 2012 by Ap

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

The templated zeolite-analogue GaPO-34 (CHA structure type) crystallises from a gel precursor Ga2O3:2H3PO4:1HF:1.7SDA:70H2O (where SDA = structure directing agent), treated hydrothermally for 24 hours at 170 °C using either pyridine or 1-methylimizadole as SDA and one of either poorly crystalline ε-Ga2O3 or γ-Ga2O3 as gallium precursor. If the same gels are stirred for periods shorter than 2 hours but treated under identical hydrothermal conditions, then a second phase crystallises, free of GaPO-34. If β-Ga2O3 is used as a reagent only the second phase is found to crystallise, irrespective of gel aging time. The competing phase, which we denote GaPO-34A, has been structurally characterised using synchrotron powder X-ray diffraction for the pyridine material, GaPO-34A(pyr), and using single-crystal X-ray diffraction for the 1-methylimiazole material, GaPO-34A(mim). The structure of GaPO-34A(pyr), P1 @#x0305;, a = 10.22682(6) Å, b = 12.09585(7) Å, c = 13.86713(8) Å, α = 104.6531(4) °, β = 100.8111(6) °, γ = 102.5228(6) °, contains 7 unique gallium sites and 6 phosphorus sites, with empirical formula [Ga7P6O24(OH)2F3(H2O)2].2(C5NH6). GaPO-34A(mim) is isostructural but is modelled as a half volume unit cell, P1 @#x0305;, a = 5.0991(2) Å, b = 12.0631(6) Å, c = 13.8405(9) Å, α = 104.626(5) °, β = 100.346(5) °, γ = 101.936(4) °, with a gallium and a bridging fluoride partially occupied and two partially occupied SDA sites. Solid-state 31P and 71Ga NMR spectroscopy confirms the structural complexity of GaPO-34A with signals resulting from overlapping lineshapes from multiple Ga and P sites, while 1H and 13C solid-state NMR spectra confirm the presence of the protonated SDA and provide evidence for disorder in the SDA. The protonated SDA is located in 14-ring one-dimensional channels with hydrogen bonding deduced from the SDA nitrogens to framework oxygen distances. Upon thermal treatment to investigate SDA removal, structure collapse occurs, which may be due the large number of bridging hydroxides and fluorides in the as-made material, and the unequal amounts of gallium and phosphorus present