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.     

Developing Reflective Practice in Information Systems Development: Further Progress on the Gestation of an Evaluative Framework

It is argued in this paper that evaluative activities in relation to systems development have traditionally focussed on the financial worth of the product. This approach has excluded the appraisal of important issues such as the process for building the product, the performance of the systems development team, the methods used and the organisational impact of the implemented System. In response to the traditional approach, which is skewed towards quantification techniques, a three stage framework is proposed. The three stages are iterative. The first being concerned with establishing an appropriate focus and resolution level for the evaluation, the second uses a control model to identify relevant outputs, appropriate sensors and comparators and performance criteria. The third is about selecting more sophisticated paradigms for assessing processes and their outputs. It is contended that although the specific focus of this paper is systems development, the framework could be used in any organisational context where products and services are developed and produced.     

Matrix control of scarring

Repair of wounds usually results in restoration of organ function, even if suboptimal. However, in a minority of situations, the healing process leads to significant scarring that hampers homeostasis and leaves the tissue compromised. This scar is characterized by an excess of matrix deposition that remains poorly organized and weakened. While we know much of the early stages of the repair process, the transition to wound resolution that limits scar formation is poorly understood. This is particularly true of the inducers of scar formation. Here, we present a hypothesis that it is the matrix itself that is a primary driver of scar, rather than being simply the result of other cellular dysregulations.     

Stimulation of olfactory ensheathing cell motility enhances olfactory axon growth

Axons of primary olfactory neurons are intimately associated with olfactory ensheathing cells (OECs) from the olfactory epithelium until the final targeting of axons within the olfactory bulb. However, little is understood about the nature and role of interactions between OECs and axons during development of the olfactory nerve pathway. We have used high resolution time-lapse microscopy to examine the growth and interactions of olfactory axons and OECs in vitro. Transgenic mice expressing fluorescent reporters in primary olfactory axons (OMP-ZsGreen) and ensheathing cells (S100ß-DsRed) enabled us to selectively analyse these cell types in explants of olfactory epithelium. We reveal here that rather than providing only a permissive substrate for axon growth, OECs play an active role in modulating the growth of pioneer olfactory axons. We show that the interactions between OECs and axons were dependent on lamellipodial waves on the shaft of OEC processes. The motility of OECs was mediated by GDNF, which stimulated cell migration and increased the apparent motility of the axons, whereas loss of OECs via laser ablation of the cells inhibited olfactory axon outgrowth. These results demonstrate that the migration of OECs strongly regulates the motility of axons and that stimulation of OEC motility enhances axon extension and growth cone activity.     

Understanding science through its history: a response to Newman

The paper is a response to William Newman’s rebuttal of a critique of his account of the origins of modern chemistry by Alan Chalmers. A way in which the nature of science can be illuminated by history of science is identified and an account of how this can be achieved in the context of a study of the work of Boyle defended in the face of Newman’s criticism. Texts from the writings of Boyle that are cited by Newman as posing problems for Chalmers’ thesis are interpreted as in fact supporting it.     

Deposition of 1.88-billion-year-old iron formations as a consequence of rapid crustal growth

Iron formations are chemical sedimentary rocks comprising layers of iron-rich and silica-rich minerals whose deposition requires anoxic and iron-rich (ferruginous) sea water. Their demise after the rise in atmospheric oxygen by 2.32?billion years (Gyr) ago has been attributed to the removal of dissolved iron through progressive oxidation or sulphidation of the deep ocean. Therefore, a sudden return of voluminous iron formations nearly 500?million years later poses an apparent conundrum. Most late Palaeoproterozoic iron formations are about 1.88?Gyr old and occur in the Superior region of North America. Major iron formations are also preserved in Australia, but these were apparently deposited after the transition to a sulphidic ocean at 1.84?Gyr ago that should have terminated iron formation deposition, implying that they reflect local marine conditions. Here we date zircons in tuff layers to show that iron formations in the Frere Formation of Western Australia are about 1.88?Gyr old, indicating that the deposition of iron formations from two disparate cratons was coeval and probably reflects global ocean chemistry. The sudden reappearance of major iron formations at 1.88?Gyr ago--contemporaneous with peaks in global mafic-ultramafic magmatism, juvenile continental and oceanic crust formation, mantle depletion and volcanogenic massive sulphide formation--suggests deposition of iron formations as a consequence of major mantle activity and rapid crustal growth. Our findings support the idea that enhanced submarine volcanism and hydrothermal activity linked to a peak in mantle melting released large volumes of ferrous iron and other reductants that overwhelmed the sulphate and oxygen reservoirs of the ocean, decoupling atmospheric and seawater redox states, and causing the return of widespread ferruginous conditions. Iron formations formed on clastic-starved coastal shelves where dissolved iron upwelled and mixed with oxygenated surface water. The disappearance of iron formations after this event may reflect waning mafic-ultramafic magmatism and a diminished flux of hydrothermal iron relative to seawater oxidants.     

Low beta diversity of herbivorous insects in tropical forests

Recent advances in understanding insect communities in tropical forests have contributed little to our knowledge of large-scale patterns of insect diversity, because incomplete taxonomic knowledge of many tropical species hinders the mapping of their distribution records. This impedes an understanding of global biodiversity patterns and explains why tropical insects are under-represented in conservation biology. Our study of approximately 500 species from three herbivorous guilds feeding on foliage (caterpillars, Lepidoptera), wood (ambrosia beetles, Coleoptera) and fruit (fruitflies, Diptera) found a low rate of change in species composition (beta diversity) across 75,000 square kilometres of contiguous lowland rainforest in Papua New Guinea, as most species were widely distributed. For caterpillars feeding on large plant genera, most species fed on multiple host species, so that even locally restricted plant species did not support endemic herbivores. Large plant genera represented a continuously distributed resource easily colonized by moths and butterflies over hundreds of kilometres. Low beta diversity was also documented in groups with differing host specificity (fruitflies and ambrosia beetles), suggesting that dispersal limitation does not have a substantial role in shaping the distribution of insect species in New Guinea lowland rainforests. Similar patterns of low beta diversity can be expected in other tropical lowland rainforests, as they are typically situated in the extensive low basins of major tropical rivers similar to the Sepik-Ramu region of New Guinea studied here.     

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.