A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer

Introduction Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear. Patients and methods This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms. Results A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59-2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11-3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45). Conclusion Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis

Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy

Background: The majority of urothelial cancers (UC) harbor alterations in retinoblastoma (Rb) pathway genes that can lead to loss of Rb tumour suppressor function. Palbociclib is an oral, selective inhibitor of CDK 4/6 that restores Rb function and promotes cell cycle arrest. Methods: In this phase II trial, patients with metastatic platinum-refractory UC molecularly selected for p16 loss and intact Rb by tumour immunohistochemistry received palbociclib 125 mg p.o. daily for 21 days of a 28-day cycle. Primary endpoint was progression-free survival at 4 months (PFS4) using a Simon’s two-stage design. Next-generation sequencing including Rb pathway alterations was conducted. Results: Twelve patients were enrolled and two patients (17%) achieved PFS4 with insufficient activity to advance to stage 2. No responses were seen. Median PFS was 1.9 months (95% CI 1.8–3.7 months) and median overall survival was 6.3 months (95% CI 2.2–12.6 months). Fifty-eight percent of patients had grade ≥3 hematologic toxicity. There were no CDKN2A alterations found and no correlation of Rb pathway alterations with clinical outcome. Conclusions: Palbociclib did not demonstrate meaningful activity in selected patients with platinum-refractory metastatic UC. Further development of palbociclib should only be considered with improved integral biomarker selection or in rational combination with other therapies

Schools out : Adam Smith and pre-disciplinary international political economy

In this article, I argue that invocations of Adam Smith in international political economy (IPE) often reveal the influence therein of a disciplinary ontological disaggregation of economic and non-economic rationality, which I claim is obscured by the tendency to map its complex intellectual contours in terms of competing schools. I trace the origins of the disciplinary characterisation of Smith as the founder of IPE's liberal tradition to invocations of his thought by centrally important figures in the perceived Austrian, Chicago and German historical schools of economics, and reflect upon the significance to IPE of the reiteration of this portrayal by apparent members of its so-called American and British schools. I additionally contrast these interpretations to those put forward by scholars who seek to interpret IPE and Smith's contribution to it in pre-disciplinary terms, which I claim reflects a distinct ontology to that attributed to the British school of IPE with which their work is often associated. I therefore contend that reflection upon invocations of Smith's thought in IPE problematises the longstanding tendency to map its intellectual terrain in terms of competing schools, reveals that the disciplinary ontological consensus that informs this tendency impacts upon articulations of its core concerns and suggests that a pre-disciplinary approach offers an alternative lens through which such concerns might be more effectively framed

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases

Rotationally driven magnetic reconnection in Saturn's dayside

Magnetic reconnection is a key process that explosively accelerates charged particles, generating phenomena such as nebular flares, solar flares and stunning aurorae. In planetary magnetospheres, magnetic reconnection has often been identified on the dayside magnetopause and in the nightside magnetodisc, where thin-current-sheet conditions are conducive to reconnection. The dayside magnetodisc is usually considered thicker than the nightside due to the compression of solar wind, and is therefore not an ideal environment for reconnection. In contrast, a recent statistical study of magnetic flux circulation strongly suggests that magnetic reconnection must occur throughout Saturn’s dayside magnetosphere. Additionally, the source of energetic plasma can be present in the noon sector of giant planetary magnetospheres. However, so far, dayside magnetic reconnection has only been identified at the magnetopause. Here, we report direct evidence of near-noon reconnection within Saturn’s magnetodisc using measurements from the Cassini spacecraft. The measured energetic electrons and ions (ranging from tens to hundreds of keV) and the estimated energy flux of ~2.6 mW m–2 within the reconnection region are sufficient to power aurorae. We suggest that dayside magnetodisc reconnection can explain bursty phenomena in the dayside magnetospheres of giant planets, which can potentially advance our understanding of quasi-periodic injections of relativistic electrons6 and auroral pulsations

Scaling ozone responses of forest trees to the ecosystem level in a changing climate

Many uncertainties remain regarding how climate change will alter the structure and function of forest ecosystems. At the Aspen FACE experiment in northern Wisconsin, we are attempting to understand how an aspen/birch/maple forest ecosystem responds to long-term exposure to elevated carbon dioxide (CO 2 ) and ozone (O 3 ), alone and in combination, from establishment onward. We examine how O 3 affects the flow of carbon through the ecosystem from the leaf level through to the roots and into the soil micro-organisms in present and future atmospheric CO 2 conditions. We provide evidence of adverse effects of O 3 , with or without co-occurring elevated CO 2 , that cascade through the entire ecosystem impacting complex trophic interactions and food webs on all three species in the study: trembling aspen ( Populus tremuloides Michx . ), paper birch ( Betula papyrifera Marsh), and sugar maple ( Acer saccharum Marsh). Interestingly, the negative effect of O 3 on the growth of sugar maple did not become evident until 3 years into the study. The negative effect of O 3 effect was most noticeable on paper birch trees growing under elevated CO 2 . Our results demonstrate the importance of long-term studies to detect subtle effects of atmospheric change and of the need for studies of interacting stresses whose responses could not be predicted by studies of single factors. In biologically complex forest ecosystems, effects at one scale can be very different from those at another scale. For scaling purposes, then, linking process with canopy level models is essential if O 3 impacts are to be accurately predicted. Finally, we describe how outputs from our long-term multispecies Aspen FACE experiment are being used to develop simple, coupled models to estimate productivity gain/loss from changing O 3 .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72464/1/j.1365-3040.2005.01362.x.pd

Clusters of galaxies: setting the stage

Clusters of galaxies are self-gravitating systems of mass ~10^14-10^15 Msun. They consist of dark matter (~80 %), hot diffuse intracluster plasma (< 20 %) and a small fraction of stars, dust, and cold gas, mostly locked in galaxies. In most clusters, scaling relations between their properties testify that the cluster components are in approximate dynamical equilibrium within the cluster gravitational potential well. However, spatially inhomogeneous thermal and non-thermal emission of the intracluster medium (ICM), observed in some clusters in the X-ray and radio bands, and the kinematic and morphological segregation of galaxies are a signature of non-gravitational processes, ongoing cluster merging and interactions. In the current bottom-up scenario for the formation of cosmic structure, clusters are the most massive nodes of the filamentary large-scale structure of the cosmic web and form by anisotropic and episodic accretion of mass. In this model of the universe dominated by cold dark matter, at the present time most baryons are expected to be in a diffuse component rather than in stars and galaxies; moreover, ~50 % of this diffuse component has temperature ~0.01-1 keV and permeates the filamentary distribution of the dark matter. The temperature of this Warm-Hot Intergalactic Medium (WHIM) increases with the local density and its search in the outer regions of clusters and lower density regions has been the quest of much recent observational effort. Over the last thirty years, an impressive coherent picture of the formation and evolution of cosmic structures has emerged from the intense interplay between observations, theory and numerical experiments. Future efforts will continue to test whether this picture keeps being valid, needs corrections or suffers dramatic failures in its predictive power.Comment: 20 pages, 8 figures, accepted for publication in Space Science Reviews, special issue "Clusters of galaxies: beyond the thermal view", Editor J.S. Kaastra, Chapter 2; work done by an international team at the International Space Science Institute (ISSI), Bern, organised by J.S. Kaastra, A.M. Bykov, S. Schindler & J.A.M. Bleeke

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe