Tribological Properties Laser-Cladded Spherical WB-Reinforced Co-Based Coatings under Low-Temperature Friction.

Three groups of spherical WB-reinforced Co-based coatings (Co coating, Co + 15%WB coating, Co + 45%WB coating) were fabricated by laser-cladded technology. The microstructure and constituent phase of spherical WB-reinforced Co-based coatings were examined through scanning electron microscopy (SEM) with energy dispersive spectrometry (EDS) and X-ray diffraction (XRD). The low-temperature tribological properties were analyzed by coefficient of friction, 2D and 3D profiles across the wear track, and wear surface morphology, respectively. The results showed that the phases in the WB-reinforced Co-based coatings are mainly γ-Co, carbides Cr23C6 and Cr7C3, WB, and WO3. Under dry sliding friction at -20 °C, the more spherical WB, the lower the friction coefficient. The wear rate of Co + 45%WB coating was as low as 3.567 × 10-4 mm3/N·m-1, indicating the outstanding wear resistance. Abrasive wear was observed on the rough surface of the WB-added coatings. Compared with dry sliding, due to the plastic deformation of micro-convexes and lubrication function in the 3.5 wt.% NaCl solution, the wear tracks on the surfaces of the three tested coatings were shallower, exhibiting distinct elongated plough grooves.

The Efficacy and Safety of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combined With Thymosin in Advanced Non-Small Cell Lung Cancer Patients Harboring Active Epidermal Growth Factor Receptor Mutations.

OBJECTIVE: To explore the efficacy and safety of EGFR-TKI combined with thymosin therapy in advanced non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. METHODS: Patients confirmed as advanced NSCLC with active EGFR mutations were recruited from August 2008 to July 2018 retrospectively. Patients treated with EGFR-TKI were classified as the EGFR-TKI group. And those received EGFR-TKI and thymosin therapy were designated as the EGFR-TKI plus thymosin group. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), tumor response and adverse effects. RESULTS: The median PFS was significantly longer in EGFR-TKI plus thymosin group than that in EGFR-TKI group (14.4 months vs. 9.2 months; HR=0.433, 95% CI 0.322 - 0.582, P<0.0001). The median OS was also prolonged in EGFR-TKI plus thymosin group than that in EGFR-TKI group (29.5 months vs. 19.8 months; HR=0.430, 95% CI 0.319 - 0.580, P<0.0001). The objective response rate in EGFR-TKI plus thymosin group and EGFR-TKI group were 60.0% versus 60.8% (P=0.918). The disease control rate was 96.9% in EGFR-TKI plus thymosin group and 97.7% in EGFR-TKI group (P=1.000). There were no significant differences in adverse effects between the two groups. The number of CD3+T cells in peripheral blood decreased significantly after treatment including both CD3+CD4+T and CD3+CD8+T subsets in EGFR-TKI group, but not in EGFR-TKI plus thymosin group. CONCLUSIONS: Combination of EGFR-TKI and thymosin can significantly prolong the PFS and OS compared with EGFR-TKI monotherapy without more adverse events, which offers a new strategy in clinic.

Hyperprogressive Disease In Cervical Small Cell Carcinoma Treated By Immune Checkpoint Inhibitor.

A new progression pattern, hyperprogressive disease (HPD), has been recently acknowledged in cancer patients accepted immune checkpoint inhibitors (ICIs). We report a unique case of cervical small cell carcinoma which showed primary resistance to pembrolizumab and was with a rapid radiological progression after the initiate of ICIs treatment. However, the detection results of multiple predictive biomarkers suggested that the patient was eligible for ICIs treatment. The whole exome sequencing showed that AKT1 E17K mutation was high (26.316%) in tumor tissue, and dynamic monitoring of circulating tumor DNA indicated that AKT1 E17K mutation rate was increasing successively and highly consistent with tumor growth in peripheral blood. Therefore, the correlation between AKT1 E17K mutation and HPD, and the role of AKT1 E17K mutation in identifying patients who might not benefit from ICIs treatment need to be further studied.

Concurrent EGFR-TKI and Thoracic Radiotherapy as First-Line Treatment for Stage IV Non-Small Cell Lung Cancer Harboring EGFR Active Mutations.

LESSONS LEARNED: This single-arm, phase II study shows that concurrent EGFR-tyrosine kinase inhibitor plus thoracic radiotherapy as the first-line treatment for stage IV non-small cell lung cancer harboring EGFR active mutations provides long-term control for the primary lung lesion, and 1-year progression-free survival (PFS) rate and median PFS are numerically higher than those of the erlotinib monotherapy.Serious adverse events are acceptable, although grade >3 radiation pneumonitis occurred in 20% of patients. BACKGROUND: Studies show effective local control by EGFR-tyrosine kinase inhibitor (TKI) combined with radiotherapy at metastatic sites in advanced lung cancer harboring EGFR active mutations. Salvage local radiotherapy is associated with prolonged progression-free survival (PFS) in local disease during EGFR-TKI treatment. However, no prospective study has been reported on concurrent EGFR-TKI and radiotherapy for primary lung lesions. This study investigated the efficacy and safety of first-line EGFR-TKI combined with thoracic radiotherapy in treating stage IV non-small cell lung cancer (NSCLC) harboring EGFR active mutations. METHODS: We conducted a single-arm, phase II clinical trial. Each patient received EGFR-TKI (erlotinib 150 mg or gefitinib 250 mg per day) plus thoracic radiotherapy (54-60 Gy/27-30 F/5.5-6 w) within 2 weeks of beginning EGFR-TKI therapy until either disease progression or intolerable adverse events (AEs) appeared. RESULTS: From January 2015 to March 2018, 401 patients were screened, and 10 patients (5 male and 5 female) were eligible. These patients had a median age of 55 years (40-75) and median follow-up of 19.8 months (5.8-34). The 1-year PFS rate was 57.1%, median PFS was 13 months, and median time to progression of irradiated lesion (iTTP) was 20.5 months. Objective response rate (ORR), was 50% and disease control rate (DCR) was 100%. The most common grade ≥3 AEs were radiation pneumonitis (20%) and rash (10%). One patient died after rejecting treatment for pneumonitis. The others received a full, systematic course of glucocorticoid therapy. Pneumonitis was all well controlled and did not relapse. CONCLUSION: Concurrent EGFR-TKI plus thoracic radiotherapy as the first-line treatment for stage IV NSCLC harboring EGFR active mutations shows a long-term control of primary lung lesion. The 1-year PFS rate and median PFS of this combined therapy are numerically higher than those of the erlotinib monotherapy. The risk of serious adverse events is acceptable.

Rab25 promotes erlotinib resistance by activating the ß1 integrin/AKT/ß-catenin pathway in NSCLC.

OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has significant therapeutic efficacy in non-small-cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long-term efficacy of EGFR-TKI. Our study aimed to investigate the role of ras-associated binding protein 25 (Rab25) in mediating EGFR-TKI resistance in NSCLC. MATERIALS AND METHODS: Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell-counting kit-8 and flow cytometry. The interaction between Rab25 and ß1 integrin was confirmed by co-immunoprecipitation. RESULTS: Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with ß1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane-ß1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/ß-catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR-TKI treatment in NSCLC patients. CONCLUSIONS: Rab25 mediates erlotinib resistance by activating the ß1 integrin/AKT/ß-catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR-TKI.

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non-small-cell lung cancer.

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib and erlotinib, is a critical issue in the treatment of patients with epidermal growth factor receptor mutant-positive non-small-cell lung cancer. Recent evidence suggests that downregulation of gene of phosphatase and tensin homolog deleted on chromosome 10 plays an important role in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in various types of cancers, including lung cancer. It was reported that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated gene (NEDD4) (also known as NEDD4-1) negatively regulated phosphatase and tensin homolog deleted on chromosome 10 protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder. Whether this process plays a role in epidermal growth factor receptor-tyrosine kinase inhibitors resistance in non-small-cell lung cancer has not been studied extensively. In view of this, we investigated the involvement of NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 in acquired erlotinib resistance with tyrosine kinase inhibitor-sensitive (HCC827) or tyrosine kinase inhibitor-resistant (Erlotinib-resistant HCC827/ER cells which harbored exon 19 deletion. Overexpression of NEDD4 in HCC827/ER cells was detected, and the reverse correlation between NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 expression in these cells was also revealed. In HCC827/ER cells with knockdown of NEDD4, phosphatase and tensin homolog deleted on chromosome 10 and p-Akt expressions were decreased; the sensitivity of HCC827/ER cells to erlotinib was partially restored. Similar results were also observed in vivo. In H1650/ER cells harboring both exon 19 and phosphatase and tensin homolog deleted on chromosome 10 deletion, expression of p-Akt and sensitivity to erlotinib were not affected by simple knockdown of NEDD4 but affected after transfection of phosphatase and tensin homolog deleted on chromosome 10 into H1650/ER cells. Our results demonstrate that NEDD4 may promote the acquired resistance of non-small-cell lung cancer cells to erlotinib by decreasing phosphatase and tensin homolog deleted on chromosome 10 protein expression. Targeted decrease in NEDD4 expression may be a potential therapeutic strategy for tyrosine kinase inhibitor-resistant non-small-cell lung cancer.