Spin currents have an important role in many proposed spintronic devices, as they govern the switching process of magnetic bits in random access memories or drive domain wall motion in magnetic shift ...registers. The generation of these spin currents has to be fast and energy efficient for realization of these envisioned devices. Recently it has been shown that femtosecond pulsed-laser excitation of thin magnetic films creates intense and ultrafast spin currents. Here we utilize this method to change the orientation of the magnetization in a magnetic bilayer by spin-transfer torque on sub-picosecond timescales. By analysing the dynamics of the magnetic bilayer after laser excitation, the rich physics governing ultrafast spin-transfer torque are elucidated opening up new pathways to ultrafast magnetization reversal, but also providing a new method to quantify optically induced spin currents generated on femtosecond timescales.
Since the meta-analysis by De Dreu and Weingart (2003b) on the effects of intragroup conflict on group outcomes, more than 80 new empirical studies of conflict have been conducted, often ...investigating more complex, moderated relationships between conflict and group outcomes, as well as new types of intragroup conflict, such as process conflict. To explore the trends in this new body of literature, we conducted a meta-analysis of 116 empirical studies of intragroup conflict (n = 8,880 groups) and its relationship with group outcomes. To address the heterogeneity across the studies included in the meta-analysis, we also investigated a number of moderating variables. Stable negative relationships were found between relationship and process conflict and group outcomes. In contrast to the results of De Dreu and Weingart, we did not find a strong and negative association between task conflict and group performance. Analyses of main effects as well as moderator analyses revealed a more complex picture. Task conflict and group performance were more positively related among studies where the association between task and relationship conflict was relatively weak, in studies conducted among top management teams rather than non-top management teams, and in studies where performance was measured in terms of financial performance or decision quality rather than overall performance.
The Southern Argentina Agile MEteor Radar (SAAMER), located at Tierra del Fuego (53.7degS, 67.7degW), has been providing near-continuous high-resolution measurements of winds and high-frequency ...gravity wave (GW) momentum fluxes of the mesopause region since May 2008. As SAAMER is located in the lee of the largest seasonal GW hot spot on Earth, this is a key location to study GWs and their interaction with large-scale motions. GW momentum flux climatologies are shown for the first time for this location and discussed in light of these unique dynamics. Particularly, the large eastward GW momentum fluxes during local winter are surprising, as these observations cannot be explained by the direct upward propagation of expected large-amplitude mountain waves (MWs) through the eastward stratospheric jet. Instead, these results are interpreted as secondary GWs propagating away from stratospheric sources over the Andes accompanying MW breaking over the Southern Andes.
Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.
In this open-label, international, phase 3 trial, we ...randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 PD-1) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.
The median overall survival in the total population was 10.3 months (95% confidence interval CI, 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).
Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).
Novel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of ...pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.
Adult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200mg every 3weeks (Q3W) or investigator’s choice of paclitaxel (175mg/m2 Q3W), docetaxel (75mg/m2 Q3W), or vinflunine (320mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.
A total of 542 patients were enrolled (pembrolizumab, n=270; chemotherapy, n=272). Median follow-up as of 26 October 2017 was 27.7months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.
Long-term results (>2 years’ follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.
ClinicalTrials.gov: NCT02256436.
The solution of large linear tomographic inverse problems is fundamentally non‐unique. We suggest to explore the non‐uniqueness explicitly by examining the null‐space of the forward operator. We show ...that with the null‐space shuttle it is possible to assess robustness in tomographic models, and we illustrate the concept for the global P‐wave model MIT‐P08. We found a broad range of acceptable solutions compatible with the travel time data. The root mean square (RMS) velocity perturbations vary from 0.2 to 0.6% in the lowermost mantle and from 0.3 to 1.3% in the upper mantle. Such large variations in average amplitudes prohibit meaningful inferences on temperature or chemical variations in the Earth from tomographic models alone. On a global scale much short wavelength structure resides in the null‐space of the forward operator, suggesting that the data do not everywhere resolve structure on the smallest length scale (<200 km) allowed by the (block) parameterization used in MIT‐P08 and similar models. This indicates that great care should be taken when interpreting such structure. As a practical measure, we suggest that only those structures for which the wave speed perturbations do not change sign within the range of models permitted by the data should be considered robust. With this criterion, the model null‐space analysis shows that the high velocity anomalies in the lower mantle, which are often interpreted as remnants of slabs of subducted lithosphere, are required by the seismic data. Low‐velocity anomalies underneath, for instance, Hawaii, Iceland, and Africa show varying degrees of robustness.
Key Points
A new method to quantify uncertainty in linear tomography
Quantify nonuniqueness in global P wave model MIT‐P08
Analyze robustness of deep slabs and mantle plumes imaged in MIT‐P08
Abstract Introduction Treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and ...enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance 1 . In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds. Methods To identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation. Results We observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide. Conclusions In conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.
Development of ready-to-use biomaterials and scaffolds is vital for further advancement of scaffold-based tissue engineering in clinical practice. Scaffolds need to mimic 3D ultrastructure, have ...adequate mechanical strength, are biocompatible, non-immunogenic and need to promote tissue regeneration in vivo. Although decellularization of native tissues seems promising to deliver scaffolds that meet these criteria, adequate decellularization of hard, poorly penetrable and poorly diffusible tissues remains challenging whilst being a very time-consuming process.
In this study, a method to decellularize hard, dense tissues using supercritical carbon-dioxide preceded by a freeze/thaw cycle and followed by several washing steps is presented, demonstrating decellularisation efficiency and substantially reduced production/handling time. Additionally, supercritical carbon-dioxide treatment was used as sterilization method, further reducing the time required to produce the final scaffold. Histological evaluation showed that, after fine-tuning of the process, a partially acellular scaffold was obtained, with preservation of glycosaminoglycans and collagen fibers, albeit that the amount of residual dsDNA was still higher then chemically decellularized tissue. Biomechanical properties of the scaffold were similar to the native, non-decellularized tissue. After sterilization with supercritical carbon-dioxide the simulated functional outcome was more similar to native trachea, when compared to sterilization using gamma irradiation.
Thus, decellularization and sterilization using supercritical carbon-dioxide with washing steps is an effective method for dense cartilaginous materials, and tuneable to meet different demands in other applications, but further optimization may be required.
Further advancement of the use of tissue engineered tracheal constructs is restricted by the lack of the ideal scaffold. Decellularized trachea is considered a promising scaffold, but the hard, poorly diffusible tissue remains challenging while forming a very time consumable process. Decellularization using supercritical carbon dioxide (scCO2) seems promising, resulting in efficient removal of cellular material while reducing production and handling time. Addition of scCO2 as a sterilization method resulted in further time reduction while improving functional outcome in comparison with traditional sterilization methods. This study presents an promising alternative method for decellularization and sterilization of dense materials, which can be tuned to meet different demands in other applications.
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Summary
Changes in environmental conditions and prokaryote physiology can strongly affect the dynamics of both the lysogenic and lytic bacteriophage replication cycles in aquatic systems. However, it ...remains unclear whether it is the nature, amplitude or frequency of these changes that alter the phage replication cycles. We performed an annual survey of three Mediterranean lagoons with contrasting levels of chlorophyll a concentration and salinity to explore how these cues and their variability influence either replication cycle. The lytic cycle was always detected and showed seasonal patterns, whereas the lysogenic cycle was often undetected and highly variable. The lytic cycle was influenced by environmental and prokaryotic physiological cues, increasing with concentrations of dissolved organic carbon, chlorophyll a, and the proportion of respiring cells, and decreasing with the proportion of damaged cells. In contrast, lysogeny was not explained by the magnitude of any environmental or physiological parameter, but increased with the amplitude of change in prokaryote physiology. Our study suggests that both cycles are regulated by distinct factors: the lytic cycle is dependent on environmental parameters and host physiology, while lysogeny is dependent on the variability of prokaryote physiology. This could lead to the contrasting patterns observed between both cycles in aquatic systems.
Studies of vertical and interhemispheric coupling during Sudden Stratospheric Warmings (SSWs) suggest that gravity wave (GW) momentum flux divergence plays a key role in forcing the middle ...atmosphere, although observational validation of GW forcing is limited. We present a whole atmosphere view of zonal winds from the surface to 100 km during the January 2013 major SSW, together with observed GW momentum fluxes in the mesopause region derived from uninterrupted high‐resolution meteor radar observations from an All‐Sky Interferometric Meteor Radar system located at Trondheim, Norway (63.4°N, 10.5°E). Observations show GW momentum flux divergence 6 days prior to the SSW onset, producing an eastward forcing with peak values of ∼+145 ± 60ms−1d−1. As the SSW evolves, GW forcing turns westward, reaching a minimum of ∼−240 ± 70ms−1d−1∼+18 days after the SSW onset. These results are discussed in light of previous studies and simulations using the Whole Atmosphere Community Climate Model with Specified Dynamics.
Key Points
Observed mesopause GW momentum flux and forcing during a major SSW are studied
Comparing observed and WACCM‐SD GW forcing shows both methods agree well
During the SSW GW forcing peaks eastward then turns strongly westward
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