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Resistance to platinum-based chemotherapy becomes a major obstacle in non-small-cell lung cancer (NSCLC) treatment. Overexpression of the excision repair cross-complementing 1 (ERCC1) gene is reported to negatively influence the effectiveness of cisplatin-based therapy for NSCLC cells. In this study, we confirm that high ERCC1 expression correlates with cisplatin resistance in NSCLC cells. Importantly, histone deacetylase inhibitors (HDACis) re-sensitize ERCC1-high NSCLC cells to cisplatin both in vitro and in vivo. Mechanistically, the HDACi induces the expression of miR-149 by acetylation and activation of E2F1, which directly targets ERCC1 and inhibits ERCC1 expression. Inhibition of miR-149 reverses the promotion effect of HDACis on cisplatin-induced DNA damage and cell apoptosis in ERCC1-high NSCLC cells. In conclusion, this study reveals a novel mechanism by which HDACis re-sensitizes ERCC1-high NSCLC cells to cisplatin via regulation of the E2F1/miR-149/ERCC1 axis, and we propose that combination of HDACis and cisplatin might hold promise to be a more effective therapeutic paradigm for ERCC1-high NSCLCs., Graphical Abstract, Overexpression of ERCC1 is reported to negatively influence the effectiveness of cisplatin-based therapy for NSCLC cells. Liu and colleagues demonstrate that HDACis could re-sensitize ERCC1-high NSCLC cells to cisplatin via regulation of the E2F1/miR-149/ERCC1 axis, and they propose that the combination of HDACis and cisplatin might hold promise to be a more effective therapeutic strategy for ERCC1-high NSCLCs.

BACKGROUND Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in China and has caused serious affect to health and life quality. However, the status stage of a patient is difficult to be accurately assessed because of dynamic changes in the condition and complex risk factors. A rapid and accurate methods to predict disease stage of COPD patients is of great significance. OBJECTIVE This study aims to explore an enhanced recurrent convolutional neural networks model for predicting correct staging of patients with COPD in China for assistant disease prevention and treatment. METHODS Data was collected from The First Affiliate Hospital of Guangzhou Medical University, which had standardized disease registration and follow-up management for 5108 patients with COPD. Our enhanced recurrent convolutional neural network consists of a bidirectional LSTM layer, a convolutional layer, a max-pooling layer, and an output layer. RESULTS The model proposed was evaluated on the real-world clinical dataset of 5108 COPD patients to predict the state stage of the disease. The performance of the proposed model achieved 93.2% in terms of accuracy, outperforming a list of baseline models. CONCLUSIONS This paper proposes an enhanced recurrent convolutional neural network model which is experimented on a real-world clinical dataset containing around 5,000 patients with COPD. The proposed model achieves the best performance on all evaluation metrics indicating its feasibility in predicting the state stage of diseases.

Objective To explore the pharmacodynamic (PD) characteristics of propofol during anesthetic recovery period with target-controlled infusion (TCI), and to identify the clinical variables related to the PD parameters. Materials and methods 20 patients scheduled for otolaryngology surgery were enrolled. After the surgery was finished, target effect site concentration was gradually decreased, blood samples were measured at 7 time points and the differences between the target and measured plasma concentration were compared. Observer's assessment of alertness/sedation (OAA/S) and Narcotrend index (NI) were used as two PD indicators by fitting sigmoid Emax model. Correlations between PD parameter and clinical variables were evaluated. Results Performance of the TCI system showed a positive bias at the end of the anesthesia sedation period and a negative bias in the anesthetic recovery period. PD parameters (EC50, r) calculated with OAA/S and NI were significantly different, EC50 of OAA/S was lower than EC50 of NI (1.53 ± 0.70 vs. 2.16 ± 0.99 µg/mL), r of OAA/S was higher than r of NI (57.07 ± 56.39 vs. 4.35 ± 4.42). Propofol dosage and hemodynamic parameters were significantly correlated with EC50 (OAA/S), lean body weight and gender were significantly correlated with EC50 (NI). Conclusion NI provided a more stable and adequate assessment of the depth of anesthesia than OAA/S, and the influence factors should be taken into account for precise dosing.

Recent studies have illuminated that blocking Ca2+ influx into effector cells is an attractive therapeutic strategy for lung injury. We hypothesize that T-type calcium channel may be a potential therapeutic target for acute lung injury (ALI). In this study, the pharmacological activity of mibefradil (a classical T-type calcium channel inhibitor) was assessed in a mouse model of lipopolysaccharide- (LPS-) induced ALI. In LPS challenged mice, mibefradil (20 and 40 mg/kg) dramatically decreased the total cell number, as well as the productions of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Mibefradil also suppressed total protein concentration in BALF, attenuated Evans blue extravasation, MPO activity, and NF-κB activation in lung tissue. Furthermore, flunarizine, a widely prescripted antimigraine agent with potent inhibition on T-type channel, was also found to protect mice against lung injury. These data demonstrated that T-type calcium channel inhibitors may be beneficial for treating acute lung injury. The important role of T-type calcium channel in the acute lung injury is encouraged to be further investigated.

Platinum-based drugs, particularly cisplatin (DDP), are used in the treatment of non-small cell lung cancer (NSCLC). However, development of drug resistance remains the major therapeutic barrier in NSCLC. The potential cisplatin resistance-related genes were identified from the global transcriptomes of cisplatin-resistant A549/DDP cells using microarray analysis. Gain- and loss-of-function assays were performed to analyze the effects of Forkhead Box Protein C2 (FOXC2) on the in vitro and in vivo sensitivity of NSCLC cells to cisplatin and its possible molecular mechanisms. Using global transcriptome analysis, we found that FOXC2 was one of the most upregulated molecules in A549/DDP cells compared with A549 cells. We further confirmed that the expression of FOXC2 was significantly increased in cisplatin-resistant NSCLC tissues. FOXC2 knockdown significantly increased the in vitro and in vivo sensitivity of A549/DDP cells to cisplatin, whereas overexpression of FOXC2 increased cisplatin resistance in cisplatin-sensitive NSCLC cells. Moreover, we found that FOXC2 promoted cisplatin resistance by induction of epithelial–mesenchymal transition (EMT) in NSCLC cells. Furthermore, FOXC2 activated the AKT/GSK3β signaling pathway, and then increased the protein expression of EMT-related transcription factor Snail. Inhibition of AKT or knockdown of Snail reversed FOXC2-induced EMT and cisplatin resistance of NSCLC cells. FOXC2 enhanced cisplatin resistance of NSCLC cells through activating AKT/GSK3β/Snail/EMT signaling pathway, which may be a potential novel therapeutic target for overcoming drug resistance in human NSCLCs.

Drug compliance is critical for patients with chronic diseases such as diabetes. In our continuous effort to find better glucose-lowering agents, an exploration for long-acting DPP-4 inhibitors had been launched. Based on our previously reported compounds bearing a pyrrolopyrimidine scaffold, the lead compound 4a (IC50 = 2.3 nM, t1/2(rat) = 5.46 h) with pharmacokinetic superiority was rapidly determined. Further SAR study indicated that the pyrrole ring was generally tolerable for variation, in which a β-substitution gave a better DPP-4 affinity. In depth evaluation of the pyrrole ring β position identified a highly potent compound 12a (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). In vivo pharmacodynamics tests demonstrated similar or even slightly better sustained DPP-4 inhibition for compounds 4a and 12a compared with the first marketed once-weekly drug trelagliptin in this category, indicating that improvements to DPP-4 inhibitory activity or pharmacokinetic profile might be feasible ways to rapidly generate long-acting DPP-4 inhibitors.