CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial.

BACKGROUND: Patients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC). PATIENTS AND METHODS: This single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR). RESULTS: Between 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months). CONCLUSIONS: The primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious

Description and Evaluation of the specified-dynamics experiment in the Chemistry-Climate Model Initiative

We provide an overview of the REF-C1SD specified-dynamics experiment that was conducted as part of phase 1 of the Chemistry-Climate Model Initiative (CCMI). The REF-C1SD experiment, which consisted of mainly nudged general circulation models (GCMs) constrained with (re)analysis fields, was designed to examine the influence of the large-scale circulation on past trends in atmospheric composition. The REF-C1SD simulations were produced across various model frameworks and are evaluated in terms of how well they represent different measures of the dynamical and transport circulations. In the troposphere there are large (∼40 %) differences in the climatological mean distributions, seasonal cycle amplitude, and trends of the meridional and vertical winds. In the stratosphere there are similarly large (∼50 %) differences in the magnitude, trends and seasonal cycle amplitude of the transformed Eulerian mean circulation and among various chemical and idealized tracers. At the same time, interannual variations in nearly all quantities are very well represented, compared to the underlying reanalyses. We show that the differences in magnitude, trends and seasonal cycle are not related to the use of different reanalysis products; rather, we show they are associated with how the simulations were implemented, by which we refer both to how the large-scale flow was prescribed and to biases in the underlying free-running models. In most cases these differences are shown to be as large or even larger than the differences exhibited by free-running simulations produced using the exact same models, which are also shown to be more dynamically consistent. Overall, our results suggest that care must be taken when using specified-dynamics simulations to examine the influence of large-scale dynamics on composition

The effect of atmospheric nudging on the stratospheric residual circulation in chemistry–climate models

We perform the first multi-model intercomparison of the impact of nudged meteorology on the stratospheric residual circulation using hindcast simulations from the Chemistry–Climate Model Initiative (CCMI). We examine simulations over the period 1980–2009 from seven models in which the meteorological fields are nudged towards a reanalysis dataset and compare these with their equivalent free-running simulations and the reanalyses themselves. We show that for the current implementations, nudging meteorology does not constrain the mean strength of the stratospheric residual circulation and that the inter-model spread is similar, or even larger, than in the free-running simulations. The nudged models generally show slightly stronger upwelling in the tropical lower stratosphere compared to the free-running versions and exhibit marked differences compared to the directly estimated residual circulation from the reanalysis dataset they are nudged towards. Downward control calculations applied to the nudged simulations reveal substantial differences between the climatological lower-stratospheric tropical upward mass flux (TUMF) computed from the modelled wave forcing and that calculated directly from the residual circulation. This explicitly shows that nudging decouples the wave forcing and the residual circulation so that the divergence of the angular momentum flux due to the mean motion is not balanced by eddy motions, as would typically be expected in the time mean. Overall, nudging meteorological fields leads to increased inter-model spread for most of the measures of the mean climatological stratospheric residual circulation assessed in this study. In contrast, the nudged simulations show a high degree of consistency in the inter-annual variability in the TUMF in the lower stratosphere, which is primarily related to the contribution to variability from the resolved wave forcing. The more consistent inter-annual variability in TUMF in the nudged models also compares more closely with the variability found in the reanalyses, particularly in boreal winter. We apply a multiple linear regression (MLR) model to separate the drivers of inter-annual and long-term variations in the simulated TUMF; this explains up to ∼75 % of the variance in TUMF in the nudged simulations. The MLR model reveals a statistically significant positive trend in TUMF for most models over the period 1980–2009. The TUMF trend magnitude is generally larger in the nudged models compared to their free-running counterparts, but the intermodel range of trends doubles from around a factor of 2 to a factor of 4 due to nudging. Furthermore, the nudged models generally do not match the TUMF trends in the reanalysis they are nudged towards for trends over different periods in the interval 1980–2009. Hence, we conclude that nudging does not strongly constrain long-term trends simulated by the chemistry–climate model (CCM) in the residual circulation. Our findings show that while nudged simulations may, by construction, produce accurate temperatures and realistic representations of fast horizontal transport, this is not typically the case for the slower zonal mean vertical transport in the stratosphere. Consequently, caution is required when using nudged simulations to interpret the behaviour of stratospheric tracers that are affected by the residual circulation

Tropospheric jet response to Antarctic ozone depletion: An update with Chemistry-Climate Model Initiative (CCMI) models

The Southern Hemisphere (SH) zonal-mean circulation change in response to Antarctic ozone depletion is re-visited by examining a set of the latest model simulations archived for the Chemistry-Climate Model Initiative (CCMI) project. All models reasonably well reproduce Antarctic ozone depletion in the late 20th century. The related SH-summer circulation changes, such as a poleward intensification of westerly jet and a poleward expansion of the Hadley cell, are also well captured. All experiments exhibit quantitatively the same multi-model mean trend, irrespective of whether the ocean is coupled or prescribed. Results are also quantitatively similar to those derived from the Coupled Model Intercomparison Project phase 5 (CMIP5) high-top model simulations in which the stratospheric ozone is mostly prescribed with monthly- and zonally-averaged values. These results suggest that the ozone-hole-induced SH-summer circulation changes are robust across the models irrespective of the specific chemistry-atmosphere-ocean coupling

Bringing It All Together: Multi-species Integrated Population Modelling of a Breeding Community

Integrated population models (IPMs) combine data on different aspects of demography with time-series of population abundance. IPMs are becoming increasingly popular in the study of wildlife populations, but their application has largely been restricted to the analysis of single species. However, species exist within communities: sympatric species are exposed to the same abiotic environment, which may generate synchrony in the fluctuations of their demographic parameters over time. Given that in many environments conditions are changing rapidly, assessing whether species show similar demographic and population responses is fundamental to quantifying interspecific differences in environmental sensitivity and highlighting ecological interactions at risk of disruption. In this paper, we combine statistical approaches to study populations, integrating data along two different dimensions: across species (using a recently proposed framework to quantify multi-species synchrony in demography) and within each species (using IPMs with demographic and abundance data).We analyse data from three seabird species breeding at a nationally important long-term monitoring site. We combine demographic datasets with island-wide population counts to construct the first multi-species Integrated Population Model to consider synchrony. Our extension of the IPM concept allows the simultaneous estimation of demographic parameters, adult abundance and multi-species synchrony in survival and productivity, within a robust statistical framework. The approach is readily applicable to other taxa and habitats

Large Impacts, Past and Future, of Ozone-Depleting Substances on Brewer-Dobson Circulation Trends: A Multimodel Assessment

Substantial increases in the atmospheric concentration of well‐mixed greenhouse gases (notably CO2), such as those projected to occur by the end of the 21st century under large radiative forcing scenarios, have long been known to cause an acceleration of the Brewer‐Dobson circulation (BDC) in climate models. More recently, however, several single‐model studies have proposed that ozone‐depleting substances might also be important drivers of BDC trends. As these studies were conducted with different forcings over different periods, it is difficult to combine them to obtain a robust quantitative picture of the relative importance of ozone‐depleting substances as drivers of BDC trends. To this end, we here analyze—over identical past and future periods—the output from 20 similarly forced models, gathered from two recent chemistry‐climate modeling intercomparison projects. Our multimodel analysis reveals that ozone‐depleting substances are responsible for more than half of the modeled BDC trends in the two decades 1980–2000. We also find that, as a consequence of the Montreal Protocol, decreasing concentrations of ozone‐depleting substances in coming decades will strongly decelerate the BDC until the year 2080, reducing the age‐of‐air trends by more than half, and will thus substantially mitigate the impact of increasing CO2. As ozone‐depleting substances impact BDC trends, primarily, via the depletion/recovery of stratospheric ozone over the South Pole, they impart seasonal and hemispheric asymmetries to the trends which may offer opportunities for detection in coming decades

Age-related decrements in dual-task performance: comparison of different mobility and cognitive tasks. A cross sectional study

This cross-sectional study investigated the age-related differences in dual-task performance both in mobility and cognitive tasks and the additive dual-task costs in a sample of older, middle-aged and young adults. 74 older adults (M = 72.63±5.57 years), 58 middle-aged adults (M = 46.69±4.68 years) and 63 young adults (M = 25.34±3.00 years) participated in the study. Participants performed different mobility and subtraction tasks under both single- and dual-task conditions. Linear regressions, repeated-measures and one-way analyses of covariance were used, The results showed: significant effects of the age on the dual and mobility tasks (p<0.05) and differences among the age-groups in the combined dual-task costs (p<0.05); significant decreases in mobility performance under dual-task conditions in all groups (p<0.05) and a decrease in cognitive performance in the older group (p<0.05). Dual-task activity affected mobility and cognitive performance, especially in older adults who showed a higher dual-task cost, suggesting that dual-tasks activities are affected by the age and consequently also mobility and cognitive tasks are negatively influenced