High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to ...investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.
In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group 14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038, while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.
Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.
ClinicalTrials.gov NCT02915432.
The purposes of this study were to compare Young's modulus values determined by shear wave ultrasound elastography (SWUE) with stiffness index obtained using a hand-held MyotonPRO device on the ...resting stiffness of gastrocnemius muscle belly and Achilles tendon; and to examine the test-retest reliability of those stiffness measurement using hand-held MyotonPRO. Twenty healthy volunteers participated in the study. The measurement values of muscle and tendon was determined in dominant legs. Each marker point was assessed using MyotonPRO and SWUE, respectively. Intra-operator reliability of MyotonPRO was established in 10 of the subjects. The correlation coefficients between the values of muscle and tendon stiffness indices determined by MyotonPRO and SWUE were calculated. Significant correlations were found for muscle and tendon stiffness and Young's modulus ranged from 0.463 to 0.544 (all P < 0.05). The intra-operator reliability ranged from good to excellent (ICC
= 0.787~0.928). These results suggest that the resting stiffness of gastrocnemius muscle belly and Achilles tendon measured by MyotonPRO is related to the Young's modulus of those quantified by SWUE. The MyotonPRO shows good intra-operator repeatability. Therefore, the present study shows that MyotonPRO can be used to assess mechanical properties of gastrocnemius muscle belly and Achilles tendon with a resting condition.
CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor ...(EGFR).
Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m2) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data.
From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40–0.75, P < 0.001 as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38–0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49–1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43–2.08, P = 0.877).
CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients.
NCT00891579.
Searching topological states in artificial systems has recently become a rapidly growing field of research. Meanwhile, significant experimental progress on observing topological phenomena has been ...made in superconducting circuits. However, topological insulator states have not yet been reported in this system. Here, for the first time, we experimentally realize a tunable dimerized spin chain model and observe the topological magnon insulator states in a superconducting qubit chain. Via parametric modulations of the qubit frequencies, we show that the qubit chain can be flexibly tuned into topologically trivial or nontrivial magnon insulator states. Based on monitoring the quantum dynamics of a single-qubit excitation in the chain, we not only measure the topological winding numbers, but also observe the topological magnon edge and defect states. Our experiment exhibits the great potential of tunable superconducting qubit chain as a versatile platform for exploring noninteracting and interacting symmetry-protected topological states.
Inconel 718 samples were fabricated by selective laser melting (SLM). The effects of line laser energy densities in the range 0.1–0.3 J/mm on the microstructure, mechanical properties, and ...deformation of these samples were investigated. The fewest pores and best mechanical properties were realized at 0.2 J/mm with a yield strength of 775 MPa, ultimate tensile strength of 1055 MPa, and elongation of 29.5%. Fine dimples were uniformly distributed on the fracture surface under 0.2 J/mm. An Electron Backscatter Diffraction (EBSD) test revealed a mixture of fine columnar and equiaxed grains that promote strength while maintaining high plasticity. The prisms cut from these samples bent outwards, indicating great residual stresses in the samples. Their deformation increased with increasing laser energy density. Therefore, stress release treatment is necessary for SLM parts.
•The tensile strength and elongation reached 1055 MPa and 29.5%, respectively.•The best mechanical properties were achieved at 0.2 J/mm, instead of 0.3 J/mm.•Orderly stacking of melt pools without stagger caused tiny pores at the overlapping.•Prisms cut from specimens bent, the bigger energy density, the bigger deformation.
We have clearly discriminated the single-, bilayer-, and multiple-layer graphene (<10 layers) on Si substrate with a 285 nm SiO2 capping layer by using contrast spectra, which were generated from the ...reflection light of a white light source. Calculations based on Fresnel's law are in excellent agreement with the experimental results (deviation 2%). The contrast image shows the reliability and efficiency of this new technique. The contrast spectrum is a fast, nondestructive, easy to be carried out, and unambiguous way to identify the numbers of layers of graphene sheet. We provide two easy-to-use methods to determine the number of graphene layers based on contrast spectra: a graphic method and an analytical method. We also show that the refractive index of graphene is different from that of graphite. The results are compared with those obtained using Raman spectroscopy.
A topological meron features a non-coplanar structure, whose order parameters in the core region are perpendicular to those near the perimeter. A meron is half of a skyrmion, and both have potential ...applications for information carrying and storage. Although merons and skyrmions in ferromagnetic materials can be readily obtained via inter-spin interactions, their behaviour and even existence in ferroelectric materials are still elusive. Here we observe using electron microscopy not only the atomic morphology of merons with a topological charge of 1/2, but also a periodic meron lattice in ultrathin PbTiO
films under tensile epitaxial strain on a SmScO
substrate. Phase-field simulations rationalize the formation of merons for which an epitaxial strain, as a single alterable parameter, plays a critical role in the coupling of lattice and charge. This study suggests that by engineering strain at the nanoscale it should be possible to fabricate topological polar textures, which in turn could facilitate the development of nanoscale ferroelectric devices.
Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, ...randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation.
Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety.
Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group.
First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.
Nowadays, the popularity of environmental, social, and governance (ESG) performance measurement has dramatically increased, particularly to listed companies, for supporting various investment ...decisions. Companies with high ESG scores imply that their ongoing business development is recognised to be economically, socially, and environmentally sustainable. From the current ESG measurement practice, the measurement frameworks are built on rating schemes, such as KLD and ASSET4, so as to derive the ESG scores for listed companies. However, such existing measurement frameworks are difficult to be implemented in small and medium enterprises (SMEs) with unstructured and non-standardised business data, especially in logistics and supply chain management (LSCM) practice. In addition, it is inevitable for listed companies to work with SMEs, for example logistics service providers, but they need a systematic framework to source the responsible SMEs to maintain the ESG performance. To address the above industrial pain-points, this study proposes an ESG development prioritisation and performance measurement framework (ESG-DPPMF) by means of the Bayesian best-worst method enabling the group decision-making capability to prioritise the ESG development areas and formulate the performance measurement scheme. Through consolidating the opinions from logistics practitioners, it is found that fair labour practice, reverse logistics and human right in supply chains are the most essential areas to further enhance ESG capabilities in the logistics industry. In addition, the viability of the ESG performance measurement has been validated, and thus the sustainable and human-centric logistics practice can be developed to achieve business sustainability.
•Emphasis on operationalising ESG concepts in small and medium logistics companies.•A framework to prioritise ESG development areas and performance measurement.•Highlights of fair labour, reverse logistics, and human rights as key ESG areas.
Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin ...of cosmological FRBs is still not settled. Here we report the detection of1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref.9). These observations show irregular short-time variation ofthe Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (au; Earth-Sun distance) ofthe source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.
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