Functional exploration of colorectal cancer genomes using Drosophila

The multigenic nature of human tumours presents a fundamental challenge for cancer drug discovery. Here we use Drosophila to generate 32 multigenic models of colon cancer using patient data from The Cancer Genome Atlas. These models recapitulate key features of human cancer, often as emergent properties of multigenic combinations. Multigenic models such as ras p53 pten apc exhibit emergent resistance to a panel of cancer-relevant drugs. Exploring one drug in detail, we identify a mechanism of resistance for the PI3K pathway inhibitor BEZ235. We use this data to identify a combinatorial therapy that circumvents this resistance through a two-step process of emergent pathway dependence and sensitivity we term ‘induced dependence’. This approach is effective in cultured human tumour cells, xenografts and mouse models of colorectal cancer. These data demonstrate how multigenic animal models that reference cancer genomes can provide an effective approach for developing novel targeted therapies

Newly formed craters on Mars located using seismic and acoustic wave data from InSight

Meteoroid impacts shape planetary surfaces by forming new craters and alter atmospheric composition. During atmospheric entry and impact on the ground, meteoroids excite transient acoustic and seismic waves. However, new crater formation and the associated impact-induced mechanical waves have yet to be observed jointly beyond Earth. Here we report observations of seismic and acoustic waves from the NASA InSight lander’s seismometer that we link to four meteoroid impact events on Mars observed in spacecraft imagery. We analysed arrival times and polarization of seismic and acoustic waves to estimate impact locations, which were subsequently confirmed by orbital imaging of the associated craters. Crater dimensions and estimates of meteoroid trajectories are consistent with waveform modelling of the recorded seismograms. With identified seismic sources, the seismic waves can be used to constrain the structure of the Martian interior, corroborating previous crustal structure models, and constrain scaling relationships between the distance and amplitude of impact-generated seismic waves on Mars, supporting a link between the seismic moment of impacts and the vertical impactor momentum. Our findings demonstrate the capability of planetary seismology to identify impact-generated seismic sources and constrain both impact processes and planetary interiors

A Global Fireball Observatory

The world's meteorite collections contain a very rich picture of what the early Solar System would have been made of, however the lack of spatial context with respect to their parent population for these samples is an issue. The asteroid population is equally as rich in surface mineralogies, and mapping these two populations (meteorites and asteroids) together is a major challenge for planetary science. Directly probing asteroids achieves this at a high cost. Observing meteorite falls and calculating their pre-atmospheric orbit on the other hand, is a cheaper way to approach the problem. The Global Fireball Observatory (GFO) collaboration was established in 2017 and brings together multiple institutions (from Australia, USA, Canada, Morocco, Saudi Arabia, the UK, and Argentina) to maximise the area for fireball observation time and therefore meteorite recoveries. The members have a choice to operate independently, but they can also choose to work in a fully collaborative manner with other GFO partners. This efficient approach leverages the experience gained from the Desert Fireball Network (DFN) pathfinder project in Australia. The state-of-the art technology (DFN camera systems and data reduction) and experience of the support teams is shared between all partners, freeing up time for science investigations and meteorite searching. With all networks combined together, the GFO collaboration already covers 0.6% of the Earth's surface for meteorite recovery as of mid-2019, and aims to reach 2% in the early 2020s. We estimate that after 5 years of operation, the GFO will have observed a fireball from virtually every meteorite type. This combined effort will bring new, fresh, extra-terrestrial material to the labs, yielding new insights about the formation of the Solar System

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee

Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin