Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.     

Salvage logging and replanting reduce understory cover and richness compared to unsalvaged unplanted sites at Mount St. Helens, Washington

The 1980 eruption of Mount St. Helens killed trees in a broad 600-km2 swath north of the crater. Over most of the blast zone, dead trees were salvage logged and Abies procera was planted, except in areas within the Mount St. Helens National Volcanic Monument. We compared salvage-replanted sites and unsalvaged sites in 1 area of the blast zone where the sites were adjacent by using twenty-five 200-m 2 plots for each treatment. Salvaged-replanted plots had significantly lower herb and shrub cover, richness, diversity, litter depth, downed woody debris, nitrate, and phosphate. Salvaged-replanted sites also had significantly more stumps, bare area, and moss cover than unsalvaged plots. Soil organic matter and nonnative species cover did not differ. Nonnative species were not important components of any plots. Nitrate, total nitrogen, organic matter, and litter were correlated with the major patterns of species distribution in a canonical correspondence analysis of the salvaged-replanted plots. In the unsalvaged plots, slope, downed woody debris, and elevation were correlated with the major patterns of species distribution.     

Event-horizon-scale structure in the supermassive black hole candidate at the Galactic Centre

The cores of most galaxies are thought to harbour supermassive black holes, which power galactic nuclei by converting the gravitational energy of accreting matter into radiation. Sagittarius A* (Sgr A*), the compact source of radio, infrared and X-ray emission at the centre of the Milky Way, is the closest example of this phenomenon, with an estimated black hole mass that is 4,000,000 times that of the Sun. A long-standing astronomical goal is to resolve structures in the innermost accretion flow surrounding Sgr A*, where strong gravitational fields will distort the appearance of radiation emitted near the black hole. Radio observations at wavelengths of 3.5 mm and 7 mm have detected intrinsic structure in Sgr A*, but the spatial resolution of observations at these wavelengths is limited by interstellar scattering. Here we report observations at a wavelength of 1.3 mm that set a size of 37(+16)(-10) microarcseconds on the intrinsic diameter of Sgr A*. This is less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow.     

Systemic Research Practices Towards the Development of an Eco-Community in Vietnam: some Joint Post-Facto Reflections

In this article we discuss how an interdisciplinary research team partnered with a variety of stakeholders concerned with and/or affected by the impacts of climate change in the Red River Delta of Vietnam. The research, undertaken from 2016 to 2018, drew upon a wide range of methods to investigate systemically these impacts – with a view to the research inputting into the development of (more) sustainable ways of living. The research solicited various accounts of the experience of climate change in the community, set up learning processes in community meetings, and created an interface with government officials positioned at commune, district, provincial, and national levels. The intention was to offer support towards developing a learning process (broadly defined as including learnings/systemic inquiry across organizational levels of the society) to pursue options for sustainable living. The article offers our post-facto reflections which render more explicit (to ourselves and for the benefit of audiences) how the research team, with Hoang as lead researcher, facilitated the inquiry process towards developing a synthesis which underscored the assets for resilience to climate change and supported interventions to strengthen such (defined) assets.

     

Hydrated silicate minerals on Mars observed by the Mars Reconnaissance Orbiter CRISM instrument

Phyllosilicates, a class of hydrous mineral first definitively identified on Mars by the OMEGA (Observatoire pour la Mineralogie, L'Eau, les Glaces et l'Activitié) instrument, preserve a record of the interaction of water with rocks on Mars. Global mapping showed that phyllosilicates are widespread but are apparently restricted to ancient terrains and a relatively narrow range of mineralogy (Fe/Mg and Al smectite clays). This was interpreted to indicate that phyllosilicate formation occurred during the Noachian (the earliest geological era of Mars), and that the conditions necessary for phyllosilicate formation (moderate to high pH and high water activity) were specific to surface environments during the earliest era of Mars's history. Here we report results from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) of phyllosilicate-rich regions. We expand the diversity of phyllosilicate mineralogy with the identification of kaolinite, chlorite and illite or muscovite, and a new class of hydrated silicate (hydrated silica). We observe diverse Fe/Mg-OH phyllosilicates and find that smectites such as nontronite and saponite are the most common, but chlorites are also present in some locations. Stratigraphic relationships in the Nili Fossae region show olivine-rich materials overlying phyllosilicate-bearing units, indicating the cessation of aqueous alteration before emplacement of the olivine-bearing unit. Hundreds of detections of Fe/Mg phyllosilicate in rims, ejecta and central peaks of craters in the southern highland Noachian cratered terrain indicate excavation of altered crust from depth. We also find phyllosilicate in sedimentary deposits clearly laid by water. These results point to a rich diversity of Noachian environments conducive to habitability.     

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.     

CO2 jets formed by sublimation beneath translucent slab ice in Mars' seasonal south polar ice cap

The martian polar caps are among the most dynamic regions on Mars, growing substantially in winter as a significant fraction of the atmosphere freezes out in the form of CO2 ice. Unusual dark spots, fans and blotches form as the south-polar seasonal CO2 ice cap retreats during spring and summer. Small radial channel networks are often associated with the location of spots once the ice disappears. The spots have been proposed to be simply bare, defrosted ground; the formation of the channels has remained uncertain. Here we report infrared and visible observations that show that the spots and fans remain at CO2 ice temperatures well into summer, and must be granular materials that have been brought up to the surface of the ice, requiring a complex suite of processes to get them there. We propose that the seasonal ice cap forms an impermeable, translucent slab of CO2 ice that sublimates from the base, building up high-pressure gas beneath the slab. This gas levitates the ice, which eventually ruptures, producing high-velocity CO2 vents that erupt sand-sized grains in jets to form the spots and erode the channels. These processes are unlike any observed on Earth.