Current methods of chemical vapour deposition (CVD) of graphene on copper are complicated by multiple processing steps and by high temperatures required in both preparing the copper and inducing ...subsequent film growth. Here we demonstrate a plasma-enhanced CVD chemistry that enables the entire process to take place in a single step, at reduced temperatures (<420 °C), and in a matter of minutes. Growth on copper foils is found to nucleate from arrays of well-aligned domains, and the ensuing films possess sub-nanometre smoothness, excellent crystalline quality, low strain, few defects and room-temperature electrical mobility up to (6.0±1.0) × 10(4) cm(2) V(-1) s(-1), better than that of large, single-crystalline graphene derived from thermal CVD growth. These results indicate that elevated temperatures and crystalline substrates are not necessary for synthesizing high-quality graphene.
Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized ...discontinuation trial with nine tumor-type cohorts.
Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).
Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.
Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.
NCT00940225.
In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved ...response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis.
Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum–pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points.
A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum–pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum–pemetrexed had died. The hazard ratio (HR) for OS was 0.87 95% confidence interval (CI) 0.67–1.12; P = 0.277; the median OS was 26.8 months (95% CI 23.5–31.5) versus 22.5 months (95% CI 20.2–28.8) for osimertinib and platinum–pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18–1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16–0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum–pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum–pemetrexed arm.
In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum–pemetrexed, which possibly reflects the high crossover rate of patients from platinum–pemetrexed to osimertinib.
ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.
•Median OS with osimertinib was 26.8 months versus 22.5 months with platinum–pemetrexed (HR 0.87, 95% CI 0.67–1.12; P = 0.277).•The lack of a significant survival benefit could reflect high percentage (73%) of platinum–pemetrexed to osimertinib crossover.•Analysis of OS adjusted for crossover showed an HR of 0.54 (95% CI 0.18–1.60).•Among patients receiving subsequent anticancer therapy, platinum chemotherapy was the most common after osimertinib (65%).•Grade ≥3 (possibly treatment-related) adverse events were observed less frequently with osimertinib (9% versus 34% with platinum–pemetrexed).
Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody–drug conjugate consisting ...of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd.
Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC.
In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% 95% confidence interval (CI) 30.0% to 52.7%, median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified.
In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.
•The phase I U31402-A-U102 study evaluated HER3-DXd in heavily pretreated patients with EGFR-mutated NSCLC.•Ninety-seven patients previously treated with EGFR TKI and PBC received HER3-DXd 5.6 mg/kg intravenously every 3 weeks.•Responses were seen across the range of HER3 expression and across diverse mechanisms of resistance to EGFR TKI therapy.•Acquired mutations in ERBB3 were characterized.•OS was 15.8 months (95% CI 10.8-21.5 months).
Malignant pleural effusion (MPE) accompanying lung adenocarcinoma indicates poor prognosis and early metastasis. This study aimed to identify genes related to MPE formation. Three tissue sample ...cohorts, seven from healthy lungs, 18 from stage I-III lung adenocarcinoma with adjacent healthy lung tissue and 13 from lung adenocarcinomas with MPE, were analysed by oligonucleotide microarray. The identified genes were verified by quantitative real-time PCR (qRT-PCR), immunohistochemical staining, and immunofluorescence confocal microscopy. 20 up- or down-regulated genes with a two-fold change in MPE cancer cells compared to healthy tissues were differentially expressed from early- to late-stage lung cancer. Of 13 genes related to cellular metabolism, aldolase A (ALDOA), sorbitol dehydrogenase (SORD), transketolase (TKT), and tuberous sclerosis 1 (TSC1) were related to glucose metabolism. qRT-PCR validated their mRNA expressions in pleural metastatic samples. Immunohistochemical staining confirmed aberrant TKT, ALDOA, and TSC1 expressions in tumour cells. Immunofluorescence confirmed TKT co-localisation and co-distribution of ALDOA with thyroid transcription factor 1-positive cancer cells. TKT regulated the proliferation, vascular endothelial growth factor secretion in vitro and in vivo vascular permeability of cancer cell. Glucose metabolic reprogramming by ALDOA, SORD, TKT and TSC1 is important in MPE pathogenesis.
Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase ...I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours.
Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course.
Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile.
These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients.
Abstract Parker Solar Probe, the closest spacecraft to the Sun, has renewed our understanding of the solar corona and the interplanetary space. One of its important findings is the prevalence of ...switchbacks, which display localized magnetic reversals along the otherwise Parker spirals. While some switchbacks might disappear quickly, others can maintain for a long period of time, and there are indications that many switchbacks strengthen from the solar corona to the interplanetary space despite their magnetic tension force, which tends to straighten the magnetic field lines. Therefore, how these switchbacks could be maintained for a long period of time remains a mystery. In this paper, we employed a 3D data-driven global full magnetohydrodynamics numerical model to explore the evolution of switchbacks formed in the dynamic corona. Our simulations indicate that two factors can affect the lifetime of a switchback. One factor is the combination of angle and leg length ensures that the switchback with greater curvature after reconnection can last longer, and the greater the angle, the more magnetic field lines that can be reconnected, and thus the longer the duration. We call this influencing factor flux tube shape factor. The other factor is the velocity shear, i.e., when the solar wind at the convex-outward turning of a switchback is faster than that at the concave-outward turning, the switchback becomes enhanced during propagation, and it weakens when the velocity difference is opposite.
Summary
The occurrence of osteoporosis in tuberculosis, a chronic infection, has rarely been evaluated. In this study, we found significantly higher incidence rates of osteoporosis (Adjusted hazard ...ratio (AHR) 1.82) and osteoporotic fracture (AHR 2.33) in tuberculosis patients than matched cohorts, which suggest that osteoporosis screening should be considered in tuberculosis patients’ follow-up program. The aim of this study is to determine the occurrence of incident osteoporosis in patients who completed anti-tuberculosis (TB) treatment.
Introduction
Chronic inflammatory disorders are associated with an increased risk of osteoporosis. Although TB is an infectious disease characterized by systemic inflammatory responses, the impact of active TB on incident osteoporosis is unclear. We used the Taiwan National Health Insurance Research Database to investigate the association between history of active TB and incident osteoporosis and osteoporotic fracture.
Methods
In this nationwide retrospective cohort study, active TB patients and their age- and sex-matched controls were identified from the National Health Insurance Research Database in Taiwan during 2000–2012. The occurrence of incident osteoporosis, osteoporotic fractures, and risk factors associated with osteoporosis among TB patients and matched controls were analyzed.
Results
We observed incident osteoporosis in 2.2% (
n
= 86) of the TB patients and in 1.1% (
n
= 162) of the matched controls. The incidence rate of osteoporosis was 4.31 and 1.80 per 1000 person-years, which was significantly higher in TB patients (
p
< 0.001). In multivariate analysis, TB was an independent risk factor for osteoporosis. The other independent factors associated with osteoporosis were older age, female sex, chronic obstructive pulmonary disease, asthma, and lower income. Moreover, we demonstrated that the occurrence of osteoporotic fracture was significantly higher in TB patients.
Conclusions
Patients with a history of active TB have a higher incidence rate of osteoporosis and osteoporotic fracture.
Radiative fluxes at the top of the atmosphere (TOA) from the Clouds and the Earth's Radiant Energy System (CERES) instrument are fundamental variables for understanding the Earth's energy balance and ...how it changes with time. TOA radiative fluxes are derived from the CERES radiance measurements using empirical angular distribution models (ADMs). This paper evaluates the accuracy of CERES TOA fluxes using direct integration and flux consistency tests. Direct integration tests show that the overall bias in regional monthly mean TOA shortwave (SW) flux is less than 0.2Wm(exp -2) and the RMSE is less than 1.1Wm(exp -2). The bias and RMSE are very similar between Terra and Aqua. The bias in regional monthly mean TOA LW fluxes is less than 0.5Wm(exp -2) and the RMSE is less than 0.8Wm(exp -)2 for both Terra and Aqua. The accuracy of the TOA instantaneous flux is assessed by performing tests using fluxes inverted from nadir- and oblique-viewing angles using CERES along-track observations and temporally and spatially matched MODIS observations, and using fluxes inverted from multi-angle MISR observations. The averaged TOA instantaneous SW flux uncertainties from these two tests are about 2.3% (1.9Wm(exp -2) over clear ocean, 1.6% (4.5Wm(exp -2) over clear land, and 2.0% (6.0Wm(exp -) over clear snow/ice; and are about 3.3% (9.0Wm(exp -2), 2.7% (8.4Wm(exp -2), and 3.7% (9.9Wm(exp -2) over ocean, land, and snow/ice under all-sky conditions. The TOA SW flux uncertainties are generally larger for thin broken clouds than for moderate and thick overcast clouds. The TOA instantaneous daytime LW flux uncertainties derived from the CERESMODIS test are 0.5% (1.5Wm(exp -2), 0.8% (2.4Wm(exp -2), and 0.7% (1.3Wm(exp -2) over clear ocean, land, and snow/ice; and are about 1.5% (3.5Wm(exp -2), 1.0% (2.9Wm(exp -2), and 1.1% (2.1Wm(exp -2) over ocean, land, and snow/ice under all-sky conditions. The TOA instantaneous nighttime LW flux uncertainties are about 0.5-1% (<2.0Wm(exp -2) for all surface types. Flux uncertainties caused by errors in scene identification are also assessed by using the collocated CALIPSO, CloudSat, CERES and MODIS data product. Errors in scene identification tend to underestimate TOA SW flux by about 0.6Wm(exp -2) and overestimate TOA daytime (nighttime) LW flux by 0.4 (0.2)Wm(exp -2) when all CERES viewing angles are considered.
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