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).
In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus ...gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.
LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.
Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
NCT01466660.
In this paper, studies on dynamic modeling, simulation and experiment of power transmission belt drives are comprehensively reviewed. In the past few decades, many investigations are conducted on ...dynamic modeling, simulation and experiment of different kinds of power transmission belt drive systems. In the dynamic modeling and simulation of the belt drive systems, surveys are focused on vibrations of a single axially moving belt span, rotational vibrations of pulley components, coupled belt-pulley vibrations and contact mechanics between the belt and pulley as well as some experimental investigations. Influences of tensioner dry friction and one-way clutch on dynamics of the belt drive systems including system rotational vibrations and coupled belt-pulley vibrations are separately reported. The investigations are also surveyed on modeling and predicting complicated belt-pulley contact behaviors like belt creeps and slips on pulleys, contact force distributions of the belt and pulley, and variation of wrap angles of a belt around pulleys, etc., which are categorized by different approaches including the creep theory, shear theory, multi-body dynamics and finite element methods. Fatigue life estimation and failure analysis of power transmission belt drives are discussed in detail as well. In addition, experimental techniques are reviewed on parameters identifications, and measurements of static and dynamic performances including energy/power loss, system vibration, dynamic belt tension, belt deformation, stress and strain distribution in the belt and pulley, and contact friction force, etc. Finally, conclusion of this work is summarized and topics of future potential studies on the power transmission belt drive systems are suggested.
Summary Background Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects ...of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor. Methods In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov , number NCT00442936. Findings 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 27% of 353 patients vs 33 10% of 343 p<0·0001), pain relief (194 55% of 353 vs 95 28% of 343 p<0·0001), and absences of phonophobia (204 58% of 353 vs 126 37% of 342 p<0·0001), photophobia (180 51% of 353 vs 99 29% of 342 p<0·0001), and nausea (229 65% of 352 vs 189 55% of 342 p=0·0061). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo. Interpretation Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. Funding Merck Research Laboratories.
An unexpected opportunity is reported to improve the sustainability of biorefineries whereby 8 wt% levoglucosenone (LGE) can be derived from unconverted saccharides in a lignin-rich biorefinery waste ...stream in a highly selective fashion (>90%). Additionally, in the process a purer lignin is obtained which can be used for further processing or materials applications. LGE is a valuable and versatile product with a plethora of applications.
This work proposes a machine-learning or artificial intelligence (AI) control of a low-drag Ahmed body with a rear slant angle φ = 35° with a view to finding strategies for efficient drag reduction ...(DR). The Reynolds number Re investigated is 1.7 × 105 based on the square root of the body cross-sectional area. The control system comprises of five independently operated arrays of steady microjets blowing along the edges of the rear window and vertical base, twenty-six pressure taps on the rear end of the body and a controller based on an ant colony algorithm for unsupervised learning of a near-optimal control law. The cost function is designed such that both DR and control power input are considered. The learning process of the AI control discovers forcing that produces a DR up to 18 %, corresponding to a drag coefficient reduction of 0.06, greatly exceeding any previously reported DR for this body. Furthermore, the discovered forcings may provide alternative solutions, i.e. a tremendously increased control efficiency given a small sacrifice in DR. Extensive flow measurements performed with and without control indicate significant alterations in the flow structure around the body, such as flow separation over the rear window, recirculation bubbles and C-pillar vortices, which are linked to the pressure rise on the window and base. The physical mechanism for DR is unveiled, along with a conceptual model for the altered flow structure under the optimum control or biggest DR. This mechanism is further compared with that under the highest control efficiency.
Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients' treatment. The current heavy ...workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses.
Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany.
Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells.
This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SnSe is a promising thermoelectric material with record-breaking figure of merit. However, to date a comprehensive understanding of the electronic structure and most critically, the self-hole-doping ...mechanism in SnSe is still absent. Here we report the highly anisotropic electronic structure of SnSe investigated by angle-resolved photoemission spectroscopy, in which a unique pudding-mould-shaped valence band with quasi-linear energy dispersion is revealed. We prove that p-type doping in SnSe is extrinsically controlled by local phase segregation of SnSe
microdomains via interfacial charge transferring. The multivalley nature of the pudding-mould band is manifested in quantum transport by crystallographic axis-dependent weak localisation and exotic non-saturating negative magnetoresistance. Strikingly, quantum oscillations also reveal 3D Fermi surface with unusual interlayer coupling strength in p-SnSe, in which individual monolayers are interwoven by peculiar point dislocation defects. Our results suggest that defect engineering may provide versatile routes in improving the thermoelectric performance of the SnSe family.
Abstract
As a novel X-ray focusing technology, lobster-eye micropore optics (MPO) feature both a wide observing field of view and true imaging capability, promising sky monitoring with significantly ...improved sensitivity and spatial resolution in soft X-rays. Since first proposed by Angel, the optics have been extensively studied, developed and trialed over the past decades. In this Letter, we report on the first-light results from a flight experiment of the Lobster Eye Imager for Astronomy, a pathfinder of the wide-field X-ray telescope of the Einstein Probe mission. The piggyback imager, launched in 2022 July, has a mostly unvignetted field of view of 18.°6 × 18.°6. Its spatial resolution is in the range of 4′–7′ in FWHM and the focal spot effective area is 2–3 cm
2
, both showing only mild fluctuations across the field of view. We present images of the Galactic center region, Sco X-1, and the diffuse Cygnus Loop nebular taken in snapshot observations over 0.5–4 keV. These are truly wide-field X-ray images of celestial bodies observed, for the first time, by a focusing imaging telescope. Initial analyses of the in-flight data show excellent agreement between the observed images and the on-ground calibration and simulations. The instrument and its characterization are briefly described, as well as the flight experiment. The results provide a solid basis for the development of the present and proposed wide-field X-ray missions using lobster-eye MPO.
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