The integrated stress response (ISR) pathway is essential for adaption of various stresses and is related to mitochondrion-to-nucleus communication. Mitochondrial dysfunction-induced reactive oxygen species (ROS) was demonstrated to activate general control nonderepressible 2 (GCN2)–eukaryotic translation initiation factor 2α (eIF2α)–activating transcription factor-4 (ATF4) pathway-mediated cisplatin resistance of human gastric cancer cells. However, whether or how ISR activation per se could enhance chemoresistance remains unclear. In this study, we used eIF2α phosphatase inhibitor salubrinal to activate the ISR pathway and found that salubrinal reduced susceptibility to cisplatin. Moreover, salubrinal up-regulated ATF4-modulated gene expression, and knockdown of ATF4 attenuated salubrinal-induced drug resistance, suggesting that ATF4-modulated genes contribute to the process. The ATF4-modulated genes, xCT (a cystine/glutamate anti-transporter), tribbles-related protein 3 (TRB3), heme oxygenase 1 (HO-1), and phosphoenolpyruvate carboxykinase 2 (PCK2), were associated with a poorer prognosis for gastric cancer patients. By silencing individual genes, we found that xCT, but not TRB3, HO-1, or PCK2, is responsible for salubrinal-induced cisplatin resistance. In addition, salubrinal increased intracellular glutathione (GSH) and decreased cisplatin-induced lipid peroxidation. Salubrinal-induced cisplatin resistance was attenuated by inhibition of xCT and GSH biosynthesis. In conclusion, our results suggest that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells.

The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs (gefitinib, erlotinib, and afatinib) combined with co-medications (metformin, statins, antacids, and steroids). Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm (log-rank test, P < 0.001). After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41–0.71) and erlotinib (HR 0.62, 95% CI 0.46–0.83). The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy (HR 1.47, 95% CI 1.08–2.01). Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure.

Background: Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated. Methods: The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells. Results: Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown–induced cell migration and invasion of gastric cancer cells. Conclusions: Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.

Background: Many female breast cancer (FBC) patients take Chinese herbal medicine (CHM) and Western medication (WM) concurrently in Taiwan. Despite the possibility of interactions between the CHM and WM mentioned in previous studies, the pattern of these coprescriptions in FBC patients remains unclear. Hence, the aim of the present study is to investigate the utilization of coprescriptions of CHM and WM among the FBC patients in Taiwan. Methods: The study was a cross-sectional survey using the sampled cohort in 2009 obtained from the National Health Insurance Research Database in Taiwan. There were 3,507 FBC patients identified from the registry for catastrophic illness patients. Ambulatory visit records, corresponding prescriptions, and the data of beneficiaries belonging to the FBC patients were further extracted. A total of 1,086 FBC patients used CHM at least once. CHM and WM prescribed within any overlapping duration were defined as coprescriptions. Results: There were 868 (80.0%) patients simultaneously receiving CHM and WM. A total of 4,927 CHM prescriptions and 6,358 WM prescriptions were prescribed concurrently. Among these coprescriptions, the most frequently used CHM was jia-wei-xiao-yao-san (21.2%), and the most frequently coprescribed WM was acetaminophen (38.9%), followed by tamoxifen (25.5%). There were 346 patients using systemic adjuvant therapy and CHM concurrently. The most commonly coprescribed CHM with chemotherapy, endocrine therapy, and trastuzumab was xiang-sha-liu-jun-zi-tang, jia-wei-xiao-yao-san, and zhi-gan-cao-tang, respectively. Conclusion: The combined use of CHM with WM is prevalent. The main purpose of combining CHM with systemic cancer treatment is to alleviate the treatment-related adverse effects. However, the combination may result in the potential risk of drug–herb interactions. Further clinical studies are needed to evaluate the efficacy and safety of the CHM and WM coprescriptions for FBC patients.

Objective: The effect of antacid therapy for patients with COPD and gastroesophageal reflux disease (GERD) remains unclear. Patients and methods: This nationwide population-based study was conducted using data from Taiwan’s National Health Insurance Research Database, and enrolled COPD patients with or without GERD. Patients with COPD who were not prescribed COPD medications were excluded. Patients with GERD who underwent upper gastrointestinal endoscopy or 24-hour pH monitoring and received at least 1 antacid were enrolled as symptomatic GERD group. The primary endpoint was acute exacerbation and mortality. Results: This study included 3,485 patients with COPD and symptomatic GERD, and 13,938 patients with COPD alone and covered 12,806.57 and 56,809.78 person-years, respectively, from 2000 to 2011. After multivariate adjustment, symptomatic GERD was associated with acute exacerbation (adjusted hazard ratio [HR]: 1.35, 95% CI: 1.23–1.48, p<0.0001) and mortality (HR: 1.42, 95% CI: 1.25–1.61, p<0.0001). In the COPD with symptomatic GERD group, use of proton pump inhibitors was associated with a lower risk of acute exacerbation and mortality (acute exacerbation, HR 0.31, 95% CI: 0.20–0.50, p<0.0001; mortality, HR 0.36, 95% CI: 0.20–0.65, p=0.0007), whereas no significant benefit was observed for histamine2-receptor antagonists. Conclusion: Use of proton pump inhibitors was associated with a lower risk of acute exacerbation and mortality in the patients with COPD and symptomatic GERD.