Search

Lung cancers harboring mesenchymal-to-epithelial transition factor (MET) genetic alterations, such as exon 14 skipping mutations or high-level gene amplification, respond well to MET-selective tyrosine kinase inhibitors (TKI). However, these agents benefit a relatively small group of patients (4%–5% of lung cancers), and acquired resistance limits response durability. An antibody–drug conjugate (ADC) targeting MET might enable effective treatment of MET-overexpressing tumors (approximately 25% of lung cancers) that do not respond to MET targeted therapies. Using a protease-cleavable linker, we conjugated a biparatopic METxMET antibody to a maytansinoid payload to generate a MET ADC (METxMET-M114). METxMET-M114 promotes substantial and durable tumor regression in xenografts with moderate to high MET expression, including models that exhibit innate or acquired resistance to MET blockers. Positron emission tomography (PET) studies show that tumor uptake of radiolabeled METxMET antibody correlates with MET expression levels and METxMET-M114 efficacy. In a cynomolgus monkey toxicology study, METxMET-M114 was well tolerated at a dose that provides circulating drug concentrations that are sufficient for maximal antitumor activity in mouse models. Our findings suggest that METxMET-M114, which takes advantage of the unique trafficking properties of our METxMET antibody, is a promising candidate for the treatment of MET-overexpressing tumors, with the potential to address some of the limitations faced by the MET function blockers currently in clinical use.

BackgroundPatients with sepsis may progress to acute respiratory distress syndrome (ARDS). Evidence of neutrophil extracellular traps (NETs) in sepsis-induced lung injury has been reported. However, the role of circulating NETs in the progression and thrombotic tendency of sepsis-induced lung injury remains elusive. The aim of this study was to investigate the role of tissue factor-enriched NETs in the progression and immunothrombosis of sepsis-induced lung injury.MethodsHuman blood samples and an animal model of sepsis-induced lung injury were used to detect and evaluate NET formation in ARDS patients. Immunofluorescence imaging, ELISA, Western blotting, and qPCR were performed to evaluate in vitro NET formation and tissue factor (TF) delivery ability. DNase, an anti-TF antibody, and thrombin inhibitors were applied to evaluate the contribution of thrombin to TF-enriched NET formation and the contribution of TF-enriched NETs to immunothrombosis in ARDS patients.ResultsSignificantly increased levels of TF-enriched NETs were observed in ARDS patients and mice. Blockade of NETs in ARDS mice alleviated disease progression, indicating a reduced lung wet/dry ratio and PaO2 level. In vitro data demonstrated that thrombin-activated platelets were responsible for increased NET formation and related TF exposure and subsequent immunothrombosis in ARDS patients.ConclusionThe interaction of thrombin-activated platelets with PMNs in ARDS patients results in local NET formation and delivery of active TF. The notion that NETs represent a mechanism by which PMNs release thrombogenic signals during thrombosis may offer novel therapeutic targets.

Ferroptosis is a newly discovered type of regulated cell death that is different from apoptosis, necrosis and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation, which induces cell death. Iron, lipid and amino acid metabolism is associated with ferroptosis. Ferroptosis is involved in the pathological development of various diseases, such as neurological diseases and cancer. Recent studies have shown that ferroptosis is also closely related to acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS), suggesting that it can be a novel therapeutic target. This article mainly introduces the metabolic mechanism related to ferroptosis and discusses its role in ALI/ARDS to provide new ideas for the treatment of these diseases.

Patients with sepsis commonly suffer from coagulation dysfunction and lead to the formation of thrombus. During the development of sepsis, neutrophils migrate from the circulating blood to infected tissues and mediate the formation of neutrophil extracellular traps (NETs) that kill pathogens. However, the overactivation of neutrophils can promote the formation of immunothrombosis and even cause disseminated intravascular coagulation (DIC), which damages microcirculation. The outcome of sepsis depends on early recognition and intervention, so clinical evaluation of NETs function may be a valuable biomarker for early diagnosis of sepsis. The interaction of NETs with platelets, complement, and endothelium mediates the formation of immunothrombosis in sepsis. Inhibiting the formation of NETs is also considered to be one of the potential treatments for sepsis. In this review, we will discuss the key role of neutrophils and NETs in sepsis and septic thrombosis, in order to reveal new mechanisms for thrombosis treatment of sepsis.

An integrated optical antenna is proposed for laser communication on the small satellite in which there are not enough internal space for large laser communication system. The proposed optical antenna is designed on a silicon-on-insulator (SOI) chip with two different grating couplers to receive and transmit the TE and TM modes respectively. The polarization angle of the incident light can be precisely measured by this optical antenna. The factors which cause the polarization angle errors are analyzed in detail. It is demonstrated that the measurement error for the polarization angle is less than 0.001° when the incident angle error is less than 0.008°. The optical antenna is sensitive to polarization angle and convenient to be installed on the surface of the carrier, providing a new approach for laser communication on the small satellite.

According to the Fick’s second law of diffusion, six analytical solutions of chloride profile in concrete were studied and discussed with regard to different boundary and initial conditions. In those analytical solutions, the most prevailing error-function solution which is based on semi-infinite assumption is the simple one, but may under-estimate the chloride content in concrete and over-rate the life time prediction of concrete structures. The experimental results show that compared with other solutions, the chloride content in concrete predicted by error-function model is the minimum, and the calculation difference produced by different analytical models should not be ignored. The influence of models on chloride content prediction is more than other environment and material coefficients in some time. In order to get a more realistic prediction model, modification to error-function model is suggested based on analysis and calculation examples concerning the boundary and edge effect.

Background Sorafenib is an oral multikinase inhibitor with antiangiogenic and antitumor activity. In most cases, the commercially available 200 mg tablet is not suitable for administration to children. We studied the chemical and physical stability of extemporaneously prepared formulations and evaluated the pharmacokinetic profile of cut tablets and smaller-dosage capsules of sorafenib in children. Procedure Commercially available 200 mg tablets of sorafenib tosylate were used to prepare liquid suspensions of sorafenib in oil and Ora-Plus®:Ora-Sweet® solution, and to prepare 5, 10, 20, 50, and 100 mg capsules. Plasma concentrations of sorafenib were measured in patients receiving capsules and cut tablets, using a validated HPLC-based method with tandem mass spectrometric detection. Results At room temperature and under refrigeration, sorafenib concentrations in Ora Plus®:Ora Sweet® were highly variable (means ranging from 75% to 131% of the intended concentration of 50 mg/ml). In oil suspension, sorafenib concentrations were inconsistent during compounding. In contrast, all smaller-dosage capsules, except the 5 mg capsule, were within 91–99% of the intended content and were stable at room temperature for at least 8 months. Sorafenib pharmacokinetic parameters in patients receiving capsules or cut tablets were consistent with those reported previously in adults and children receiving intact tablets. Conclusions Sorafenib is not stable in an oral suspension prepared from commercially available tablets, but compounded capsules in smaller-dosage forms that can be sprinkled on food or cut tablets are alternatives for administration to children who need smaller doses based on body surface area or cannot swallow tablets. Pediatr Blood Cancer 2013;60:1642–1646. © 2013 Wiley Periodicals, Inc.

Acquiring enough durability for concrete structures in their design phase is a crucial step against unexpected deterioration during their service life. This article gives an extensive and in-depth review of the first Chinese national guide, CCES01-2004, destined exclusively for durability design of concrete structures. Based on the state-of-art knowledge on durability and in place experiences, this guide formulates its durability requirements from several fundamental concepts: environmental action, durability limit state and structure service life. For each environmental class and expected service life, the guide details its requirements on raw material constituents, concrete curing conditions, material performance as well as structure details, in particular the concrete cover to reinforcement steel. The relevant quantitative requirements are compared with those from other codes such as EuroCode2, EN206, ACI318 and CSA. As a special case, the durability of post-tensioned prestressed concrete structures is treated separately and a multi-layer, environment-based strategy is proposed for the prestress tendon and anchorage protection. At the end, the remaining crucial questions are brought forth for durability design of concrete structures.

In recent years, soil nailing has been widely used to stabilize excavated steep slopes. Its design is often controlled by the allowable deformation level especially when buildings and/or other underground facilities exit near the excavation. In this paper a three-dimensional (3-D) finite element model (FEM) has been developed for the deformation analysis of nailed soil structures. In this model, the soil nonlinearity, the soil–nail interaction and the staged construction are all considered. Parametric studies are carried out to investigate some influence factors on the deformation behavior. An engineering case is also analyzed and the predicted soil movements at various stages of excavation are compared with field measurements. Good agreement between the prediction and the measurements proves the reliability of the model.