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Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. Treatment of PDGFRA-driven HGG with targeted agents, such as the tyrosine kinase inhibitor dasatinib, has failed in the clinic. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRA-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. Methods: Dose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. De novo tumors were generated in mice using intra-uterine electroporation (IUE) by injecting PB plasmids of TP53 mutation, PDGFRA mutation and H3K27M mutation (PPK) in the lateral vertical of mice embryos. Two children with recurrent PDGFRA-driven HGG were treated with dasatinib and everolimus with correlate CSF analysis. Results: Dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a dose-dependent reduction of PDGFRA and pPDGFRA. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Two children with recurrent PDGFRA-driven HGG treated with dasatinib and everolimus survived six months and nine months after progression. A paired CSF sample from the patient with PDGFRA-amplified HGG showed 50% increase in CSF dasatinib levels after the addition of everolimus. Conclusion: Efficacy of dasatinib treatment of PDGFRA-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population. Clinical Trial Registration ID # NCT03352427 .

International audience; The small size of the SETI workforce is a major problem for NASA and the search for life elsewhere in the universe. The Astro2020 Decadal should address this issue by making nurturing the field an explicit priority for the next decade.

Human influence on the biosphere has been evident at least since the development of widespread agriculture, and some stratigraphers have suggested that the activities of modern civilization indicate a geological epoch transition. The study of the anthropocene as a geological epoch, and its implication for the future of energy-intensive civilizations, is an emerging transdisciplinary field in which astrobiology can play a leading role. Habitability research of Earth, Mars, and exoplanets examines extreme cases relevant for understanding climate change as a planetary process. Energy-intensive civilizations will also face thermodynamic limits to growth, which provides an important constraint for estimating the longevity of human civilization and guiding the search for extraterrestrial intelligence. We recommend that missions concepts such as LUVOIR, HabEx, and OST be pursued in order to make significant progress toward understanding the future evolution of life on our planet and the possible evolution of technological, energy-intensive life elsewhere in the universe., A white paper on "Astrobiology Science Strategy" submitted to the NAS

Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins are key regulators of tissue and lineage-specific gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this has not been validated in human DIPG, nor has the regulation and targetability of ID1 been explored in DIPG. Analysis of multi-focal post-mortem tumor and normal brain tissue (n=52) as well as multiple human datasets revealed ID1 to be elevated in DIPG. Elevated ID1 was found to correlate with reduced survival in DIPG. In a multi-focal autopsy DIPG case, we found ID1 expression to be heterogeneous and to correlate with tumor invasion. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to quantify H3K27ac and H3K27me3 at ID1 gene regulatory regions (promoters/enhancers) in multi-focal post-mortem tissue. The ID1 loci was found to be epigenetically poised for up-regulation (elevated H3K27ac and low H3K27me3) in DIPG tissue, regardless of H3 or ACVR1 mutation status, compared to normal brain. Analysis of publically-available ISH and ChIP-sequencing data revealed elevated ID1 expression and ID1-enhancer H3K27ac in prenatal mouse hindbrain compared to prenatal forebrain, prenatal midbrain, and all postnatal brain regions. ID1 shRNA-mediated knockdown of primary human H3K27M DIPG cells (DIPG007) resulted in significantly reduced invasion and migration. As cannabidiol (CBD) has successfully been used to therapeutically target ID1 in pre-clinical models of adult human cancers, we treated DIPG007 cells with CBD and found reduced viability at clinically relevant dosing (IC50=2.4 uM) with dose-dependent reduction in ID1 protein. ID1 knockdown and CBD treatment studies in murine models of DIPG are ongoing. These findings indicate that a multifactorial (genetic and regionally-based) epigenetic upregulation of ID1 drives DIPG invasiveness and is targetable with CBD.

Nearby Type III (galaxy-spanning) Kardashev supercivilizations would have high mid-infrared (MIR) luminosities. We have used the Wide-field Infrared Survey Explorer (WISE) to survey ~$1 \times 10^5$ galaxies for extreme MIR emission, $10^3$ times more galaxies than the only previous such search. We have calibrated the WISE All-sky Catalog pipeline products to improve its photometry for extended sources. We present 563 extended sources with $|b| \ge 10$ and red MIR colors, having visually vetted them to remove artifacts. No galaxies in our sample host an alien civilization reprocessing more than 85% of its starlight into the MIR, and only 50 galaxies, including Arp 220, have MIR luminosities consistent with >50% reprocessing. Ninety of these (likely) extragalactic sources have little literature presence; in most cases they are likely barely resolved galaxies or pairs of galaxies undergoing large amounts of star formation. Five are new to science and deserve further study. The Be star 48 Librae sits within a MIR nebula, and we suggest that it may be creating dust. WISE, 2MASS, and Spitzer imagery shows that IRAS 04287+6444 is consistent with a previously unnoticed, heavily extinguished cluster of young stellar objects. We identify five "passive" (i.e. red) spiral galaxies with unusually high MIR and low NUV luminosity. We search a set of optically "dark" HI galaxies for MIR emission, and find none. These 90 poorly understood sources and five anomalous passive spirals deserve follow-up via both SETI and conventional astrophysics., ApJS 217 25. 44pp, 9 tables, 25 figures. Due to limitations of arXiv LaTeX compilation, figures are sub-optimally placed and tables are not landscape. See http://astro.psu.edu/~jtwright/Dyson/GHAT3.pdf for version with full resolution figures and fully legible tables

Figure S1. Serial dilution of K27M mutant oligonucleotide in constant background of wild-type DNA demonstrates consistent detection down to at least 2% VAF under typical experimental conditions, with the possibility of detection at even lower VAF under ideal conditions. One such dilution series is shown above, with (a) showing number of droplets positive for mutant or wild-type H3F3A sequence and (b) showing the corresponding VAF values. Figure S2. Plot of droplets (blue â positive mutant H3F3A K27M, green â positive wildtype H3F3A, grey â negative droplets) from ddPCR performed on (a) non-tumor human CSF spiked with synthetic K27M mutant sequence oligonucleotide and (b) non-tumor human CSF alone. (DOCX 268 kb)

Supplemental Information. Detailed methods and H3F3A K27M assay design. (DOCX 28 kb)

Supplemental Information. Detailed methods and H3F3A K27M assay design. (DOCX 28 kb)

Figure S1. Serial dilution of K27M mutant oligonucleotide in constant background of wild-type DNA demonstrates consistent detection down to at least 2% VAF under typical experimental conditions, with the possibility of detection at even lower VAF under ideal conditions. One such dilution series is shown above, with (a) showing number of droplets positive for mutant or wild-type H3F3A sequence and (b) showing the corresponding VAF values. Figure S2. Plot of droplets (blue â positive mutant H3F3A K27M, green â positive wildtype H3F3A, grey â negative droplets) from ddPCR performed on (a) non-tumor human CSF spiked with synthetic K27M mutant sequence oligonucleotide and (b) non-tumor human CSF alone. (DOCX 268 kb)