Background Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multimodal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high-throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified actinomycin D (ACTD) to be highly cytotoxic over a panel of 12 patient-derived glioma stemlike cell (GSC) lines. ACTD is an antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for GBM in 3-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma. Methods Twelve patient-derived GSC lines were screened at 10 µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established half-maximal inhibitory concentrations (IC50). Downregulation of sex determining region Y–box 2 (Sox2), a stem cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue. Results Treatment with ACTD was shown to significantly reduce tumor growth in 2 recurrent GBM patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo. Conclusion These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression. Key Points 1. High-throughput chemosensitivity data demonstrated the broad efficacy of actinomycin D, which was validated in 3 preclinical models of glioblastoma. 2. Actinomycin D downregulated Sox2 in vitro and in vivo, indicating that this agent could target the stem cell population of GBM tumors.

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Nearly all of Greenland's bedrock geology is inaccessible because it is covered by the Greenland Ice Sheet. Therefore, geophysical investigations are especially important in furthering our understanding of Greenland's subglacial lithospheric structure. Greenland is a region of interest as its lithosphere contains cratonic material and records the history of Archean, Proterozoic, and Paleozoic orogenies and could provide insight into the history of the Iceland plume (e.g., Henriksen et al., 2009). The majority of Greenland is Precambrian and has been modified by multiple tectonic (orogenic and rifting) events (e.g., Henriksen et al., 2009). Of particular note is the Trans-Hudson Orogeny, which was a widespread set of plate collisions that helped to build Laurentia around 1.8 Ga (e.g., St-Onge et al., 2009). Orogenic belts from this event can be found across North America; in Greenland, this includes the Rinkian and Nagssugtoqidian belts that bound major crustal blocks (e.g.

The surfaces of icy moons are covered by fractures, other tectonic features, and active or ancient remains of cryovolcanism. These observations suggest active or recent tectonics, but there is still much unknown about the specific conditions surrounding the formation of these features. One important process leading to the fracture of the ice shell is the freezing and consequent pressurization of its ocean, because water expands upon freezing. However, the influence of dissolved non‐condensable gases (herein referred to as volatiles) on the aforementioned dynamics remains poorly constrained. In this study, we present a new experimental investigation to explore the effect of dissolved volatiles in the internal pressure evolution of 10 cm diameter water spheres subjected to freezing temperatures between ~−60°C and ~−20°C. Our experiments reveal that spheres with a reduced initial amount of volatiles dissolved undergo an abrupt transition with dramatic increase of (a) the time between consecutive ice shell fractures and (b) the pressure required to break the shell. We show from a simple numerical model that this transition occurs when exsolution (i.e., nucleation and growth of bubbles) occurs and the fluid inside the shell becomes significantly more compressible. Exsolution is, in turn, triggered by the gradual thickening of the ice shell, which increases the concentration of dissolved volatiles and eventually leads to saturation. These results suggest that the content of volatiles of icy satellites plays a significant role in their geologic history and potential for habitability.

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Photosensitizers (PS) are used in photodynamic therapy to treat several cancers. The efficacy of photodynamic therapy (PDT) could be further improved by overcoming aggregation-dependent quenching of PS and by improving the biodistribution of the PS. In this work we attempted to overcome these issues by conjugating a PS with a lipid molecule and tested the liposomes prepared with this PS conjugated lipid for PDT. A novel lipid-porphyrin conjugate (1 : 1) was synthesized by attaching a PS, 5-(4-methoxycarbonylphenyl)-10,15,20-triphenyl-H,H-porphine, to the head group of a glutamide lipid. Two liposomal preparations, with egg phosphatidylcholine as the bulk lipid, were prepared viz. liposomes with PS conjugated lipid (LPSL) and PS entrapped in liposomes (PSL). At equimolar concentrations of the PS, both liposomal preparations were found to generate comparable amounts of reactive oxygen species as free PS upon light exposure. Electron micrographs and dynamic light scattering measurements indicated uniform and circular liposomes of 150 nm in size and near neutral zeta potential. Uptake of these liposomes by the human ovarian carcinoma cell line, SK-OV-3, was shown by FACS and confocal microscopy. Upon light exposure, the LPSL, i.e., with the conjugate lipid, have shown a substantial decrease (>4 times) in the PS requirement compared to PSL or free PS in its ability to cause light mediated cell death of SK-OV-3 cells. The light mediate cell death by LPSL was shown to be not dependent on the bulk properties of the lipid. Our data suggest a potential benefit of conjugating PS with a lipid in improving the efficiency of PDT.

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