To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell lung cancer (NSCLC).
PK dependencies in OS were ...evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan-Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL
), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL
subgroups.
A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma HR = 0.98; 95% confidence interval (CI), 0.94-1.02 and NSCLC (HR = 0.98; 95% CI, 0.95-1.01); however, a strong CL
-OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72-3.80 and NSCLC HR = 2.64; 95% CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL
paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL
-OS association (multivariate-adjusted CL
HR = 1.64; 95% CI, 1.06-2.52 for melanoma and HR = 1.88; 95% CI, 1.22-2.89 for NSCLC).
These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL
with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.
.
The HadGEM2 AGCM is used to determine the most important anthropogenic aerosols in the Indian monsoon using experiments in which observed trends in individual aerosol species are imposed. Sulfur ...dioxide (SD) emissions are shown to impact rainfall more strongly than black carbon (BC) aerosols, causing reduced rainfall especially over northern India. Significant perturbations due to BC are not noted until its emissions are scaled up in a sensitivity test, resulting in rainfall increases over northern India due to the elevated heat pump mechanism, enhancing convection during the premonsoon, and bringing forward the monsoon onset. Second, the impact of anthropogenic aerosols is compared to that of increasing greenhouse-gas concentrations and observed sea surface temperature (SST) warming. The tropospheric temperature gradient driving the monsoon shows weakening when forced by either SD or imposed SST trends. However, the observed SST trend is dominated by warming in the deep tropics; when the component of SST trend related to aerosol emissions is removed, further warming is found in the extratropical Northern Hemisphere that tends to offset monsoon weakening. This suggests caution is needed when using SST forcing as a proxy for greenhouse warming. Finally, aerosol emissions are decomposed into those from the Indian region and those elsewhere in pairs of experiments with SD and BC. Both local and remote aerosol emissions are found to lead to rainfall changes over India; for SD, remote aerosols contribute around 75% of the rainfall decrease over India, while for BC the remote forcing is even more dominant.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Arabian Sea is an important moisture source for Indian monsoon rainfall. The skill of climate models in simulating the monsoon and its variability varies widely, while Arabian Sea cold sea ...surface temperature (SST) biases are common in coupled models and may therefore influence the monsoon and its sensitivity to climate change. We examine the relationship between monsoon rainfall, moisture fluxes and Arabian Sea SST in observations and climate model simulations. Observational analysis shows strong monsoons depend on moisture fluxes across the Arabian Sea, however detecting consistent signals with contemporaneous summer SST anomalies is complicated in the observed system by air/sea coupling and large-scale induced variability such as the El Niño-Southern Oscillation feeding back onto the monsoon through development of the Somali Jet. Comparison of HadGEM3 coupled and atmosphere-only configurations suggests coupled model cold SST biases significantly reduce monsoon rainfall. Idealised atmosphere-only experiments show that the weakened monsoon can be mainly attributed to systematic Arabian Sea cold SST biases during summer and their impact on the monsoon-moisture relationship. The impact of large cold SST biases on atmospheric moisture content over the Arabian Sea, and also the subsequent reduced latent heat release over India, dominates over any enhancement in the land-sea temperature gradient and results in changes to the mean state. We hypothesize that a cold base state will result in underestimation of the impact of larger projected Arabian Sea SST changes in future climate, suggesting that Arabian Sea biases should be a clear target for model development.
Many previous studies have demonstrated a high uncertainty in the relationship between El Niño–Southern Oscillation (ENSO) and the North Atlantic Oscillation (NAO). In the present work, decadal ...modulation by the Atlantic multidecadal oscillation (AMO) is investigated as a possible cause of the nonstationary ENSO–NAO relationship based on observed and reanalysis data. It is found that the negative ENSO–NAO correlation in late winter is significant only when ENSO and the AMO are in phase (AMO+/El Niño and AMO−/La Niña). However, no significant ENSO-driven atmospheric anomalies can be observed over the North Atlantic when ENSO and the AMO are out of phase (AMO−/El Niño and AMO+/La Niña). Further analysis indicates that the sea surface temperature anomaly (SSTA) in the tropical North Atlantic (TNA) plays an essential role in this modulating effect. Because of broadly analogous TNA SSTA responses to both ENSO and the AMO during late winter, a warm SSTA in the TNA is evident when El Niño occurs during a positive AMO phase, resulting in a significantly weakened NAO, and vice versa when La Niña occurs during a negative AMO phase. In contrast, neither the TNA SSTA nor the NAO shows a prominent change under out-of-phase combinations of ENSO and AMO. The AMO modulation and the associated effect of the TNA SSTA are shown to be well reproduced by historical simulations of the HadCM3 coupled model and further verified by forced experiments using an atmospheric circulation model. These offer hope that similar models will be able to make predictions for the NAO when appropriately initialized.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing.
Methods
Molecular conformation, ...polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields.
Results
The form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability.
Conclusion
Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.
ERA-Interim reanalysis data from the past 35 years have been used with a newly developed feature tracking algorithm to identify Indian monsoon depressions originating in or near the Bay of Bengal. ...These were then rotated, centralized, and combined to give a fully three-dimensional 106-depression composite structure—a considerably larger sample than any previous detailed study on monsoon depressions and their structure. Many known features of depression structure are confirmed, particularly the existence of a maximum to the southwest of the center in rainfall and other fields and a westward axial tilt in others. Additionally, the depressions are found to have significant asymmetry owing to the presence of the Himalayas, a bimodal midtropospheric potential vorticity core, a separation into thermally cold (~−1.5 K) and neutral (~0 K) cores near the surface with distinct properties, and the center has very large CAPE and very small CIN. Variability as a function of background state has also been explored, with land–coast–sea, diurnal, ENSO, active–break, and Indian Ocean dipole contrasts considered. Depressions are found to be markedly stronger during the active phase of the monsoon, as well as during La Niña. Depressions on land are shown to be more intense and more tightly constrained to the central axis. A detailed schematic diagram of a vertical cross section through a composite depression is also presented, showing its inherent asymmetric structure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS ...in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC‐derived motor neurons, decreased cell survival is correlated with dysfunction in Ca2+ homeostasis, reduced levels of the antiapoptotic protein Bcl‐2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC‐derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063–2078
This study presents a comprehensive characterization of cellular pathways that are contributing to cell death in iPSC‐derived motor and cortical neurons from ALS/FTD patients carrying pathogenic hexanucleotide repeats in the C9orf72 gene. The apoptotic pathway that we identified in the C9orf72 neurons involves ER calcium elevation and stress, followed by mitochondrial alterations, the release of cytochrome c from the mitochondria and cleavage of caspase‐3. Aggregates positive for p62 were detected in these neurons along with high frequency of stress granules, indicating altered proteostatis in the C9orf72 motor and cortical neurons.
Abstract
The global monsoon is characterised by transitions between pronounced dry and wet seasons, affecting food security for two-thirds of the world’s population. Rising atmospheric CO
2
...influences the terrestrial hydrological cycle through climate-radiative and vegetation-physiological forcings. How these two forcings affect the seasonal intensity and characteristics of monsoonal precipitation and runoff is poorly understood. Here we use four Earth System Models to show that in a CO
2
-enriched climate, radiative forcing changes drive annual precipitation increases for most monsoon regions. Further, vegetation feedbacks substantially affect annual precipitation in North and South America and Australia monsoon regions. In the dry season, runoff increases over most monsoon regions, due to stomatal closure-driven evapotranspiration reductions and associated atmospheric circulation change. Our results imply that flood risks may amplify in the wet season. However, the lengthening of the monsoon rainfall season and reduced evapotranspiration will shorten the water resources scarcity period for most monsoon regions.
There is a large range of future aerosol emissions scenarios explored in the Shared Socioeconomic Pathways (SSPs), with plausible pathways spanning a range of possibilities from large global ...reductions in emissions by 2050 to moderate global increases over the same period. Diversity in emissions across the pathways is particularly large over Asia. Rapid reductions in anthropogenic aerosol and precursor emissions between the present day and the 2050s lead to enhanced increases in global and Asian summer monsoon precipitation relative to scenarios with weak air quality policies. However, the effects of aerosol reductions do not persist to the end of the 21st century for precipitation, when instead the response to greenhouse gases dominates differences across the SSPs. The relative magnitude and spatial distribution of aerosol changes are particularly important for South Asian summer monsoon precipitation changes. Precipitation increases here are initially suppressed in SSPs 2-4.5, 3-7.0, and 5-8.5 relative to SSP1-1.9 when the impact of remote emission decreases is counteracted by continued increases in South Asian emissions.
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