The Expression of Ecotropic Virus Integration Site-1 in Seven Cancer Cell Lines

The ecotropic virus integration site-1 (EVI1) gene is a transcriptional repressor implicated in the control of cell proliferation and frequently over-expressed in cancerous cells. I investigated the expression of this gene across seven cancer cell lines of varying morphologies. The tested lines included leukemia lines Kasumi-3, U937, MOLT-4, and CEM, breast cancer line MCF7, colorectal cancer line HT-29, and glioblastoma line M059K. Kasumi-3 and HT-29 are documented to have high EVI1 expression. Protein concentrations were normalized with respect to actin using SDS-PAGE and Western blotting. Western blots for EVI1 showed expression of an unidentified protein with a molecular weight of 50-53kD in all lines except for Kasumi-3, which had no detectable protein expression. The intensities of these bands were measured and normalized with scaling factors determined from the Western blot for actin. The expression of EVI1 may be below the detection threshold of this blotting system, making visualization of the protein difficult

Art: A Handbook for Morality

Morals begin with parental instructions and pure bribery, such as promising playtime if children follow instructions and putting them in time-out if they act out inappropriately. However, over time, this outwardly enforced moral code must become internalized for a person to truly be ethical. Internalization happens when a person develops a sense of boundaries and behavior to live by without prompting. This process of creating standards draws on one’s experiences and knowledge of how the world views and responds to certain actions. The moral lessons present in art, which everyone is exposed to beginning at a very young age, help shape this knowledge by modeling situations and identifying wanted and unwanted behavior. Therefore, cultural values that have lasted through several generations can be passed on and established as a standard from a very young age. Over time, one decides based on such values what is acceptable behavior and what is “beneath” oneself, and this sense becomes a moral code

Clinical Applications of PD-L1 Bioassays for Cancer Immunotherapy

Programmed death ligand 1 (PD-L1) has emerged as a biomarker that can help to predict responses to immunotherapies targeted against PD-L1 and its receptor (PD-1). Companion tests for evaluating PD-L1 expression as a biomarker of response have been developed for many cancer immunotherapy agents. These assays use a variety of detection platforms at different levels (protein, mRNA), employ diverse biopsy and surgical samples, and have disparate positivity cutoff points and scoring systems, all of which complicate the standardization of clinical decision-making. This review summarizes the current understanding and ongoing investigations regarding PD-L1 expression as a potential biomarker for clinical outcomes of anti-PD-1/PD-L1 immunotherapy

Changing Mantle Sources and the Effects of Crustal Passage on the Steens Basalt, SE Oregon: Chemical and Isotopic Constraints

Continental flood basalts are more prone to compositional modification from passage through thicker and (or) more felsic crust in comparison to their oceanic counterparts. The Steens Basalt in southeast Oregon (~17 Ma) is among the oldest and most mafic members of the Columbia River Basalt Group and provides a record of the early stages of flood basalt volcanism. We evaluate the balance of mantle sources in time during the onset of Columbia River Basalt Group magmatism and assess the effect of crustal passage using stratigraphically controlled Sr, Nd, Pb, Hf, Os, and O isotopic compositions, as well as whole rock major and trace element data. Mixing models indicate that depleted and enriched mantle sources identified by previous workers contribute in varying proportions during the life of the magmatic system, with the greatest contribution by depleted mantle when eruption rate and presumed intrusion rate increase. During waxing, enrichment of δ18O in some flows signals cryptic deep fractionation of abundant clinopyroxene followed by shallow fractionation of olivine ± clinopyroxene ± plagioclase. Os concentrations are among the highest worldwide at a given MgO (0.29–0.86 ppb at 6.0 to 10.9 wt.%). We argue that high Os results from scavenging of sulfides by recharging magmas passing through earlier crystallized magmas. Elevated 87Sr/86Sr in the latest stage supports modest assimilation of partial melts from mafic accreted terranes, facilitated by thermal priming of crust by persistent magmatism. This work provides a more detailed schematic view of the Steens Basalt magmatic system, from mantle origin through crustal staging

Clinical applications of PD-L1 bioassays for cancer immunotherapy

Abstract Programmed death ligand 1 (PD-L1) has emerged as a biomarker that can help to predict responses to immunotherapies targeted against PD-L1 and its receptor (PD-1). Companion tests for evaluating PD-L1 expression as a biomarker of response have been developed for many cancer immunotherapy agents. These assays use a variety of detection platforms at different levels (protein, mRNA), employ diverse biopsy and surgical samples, and have disparate positivity cutoff points and scoring systems, all of which complicate the standardization of clinical decision-making. This review summarizes the current understanding and ongoing investigations regarding PD-L1 expression as a potential biomarker for clinical outcomes of anti-PD-1/PD-L1 immunotherapy

Oxygen isotope heterogeneity of arc magma recorded in plagioclase from the 2010 Merapi eruption (Central Java, Indonesia)

Chemical and isotopic compositions of magmatic crystals provide important information to distinguish between deep juvenile and crustal contributions. In this work, high-resolution multicollector secondary ion mass spectrometry data reveal strong variations of δ18O values in three plagioclase crystals (800–1700 μm) from two representative basaltic andesite samples of the 2010 Merapi eruption (Central Java, Indonesia). The δ18O values (from 4.6‰ to 7.9‰) are interpreted to reflect oxygen isotope heterogeneity in the melt composition during plagioclase growth. The lowest δ18O values (4.6–6.6‰) are found in anorthite-rich cores (An82–97), whereas higher δ18O values (5.7–7.9‰) are found in anorthite-poorer zones (An33–86), typically in crystal rims. Combining these new plagioclase δ18O data with δ18O of calc-silicate crustal xenoliths erupted between 1994 and 1998, the composition of glass inclusions hosted by the anorthite-rich plagioclase (An82–92), available experimental data, and the results of thermodynamic modeling using the Magma Chamber Simulator code, we conclude that the abundant anorthite-rich cores crystallized from a mantle-derived hydrous basaltic to basaltic trachyandesite melt that recharged a deeper (200–600 MPa) magma storage zone, whereas lower anorthite zones crystallized at shallower levels (100–200 MPa). The oxygen isotope variations in the plagioclase are explained by a two-stage model of interaction of the hydrous, mafic mantle-derived magma (1) with old crustal rocks depleted in 18O due to high temperature alteration that yielded the low δ18O values in the anorthite-rich cores at deep levels (13–20 km), and later (2) with 18O-enriched carbonate material that yielded the high δ18O values in anorthite-poorer zones at shallow levels (∼4.5–9 km). Thermodynamic modeling is consistent with ∼18 wt.% assimilation of crustal calc-silicate material at 925–950 °C and 100–200 MPa by the 2010 Merapi basaltic andesite magma prior to eruption. Timescales for plagioclase phenocryst growth and residence in the magmatic plumbing system are ⩽34 years. The combined data thus reveal efficient magma recharge and crustal assimilation processes that characterize the open-system magma storage and transport systems associated with the 2010 Merapi eruption

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.We want to thank the CNIO Core Facilities for their excellent assistance. We also thank F.X. Real, O. Marin, M. Serrano, O. Fernandez-Capetillo and M. Soengas for critically reading the manuscript, P. Bos for advice with CD8+ T cell experiments, J. Massague (MSKCC) for the BrM cell lines, MEDA for Legasil, M. A. Perez (University of Copenhagen), H. Peinado (CNIO), M. Soengas (CNIO) and M. Squatrito (CNIO) for reagents. This work was supported by MINECO grants MINECO-Retos SAF201457243-R (M.V.), MINECO-Europa Excelencia SAF2015-62547-ERC (M.V.), FERO Grant for Research in Oncology (M.V.), Melanoma Research Alliance Young Investigator Award (M.V.), AECC Coordinated Translational Groups (M.V., E.M.-S. and S.R.y.C), SEOM (J.B.-B.), Pfizer WI190764 (J.B.-B.), Meda Pharma (J.B.-B.), Armangue Family Fund (JA.M. and J.B.-B.), La Caixa-Severo Ochoa International PhD Program Fellowship (L.Z.), FCT PhD Fellowship SFRH/BD/100089/2014 (C.M.), the Fulbright Program (W.B.). M.V. is a Ramon y Cajal Investigator (RYC-2013-13365). This work is dedicated to the memory of Maria Jesus Cortes Garin.S

Hadean zircon formed due to hydrated ultramafic protocrust melting

International audienceHadean zircons, from the Jack Hills (JHZ) and other localities, are currently the only window into the earliest terrestrial felsic crust, whose formation remains enigmatic. Based upon new experimental results, generation of such early crust has been hypothesized to involve the partial melting of hydrated peridotite interacting with basaltic melt at low pressure (<10 km), but it has yet to be demonstrated that such liquids can indeed crystallize zircons comparable to JHZ. Thermodynamic and geochemical modeling are used here to test this hypothesis. The predicted zircon saturation temperatures of <750°C together with the model zircon Th, U, Nb, Hf, Y and rare-earth element (REE) contents at 700°C, δ18OVSMOW signatures and co-crystallizing mineral assemblage are compared to those of the JHZ. This comparison is favorable with respect to crystallization temperature, most trace element contents and mineral inclusions in zircon. Discrepancy in δ18OVSMOW signatures may be explained by hotter conditions of Hadean protocrust hydration. Finally, this work supports the idea that felsic magma generation at shallow depth involving a primordial weathered ultramafic protocrust and local basaltic intrusions is indeed a viable mechanism for the formation of felsic crust on the early Earth

Hydrated Peridotite – Basaltic Melt Interaction Part I: Planetary Felsic Crust Formation at Shallow Depth

International audienceCurrent theories suggest that the first continental crust on Earth, and possibly on other terrestrial planets, may have been produced early in their history by direct melting of hydrated peridotite. However, the conditions, mechanisms and necessary ingredients for this crustal formation remain elusive. To fill this gap, we conducted time-series experiments to investigate the reaction of serpentinite with variable proportions (from 0 to 87 wt%) of basaltic melt at temperatures of 1,250-1,300°C and pressures of 0.2-1.0 GPa (corresponding to lithostatic depths of ∼5-30 km). The experiments at 0.2 GPa reveal the formation of forsterite-rich olivine (Fo 90-94) and chromite coexisting with silica-rich liquids (57-71 wt% SiO 2). These melts share geochemical similarities with tonalitetrondhjemite-granodiorite rocks (TTG) identified in modern terrestrial oceanic mantle settings. By contrast, liquids formed at pressures of 1.0 GPa are poorer in silica (∼50 wt% SiO 2). Our results suggest a new mechanism for the formation of the embryonic continental crust via aqueous fluid-assisted partial melting of peridotite at relatively low pressures (∼0.2 GPa). We hypothesize that such a mechanism of felsic crust formation may have been widespread on the early Earth and, possibly on Mars as well, before the onset of modern plate tectonics and just after solidification of the first ultramaficmafic magma ocean and alteration of this primitive protocrust by seawater at depths of less than 10 km