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.
We present a model of a time‐dependent three‐dimensional magnetohydrodynamics simulation of the sub‐Alfvenic solar corona and super‐Alfvenic solar wind with temporally varying solar‐surface boundary ...magnetic field data. To (i) accommodate observational data with a somewhat arbitrarily evolving solar photospheric magnetic field as the boundary value and (ii) keep the divergence‐free condition, we developed a boundary model, here named Confined Differential Potential Field model, that calculates the horizontal components of the magnetic field, from changes in the vertical component, as a potential field confined in a thin shell. The projected normal characteristic method robustly simulates the solar corona and solar wind, in response to the temporal variation of the boundary Br. We conduct test MHD simulations for two periods, from Carrington Rotation number 2009 to 2010 and from Carrington Rotation 2074 to 2075 at solar maximum and minimum of Cycle 23, respectively. We obtained several coronal features that a fixed boundary condition cannot yield, such as twisted magnetic field lines at the lower corona and the transition from an open‐field coronal hole to a closed‐field streamer. We also obtained slight improvements of the interplanetary magnetic field, including the latitudinal component, at Earth.
Key Points
A simple model to introduce the time evolution of the solar corona
Nonpotential features of the solar corona are obtained
Improvement in producing interplanetary magnetic field is achieved
A new data product from the
Helioseismic and Magnetic Imager
(HMI) onboard the
Solar Dynamics Observatory
(SDO) called Space-weather HMI Active Region Patches (SHARPs) is now available. SDO/HMI is ...the first space-based instrument to map the full-disk photospheric vector magnetic field with high cadence and continuity. The SHARP data series provide maps in patches that encompass automatically tracked magnetic concentrations for their entire lifetime; map quantities include the photospheric vector magnetic field and its uncertainty, along with Doppler velocity, continuum intensity, and line-of-sight magnetic field. Furthermore, keywords in the SHARP data series provide several parameters that concisely characterize the magnetic-field distribution and its deviation from a potential-field configuration. These indices may be useful for active-region event forecasting and for identifying regions of interest. The indices are calculated per patch and are available on a twelve-minute cadence. Quick-look data are available within approximately three hours of observation; definitive science products are produced approximately five weeks later. SHARP data are available at
jsoc.stanford.edu
and maps are available in either of two different coordinate systems. This article describes the SHARP data products and presents examples of SHARP data and parameters.
Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to ...augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E
release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E
biosythesis favors CD103
dendritic cell activation that primes a Tc1-polarized CD8
T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E
blockade as a strategy to harness ICD.
Solid-state single spins are promising resources for quantum sensing, quantum-information processing and quantum networks, because they are compatible with scalable quantum-device engineering. ...However, the extension of their coherence times proves challenging. Although enrichment of the spin-zero
C and
Si isotopes drastically reduces spin-bath decoherence in diamond and silicon, the solid-state environment provides deleterious interactions between the electron spin and the remaining spins of its surrounding. Here we demonstrate, contrary to widespread belief, that an impurity-doped (phosphorus) n-type single-crystal diamond realises remarkably long spin-coherence times. Single electron spins show the longest inhomogeneous spin-dephasing time (Formula: see text ms) and Hahn-echo spin-coherence time (T
≈ 2.4 ms) ever observed in room-temperature solid-state systems, leading to the best sensitivities. The extension of coherence times in diamond semiconductor may allow for new applications in quantum technology.
We present a treatment of observation‐based time‐dependent boundary conditions for the inner boundary sphere in the time‐dependent three‐dimensional MHD simulations of the global solar wind. With ...this boundary treatment, we obtain super‐Alfvenic MHD solutions of time‐dependent co‐rotating solar wind structures. The boundary variables on the inner boundary sphere, at 50 solar radii in this study, are assumed to change linearly from one instant to the next. A new feature is that, in order to maintain the divergence‐free condition of the magnetic field, the changes of the time‐dependent boundary magnetic field are expressed as the potential field in a thin shell volume. The solar magnetic field data from the Wilcox Solar Observatory (WSO) and the solar wind speed data from the interplanetary scintillation (IPS) observations at Nagoya University, Japan, are used as the input boundary data. The solar wind simulated with the time‐dependent boundary condition is compared with the near‐Earth and Ulysses in situ measurement data and the solar wind simulated with the fixed boundary condition over a 7‐month period in 1991. Reasonable agreements with the in situ measurements are obtained. The differences between the two simulations in the interplanetary field line paths are significant. The three‐dimensional time‐dependent MHD solution of the global solar wind will help enhance space weather models and other fields in heliophysics.
Key Points
The time‐dependent boundary model is applied to the solar wind MHD model
The results, especially IMF, are significantly different from previous models
This model allows the long‐term solar wind simulation
Ambient seismic noise or microtremor observations used in spatial auto-correlation (SPAC) array methods consist of a wide frequency range of surface waves from the frequency of about 0.1 Hz to ...several tens of Hz. The wavelengths (and hence depth sensitivity of such surface waves) allow determination of the site S-wave velocity model from a depth of 1 or 2 m down to a maximum of several kilometres; it is a passive seismic method using only ambient noise as the energy source. Application usually uses a 2D seismic array with a small number of seismometers (generally between 2 and 15) to estimate the phase velocity dispersion curve and hence the S-wave velocity depth profile for the site. A large number of methods have been proposed and used to estimate the dispersion curve; SPAC is the one of the oldest and the most commonly used methods due to its versatility and minimal instrumentation requirements. We show that direct fitting of observed and model SPAC spectra generally gives a superior bandwidth of useable data than does the more common approach of inversion after the intermediate step of constructing an observed dispersion curve. Current case histories demonstrate the method with a range of array types including two-station arrays, L-shaped multi-station arrays, triangular and circular arrays. Array sizes from a few metres to several-km in diameter have been successfully deployed in sites ranging from downtown urban settings to rural and remote desert sites. A fundamental requirement of the method is the ability to average wave propagation over a range of azimuths; this can be achieved with either or both of the wave sources being widely distributed in azimuth, and the use of a 2D array sampling the wave field over a range of azimuths. Several variants of the method extend its applicability to under-sampled data from sparse arrays, the complexity of multiple-mode propagation of energy, and the problem of precise estimation where array geometry departs from an ideal regular array. We find that sparse nested triangular arrays are generally sufficient, and the use of high-density circular arrays is unlikely to be cost-effective in routine applications. We recommend that passive seismic arrays should be the method of first choice when characterizing average S-wave velocity to a depth of 30 m (
V
s
30) and deeper, with active seismic methods such as multichannel analysis of surface waves (MASW) being a complementary method for use if and when conditions so require. The use of computer inversion methodology allows estimation of not only the S-wave velocity profile but also parameter uncertainties in terms of layer thickness and velocity. The coupling of SPAC methods with horizontal/vertical particle motion spectral ratio analysis generally allows use of lower frequency data, with consequent resolution of deeper layers than is possible with SPAC alone. Considering its non-invasive methodology, logistical flexibility, simplicity, applicability, and stability, the SPAC method and its various modified extensions will play an increasingly important role in site effect evaluation. The paper summarizes the fundamental theory of the SPAC method, reviews recent developments, and offers recommendations for future blind studies.
Development of microbiota-directed foods (MDFs) that selectively increase the abundance of beneficial human gut microbes, and their expressed functions, requires knowledge of both the bioactive ...components of MDFs and the mechanisms underlying microbe-microbe interactions. Here, gnotobiotic mice were colonized with a defined consortium of human-gut-derived bacterial strains and fed different combinations of 34 food-grade fibers added to a representative low-fiber diet consumed in the United States. Bioactive carbohydrates in fiber preparations targeting particular Bacteroides species were identified using community-wide quantitative proteomic analyses of bacterial gene expression coupled with forward genetic screens. Deliberate manipulation of community membership combined with administration of retrievable artificial food particles, consisting of paramagnetic microscopic beads coated with dietary polysaccharides, disclosed the contributions of targeted species to fiber degradation. Our approach, including the use of bead-based biosensors, defines nutrient-harvesting strategies that underlie, as well as alleviate, competition between Bacteroides and control the selectivity of MDF components.
Display omitted
•In vivo screen for fibers targeting specific human gut taxa in a defined community•Proteomics and forward genetics identify bioactive nutrients and their utilization•Interspecies competition controls the outcome of fiber-based microbiota manipulation•Artificial food particles as biosensors of community-wide glycan degradation
An in vivo approach that includes administration of artificial food particles explains mechanisms by which different human gut microbes utilize bioactive components of dietary fibers and paves a path towards the development of microbiota-directed foods that provide metabolic benefits to the host.
ABSTRACT We analyze a three-dimensional (3D) magnetic structure and its stability in large solar active region (AR) 12192, using the 3D coronal magnetic field constructed under a nonlinear force-free ...field (NLFFF) approximation. In particular, we focus on the magnetic structure that produced an X3.1-class flare, which is one of the X-class flares observed in AR 12192. According to our analysis, the AR contains a multiple-flux-tube system, e.g., a large flux tube, with footpoints that are anchored to the large bipole field, under which other tubes exist close to a polarity inversion line (PIL). These various flux tubes of different sizes and shapes coexist there. In particular, the latter are embedded along the PIL, which produces a favorable shape for the tether-cutting reconnection and is related to the X-class solar flare. We further found that most of magnetic twists are not released even after the flare, which is consistent with the fact that no observational evidence for major eruptions was found. On the other hand, the upper part of the flux tube is beyond a critical decay index, essential for the excitation of torus instability before the flare, even though no coronal mass ejections were observed. We discuss the stability of the complicated flux tube system and suggest the reason for the existence of the stable flux tube. In addition, we further point out a possibility for tracing the shape of flare ribbons, on the basis of a detailed structural analysis of the NLFFF before a flare.
Abstract
We carried out new CO(
J
= 2–1) observations toward the mixed-morphology supernova remnant (SNR) W49B with the Atacama Large Millimeter/submillimeter Array. We found that CO clouds at ∼10 km ...s
−1
show a good spatial correspondence to the synchrotron radio continuum as well as to an X-ray deformed shell. The bulk mass of molecular clouds accounts for the western part of the shell, not the eastern shell, where near-infrared H
2
emission is detected. The molecular clouds at ∼10 km s
−1
show higher kinetic temperatures of ∼20–60 K, suggesting that modest shock heating occurred. The expanding motion of the clouds with Δ
V
∼ 6 km s
−1
was formed by strong winds from the progenitor system. We argue that the barrel-like structure of Fe-rich ejecta was possibly formed not only by an asymmetric explosion, but also by interactions with dense molecular clouds. We also found a negative correlation between the CO intensity and the electron temperature of recombining plasma, implying that the origin of the high-temperature recombining plasma in W49B can be understood to be the thermal conduction model. The total energy of accelerated cosmic-ray protons
W
p
is estimated to be ∼2 × 10
49
erg by adopting an averaged gas density of ∼650 ± 200 cm
−3
. The SNR age–
W
p
diagram indicates that W49B shows one of the highest in situ values of
W
p
among gamma-ray-bright SNRs.
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