The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
In this study, we investigate the impact of the dynamic behavior of photovoltaic (PV) power generation systems on short-term voltage stability of the transmission system. First, the impact of the ...fault ride-through capability of a PV model is studied by setting several recovery speeds of the active current output when the operation of the PV system is interrupted because of a voltage sag. The results are analyzed by using transient P-V curves and a stability boundary, which has been proposed in our previous research. Further, we show that the installation of PVs severely impairs the short-term voltage stability if the PVs shut off after a voltage sag, and its recovery speed is low. Next, two countermeasures to control short-term voltage instability phenomena are tested. One is the operation of the PV system at a leading power factor in the normal state, and the other is the dynamic reactive power control by the inverters of the PV system after a voltage sag. Numerical examples are carried out for a one-load infinite-bus power system and a five-machine five-load power system. The results show that these countermeasures can play a substantial role in preventing the voltage instability phenomena caused when a PV system is suddenly interrupted because of a fault.
Observations of polar mesospheric clouds have revealed the presence of solid ice particles in the upper mesosphere at high latitudes; however, their formation mechanism remains uncertain. In this ...study, we investigated the formation process of ice particles through nucleation from small amounts of water vapor at low temperatures. Previous studies that used classical nucleation theory have shown that amorphous solid water particles can nucleate homogeneously at conditions that are present in the mesosphere. However, the rate predictions for water in classical nucleation theory disagree with experimental measurements by several orders of magnitude. We adopted a semi-phenomenological model for the nucleation process, which corrects the evaluation of the molecular cluster formation energy using the second virial coefficient, which agrees with both experiments and molecular dynamics simulations. To calculate the nucleation process, we applied atmospheric conditions for the temperature, pressure, numerical density of dust grains, and cooling rate. The results indicate that homogeneous water nucleation is extremely unlikely to occur in the mesosphere, while heterogeneous nucleation occurs effectively. Dust grains generated by meteor ablation can serve as nuclei for heterogeneous nucleation. We also showed that the ice can form directly in a crystalline state, rather than an amorphous state.
Abstract
While satellite-based global navigation systems have become essential tools in our daily lives, their effectiveness is often hampered by the fact that the signals cannot be accessed in ...underground, indoor, or underwater environments. Recently, a novel navigation system has been invented to address this issue by utilizing the characteristics of the ubiquitous and highly penetrative cosmic-ray muons. This technique, muometric navigation, does not require active signal generation and enables positioning in the aforementioned environments within a reference coordinate defined by the three-dimensional positions of multiple detectors. In its first phase of development, these reference detectors had to be connected to the receivers via a wired configuration to guarantee precise time synchronization. This work describes more versatile, wireless muometric navigation system (MuWNS), which was designed in conjunction with a cost-effective, crystal-oscillator-based grandmaster clock and a performance evaluation is reported for shallow underground/indoor, deep underground and undersea environments. It was confirmed that MuWNS offers a navigation quality almost equivalent to aboveground GPS-based handheld navigation by determining the distance between the reference frame and the receivers within a precision range between 1 and 10 m.
The relationship between cesium (Cs) adsorption on clay minerals with various expandabilities and Cs mobility in environment was investigated using sequential extraction, batch adsorption, X-ray ...diffraction (XRD), generalized adsorption model (GAM), and Cs LIII-edge extended X-ray absorption fine structure (EXAFS) analyses with molecular simulations using the density functional theory (DFT). In particular, the difference between the affinities of illite (non-expansion) and vermiculite (intermediate expansion) for Cs and the effect of humic acid (HA) addition on the Cs/clay mineral system were highlighted in this study. These two factors affect Cs mobility and bioavailability in surface soil and sediments.
The batch adsorption results showed that Cs adsorption was inhibited to some extent in the ternary clay+HA+Cs system because of (i) the blocked access of Cs to the frayed edge site (FES) and type II site inner–sphere (IS) complex in GAM by HA, and (ii) the reduced availability of the interlayer site in vermiculite. EXAFS analysis further confirmed that the adsorbed Cs in clay minerals was drastically changed by the sequential addition of HA. In addition, the dominant IS complex in the illite+Cs and illite+Cs+HA systems (in which HA was added after Cs adsorption on illite) can be converted to the outer–sphere (OS) complex largely in the illite+HA+Cs system (in which HA was added prior to Cs adsorption). These results are consistent with the sequential extraction and GAM results.
The IS complex of dehydrated Cs+ mainly formed at the FES and interlayer site on illite (non-expansion) without resulting in any illite structural changes. However, on vermiculite (intermediate expansion), the dehydrated Cs+ can be adsorbed as an IS complex associated with the siloxane group of the di-trigonal cavity in the tetrahedral SiO4 sheet. This adsorption is accompanied by collapse of the layer, which can be easily coated by HA molecules to prevent Cs fixation. However, a nearly complete OS complex was observed at the planar site of montmorillonite (large expansion). These processes were confirmed by sequential extraction, batch adsorption, XRD, and EXAFS, which clearly showed that Cs mobility in soil highly depends on clay mineral expandability, natural organic matter (NOM), and the coupling of both effects. The atomic-scale information given by EXAFS is consistent with the distribution data from adsorption experiments, GAM, sequential extraction, and DFT. These results can be used as a basis for a clearer understanding of Cs behavior in natural systems.
Precise time synchronization is an essential technique required for financial transaction systems, industrial automation and control systems, as well as land and ocean observation networks. However, ...the time synchronization signals based on the global-positioning-system (GPS), or global-navigation-satellite-system, are sometimes unavailable or only partially available in indoor, underground and underwater environments. In this work, the simultaneous and penetrative natures of the muon component of the extended air shower (EAS) were used as signals for time synchronization in environments with little or no GPS coverage. CTS was modeled by combining the results of previous EAS experiments with OCXO holdover precision measurements. The results have shown the capability of CTS to reach perpetual local time synchronization levels of less than 100 ns with a hypothetical detector areal coverage of larger than 2 × 10
. We anticipate this level of areal coverage is attainable and cost-effective for use in consumer smartphone networks and dense underwater sensor networks.
Standard laboratory coagulation tests (SLTs) such as prothrombin time/international normalized ratio or partial thromboplastin time are frequently used to assess coagulopathy and to guide haemostatic ...interventions. However, this has been challenged by numerous reports, including the current European guidelines for perioperative bleeding management, which question the utility and reliability of SLTs in this setting. Furthermore, the arbitrary definition of coagulopathy (i.e. SLTs are prolonged by more than 1.5-fold) has been questioned. The present study aims to review the evidence for the usefulness of SLTs to assess coagulopathy and to guide bleeding management in the perioperative and massive bleeding setting. Medline was searched for investigations using results of SLTs as a means to determine coagulopathy or to guide bleeding management, and the outcomes (i.e. blood loss, transfusion requirements, mortality) were reported. A total of 11 guidelines for management of massive bleeding or perioperative bleeding and 64 studies investigating the usefulness of SLTs in this setting were identified and were included for final data synthesis. Referenced evidence for the usefulness of SLTs was found in only three prospective trials, investigating a total of 108 patients (whereby microvascular bleeding was a rare finding). Furthermore, no data from randomized controlled trials support the use of SLTs. In contrast, numerous investigations have challenged the reliability of SLTs to assess coagulopathy or guide bleeding management. There is actually no sound evidence from well-designed studies that confirm the usefulness of SLTs for diagnosis of coagulopathy or to guide haemostatic therapy.
Thus far, a perfectly secure encryption key storage system doesn't exist. As long as key storage is connected to a network system, there is always a chance that it can be cracked. Even if storage is ...not continually connected to a network system; it is repeatedly necessary for an individual to access storage to upload and download the data; hence there is always a loophole with every conventional encryption key storage system. By utilizing the penetrative nature of cosmic-ray muons, the COSMOCAT (Cosmic coding and transfer) technique may tackle this problem by eliminating the requirement for any network connection to data storage. COSMOCAT was invented as a post quantum key generation and distribution technique for wireless near field communication. However, in its first stage of development, COSMOCAT relied on standard comparators and Global Positioning System (GPS) or other Global Navigation Satellite Systems (GNSS) for key generation. Temporal jitters of the signals outputted from comparators and frequency fluctuations in GPS-disciplined oscillators degraded the key strength and the efficiency of both the key generation and distribution. New strategies are tested in this paper to improve these factors. As a result, the key strength and the key authenticating rate limit are respectively improved by 4 orders of magnitude and more than 5 orders of magnitude. As a consequence, it has become possible to propose a practical methodology for a new key storage and authentication strategy which has the potential to be an impregnable defense against any kind of cyber/physical attack to data storage. Practical applications of COSMOCATS-based symmetric-key cryptosystems to an electronic digital signing system, communication, and cloud storage are also discussed.
We examined the excitations of planetesimals caused by the resonances of a giant planet in a protoplanetary gas disk. The highly excited planetesimals generate bow shocks, the mechanism of which ...results in chondrule formation, crystallization of silicate dust, and evaporation of icy planetesimals. The planetesimals beyond 2:1 resonance migrate owing to the gas drag and obtain the maximum eccentricity around 3:1 resonance, which is located at approximately half the planetary distance. The eccentricity depends on the parameters of the planetesimals and the Jovian planet, such as size and location, and the gas density of the disk. The maximum relative velocity of a 100 km sized planetesimal with respect to the gas disk reaches up to ∼12 km s−1 in the case of Jupiter owing to secular resonance, which occurs because of the disk's gravity. We find that if a Jovian-mass planet is located within 10 au, the planetesimals larger than 100 km gain sufficient velocity to cause the melting of chondrule precursors and crystallization of the silicate. The maximum velocity is higher for large planetesimals and eccentric planets. Planetesimals are trapped temporarily in the resonances and continue to have high speed over 1 Myr after the formation of a Jovian planet. This duration fits into the timescale of chondrule formation suggested by the isotopic data. The evaporation of icy planetesimals occurs when a Jovian planet is located within 15 au. This mechanism can be a new indicator of planet formation in exosystems if some molecules ejected from icy planetesimals are detected.
Accurate traceability of time is prerequisite to the proper functioning of many necessary aspects of our modern life including making financial transactions, managing automated technology and ...navigating the transport of goods and human beings. One of the most reliable international time references is the Coordinated Universal Time (UTC) that can be distributed wirelessly in principle. However, this wireless option is currently limited to GPS and other global navigation satellite systems. GPS signals are weak and easily affected by environmental conditions. Moreover, since GPS signals are unencrypted, the possibility of a signal spoofing attack remains a continuous threat. Prior works showed the potential of the alternative wireless time synchronization technique called Cosmic Time Synchronization (CTS), in which, clocks are located 50 m apart were wirelessly synchronized with a sub-microsecond level accuracy, and its operation time was limited to 20 min. However, for the actual implementation of CTS to real-life situations, these distance and stability values are not sufficient. In this study, we constructed a dedicated CTS facility and conducted a long-haul (180 m) CTS demonstration. As a result, it was verified that this long-range CTS is capable of maintaining stable sub-microsecond time synchronization for 3 days with a granularity of 148.8 ns (SD) and an offset of 22.97 ns. Since the current version of CTS can now operate over an area that has been enlarged by more than one order of magnitude, it is possible to utilize for more diverse applications, and the application to a banking synchronization system is proposed. As a case study, it is shown that CTS now has the capability to offer wireless time synchronization service to large clusters of financial firms in large cities. With its accurate time dissemination (the metrological traceability to UTC), its reasonable cost, and its hack-proof, stable design, this latest CTS model has the capacity to improve the accuracy of timing for a wide variety of sectors.
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