Explore the vast range of titles available.

Background To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Methods Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. Results The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3–1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n  = 3; comparator, n  = 4). 2.8% ( n  = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% ( n  = 76) had low RET gene copy number gain (4–6 copies in ≥40% of tumor cells) and 8.3% ( n  = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET -rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. Conclusions We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. Trial registration Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).

The Coupled Model Intercomparison Project phase 6 (CMIP6) HighResMIP is a new experimental design for global climate model simulations that aims to assess the impact of model horizontal resolution on climate simulation fidelity. We describe a hierarchy of global coupled model resolutions based on the Hadley Centre Global Environment Model 3 – Global Coupled vn 3.1 (HadGEM3-GC3.1) model that ranges from an atmosphere–ocean resolution of 130 km–1∘ to 25 km–1/12∘, all using the same forcings and initial conditions. In order to make such high-resolution simulations possible, the experiments have a short 30-year spinup, followed by at least century-long simulations with constant forcing to assess drift.We assess the change in model biases as a function of both atmosphere and ocean resolution, together with the effectiveness and robustness of this new experimental design. We find reductions in the biases in top-of-atmosphere radiation components and cloud forcing. There are significant reductions in some common surface climate model biases as resolution is increased, particularly in the Atlantic for sea surface temperature and precipitation, primarily driven by increased ocean resolution. There is also a reduction in drift from the initial conditions both at the surface and in the deeper ocean at higher resolution. Using an eddy-present and eddy-rich ocean resolution enhances the strength of the North Atlantic ocean circulation (boundary currents, overturning circulation and heat transport), while an eddy-present ocean resolution has a considerably reduced Antarctic Circumpolar Current strength. All models have a reasonable representation of El Niño–Southern Oscillation. In general, the biases present after 30 years of simulations do not change character markedly over longer timescales, justifying the experimental design.

The study of fire history and driving mechanisms at long time scales can provide a theoretical background for future fire management in forested regions. The alpine lake sediments from Daye Lake in the Qinling Mountains, east‐central China, were used to explore the influence of climate, vegetation and human activity on fires since the LGM, based on charcoals and black carbon. During the last glacial period, fire activity was mostly controlled by regional aridity under a weak East Asian summer monsoon, while human‐induced fires were commonly dominated in the late Holocene. Fire activity was found to be linked to biomass through temperature variability. The biofuel dominated by conifers induced high intensity fires in the last glacial, and herbs contributed more to the high fire frequency over the mid‐late Holocene. With predicted future rising temperatures, increased vegetation cover and extreme climate events may increase the fire risk in the region. Plain Language Summary Fire activity has an important influence on climate changes and carbon cycling. Understanding past fire history and its driving mechanisms are essential to mitigate the impact of fires. Here, we present fire records from alpine lake sediments in the Qinling Mountains since the LGM. Results indicate that climatological drought under a prevailing weak East Asian summer monsoon increased fire activity during 21.6–11.7 cal ka BP, while human‐induced fires became more common in the late Holocene due to land use, for example, the forest clearing for agriculture and the warfare. And high temperature increases fuel loads, resulting in more fires. Moreover, vegetation types with varying biofuel supply also influence fire activity. We suggest that fire risk may increase in the region with future rising temperature. Our results have implications for understanding fire history and management in other transitional vegetation zones globally. Key Points The prevailing weak East Asian summer monsoon mostly controlled fire activity during the last glacial, whilst human activity became common through the Holocene The conifers induced high intensity fires in the last glacial and herbs contributed more to high fire frequency over the mid‐late Holocene Forest resources in east‐central China will face the increased fire risks in the context of global warming and increasing vegetation cover

The oscillatory behaviour of the climate system on decadal timescales before the instrumental record is hard to quantify. However, knowledge of this variability is important for putting current changes in context and for supporting reliable future predictions. Here we investigate the recurrent component of Holocene climate variability in the North Atlantic sector from 10,500 to 2,000 years ago by conducting a frequency analysis of both an annually laminated climate record from a lake in England and outputs from a long transient simulation of the Atlantic meridional overturning circulation. We find consistent decadal variability over the past 6,700 years and before 8,500 years before present, probably reflecting predominance of solar and ocean forcings. Between these dates, climate variability was dampened on decadal timescales. Our results suggest that meltwater discharge into the North Atlantic and the subsequent hydrographic changes, from the opening of the Hudson Bay until the final collapse of the Laurentide Ice Sheet, disrupted the decadal cyclic signals for more than a millennium. Given the current acceleration of the Greenland Ice Sheet melting in response to global warming, this study provides long-term evidence of potential challenges predicting future patterns of the climate system.Meltwater discharge to the mid-Holocene North Atlantic disrupted decadal climate variability, suggesting future melting on Greenland may hinder climate predictability in the region, according to an annually laminated lake-sediment record and transient model simulations.

Understanding the resilience of early societies to climate change is an essential part of exploring the environmental sensitivity of human populations. There is significant interest in the role of abrupt climate events as a driver of early Holocene human activity, but there are very few well-dated records directly compared with local climate archives. Here, we present evidence from the internationally important Mesolithic site of Star Carr showing occupation during the early Holocene, which is directly compared with a high-resolution palaeoclimate record from neighbouring lake beds. We show that—once established—there was intensive human activity at the site for several hundred years when the community was subject to multiple, severe, abrupt climate events that impacted air temperatures, the landscape and the ecosystem of the region. However, these results show that occupation and activity at the site persisted regardless of the environmental stresses experienced by this society. The Star Carr population displayed a high level of resilience to climate change, suggesting that postglacial populations were not necessarily held hostage to the flickering switch of climate change. Instead, we show that local, intrinsic changes in the wetland environment were more significant in determining human activity than the large-scale abrupt early Holocene climate events. A high-resolution local palaeoclimatic archive is correlated to the early Holocene human behavioural record at the British Mesolithic site of Star Carr. Despite environmental stresses at this time, intensive human activity persisted over centuries, suggesting resilience to climate change.