Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell ...lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown.
In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 AUC5) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival.
The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval CI, 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%).
Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).
P‐glycoprotein P‐gp or the ATP‐binding cassette transporter B1 (ABCB1) is an important participant in multidrug resistance of cancer cells, yet the precise function of this arthropod transporter is ...unknown. The aim of this study was to determine the importance of P‐gp for susceptibility to insecticides in the beet armyworm (Spodoptera exigua) using clustered regularly interspaced short palindromic repeats/CRISPR‐associated 9 (CRISPR/Cas9) gene‐editing technology. We cloned an open reading frame (ORF) encoding the S. exigua P‐gp protein (SeP‐gp) predicted to display structural characteristics common to P‐gp and other insect ABCB1 transporters. A knockout line with a frame shift deletion of four nucleotides in the SeP‐gp ORF was established using the CRISPR/Cas9 gene‐editing system to test its potential role in determining susceptibility to chemical insecticides or insecticidal proteins from the bacterium Bacillus thuringiensis (Bt). Results from comparative bioassays demonstrate that knockout of SeP‐gp significantly increases susceptibility of S. exigua by around threefold to abamectin and emamectin benzoate (EB), but not to spinosad, chlorfenapyr, beta‐cypermethrin, carbosulfan indoxacarb, chlorpyrifos, phoxim, diafenthiuron, chlorfluazuron, chlorantraniliprole or two Bt toxins (Cry1Ca and Cry1Fa). Our data support an important role for SeP‐gp in susceptibility of S. exigua to abamectin and EB and imply that overexpression of SeP‐gp may contribute to abamectin and EB resistance in S. exigua.
Two-mode interferometers lay the foundations for quantum metrology. Instead of exploring quantum entanglement in the two-mode interferometers, a single bosonic mode also promises a measurement ...precision beyond the shot-noise limit (SNL) by taking advantage of the infinite-dimensional Hilbert space of Fock states. Here, we demonstrate a single-mode phase estimation that approaches the Heisenberg limit (HL) unconditionally. Due to the strong dispersive nonlinearity and long coherence time of a microwave cavity, quantum states of the form Formula: see text can be generated, manipulated and detected with high fidelities, leading to an experimental phase estimation precision scaling as ∼N
. A 9.1 dB enhancement of the precision over the SNL at N = 12 is achieved, which is only 1.7 dB away from the HL. Our experimental architecture is hardware efficient and can be combined with quantum error correction techniques to fight against decoherence, and thus promises quantum-enhanced sensing in practical applications.
Spitzer data at 24, 70, and 160 {mu}m and ground-based H{alpha} images are analyzed for a sample of 189 nearby star-forming and starburst galaxies to investigate whether reliable star formation rate ...(SFR) indicators can be defined using the monochromatic infrared dust emission centered at 70 and 160 {mu}m. We compare recently published recipes for SFR measures using combinations of the 24 {mu}m and observed H{alpha} luminosities with those using 24 {mu}m luminosity alone. From these comparisons, we derive a reference SFR indicator for use in our analysis. Linear correlations between SFR and the 70 {mu}m and 160 {mu}m luminosity are found for L(70) {approx_gt} 1.4 x 10{sup 42} erg s{sup -1} and L(160) {approx_gt} 2 x 10{sup 42} erg s{sup -1}, corresponding to SFR {approx_gt} 0.1-0.3 M{sub sun} yr{sup -1}, and calibrations of SFRs based on L(70) and L(160) are proposed. Below those two luminosity limits, the relation between SFR and 70 {mu}m (160 {mu}m) luminosity is nonlinear and SFR calibrations become problematic. A more important limitation is the dispersion of the data around the mean trend, which increases for increasing wavelength. The scatter of the 70 {mu}m (160 {mu}m) data around the mean is about 25% (factor {approx}2) larger than the scatter of the 24 {mu}m data. We interpret this increasing dispersion as an effect of the increasing contribution to the infrared emission of dust heated by stellar populations not associated with the current star formation. Thus, the 70 (160) {mu}m luminosity can be reliably used to trace SFRs in large galaxy samples, but will be of limited utility for individual objects, with the exception of infrared-dominated galaxies. The nonlinear relation between SFR and the 70 and 160 {mu}m emission at faint galaxy luminosities suggests a variety of mechanisms affecting the infrared emission for decreasing luminosity, such as increasing transparency of the interstellar medium, decreasing effective dust temperature, and decreasing filling factor of star-forming regions across the galaxy. In all cases, the calibrations hold for galaxies with oxygen abundance higher than roughly 12 +log(O/H) {approx} 8.1. At lower metallicity, the infrared luminosity no longer reliably traces the SFR because galaxies are less dusty and more transparent.
Summary Objective Dietary loading has been reported to have an effect on temporomandibular joint (TMJ) remodeling via periodontal-muscular reflex. We therefore examined whether reducing dietary ...loading decreased TMJ degradation induced by the unilateral anterior crossbite prosthesis as we recently reported. Methods Forty 6-week-old female C57BL/6J mice were randomly divided into two experimental and two control groups. One experimental and one control group received small-size diet and the other two groups received large-size diet. Unilateral anterior crossbite prosthesis was created in the two experimental groups. The TMJ samples were collected 3 weeks after experimental operation. Histological changes in condylar cartilage and subchondral bone were assessed by Hematoxylin & Eosin, toluidine blue, Safranin O and tartrate-resistant acid phosphatase staining. Real-time polymerase chain reaction (PCR) and/or immunohistochemistry were performed to evaluate the expression levels of Collagen II, Aggrecan, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and RANKL/RANK/OPG in TMJ condylar cartilage and/or subchondral bone. Results Thinner and degraded cartilage, reduced cartilage cellular density, decreased expression levels of Collagen II and Aggrecan, loss of subchondral bone and enhanced osteoclast activity were observed in TMJs of both experimental groups. However, the cartilage degradation phenotype was less severe and cartilage ADAMTS-5 mRNA was lower while OPG/RANKL ratio in cartilage and subchondral bone was higher in the small-size than large-size diet experimental group. No differences of histomorphology and the tested molecules were found between the two control groups. Conclusions The current findings suggest that a lower level of functional loading by providing small-size diet could reduce TMJ degradation induced by the biomechanical stimulation from abnormal occlusion.
Elastocaloric (EC) effect refers to the rapid cooling in shape memory alloys (SMAs) during reverse transformation from martensite to austenite under adiabatic conditions. We present a very ...comprehensive study of the EC response far extending the existing literature by studying the effect of loading states (tension and compression), long-term cycling, strain localization, and deformation temperatures in several SMAs including CuZnAl, NiTi, NiTiCu, Ni2FeGa and NiTiHf13.3. We found a temperature change of 14.2 °C in CuZnAl, 18.2 °C in NiTi, 15.2 °C in NiTiCu, 13.5 °C in Ni2FeGa, and 6.95 °C in NiTiHf13.3 upon reverse transformation depending on the entropy change (as high as 60 J/kg K), the stress hysteresis, the inhomogeneity of the transformation and the number of superelastic cycles. A gradual deterioration of the EC effect in tension develops, while in compression the EC effect can be sustained much longer (in excess of 104 cycles). The Ni2FeGa SMAs possess an operational EC temperature window of nearly 200 °C, which is the widest among the chosen SMAs. With over one hundred experiments reported in one study, this paper represents an authoritative summary of the EC capabilities of a wide range of SMAs.
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In this work, a critical comparison between three different numerical approaches for the computational modelling of quasi-brittle structural failure is presented. Among the many finite element ...approaches devised to solve the problem, both using continuous and discontinuous methods, the present study examines the relative performance of the XFEM, the mixed strain/displacement FE and phase-field models. These numerical techniques are selected as the current representatives of embedded, smeared and regularized models for analyzing the phenomenon of fracture with different mathematical descriptions for the cracking induced discontinuities in the displacement and strain fields. The present investigation focusses on the main differences of the formulation of these models both at the continuum and discrete level and discusses the main assets and burdens that ensue in their practical application. The relative advantages and difficulties related to their use in the computation of localized structural failure in engineering practice are evaluated against a 10-point checklist that cover the main challenges met by these models. The paper includes an extensive comparison of selected numerical benchmark problems analyzed with the three examined methods. Relative performance is assessed in terms of load capacity, force–displacement curves, crack paths, collapse mechanisms, cost-efficiency and other key issues.
Summary
Background
The sensitivity of current upper limit of normal (ULN) of serum alanine aminotransferase (ALT) levels for detecting chronic liver disease has been challenged recently.
Aim
To ...identify modulating factors for serum ALT levels and to refine its ULN threshold.
Methods
We enrolled 34 346 consecutive subjects who completed the health check‐up at Taipei Veterans General Hospital from 2002 to 2009. ULN was set for healthy ALT level to the 95th percentile of the reference healthy population.
Results
A group of 21 282 subjects were used as a training set to define an ULN with the highest sensitivity; afterwards, this ULN was validated in another set of 13 064 subjects. A reference healthy population was selected from the training set after excluding subjects with any abnormalities in independent risk factors associated with elevated serum ALT level (>40 IU/L) by multivariate analysis like body mass index, waist circumference, glucose, cholesterol, high‐density lipoprotein‐cholesterol, triglyceride, hepatitis B virus surface antigen, anti‐hepatitis C virus antibody and fatty liver. The new ULN of serum ALT level defined as the 95% percentile in the healthy population were 21 IU/L and 17 IU/L for men and women respectively. These cut‐off values had the highest Youden's index and areas under the corresponding receiver operating curves among four widely applied thresholds in both the training and validation sets.
Conclusions
The suggested threshold of upper limit of normal provides better discrimination between healthy and unhealthy status. Viral hepatitis, metabolic syndrome and fatty liver are the major risk factors of elevated serum alanine aminotransferase levels.
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