Combining data from the distributed GRUAN site Lauder-Invercargill, New Zealand, to provide a site atmospheric state best estimate of temperature

A site atmospheric state best estimate (SASBE) of the temperature profile above the GCOS (Global Climate Observing System) Reference Upper-Air Network (GRUAN) site at Lauder, New Zealand, has been developed. Data from multiple sources are combined within the SASBE to generate a high temporal resolution data set that includes an estimate of the uncertainty on every value. The SASBE has been developed to enhance the value of measurements made at the distributed GRUAN site at Lauder and Invercargill (about 180km apart), and to demonstrate a methodology which can be adapted to other distributed sites. Within GRUAN, a distributed site consists of a cluster of instruments at different locations. The temperature SASBE combines measurements from radiosondes and automatic weather stations at Lauder and Invercargill, and ERA5 reanalysis, which is used to calculate a diurnal temperature cycle to which the SASBE converges in the absence of any measurements. The SASBE provides hourly temperature profiles at 16 pressure levels between the surface and 10hPa for the years 1997 to 2012. Every temperature value has an associated uncertainty which is calculated by propagating the measurement uncertainties, the ERA5 ensemble standard deviations, and the ERA5 representativeness uncertainty through the retrieval chain. The SASBE has been long-term archived and is identified using the digital object identifier https://doi.org/10.5281/zenodo.1195779. The study demonstrates a method to combine data collected at distributed sites. The resulting best-estimate temperature data product for Lauder is expected to be valuable for satellite and model validation as measurements of atmospheric essential climate variables are sparse in the Southern Hemisphere. The SASBE could, for example, be used to constrain a radiative transfer model to provide top-of-the-atmosphere radiances with traceable uncertainty estimates

Nova Geminorum 1912 and the Origin of the Idea of Gravitational Lensing

Einstein's early calculations of gravitational lensing, contained in a scratch notebook and dated to the spring of 1912, are reexamined. A hitherto unknown letter by Einstein suggests that he entertained the idea of explaining the phenomenon of new stars by gravitational lensing in the fall of 1915 much more seriously than was previously assumed. A reexamination of the relevant calculations by Einstein shows that, indeed, at least some of them most likely date from early October 1915. But in support of earlier historical interpretation of Einstein's notes, it is argued that the appearance of Nova Geminorum 1912 (DN Gem) in March 1912 may, in fact, provide a relevant context and motivation for Einstein's lensing calculations on the occasion of his first meeting with Erwin Freundlich during a visit in Berlin in April 1912. We also comment on the significance of Einstein's consideration of gravitational lensing in the fall of 1915 for the reconstruction of Einstein's final steps in his path towards general relativity.Comment: 31 p

nab-paclitaxel plus durvalumab in patients with previously treated advanced stage non-small cell lung cancer (ABOUND.2L+)

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC. Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety. Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred. Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted. Clinical Trial Registration: ClinicalTrials.gov registration (NCT02250326). EudraCT number: 2014-001105-41.This work was supported by Bristol Myers Squibb Company, Princeton, New Jersey. The sponsor was involved in the design of the study as well as in the collection, analysis, and interpretation of the data. The sponsor agreed to the decision to submit the article for publication.Ye

Dysregulation of Rho GTPases in the αPix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits

Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor αPIX/Cool-2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that αPix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of αPix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated αPix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of αPix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. In conclusion, we suggest that imbalance in activity of different Rho GTPases may underlie altered neuronal connectivity and impaired synaptic function and cognition in αPix/Arhgef6 knockout mic

Phase II Trial with Carboplatin and Bendamustine in Patients with Extensive Stage Small-Cell Lung Cancer

Background:Bendamustine is an alkylating agent with hybrid activity and proven efficacy in small-cell lung cancer associated with a favorable toxicity rate. This phase II study of carboplatin/bendamustine was conducted to evaluate the efficacy of this combination in patients with extensive disease small-cell lung cancer (ED-SCLC).Methods:Fifty-six untreated patients with ED-SCLC were enrolled. Their median age was 63 years. Sixty-seven percent of patients were male and 18% had a World Health Organization performance status of 2. Bendamustine was administered as a 30- to 60-minute infusion at a dose of 80 mg/m2 on days 1 and 2, and carboplatin was given at an area under the curve of 5 on day 1 of a 21-day cycle.Results:Fifty-five patients were assessable for response and toxicity. The overall response rate was 72.7% (95% confidence interval: 59%–84%), with one complete remission (1.8%). The median time to progression was 5.2 months (95% confidence interval: 4.2–5.6). At the time of evaluation, 71% of the patients had died. The median survival time reached 8.3 months (95% confidence interval: 6.6–9.9). The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (46%), thrombopenia (26%), anemia (15%), and infections (11%). Toxic death was recorded in two patients (3.6%).Conclusions:The carboplatin/bendamustine regimen is a well-tolerated cytostatic combination in ED-SCLC with activity comparable with that of other platinum-based regimens. Further investigations, such as a phase III trial, are currently planned