Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

Sarcoidosis has significant heterogeneity involving multiple organs; treatment of the disease is a significant therapeutic challenge due to the difficulties in accurately monitoring disease activity and estimating prognosis. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) plays an important role in assessing the metabolic activity. However, there is not enough evidence about the influence of this method in the clinical management and prognosis prediction for sarcoidosis. This study aims to investigate the clinical utility of ¹⁸F-FDG PET/CT for therapeutic evaluation and prognostic prediction in sarcoidosis. We had retrospectively enrolled 23 patients with sarcoidosis assigned to receive systemic glucocorticoids. All patients underwent baseline ¹⁸F-FDG PET/CT before initiating therapy and follow-up ¹⁸F-FDG PET/CT within 3 months after the therapy. The metabolic and clinical responses were classified. The baseline ¹⁸F-FDG PET/CT showed increased uptake in all patients. Based solely on biopsy-proven sites, the sensitivity of ¹⁸F-FDG PET/CT was 91.7%, and the sensitivity improved to 100% after excluding skin involvement. In the subsequent follow-up PET scans within 3 months after glucocorticoids therapy, the SUVmax were variously decreased except one; there are significant differences in the clinical remission rates and the relapse rates between patients with a favorable response and cases with no response on follow-up PET scan, the increasing metabolic response was associated with the increase in clinical remission rates and the reduction in recurrence rates. In conclusion, the present study shows that ¹⁸F-FDG PET/CT is an effective way to monitor the early therapeutic reaction and is helpful in predicting the long-term prognosis of sarcoidosis.

This study aims to carry out a high-temperature exposure assessment for graphene oxide (GO) reinforced cement in terms of weight loss, flexural strength, and compressive strength. Different additive amounts of GO in cement are experimentally studied to unfold its effect on enhancing the mechanical performance of prepared GO reinforced cement. Temperatures are chosen as room temperature, 200, 400, 600, and 800°C, corresponding to different reaction status of cement. It is found that as the temperature increases, the water evaporates from the GO reinforced cement. Evaporated quantity of water relies on the reaction status, and the relation between weight loss and temperature is provided. Benefiting from the bonding effects of GO, hydrated calcium silicate hydrate (C–S–H) is chemically produced and, thus, a reticular bridging system, which is greatly helpful to enhance the flexural strength, is formed. Unlike flexural strength, adding GO into cement statistically has little effect on the compressive strength, except when the temperature rises up to 800°C due to the occurrence of decarburization from dehydration.

Autophagy and glycolysis are associated with osimertinib resistance. The energy complement and dynamic balance between these two processes make it difficult to block the process of drug resistance; breaking the complementary relationship between them may effectively overcome drug resistance. However, the exact mechanisms and the key players for regulating autophagy and glycolysis remain unclear. In this study, we demonstrate that autophagy and glycolysis levels in osimertinib-resistant cells were markedly higher than parental cells, and a dynamic balance existed between them. Inhibition of the class III phosphoinositide 3-kinase vacuolar protein sorting 34 (VPS34) with 3-methyladenine or small interfering RNA can not only inhibit abnormally enhanced autophagy but also inhibit glycolysis by inhibiting the location of epidermal growth factor receptor (EGFR) and the expression of hexokinase II. By demonstrating that VPS34 is the key player controlling autophagy and glycolysis simultaneously, our study may provide a new strategy for overcoming osimertinib resistance for treatment of EGFR-mutant non-small cell lung cancer patients.

Introduction: N‐acetylcysteine (NAC) prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, the value of NAC inhalation in the treatment of patients with AECOPD is still poorly understood. The study was conducted to evaluate the efficacy of NAC inhalation in AECOPD patients requiring hospitalization.Methods: In this single institutional, retrospective cohort study, all patients with AECOPD requiring hospitalization between January 2021 and January 2022 were included. Patients were divided into NAC group and Non‐NAC group according to whether being treated with NAC inhalation and were matched using the propensity score. The primary outcome was a composite of progression to ventilation requirement, in‐hospital mortality and readmission for AECOPD within 30 days. The effect on the mean hospitalized days, blood gas indexes and the incidence rate of adverse drug events were compared between the two groups.Results: Ninety‐six patients in the NAC group were matched with 96 patients in the Non‐NAC group. The differences in the primary composite end point (NAC group vs Non‐NAC group, 5.2% vs 16.7%; P = 0.011) were significant. The median time to discharge was shorter in the NAC group (8.3 vs. 9.1 days, P = 0.030). The NAC group presented a larger increase in partial pressure of arterial oxygen (P_aO₂) and a higher ratio of self‐reported symptomatic improvement from admission to day 5. There was no definite difference between the two groups in the frequency of adverse event.Conclusion: NAC inhalation is associated with an improved clinical outcome. A further study should be conducted to confirm the clinical usefulness of NAC inhalation in AECOPD patients.