Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand

Aims/hypothesis Our aims were to compare osteoclastic activity between patients with acute Charcot’s osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). Methods Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices. Results In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p = 0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p < 0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264 ± 0.06% to 41.6 ± 8.1%, p < 0.0001) and diabetic control (0.000 ± 0.00% to 14.2 ± 16.5%, p < 0.0001) patients, and also in healthy control participants (0.004 ± 0.01% to 10.5 ± 1.9%, p < 0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6 ± 8.1% to 5.9 ± 2.4%, p = 0.001), this suppression was not as complete as in diabetic control patients (14.2 ± 16.5% to 0.45 ± 0.31%, p = 0.001) and in healthy control participants (from 10.5 ± 1.9% to 0.00 ± 0.00%, p < 0.0001). Conclusions/interpretation These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot’s osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway

Observation of Excess J/ψ Yield at Very Low Transverse Momenta in Au+Au Collisions at sqrt[s_{NN}]=200 GeV and U+U Collisions at sqrt[s_{NN}]=193 GeV.

We report on the first measurements of J/ψ production at very low transverse momentum (p_{T}<0.2  GeV/c) in hadronic Au+Au collisions at sqrt[s_{NN}]=200  GeV and U+U collisions at sqrt[s_{NN}]=193  GeV. Remarkably, the inferred nuclear modification factor of J/ψ at midrapidity in Au+Au (U+U) collisions reaches about 24 (52) for p_{T}<0.05  GeV/c in the 60%-80% collision centrality class. This noteworthy enhancement cannot be explained by hadronic production accompanied by cold and hot medium effects. In addition, the dN/dt distribution of J/ψ for the very low p_{T} range is presented for the first time. The distribution is consistent with that expected from the Au nucleus and shows a hint of interference. Comparison of the measurements to theoretical calculations of coherent production shows that the excess yield can be described reasonably well and reveals a partial disruption of coherent production in semicentral collisions, perhaps due to the violent hadronic interactions. Incorporating theoretical calculations, the results strongly suggest that the dramatic enhancement of J/ψ yield observed at extremely low p_{T} originates from coherent photon-nucleus interactions. In particular, coherently produced J/ψ's in violent hadronic collisions may provide a novel probe of the quark-gluon plasma

Measurement of inclusive J/ψ suppression in Au+Au collisions at sNN=200 GeV through the dimuon channel at STAR

J/ψ suppression has long been considered a sensitive signature of the formation of the Quark-Gluon Plasma (QGP) in relativistic heavy-ion collisions. In this letter, we present the first measurement of inclusive J/ψ production at mid-rapidity through the dimuon decay channel in Au+Au collisions at sNN=200 GeV with the STAR experiment. These measurements became possible after the installation of the Muon Telescope Detector was completed in 2014. The J/ψ yields are measured in a wide transverse momentum (pT) range of 0.15 GeV/c to 12 GeV/c from central to peripheral collisions. They extend the kinematic reach of previous measurements at RHIC with improved precision. In the 0-10% most central collisions, the J/ψ yield is suppressed by a factor of approximately 3 for pT>5 GeV/c relative to that in p+p collisions scaled by the number of binary nucleon-nucleon collisions. The J/ψ nuclear modification factor displays little dependence on pT in all centrality bins. Model calculations can qualitatively describe the data, providing further evidence for the color-screening effect experienced by J/ψ mesons in the QGP

Charge-dependent pair correlations relative to a third particle in p + Au and d + Au collisions at RHIC

Quark interactions with topological gluon configurations can induce chirality imbalance and local parity violation in quantum chromodynamics. This can lead to electric charge separation along the strong magnetic field in relativistic heavy-ion collisions – the chiral magnetic effect (CME). We report measurements by the STAR collaboration of a CME-sensitive observable in p+Au and d+Au collisions at 200 GeV, where the CME is not expected, using charge-dependent pair correlations relative to a third particle. We observe strong charge-dependent correlations similar to those measured in heavy-ion collisions. This bears important implications for the interpretation of the heavy-ion data

Measurements of the transverse-momentum-dependent cross sections of J /ψ production at mid-rapidity in proton+proton collisions at s =510 and 500 GeV with the STAR detector

We present measurements of the differential cross sections of inclusive J/ψ meson production as a function of transverse momentum (pTJ/ψ) using the μ+μ- and e+e- decay channels in proton+proton collisions at center-of-mass energies of 510 and 500 GeV, respectively, recorded by the STAR detector at the Relativistic Heavy Ion Collider. The measurement from the μ+μ- channel is for

Bulk properties of the system formed in Au+Au collisions at sNN =14.5 GeV at the BNL STAR detector

We report systematic measurements of bulk properties of the system created in Au+Au collisions at sNN=14.5 GeV recorded by the STAR detector at the Relativistic Heavy Ion Collider (RHIC). The transverse momentum spectra of π±, K±, and p(p) are studied at midrapidity (|y|<0.1) for nine centrality intervals. The centrality, transverse momentum (pT), and pseudorapidity (η) dependence of inclusive charged particle elliptic flow (v2), and rapidity-odd charged particles directed flow (v1) results near midrapidity are also presented. These measurements are compared with the published results from Au+Au collisions at other energies, and from Pb+Pb collisions at sNN=2.76 TeV. The results at sNN=14.5 GeV show similar behavior as established at other energies and fit well in the energy dependence trend. These results are important as the 14.5-GeV energy fills the gap in μB, which is of the order of 100 MeV, between sNN=11.5 and 19.6 GeV. Comparisons of the data with UrQMD and AMPT models show poor agreement in general

Carbon Dioxide in Geochemically Heterogeneous Melt Inclusions From Mount Etna, Italy

Mt. Etna is among the largest global volcanic outgassers with respect to carbon and sulfur, yet questions remain regarding the source of these volatiles and their systematics in the crust and mantle. The importance of heterogeneous mantle sources, mixing, crustal assimilation and disequilibrium degassing are investigated using melt inclusions erupted during the A.D. 1669 eruption of Mt. Etna, Italy. We find that the melt inclusion compositions define a mixing array between two geochemically distinct melts. One end‐member melt is depleted in light rare Earth elements (LREE) and enriched in strontium (Sr), carbon and sulfur; the other is enriched in LREE and depleted in Sr, carbon and sulfur. We infer, through modeling, that the melts may either have been generated by melting a mantle source that includes a recycled oceanic crustal component; or they may have assimilated carbonate material in the crust. The resulting LREE‐depleted, Sr‐enriched melts were also alkali‐rich, which enhanced the solubility of carbon and sulfur. The LREE‐depleted, Sr‐ and volatile‐rich melt ascended through the crust and likely became supersaturated with respect to CO2 and sulfur. The melt intruded into a LREE‐enriched, relatively degassed magma body in the shallow crust, cooled rapidly and vesiculated, likely triggering eruption. The melt inclusion array trapped by growing olivines during this intrusion process records a snapshot of incomplete mixing between the two melts. Mt. Etna is renowned for the large increases in CO2 gas fluxes shortly before and during eruption. The intrusion of supersaturated, CO2‐enhanced magmas into shallow reservoirs may be a common process at Mt. Etna

World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection

The genetic trait of lactase persistence (LP) is associated with at least five independent functional single nucleotide variants in a regulatory region about 14 kb upstream of the lactase gene [-13910*T (rs4988235), -13907*G (rs41525747), -13915*G (rs41380347), -14009*G (rs869051967) and -14010*C (rs145946881)]. These alleles have been inferred to have spread recently and present-day frequencies have been attributed to positive selection for the ability of adult humans to digest lactose without risk of symptoms of lactose intolerance. One of the inferential approaches used to estimate the level of past selection has been to determine the extent of haplotype homozygosity (EHH) of the sequence surrounding the SNP of interest. We report here new data on the frequencies of the known LP alleles in the 'Old World' and their haplotype lineages. We examine and confirm EHH of each of the LP alleles in relation to their distinct lineages, but also show marked EHH for one of the older haplotypes that does not carry any of the five LP alleles. The region of EHH of this (B) haplotype exactly coincides with a region of suppressed recombination that is detectable in families as well as in population data, and the results show how such suppression may have exaggerated haplotype-based measures of past selection