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Chen-Lin Yu,1,2,* Hsiang-Lin Lee,3,4,* Shun-Fa Yang,2,5 Shih-Wei Wang,1,6 Ching-Pin Lin,4,7 Yi-Hsien Hsieh,2,5 Hui-Ling Chiou8,9 1Institute of Biomedical Science, Mackay Medical College, New Taipei City, Taiwan; 2Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 3Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan; 4School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 5Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 6Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Division of Hepatology and Gastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 8School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan; 9Department of Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Yi-Hsien Hsieh; Hui-Ling Chiou, Tel +886-4-2473-0022, Fax +886-4- 2472-3229, Email hyhsien@csmu.edu.tw; hlchiou@csmu.edu.twObjective: Protodioscin (PD), a steroidal saponin, has a diverse pharmacological activity including neuroprotection, male fertility improvement, and cytotoxicity against various cancers cell lines of different origins. However, the effect of PD on hepatocellular carcinoma (HCC) is still unclear.Methods: Cell viability, colony formation and flow cytometry analysis for apoptosis profile, mitochondrial membrane potential endoplasmic reticulum (ER) expansion were employed to determine the effect of PD against HCC cells. Transient transfection of siRNA, immunofluorescent imaging and immunoprecipitation were used to elucidate the anti-cancer mechanism of PD. The in vivo toxicity and efficacy of PD were assessed by a xenograft mouse model.Results: PD induced apoptosis, loss of mitochondrial membrane potential and ER expansion in HCC cells. Either downregulation of Mfn1 or Bak reversed PD-induced apoptosis and loss of mitochondrial membrane potential. Further analysis revealed that Mfn1 and Bak will form a complex with IP3R to facilitate the transfer of Ca2+ from ER to mitochondria and apoptosis. In addition, our tumour xenograft model further verifies the in vivo anti-tumour effect of PD.Conclusion: Our study sheds light on the understanding of the anti-HCC effects of PD and may open new aspects for the development of novel treatment for human hepatocellular carcinoma.Graphical Abstract: Keywords: hepatocellular carcinoma, protodioscin, mitochondrial, apoptosis, endoplasmic reticulum

Chi-Ho Chan,1 Shun-Fa Yang,2,3 Han-Wei Yeh,4 Ying-Tung Yeh,5–7 Yu-Hsun Wang,2 Ying-Hock Teng,8,9 Chao-Bin Yeh8,9 1Department of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 2Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China; 3Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 4School of Medicine, Chang Gung University, Taoyuan City, Taiwan, Republic of China; 5Graduate School of Dentistry, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 6School of Dentistry, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 7Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China; 8Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China; 9Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China Background: Burns are the main cause of accidental injury, and pneumonia is a common respiratory disease in humans.Aim: The purpose of this study was to investigate the relationship between burn injury and pneumonia.Patients and methods: A nationwide population-based cohort study was conducted using data from the National Health Insurance Research Database in Taiwan. We identified and enrolled 2,893 subjects with burn injury, who were individually matched to 2,893 subjects in the comparison group by using the propensity score. Furthermore, we used a self-controlled case-series design to estimate the temporal association between burn injury and pneumonia.Results: Exposure to burn injury revealed a higher risk of pneumonia than that to non-burn injury within 1 year. The Cox proportional hazards model revealed that, compared with the non-burn injury, burn injury yielded a 2.39-fold (95% CI=1.44–3.96) increase in risk of pneumonia. The exposure period of burn injury within 30 days showed 2.76-fold increase in risk of pneumonia (95% CI=1.44–3.96) compared with that in the baseline period.Conclusion: Burn injury was associated with a significant increased risk of pneumonia, especially occurring within 30 days. Keywords: burn injury, pneumonia, odds ratio

Chun-Bing Chen,1–6 Ming-Ying Wu,1–4 Chau Yee Ng,1–5 Chun-Wei Lu,1–6 Jennifer Wu,1–4,6 Pei-Han Kao,1–4,6 Chan-Keng Yang,4–7 Meng-Ting Peng,4,6–7 Chen-Yang Huang,4,6–7 Wen-Cheng Chang,4,6–7 Rosaline Chung-Yee Hui,1–4 Chih-Hsun Yang,1–4 Shun-Fa Yang,8,9 Wen-Hung Chung,1–4,6,10,11 Shih-Chi Su1–4,10 1Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; 2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan; 3Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan; 4College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; 7Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan; 8Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; 9Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan; 10Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; 11Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China Abstract: With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5–91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management. Keywords: acute generalized exanthematous pustulosis, drug rash, eosinophilia, Stevens–Johnson syndrome, toxic epidermal necrolysis, targeted therapy, immunotherapy