BackgroundAntibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application.MethodMonoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice.ResultsH5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC50 at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON+/CD44+/ESA+ phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg.ConclusionH5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.
Nano-cemented carbide is a novel material, which is superior to common cemented carbide on physical and mechanical properties, such as high hardness, toughness, flexural strength and higher wear resisting property. It is proposed to have wide application prospect to tools and mould manufacturing. In this paper, ELID grinding technique is applied to grind nano-cemented carbide tools. And the ground surface quality, cutting edge radius, and machinability of nano-cemented carbide tools are studied, compared with common cemented carbide. It is demonstrated by experimental results that nano-cemented carbide has higher grinding surface quality with less surface flaw than that of common cemented carbide. The cutting edge radius of nano-cemented carbide tool is less than that of common cemented carbide tool. Under the same conditions, the tool life of nano-cemented carbide is 1~2 times longer than that of common cemented carbide. The research results indicate that ELID grinding technique is suitable for grinding cemented carbide tools. Nano-cemented carbide tools have better machinability than common cemented carbide tools.
Analyzing the attractiveness of point-of-interests (POIs) in a city is very important to business location selection, market analysis, traffic management, and urban planning. Recently Analyzing the attractiveness of POIs based on GPS data calls scholars’ attention. However, the existing methods ignore the variation of POI’s attractiveness owing to its categories and the time-slots. Therefore, we propose a novel approach of analyzing POIs’ attractiveness variation based on taxis’ trajectories. According to the situation of taxis’ stopping nearby the POIs which belongs to certain categories in different time-slots, we can compute the POIs’ attractiveness. Furthermore, the law of citizens activity can be analyzed and provide reference to urban planning.
Air cooling is a near dry machining method, which cools cutting area and evacuates chips using low temperature cold wind instead of cutting liquid. It can decrease tool wear, increase tool life, reduce machining cost and bring no chemical pollution. In this paper, air cooling test was carried on, in which vortex tube was used for cooling and high hardness bear steel GCr15 was machined by PCBN tool. Experiment results indicated that cold air from vortex tube has a significant effect on cutting force, cutting temperature and chip formation process. This paper’s conclusions will have a great reference value for the practical application of air cooling technology.
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