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Wei-Fan Ou,1 Pei-Ya Liao,1 Yu-Wei Hsu,2,3 Yen-Hsiang Huang,1,4– 6 Kuo-Hsuan Hsu,6,7 Jeng-Sen Tseng,1,4– 6,8 Gee-Chen Chang,4,9– 11 Tsung-Ying Yang1,6,12 1Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 2Cancer Prevention and Control Center, Taichung Veterans General Hospital, Taichung, Taiwan; 3Computer and Communications Center, Taichung Veterans General Hospital, Taichung, Taiwan; 4Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; 5College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 6Lung Cancer Comprehensive Care and Research Center, Taichung Veterans General Hospital, Taichung, Taiwan; 7Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 8Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 9Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 10School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 11Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 12Department of Life Sciences, National Chung Hsing University, Taichung, TaiwanCorrespondence: Jeng-Sen Tseng, Lung Cancer Comprehensive Care and Research Center, Taichung Veterans General Hospital, No. 1650, Sect. 4, Taiwan Boulevard, Taichung, 407, Taiwan, Tel +886-4-23592525 ext. 3232, Fax +886-4-23741320, Email tzeng64@gmail.comBackground: Antiangiogenetic therapy and lung cancer, per se, are associated with an increased risk of thromboembolic events (TE). We aim to evaluate the pattern and outcome of TE as well as its influence on survival time of advanced non-small cell lung cancer (NSCLC) patients receiving antiangiogenic therapy.Methods: This was a retrospective cohort study, which included advanced NSCLC patients receiving antiangiogenic therapy. All TE were confirmed by objective image studies. We disclosed the presentation and risk factors of TE and evaluated its influence on outcome.Results: A total of 427 patients were included. TE occurred in 43 patients (10.1%). Deep vein thrombosis (DVT) was the most common TE (n = 20). Up to 46.2% of DVT did not occur in the typical lower extremities. Two patients died of TE. Among patients with continuous use or reuse of antiangiogenetic therapy, 18.2% had recurrent TE events. At the occurrence of TE, 28 patients experienced progressive disease (TE with PD), while tumor status remained stable in another 15 patients (TE without PD). The post-TE survival of patients without and with PD were 8.9 months (95% CI 3.9– 13.9) vs 2.2 months (95% CI 0.1– 4.3), P = 0.012. As compared with patients without TE (31.4 months [95% CI 27.1– 35.7]), TE with PD patients experienced a significantly shorter overall survival (20.1 months [95% CI 15.5– 24.6]), but TE without PD patients had comparable survival time (32.7 months [95% CI 7.4– 28.1]) (P = 0006). The use of hormone analogue and proteinuria predicted the events among TE with PD group (aOR 2.79 [95% CI 1.13=6.92]; P = 0.027) and TE without PD group (aOR 4.30 [95% CI 1.13– 16.42]; P = 0.033), respectively.Conclusion: Owing to the different risk factors and influences on the survival time, TE with and without PD may be two different disease entities.Keywords: non-small cell lung cancer, NSCLC, antiangiogenesis, bevacizumab, ramucirumab, thromboembolism

Ming-Yang Lee,1–3 Ming-Fang Wu,4,5 Shur-Hueih Cherng,6 Ling-Yen Chiu,7 Tsung-Ying Yang,8,9 Gwo-Tarng Sheu5,7,10 1Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City, Taiwan; 2Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Chiayi City, Taiwan; 3Graduate Institute of Natural Healing Science, Nanhua University, Chiayi City, Taiwan; 4School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 5Divisions of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 6Department of Biotechnology, Hung Kuang University, Taichung, Taiwan; 7Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 8Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 9Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 10Immunology Research Center, Chung Shan Medical University, Taichung, Taiwan Purpose: Tissue transglutaminase 2 (TG2) is a stress-regulated protein and associated with cancer cell survival. However, the effects of TG2 expression in human non-small-cell lung cancer (NSCLC) cells on reactive oxygen species (ROS) production and redox homeostasis have not been fully elucidated.Materials and methods: We investigated the TG2 expression and activity in A549, H1299, H1355, and H460 lung cancer cells by Western blots and quantitative polymerase chain reaction assay. The enzyme-linked immunosorbent assay was used for transglutaminase activity. The epigenetic expression was characterized with histone deacetylase inhibitor trichostatin A and DNA methyltransferase inhibitor 5-Aza treatment. TG2 expression was inhibited by siRNA transfection and the intracellular calcium was measured by Flow-3AM assay, apoptosis was analyzed by Annexin V/propidium iodide assay, and intracellular ROS was detected by fluorescence-activated cell sorting analysis. The ROS scavenger N-acetyl-L-cysteine (NAC) was applied to reduce TG2-knockdown-induced oxidative stress.Results: Only A549 cells expressing high levels of TG2 correlated with high TG2 activity. The expression of TG2 can be regulated by epigenetic regulation in A549, H1299, and H1355 cells. The data also show that TG2 reduction induces apoptosis in A549 and H1299 cells. Furthermore, increased intracellular ROS and calcium levels were both detected in TG2-reduced cells. Moreover, endoplasmic reticulum stress inhibitor (salubrinal) and antioxidant NAC were able to reduce ROS and calcium levels to recover cell viability. Interestingly, the extrinsic and intrinsic apoptosis pathways were activated with a p53 independence upon TG2 reduction. TG2 reduction not only attenuated AKT activation but also reduced superoxide dismutase 2 (SOD2) expression. Exogenous NAC partially recovered SOD2 expression, indicating that mitochondrial-mediated apoptosis accounts for a part of but not all of the TG2-reduction-related death.Conclusion: TG2 plays a protection role in NSCLC cell lines. Regardless of the endogenous level of TG2 and p53 status, reduction of TG2 may result in oxidative stress that induces apoptosis. Therefore, target TG2 expression represents a logical strategy for NSCLC management. Keywords: caspases, oxidative stress, redox homeostasis, NAC, AKT, SOD2