High-current pulse electron beam (HCPEB) is an advanced surface modification technology developed in recent decades. This paper focuses on the effect of 0.3 wt.% graphene on the electrical conductivity and microhardness of HCPEB-treated Al-20TiC composites. The SEM results show that the titanium carbide was uniformly distributed in the aluminum matrix of the initial sample. Conversely, the graphene showed a small aggregation, and there were holes and cracks on the top surface of the sample. After HCPEB modification, the agglomeration of graphene gradually improved, and the number of surface pores reduced. The X-ray diffraction results show that after HCPEB treatment, the aluminum diffraction peak widened and shifted to a higher angle and the grain was significantly refined. Compared with the initial Al-20TiC composite samples, the conductivity of graphene-modified HCPEB-treated sample increased by 94.3%. The microhardness test results show that the microhardness of the graphene-modified HCPEB-treated sample increased by 18.4%, compared with the initial Al-20TiC composite samples. This enhancement of microhardness is attributed to the joint effects of fine grain strengthening, dispersion strengthening of the second phase, solution strengthening and dislocation strengthening. In brief, HCPEB has good application prospects for powder metallurgy in future.
Background: Tyrosine kinase inhibitors (TKIs) therapy is a standard treatment for patients with advanced non-small-cell lung carcinoma (NSCLC) when activating epidermal growth factor receptor (EGFR) mutations are detected. However, except for the well-studied EGFR mutations, most EGFR mutations lack treatment regimens. Methods: We constructed two EGFR variant libraries containing substitutions, deletions, or insertions using the saturation mutagenesis method. All the variants were located in the EGFR mutation hotspot (exons 18-21). The sensitivity of these variants to afatinib, erlotinib, gefitinib, icotinib, and osimertinib was systematically studied by determining their enrichment in massively parallel cytotoxicity assays using an endogenous EGFR-depleted cell line, PC9. Results: A total of 3,914 and 70,475 variants were detected in the constructed EGFR Substitution-Deletion (Sub-Del) and exon 20 Insertion (Ins) libraries, accounting for 99.3% and 55.8% of the designed variants, respectively. Of the 3,914 Sub-Del variants, 813 were highly enriched in the reversible TKI (erlotinib, gefitinib, icotinib) cytotoxicity assays and 51 were enriched in the irreversible TKI (afatinib, osimertinib) cytotoxicity assays. For the 70,475 Ins variants, insertions at amino acid positions 770-774 were highly enriched in all the five TKI cytotoxicity assays. Moreover, the top 5% of the enriched insertion variants included a glycine or serine insertion at high frequency. Conclusions: We present a comprehensive reference for the sensitivity of EGFR variants to five commonly used TKIs. The approach used here should be applicable to other genes and targeted drugs.
Background: Tyrosine kinase inhibitors (TKIs) therapy is a standard treatment for patients with advanced non-small-cell lung carcinoma (NSCLC) when activating epidermal growth factor receptor (EGFR) mutations are detected. However, except for the well-studied EGFR mutations, most EGFR mutations lack treatment regimens.Methods: We constructed two EGFR variant libraries containing substitutions, deletions, or insertions using the saturation mutagenesis method. All the variants were located in the EGFR mutation hotspot (exons 18-21). The sensitivity of these variants to afatinib, erlotinib, ge tinib, icotinib, and osimertinib was systematically studied by determining their enrichment in massively parallel cytotoxicity assays using an endogenous EGFR-depleted cell line, PC9.Results: A total of 3,914 and 70,475 variants were detected in the constructed EGFR Substitution-Deletion (Sub-Del) and exon 20 Insertion (Ins) libraries, accounting for 99.3% and 55.8% of the designed variants, respectively. Of the 3,914 Sub-Del variants, 813 were highly enriched in the reversible TKI (erlotinib, ge tinib, icotinib) cytotoxicity assays and 51 were enriched in the irreversible TKI (afatinib, osimertinib) cytotoxicity assays. For the 70,475 Ins variants, insertions at amino acid positions 770-774 were highly enriched in all the ve TKI cytotoxicity assays. Moreover, the top 5% of the enriched insertion variants included a glycine or serine insertion at high frequency.Conclusions: We present a comprehensive reference for the sensitivity of EGFR variants to ve commonly used TKIs. The approach used here should be applicable to other genes and targeted drugs. Signi cance StatementMutation-directed cancer precision medicine requires pre-interpretation of variants response on targeted drugs. For Asian lung adenocarcinoma patients, epidermal growth factor receptor (EGFR) is a commonly mutated gene with many rare mutations that lack drug response interpretations. We conducted a systematic cytotoxicity screening of EGFR mutations on ve tyrosine kinase inhibitors. We found that patients with rare EGFR mutations are most likely to bene t from osimertinib therapy compared to afatinib, erlotinib, ge tinib, or icotinib therapy. This study provides the rst case of deep mutational scanning that simultaneously assayed substitution, deletion, and insertion variants. This approach is applicable for other oncogenes and targeted drugs.
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