Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Classical activating mutations (exon 19 deletions and the ...L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). However, low frequency mutations including point mutations, deletions, insertions and duplications occur within exons 18–25 of the EGFR gene in NSCLC and are associated with poorer responses to EGFRi. Despite an increased uptake of more sensitive detection methods to identify rare EGFR mutations in patients, our understanding of the biology of these rare EGFR mutations is poor compared to classical mutations. In particular, clinical data focused on these mutations is lacking due to their rarity and challenges in trial recruitment, resulting in an absence of effective treatment strategies for many low frequency EGFR mutations. In this review, we describe the structural and mechanistic features of rare EGFR mutations in NSCLC and discuss the preclinical and clinical evidence for EGFRi response for individual rare EGFR mutations. We also discuss EGFRi sensitivity for complex EGFR mutations, and conclude by offering a perspective on the outstanding questions and future steps required to make advances in the treatment of NSCLC patients that harbour rare EGFR mutations.
Illusory Late Heavy Bombardments Boehnke, Patrick; Harrison, T. Mark
Proceedings of the National Academy of Sciences - PNAS,
09/2016, Letnik:
113, Številka:
39
Journal Article
Recenzirano
Odprti dostop
The Late Heavy Bombardment (LHB), a hypothesized impact spike at ∼3.9 Ga, is one of the major scientific concepts to emerge from Apollo-era lunar exploration. A significant portion of the evidence ...for the existence of the LHB comes from histograms of 40Ar/39Ar “plateau” ages (i.e., regions selected on the basis of apparent isochroneity). However, due to lunar magmatism and overprinting from subsequent impact events, virtually all Apollo-era samples show evidence for 40Ar/39Ar age spectrum disturbances, leaving open the possibility that partial 40Ar* resetting could bias interpretation of bombardment histories due to plateaus yielding misleadingly young ages. We examine this possibility through a physical model of 40Ar* diffusion in Apollo samples and test the uniqueness of the impact histories obtained by inverting plateau age histograms. Our results show that plateau histograms tend to yield age peaks, even in those cases where the input impact curve did not contain such a spike, in part due to the episodic nature of lunar crust or parent body formation. Restated, monotonically declining impact histories yield apparent age peaks that could be misinterpreted as LHB-type events. We further conclude that the assignment of apparent 40Ar/39Ar plateau ages bears an undesirably high degree of subjectivity. When compounded by inappropriate interpretations of histograms constructed from plateau ages, interpretation of apparent, but illusory, impact spikes is likely.
Ancient zircons from Western Australia's Jack Hills preserve a record of conditions that prevailed on Earth not long after its formation. Widely considered to have been a uniquely violent period ...geodynamically, the Hadean Eon 4.5 to 4.0 billion years ago (Ga) has recently been interpreted by some as far more benign--possibly even characterized by oceans like those of the present day. Knowledge of the crystallization temperatures of the Hadean zircons is key to this debate. A thermometer based on titanium content revealed that these zircons cluster strongly at approximately700°C, which is indistinguishable from temperatures of granitoid zircon growth today and strongly suggests a regulated mechanism producing zircon-bearing rocks during the Hadean. The temperatures substantiate the existence of wet, minimum-melting conditions within 200 million years of solar system formation. They further suggest that Earth had settled into a pattern of crust formation, erosion, and sediment recycling as early as 4.35 Ga.
Evidence of life on Earth is manifestly preserved in the rock record. However, the microfossil record only extends to ∼3.5 billion years (Ga), the chemofossil record arguably to ∼3.8 Ga, and the rock ...record to 4.0 Ga. Detrital zircons from Jack Hills, Western Australia range in age up to nearly 4.4 Ga. From a population of over 10,000 Jack Hills zircons, we identified one >3.8-Ga zircon that contains primary graphite inclusions. Here, we report carbon isotopic measurements on these inclusions in a concordant, 4.10 ± 0.01-Ga zircon. We interpret these inclusions as primary due to their enclosure in a crack-free host as shown by transmission X-ray microscopy and their crystal habit. Their δ13CPDB of −24 ± 5‰ is consistent with a biogenic origin and may be evidence that a terrestrial biosphere had emerged by 4.1 Ga, or ∼300 My earlier than has been previously proposed.
Microalgae are a promising alternative source of lipid for biodiesel production. One of the most important decisions is the choice of species to use. High lipid productivity is a key desirable ...characteristic of a species for biodiesel production. This paper reviews information available in the literature on microalgal growth rates, lipid content and lipid productivities for 55 species of microalgae, including 17 Chlorophyta, 11 Bacillariophyta and five Cyanobacteria as well as other taxa. The data available in the literature are far from complete and rigorous comparison across experiments carried out under different conditions is not possible. However, the collated information provides a framework for decision-making and a starting point for further investigation of species selection. Shortcomings in the current dataset are highlighted. The importance of lipid productivity as a selection parameter over lipid content and growth rate individually is demonstrated.
The long-favored paradigm for the development of continental crust is one of progressive growth beginning at approximately4 billion years ago (Ga). To test this hypothesis, we measured initial ...¹⁷⁶Hf/¹⁷⁷Hf values of 4.01- to 4.37-Ga detrital zircons from Jack Hills, Western Australia. epsilonsubscript Hf (deviations of ¹⁷⁶Hf/¹⁷⁷Hf from bulk Earth in parts per 10⁴) values show large positive and negative deviations from those of the bulk Earth. Negative values indicate the development of a Lu/Hf reservoir that is consistent with the formation of continental crust (Lu/Hf approximately 0.01), perhaps as early as 4.5 Ga. Positive epsilonsubscript Hf deviations require early and likely widespread depletion of the upper mantle. These results support the view that continental crust had formed by 4.4 to 4.5 Ga and was rapidly recycled into the mantle.
Subfossil pollen and plant macrofossil data derived from
14
C-dated sediment profiles can provide quantitative information on glacial and interglacial climates. The data allow climate variables ...related to growing-season warmth, winter cold, and plant-available moisture to be reconstructed. Continental-scale reconstructions have been made for the mid-Holocene (MH, around 6 ka) and Last Glacial Maximum (LGM, around 21 ka), allowing comparison with palaeoclimate simulations currently being carried out as part of the fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change. The synthesis of the available MH and LGM climate reconstructions and their uncertainties, obtained using modern-analogue, regression and model-inversion techniques, is presented for four temperature variables and two moisture variables. Reconstructions of the same variables based on surface-pollen assemblages are shown to be accurate and unbiased. Reconstructed LGM and MH climate anomaly patterns are coherent, consistent between variables, and robust with respect to the choice of technique. They support a conceptual model of the controls of Late Quaternary climate change whereby the first-order effects of orbital variations and greenhouse forcing on the seasonal cycle of temperature are predictably modified by responses of the atmospheric circulation and surface energy balance.
Warm storage for arc magmas Barboni, Mélanie; Boehnke, Patrick; Schmitt, Axel K. ...
Proceedings of the National Academy of Sciences - PNAS,
12/2016, Letnik:
113, Številka:
49
Journal Article
Recenzirano
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Felsic magmatic systems represent the vast majority of volcanic activity that poses a threat to human life. The tempo and magnitude of these eruptions depends on the physical conditions under which ...magmas are retained within the crust. Recently the case has been made that volcanic reservoirs are rarely molten and only capable of eruption for durations as brief as 1,000 years following magma recharge. If the “cold storage” model is generally applicable, then geophysical detection of melt beneath volcanoes is likely a sign of imminent eruption. However, some arc volcanic centers have been active for tens of thousands of years and show evidence for the continual presence of melt. To address this seeming paradox, zircon geochronology and geochemistry from both the frozen lava and the cogenetic enclaves they host from the Soufrière Volcanic Center (SVC), a long-lived volcanic complex in the Lesser Antilles arc, were integrated to track the preeruptive thermal and chemical history of the magma reservoir. Our results show that the SVC reservoir was likely eruptible for periods of several tens of thousands of years or more with punctuated eruptions during these periods. These conclusions are consistent with results from other arc volcanic reservoirs and suggest that arc magmas are generally stored warm. Thus, the presence of intracrustal melt alone is insufficient as an indicator of imminent eruption, but instead represents the normal state of magma storage underneath dormant volcanoes.
Semi-competing risks refer to the time-to-event analysis setting, where the occurrence of a non-terminal event is subject to whether a terminal event has occurred, but not vice versa. Semi-competing ...risks arise in a broad range of clinical contexts, including studies of preeclampsia, a condition that may arise during pregnancy and for which delivery is a terminal event. Models that acknowledge semi-competing risks enable investigation of relationships between covariates and the joint timing of the outcomes, but methods for model selection and prediction of semi-competing risks in high dimensions are lacking. Moreover, in such settings researchers commonly analyze only a single or composite outcome, losing valuable information and limiting clinical utility-in the obstetric setting, this means ignoring valuable insight into timing of delivery after preeclampsia has onset. To address this gap, we propose a novel penalized estimation framework for frailty-based illness-death multi-state modeling of semi-competing risks. Our approach combines non-convex and structured fusion penalization, inducing global sparsity as well as parsimony across submodels. We perform estimation and model selection via a pathwise routine for non-convex optimization, and prove statistical error rate results in this setting. We present a simulation study investigating estimation error and model selection performance, and a comprehensive application of the method to joint risk modeling of preeclampsia and timing of delivery using pregnancy data from an electronic health record.
Constraining crustal silica on ancient Earth Keller, C. Brenhin; Harrison, T. Mark
Proceedings of the National Academy of Sciences - PNAS,
09/2020, Letnik:
117, Številka:
35
Journal Article
Recenzirano
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Accurately quantifying the composition of continental crust on Hadean and Archean Earth is critical to our understanding of the physiography, tectonics, and climate of our planet at the dawn of life. ...One longstanding paradigm involves the growth of a relatively mafic planetary crust over the first 1 to 2 billion years of Earth history, implying a lack of modern plate tectonics and a paucity of subaerial crust, and consequently lacking an efficient mechanism to regulate climate. Others have proposed a more uniformitarian view in which Archean and Hadean continents were only slightly more mafic than at present. Apart from complications in assessing early crustal composition introduced by crustal preservation and sampling biases, effects such as the secular cooling of Earth’s mantle and the biologically driven oxidation of Earth’s atmosphere have not been fully investigated.We find that the former complicates efforts to infer crustal silica from compatible or incompatible element abundances, while the latter undermines estimates of crustal silica content inferred from terrigenous sediments. Accounting for these complications, we find that the data are most parsimoniously explained by a model with nearly constant crustal silica since at least the early Archean.
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