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Chih-Hsun Wu,1,2 Wei-Han Chou,3 Yi-Hsun Long,2 Hao-Han Yang,1 Tung Lin,1 Chi-Cheng Yang,1,4 Wei-Zen Sun,3 Chih-Cheng Chen,5 Chih-Peng Lin3 1Department of Psychology, National Chengchi University, Taipei, Taiwan; 2Clinical Psychology Center, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Anesthesiology, National Taiwan University Hospital, Taipei, Taiwan; 4Holistic Mental Health Center, Taipei City Hospital, Taipei, Taiwan; 5Institute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanCorrespondence: Chih-Peng Lin, Department of Anesthesiology, National Taiwan University Hospital, 7 Chung Shan S. Road, Taipei, 100225, Taiwan, Tel +886 2 23123456 #262158, Fax +886 2 23415736, Email cplin0123@gmail.comPurpose: People with pain problems are highly vulnerable to cultural disparities, and it is imperative to reduce these inequalities. This cross-sectional study aimed to develop a culturally sensitive Chronic Pain Cognition Scale (CPCS) for Chinese-/Chinese dialect-speaking populations and investigate its psychometric properties.Patients and Methods: Adult patients with chronic low back pain or chronic neck pain who visited pain clinics at a medical center in northern Taiwan were enrolled. Participants completed the demographic, intensity of pain, and two other related sensations, “Sng (痠)” and “Ma (麻)”, often reported in Chinese-speaking populations, CPCS, Chronic Pain Acceptance Questionnaire-8, and Pain Self-Efficacy Questionnaire.Results: 200 patients were included. Patients’ mean age was 64.84 ± 14.33, 126 (63.0%) were female, and 83 (41.5%) had 13+ years of education. The average duration of pain was 77.25 ± 97.46 months, the intensity of pain was 6.04 ± 2.50, Ma was 3.43 ± 3.24, and Sng was 4.54 ± 3.14. The CPCS comprised four factors: pain impact (how pain impact one’s life), losing face (how one being disrespected due to pain), helplessness, and avoidance, with good structural validity and adequate reliability (Cronbach α, 0.60– 0.81) and satisfactory criterion-related validity. Moreover, losing face, an essential concept in Chinese relationalism, was significantly related to pain, Sng, and Ma (r = 0.19, 0.15 and 0.16), but not to pain acceptance or self-efficacy, indicating a culturally specific element in pain measurement.Conclusion: The CPCS has good psychometric properties and is suitable for evaluating chronic pain in the clinical setting, and might be generalizable to other Chinese-/Chinese dialect-speaking populations.Keywords: low back pain, neck pain, pain impact, losing face, helplessness, avoidance

Je-Yang Jau,1 Terry BJ Kuo,1– 3 Lieber PH Li,1,4– 6 Tien-Yu Chen,1,7 Ying-Shuo Hsu,1,8,9 Chun-Ting Lai,1,2 Weng-Cheu Yue,10 Pin-Hsuan Huang,11 Cheryl CH Yang1,2,4,12,13 1Institute of Brain Science, National Yang-Ming Chiao-Tung University, Taipei, Taiwan; 2Sleep Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; 3Tsoutun Psychiatric Center, Ministry of Health and Welfare, Nantou, Taiwan; 4Department of Otolaryngology, Cheng Hsin General Hospital, Taipei, Taiwan; 5Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; 6Department of Speech Language Pathology and Audiology, College of Health Technology, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; 7Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 8Department of Otolaryngology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 9School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 10DP Dental, Singapore; 11Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan; 12Department of Education and Research, Taipei City Hospital, Taipei, Taiwan; 13Brain Research Center, National Yang Ming Chiao Tung University, Taipei, TaiwanCorrespondence: Cheryl CH Yang, Institute of Brain Science, National Yang-Ming Chiao-Tung University, No. 155, Sec. 2, Li-Nong St., Beitou, Taipei, 11221, Taiwan, Tel +886-2-28267058, Fax +886-2-28273123, Email cchyang@ym.edu.tw Lieber PH Li, Department of Otolaryngology, Cheng Hsin General Hospital, No. 45, Cheng Hsin St., Beitou, Taipei, 11221, Taiwan, Tel +886-2-28264400, Email lieber.chgh@gmail.comPurpose: This study aimed to investigate (1) the role of mouth puffing phenomenon and upper airway features in obstructive sleep apnea (OSA) and (2) whether mouth-taping during sleep alleviated the severity of OSA.Participants and Methods: Seventy-one participants underwent a two-night home sleep test (the first day sleeping normally; the second day sleeping with their mouths being taped); their oximetry desaturation index (ODI) and mouth puffing signals (non-mouth puffing, complete mouth puffing, intermittent mouth puffing (IMP), and side mouth puffing) were detected by a validated fingertip pulse oximeter and a mouth puffing detector. The participants were grouped into the ODI-improved group and the ODI-not-improved group according to their sleeping test results. The radiograph was taken by cone-beam computed tomography and cephalometries. Upper airway features including airways, soft tissues, and oral cavity variables were measured.Results: Participants with severe OSA showed a higher IMP percentage compared with those with normal, mild, and moderate OSA (severe: 33.78%, moderate: 22.38%, mild: 14.55%, normal: 0.31%, p < 0.001). In all participants, the ODI and the percentage of SpO2 under 90 (T90) were positively related to body mass index (BMI) (r = 0.310 and 0.333, respectively), while ODI and T90 were negatively correlated with the minimum width of the airway (r = − 0.473 and − 0.474, respectively); all mentioned relationships were significant (p < 0.05).Conclusion: IMP proportions were found to be higher in the half of participants whose ODI did not improve after mouth-taping and in those with severe OSA. Moreover, OSA patients with higher ODI, higher T90, and higher proportions of IMP were more likely to have a narrower upper airway.Keywords: mouth breathing, mouth puffing, sleep phenomena, oximeter, sleep apnea, accelerometer

Tanavij Pannoi,1,2 Chissanupong Promchai,3 Penjamaporn Apiromruck,3 Suwikran Wongpraphairot,4 Chen-Chang Yang,1,5,6 Wen-Chi Pan1,5 1International Health Program, Institute of Public Health, National Yang Ming Chiao Tung University, Taipei City, Taiwan; 2Department of Pharmaceutical Care, School of Pharmacy, Walailak University, Nakhon-Si-Thammarat, Thailand; 3Department of Pharmacy, Songklanagarind Hospital, Prince of Songkla University, Songkla, Thailand; 4Department of Nephrology Unit, Songklanagarind Hospital, Prince of Songkla University, Songkla, Thailand; 5Institute of Environmental and Occupational Health Sciences, National Yang Ming Chiao Tung University, Taipei City, Taiwan; 6Department of Occupational Medicine and Clinical Toxicology, Taipei Veteran General Hospital, Taipei City, TaiwanCorrespondence: Wen-Chi Pan, Institute of Environmental and Occupational Health Sciences, National Yang Ming Chiao Tung University, No. 155, Sec.2, Li-Nong St, Taipei City, 11221, Taiwan, Tel +886-228-267-000 &num;67057, Fax +886-2-28218165, Email wenchipan@nycu.edu.twPurpose: Potential adverse outcomes of Proton pump inhibitors (PPIs) have increasingly been reported. The potential risks to PPIs include hypomagnesemia and chronic kidney disease (CKD). Unlike a real-world electronic medical record (RW-EMR) with active-comparator design, claim databases and special population cohort with non-user design, using in previous studies, resulted in a wide range of strength of association with indication bias. This study aimed to measure the total effect of association between PPIs use and CKD incidence using Thai RW-EMR.Patients and Methods: A retrospective hospital-based cohort was applied into this study. Electronic medical records and administrative data of out- and inpatient were retrieved from October 1st, 2010 to September 30th, 2017. On-treatment with grace period as well as propensity score matching was used in data analysis. Cox proportional hazard models were applied to evaluate the PPIs-CKD association.Results: Of all 63,595 participants, a total of 59,477 new PPIs and 4118 Histamine 2-receptor antagonist (H2RA) users were eligible for follow-up. As compared with H2RA, the PPI users were non-elderly and more likely being female. The association of PPIs with CKD was statistically significant (adjusted hazard ratio [HR] = 3.753, 95% CI = 2.385– 5.905). The HR were not statistically different by concomitant use PPIs with NSAIDs and by medication possession ratio levels.Conclusion: The association between PPIs and CKD incidence was statistically significant in this hospital-based cohort. However, self-treatment with over-the-counter PPIs, as well as, smoking, drinking alcohol and body mass index could not be fully retrieved, affecting the estimation of treatment effect.Keywords: proton-pump inhibitors, chronic kidney disease, retrospective cohort, hospital-based medical database

Chia-Lin Chou,1,2 Tzu-Ju Chen,1,3– 5 Wan-Shan Li,1,3,5 Sung-Wei Lee,6 Ching-Chieh Yang,7,8 Yu-Feng Tian,2 Cheng-Yi Lin,9 Hong-Lin He,10 Hung-Chang Wu,8,11 Yow-Ling Shiue,5,12 Chien-Feng Li,12– 14 Yu-Hsuan Kuo5,8,11,12 1Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan; 2Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan; 3Department of Pathology, Chi Mei Medical Center, Tainan, 710, Taiwan; 4Department of Clinical Pathology, Chi Mei Medical Center, Tainan, 710, Taiwan; 5Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan; 6Department of Radiation Oncology, Chi Mei Medical Center, Liouying, 736, Taiwan; 7Department of Radiation Oncology, Chi Mei Medical Center, Tainan, 710, Taiwan; 8College of Pharmacy and Science, Chia Nan University, Tainan, Taiwan; 9Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, 710, Taiwan; 10Department of Pathology, E-DA Hospital & E-DA Cancer Hospital, I-Shou University, Kaohsiung, 82445, Taiwan; 11Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan; 12Institute of Precision Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan; 13Department of Medical Research, Chi Mei Medical Center, Tainan, 710, Taiwan; 14National Institute of Cancer Research, National Health Research Institutes, Miaoli County, 35053, TaiwanCorrespondence: Yu-Hsuan Kuo; Chien-Feng Li, No. 901, Zhonghua Road Yongkang Dist, Tainan City, Taiwan, Tel +886-6-2812811, Fax +886-6-2510218 ; Fax +886-6-2510218, Email beethovan@gmail.com; angelo.p@yahoo.com.twPurpose: For locally advanced rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) allows tumor downstaging and makes curative radical proctectomy possible. However, we lack a genetic biomarker to predict cancer prognosis or treatment response. We investigated the association between ubiquitin D (UBD) expression and clinical outcomes in rectal cancer patients receiving CCRT.Patients and Methods: We analyzed the genes associated with the protein modification process (GO:0036211) and identified the UBD gene as the most relevant among the top 7 differentially expressed genes associated with CCRT resistance. We collected tissue specimens from 172 rectal cancer patients who had received CCRT followed by a curative proctectomy. We examine the relationship between UBD expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MeFS) and disease-specific survival.Results: Upregulated UBD expression was associated with lower pre-CCRT tumor T stage (P = 0.009), lower post-CCRT tumor T stage (P < 0.001), lower post-CCRT nodal stage (P < 0.001), less vascular invasion (P = 0.015), and better tumor regression (P < 0.001). Using univariate analysis, we found that high UBD expression was correlated with better disease-free survival (DFS) (P < 0.0001), local recurrence-free survival (LRFS) (P < 0.0001) and MeFS (P < 0.0001). Moreover, multivariate analysis demonstrated that high UBD expression was associated with superior DFS (P < 0.001), LRFS (P = 0.01), and MeFS (P = 0.004).Conclusion: UBD upregulation was linked to better clinical prognosis, favorable pathological features, and good treatment response in rectal cancer patients undergoing CCRT. These results suggest UBD is a biomarker for rectal cancer.Keywords: ubiquitin D, UBD, FAT10, rectal cancer, concurrent chemoradiotherapy

Chun-Cheng Yang,1,&ast; Guang-Xiao Meng,1,&ast; Zhao-Ru Dong,1,&ast; Tao Li1,2 1Department of General Surgery, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 2Department of Hepatobiliary Surgery, The Second Hospital of Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Li Tel +86-531-82166651Email litao7706@163.comAbstract: The Rab GTPase family contains almost 70 genes in the human genome and acts as the key regulator of intracellular membrane trafficking in human cells. The dysregulation of Rab GTPase has been shown to be associated with multiple human diseases, ranging from neurodegeneration, and infection to cancer. Rab GTPases not only play important roles in genome replication, morphogenesis and the release of hepatitis B virus (HBV) or hepatitis C virus (HCV), but also contribute to hepatitis-related hepatocarcinogenesis and hepatocellular carcinoma (HCC) progression. The alteration of Rab GTPase expression in HCC plays an important role in tumour cell proliferation, invasion and migration. Notably, the expression of Rab genes can be regulated by some noncoding RNAs, such as miRNAs and circRNAs. Thus, Rab GTPases can serve as promising rational and therapeutic targets for HCC treatments. In this review, we summarized recent advancements in this field focusing on Rab GTPases in HCC.Keywords: Rab GTPase, membrane trafficking, hepatocellular carcinoma, therapeutic target

Yu-Min Lin,1 Chia-Lin Chou,2,3 Yu-Hsuan Kuo,4,5 Hung-Chang Wu,4,6 Chia-Jen Tsai,7 Chung-Han Ho,8,9 Yi-Chen Chen,8 Ching-Chieh Yang,6,7,&ast; Cheng‐Wei Lin10– 12,&ast; 1Division of Hepatogastroenterology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; 2Division of Colorectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan; 3Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan; 4Division of Hematology and Oncology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; 5Department of Cosmetic Science, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan; 6Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan; 7Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan; 8Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan; 9Department of Information Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan; 10Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 11Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; 12Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Chieh YangDepartment of Radiation Oncology Chi-Mei Medical Center, No. 901, Zhonghua Road, Yung Kang District, Tainan City, 701, Taiwan, Republic of ChinaTel +88662812811Email cleanclear0905@gmail.comCheng‐Wei LinDepartment of Biochemistry and Molecular Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu ‐ Xing Street, Taipei, 11031, Taiwan, Republic of ChinaEmail cwlin@tmu.edu.twPurpose: A lymph node (LN) yield ≥ 12 is required to for accurate determination of nodal status for colorectal cancer but cannot always be achieved after neoadjuvant therapy. This study aims to determine the difference in LN yield from rectal cancer patients treated with and without neoadjuvant therapy and the effects of specific LN yields on survival.Patients and Methods: The study cohort included a total of 4344 rectal cancer patients treated between January 2007 and December 2015, 2260 (52.03%) of whom received neoadjuvant therapy. Data were retrieved from the Taiwan nationwide cancer registry database. The minimum acceptable LN yield below 12 was investigated using the maximum area under the ROC curve.Results: The median LN yield was 12 (8– 17) for patients who received neoadjuvant therapy and 17 (13– 24) for those who did not. The recommended LN yield ≥ 12 was achieved in 82.73% of patients without and 57.96% of those with neoadjuvant therapy (p < 0.0001). Patients with LN yield ≥ 12 had a higher OS probability than did those with LN < 12 (OR, 1.33; 95% CI, 1.06– 1.66; p = 0.0124). However, the predictive accuracy for survival was greater for LN yield ≥ 10 (AUC, 0.7767) than cut-offs of 12, 8, or 6, especially in patients with pathologically-negative nodes (AUC, 0.7660).Conclusion: Neoadjuvant therapy significantly reduces the LN yield in subsequent surgery. A lower yield (LN ≥ 10) may be adequate for nodal evaluation in rectal cancer patients after neoadjuvant therapy.Keywords: rectal cancer, neoadjuvant therapy, lymph node yield, quality, survival

Chien-Chung Yang,1,2 Chuen-Mao Yang3– 5 1Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Kwei-San, Tao-Yuan, 33302, Taiwan; 2School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, 33302, Taiwan; 3Department of Pharmacology, College of Medicine, China Medical University, Taichung, 40402, Taiwan; 4Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, Taichung, 40402, Taiwan; 5Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University, Taichung, 41354, TaiwanCorrespondence: Chuen-Mao Yang No. 91, Hsueh-Shih Road, Taichung, 40402, TaiwanTel +886-4-22053366 (ext. 2229)Email chuenmao@mail.cmu.edu.twAbstract: Several pro-inflammatory factors and proteins have been characterized that are involved in the pathogenesis of inflammatory diseases, including acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, induced by oxidative stress, cytokines, bacterial toxins, and viruses. Reactive oxygen species (ROS) act as secondary messengers and are products of normal cellular metabolism. Under physiological conditions, ROS protect cells against oxidative stress through the maintenance of cellular redox homeostasis, which is important for proliferation, viability, cell activation, and organ function. However, overproduction of ROS is most frequently due to excessive stimulation of either the mitochondrial electron transport chain and xanthine oxidase or reduced nicotinamide adenine dinucleotide phosphate (NADPH) by pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor α. NADPH oxidase activation and ROS overproduction could further induce numerous inflammatory target proteins that are potentially mediated via Nox/ROS-related transcription factors triggered by various intracellular signaling pathways. Thus, oxidative stress is considered important in pulmonary inflammatory processes. Previous studies have demonstrated that redox signals can induce pulmonary inflammatory diseases. Thus, therapeutic strategies directly targeting oxidative stress may be effective for pulmonary inflammatory diseases. Therefore, drugs with anti-inflammatory and anti-oxidative properties may be beneficial to these diseases. Recent studies have suggested that traditional Chinese medicines, statins, and peroxisome proliferation-activated receptor agonists could modulate inflammation-related signaling processes and may be beneficial for pulmonary inflammatory diseases. In particular, several herbal medicines have attracted attention for the management of pulmonary inflammatory diseases. Therefore, we reviewed the pharmacological effects of these drugs to dissect how they induce host defense mechanisms against oxidative injury to combat pulmonary inflammation. Moreover, the cytotoxicity of oxidative stress and apoptotic cell death can be protected via the induction of HO-1 by these drugs. The main objective of this review is to focus on Chinese herbs and old drugs to develop anti-inflammatory drugs able to induce HO-1 expression for the management of pulmonary inflammatory diseases.Keywords: inflammatory mediators, tracheal smooth muscle cells, pulmonary alveolar epithelial cells, ROS, Nrf2, HO-1

Chien-Chung Yang,1,2 Li-Der Hsiao,3 Chuen-Mao Yang3– 5 1Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Kwei-San, Tao-Yuan 33302, Taiwan; 2School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan 33302, Taiwan; 3Department of Pharmacology, College of Medicine, China Medical University, Taichung 40402, Taiwan; 4Program for Biotch Pharmaceutical Industry, China Medical University, Taichung 40402, Taiwan; 5Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University, Wufeng, Taichung 41354, TaiwanCorrespondence: Chuen-Mao Yang Tel +886-4-22053366 (ext. 2229)Email chuenmao@mail.cmu.edu.twPurpose: Neuroinflammation, characterized by the increased expression of inflammatory proteins such as matrix metalloproteinases (MMPs), plays a critical role in neurodegenerative disorders. Lipopolysaccharide (LPS) has been shown to upregulate MMP-9 expression through the activation of various transcription factors, including activator protein 1 (AP-1) and forkhead box protein O1 (FoxO1). The flavonoid 3,5,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one (galangin) has been demonstrated to possess antioxidant and anti-inflammatory properties in various types of cells. Here, we investigated the mechanisms underlying the inhibitory effect of galangin on LPS-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells).Methods: Pharmacological inhibitors and siRNAs were employed to explore the effects of galangin on LPS-challenged RBA-1 cells. Gelatin zymography, Western blotting, real-time PCR, and a luciferase reporter assay were used to detect MMP-9 activity, protein expression, mRNA levels, and promoter activity, respectively. The protein kinases involved in the LPS-induced MMP-9 expression were determined by Western blot. A chromatin immunoprecipitation (ChIP) assay was employed to evaluate the activity of c-Jun at the MMP-9 promoter.Results: Galangin treatment attenuated the LPS-mediated induction of MMP-9 protein and mRNA expression, as well as the activity at the MMP-9 promoter. In addition, galangin exerted its inhibitory effects on MMP-9 expression through suppressing the LPS-stimulated activation of proline-rich tyrosine kinase (Pyk2), platelet-derived growth factor receptor beta (PDGFRβ), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), and mitogen-activated protein kinases (MAPKs). Pretreatment with galangin attenuated the LPS-induced phosphorylation of c-Jun and FoxO1. LPS-induced cell migration was also suppressed by galangin pretreatment.Conclusion: Galangin attenuates the LPS-induced inflammatory responses, including the induction of MMP-9 expression and cell migration, via inhibiting Pyk2/PDGFRβ/PI3K/Akt/mTOR/JNK1/JNK2 and p44/p42 MAPK cascade-dependent AP-1 and FoxO1 activities. These results provide new insights into the mechanisms through which galangin mitigates LPS-induced inflammatory responses, and suggest novel strategies for the management of LPS-related brain diseases.Keywords: neuroinflammation, astrocytes, LPS, matrix metalloproteinase, protein kinases, Chinese herbal medicine

Chien-Chung Yang,1,2 Li-Der Hsiao,3 Hui-Ching Tseng,3 Ching-Ming Kuo,3 Chuen-Mao Yang3,4 1Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Tao-Yuan 33302, Taiwan; 2School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan; 3Department of Pharmacology, College of Medicine, China Medical University, Taichung 40402, Taiwan; 4Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University, Taichung 41354, TaiwanCorrespondence: Chuen-Mao Yang Tel +886 4-22053366 (Ext. 2229)Email chuenmao@mail.cmu.edu.twPurpose: Neuroinflammation plays a crucial role in neurodegenerative diseases. Matrix metalloproteinases (MMPs) are a landmark of neuroinflammation. Lipopolysaccharide (LPS) has been demonstrated to induce MMP-9 expression. The mechanisms underlying LPS-induced MMP-9 expression have not been completely elucidated in astrocytes. Nuclear factor-kappaB (NF-κB) is well known as one of the crucial transcription factors in MMP-9 induction. Moreover, reactive oxygen species (ROS) could be an important mediator of neuroinflammation. Here, we differentiated whether ROS and NF-κB contributed to LPS-mediated MMP-9 expression in rat brain astrocytes (RBA-1). Besides, pristimerin has been revealed to possess antioxidant and anti-inflammatory effects. We also evaluated the effects of pristimerin on LPS-induced inflammatory responses.Methods: RBA-1 cells were used for analyses. Pharmacological inhibitors and siRNAs were used to evaluate the signaling pathway. Western blotting and gelatin zymography were conducted to evaluate protein and MMP-9 expression, respectively. Real-time PCR was for mRNA expression. Wound healing assay was for cell migration. 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate (H2DCF-DA) and dihydroethidium (DHE) staining were for ROS generation. Immunofluorescence staining was conducted to assess NF-κB p65. Promoter-reporter gene assay and chromatin immunoprecipitation (ChIP) assay were used to detect promoter activity and the association of nuclear proteins with the promoter.Results: Our results showed that the increased level of ROS generation was attenuated by edaravone (a ROS scavenger), apocynin (APO; an inhibitor of p47Phox), diphenyleneiodonium (DPI; an inhibitor of NOX), and pristimerin in RBA-1 cells exposed to LPS. Besides, pretreatment with APO, DPI, edaravone, Bay11-7082, and pristimerin also inhibited the phosphorylation, nuclear translocation, promoter binding activity of NF-κB p65 as well as upregulation of MMP-9 expression-mediated cell migration in RBA-1 cells challenged with LPS.Conclusion: These results suggested that LPS enhances the upregulation of MMP-9 through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)/ROS-dependent NF-κB activity. These results also provide new insights into the mechanisms by which pristimerin attenuates LPS-mediated MMP-9 expression and neuroinflammatory responses.Keywords: neuroinflammation, NOX, ROS, LPS, MMP-9, pristimerin, astrocytes

Chia-Lin Chou,1,2 Tzu-Ju Chen,2– 4 Cheng-Yi Lin,5 Sung-Wei Lee,6 Shih-Chang Wang,7 Shou-Sheng Chu,7 Ching-Chieh Yang7,8 1Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan; 2Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; 3Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan; 4Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan; 6Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 7Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan; 8Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, TaiwanCorrespondence: Ching-Chieh YangDepartment of Radiation Oncology, Chi-Mei Medical Center, No. 901 Zhonghua Road, Yung Kang District, Tainan City 701, TaiwanTel +88662812811-53501Email cleanclear0905@gmail.comBackground: In a data mining search for potential therapeutic targets to improve the outcome of rectal cancer, we identified PCSK1 as the cell–cell signaling gene most significantly associated with poor response to concurrent chemoradiotherapy (CCRT). This study aims to investigate the prognostic value of PCSK1 expression in rectal cancer patients who underwent neoadjuvant CCRT.Methods: Endoscopic biopsy specimens from 172 rectal cancer patients receiving neoadjuvant CCRT followed by curative surgery were assessed immunohistochemically for PCSK1 expression, and H-scores were determined. Expression levels of PCSK1 were further analyzed for correlations with clinicopathologic features, tumor regression grade, metastasis-free survival, disease-specific survival, and recurrence-free survival.Results: PCKS1 overexpression was significantly associated with pretreatment tumor status (T3– 4; p = 0.009), pretreatment nodal status (N1– 2; p < 0.001), posttreatment tumor status (T3– 4; p < 0.001), posttreatment nodal status (N1– 2; p < 0.001), vascular invasion (p = 0.003), and perineurial invasion (p = 0.023). PCKS1 overexpression was also found to be significantly associated with a lower degree of tumor regression (p < 0.001). In the univariate analysis, PCSK1 overexpression was significantly associated with lower disease-specific survival, metastasis-free survival, and recurrence-free survival (p < 0.005). PCSK1 overexpression remained an independent prognostic factor of lower disease-specific survival (p = 0.003; hazard ratio, 5.478) in the multivariate analysis.Conclusion: Determination of PCSK1 overexpression may be useful for identifying rectal cancer patients at risk for a poor response and worse survival after CCRT.Keywords: PCSK1, rectal cancer, chemoradiotherapy, response, survival

Chuan-Chi Yang,1,2 Wu-Chien Chien,3–5 Chi-Hsiang Chung,3,4,6 Yia-Ping Liu,2,7–9 Chin-Bin Yeh,2 Kuang-Huei Chen,1 Szu-Nian Yang,1,9,10 Hsin-An Chang,2,11 Yu-Chen Kao,2,12 Wan-Chun Lu,2 Nian-Sheng Tzeng2,11 1Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, ROC; 2Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC; 3Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC; 4School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC; 5Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC; 6Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC; 7Department of Psychiatry, Chen-Hsin General Hospital, Taipei, Taiwan, ROC; 8Institute of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC; 9Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC; 10Headquarters, Tri-Service General Hospital, Beitou Branch, National Defense Medical Center, Taipei, Taiwan, ROC; 11Student Counseling Center, National Defense Medical Center, Taipei, Taiwan, ROC; 12Department of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, National Defense Medical Center, Taipei, Taiwan, ROCCorrespondence: Nian-Sheng TzengDepartment of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, 325, Chung-Gung Road, Sec 2, Nei-Hu District 114, Taipei, Taiwan, ROCTel +886-2-87927299 ext 13674Email pierrens@mail.ndmctsgh.edu.twBackground: The associations between the human immunodeficiency virus (HIV) and dementias are as yet to be studied in Taiwan. The aim of this study is to clarify as to whether HIV infections are associated with the risk of dementia.Methods: A total of 1,261 HIV-infected patients and 3,783 controls (1:3) matched for age and sex were selected between January 1 and December 31, 2000 from Taiwan’s National Health Insurance Research Database (NHIRD). Fine and Gray’s survival analysis (competing with mortality) analyzed the risk of dementias during the 15-year follow up. The association between the highly active antiretroviral therapy (HAART) and dementia was analyzed by stratifying the HAART status among the HIV subjects.Results: During the follow-up period, 25 in the HIV group (N= 1,261) and 227 in the control group (N= 3,783) developed dementia (656.25 vs 913.15 per 100,000 person-years). Fine and Gray’s survival analysis revealed that the HIV patients were not associated with an increased risk of dementia, with the adjusted hazard ratio (HR) as 0.852 (95% confidence interval [CI]: 0.189–2.886, p=0.415) after adjusting for sex, age, comorbidities, geographical region, and the urbanization level of residence. There was no significant difference between the two groups of HIV-infected patients with or without HAART in the risk of dementia.Conclusion: This study found that HIV infections, either with or without HAART, were not associated with increased diagnoses of neurodegenerative dementias in patients older than 50 in Taiwan.Keywords: human immunodeficiency virus, highly active antiretroviral therapy, dementia, National Health Insurance Research Database, cohort study

Ting-Wen Chung,*,1 Chi-Chien Lin,2,3,* Shih-Chao Lin,4 Hong-Lin Chan,1 Ching-Chieh Yang5,61Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, Hsinchu 300, Taiwan; 2Institute of Biomedical Science, National Chung‑hsing University, Taichung 402, Taiwan; 3Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan; 4National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA; 5Department of Radiation Oncology, Chi-Mei Medical Center, Tainan 710, Taiwan; 6Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan*These authors contributed equally to this workBackground: Kurarinone, a prenylated flavonone isolated from the roots of Sophora flavescens, is known to be cytotoxic against many human cancer cells but not human small cell lung carcinoma (SCLC) yet. Also, the exact molecular mechanism of kurarinone for induction cytotoxicity remains unknown.Material and methods: We investigated the effects of kurarinone on cell proliferation, apoptosis, and migration in H1688 SCLC cells. Cell viability was determined by the MTT assay. Apoptotic indices such as cell cycle, mitochondrial membrane potential, cytochrome c release, caspase activity, and death receptors were evaluated by flow cytometry. Transwell migration and invasion assays were also included.Results: Our results indicated that kurarinone significantly decreased H1688 cell viability and induced the accumulation of sub-G1 fractions by activating caspase-3, -9, and PARP cleavage accompanied by the elevated release of cytochrome c and mitochondrial dysfunction in H1688 cells. Additionally, kurarinone promoted Fas and TRAIL receptor-1 and -2 expression via the caspase-8/Bid pathway, suggesting that kurarinone triggered apoptosis via the mitochondria-mediated and receptor-mediated apoptotic pathways. We also observed that kurarinone repressed migration and invasion capabilities of SCLC cells by suppressing the expression of epithelial-mesenchymal transition-related proteins and matrix metalloproteinases.Conclusion: Our findings provided evidence that kurarinone can induce apoptosis in SCLC cells via multiple mechanisms and delayed the cell migration and invasion of SCLC cells.Keywords: kurarinone, small cell lung carcinoma, apoptosis, caspase, migration, invasiveness

Chu-Ching Yang,1,* Chi-Feng Hung,2,* Bing-Huei Chen1 1Department of Food Science, 2School of Medicine, Fu Jen Catholic University, Taipei, Taiwan *These authors contributed equally to this work Abstract: Coffee grounds, a waste by-product generated after making coffee, contains approximately 15% coffee oil which can be used as a raw material in cosmetics. Algae oil rich in docosahexaenoic acid (DHA) has been demonstrated to possess anticancer and anti-inflammation functions. The objectives of this study were to develop a gas chromatography-mass spectrometry (GC-MS) method for the determination of fatty acids in coffee oil and algae oil and prepare a nanoemulsion for studying its inhibition effect on ultraviolet A-induced skin damage in mice and growth of melanoma cells B16-F10. A total of 8 and 5 fatty acids were separated and quantified in coffee oil and algae oil by GC-MS, respectively, with linoleic acid (39.8%) dominating in the former and DHA (33.9%) in the latter. A nanoemulsion with a particle size of 30 nm, zeta potential -72.72 mV, and DHA encapsulation efficiency 100% was prepared by using coffee oil, algae oil, surfactant (20% Span 80 and 80% Tween 80), and deionized water. Differential scanning calorimetry (DSC) analysis revealed a high stability of nanoemulsion when heated up to 110°C at a pH 6, whereas no significant changes in particle size distribution and pH occurred over a 90-day storage period at 4°C. Animal experiments showed that a dose of 0.1% coffee oil-algae oil nanoemulsion was effective in mitigating trans-epidermal water loss, skin erythema, melanin formation, and subcutaneous blood flow. Cytotoxicity test implied effective inhibition of melanoma cell growth by nanoemulsion with an IC50 value of 26.5 µg/mL and the cell cycle arrested at G2/M phase. A dose-dependent upregulation of p53, p21, cyclin B, and cyclin A expressions and downregulation of CDK1 and CDK2 occurred. Also, both Bax and cytochrome c expressions were upregulated and bcl-2 expression downregulated, accompanied by a rise in caspase-3, caspase-8, and caspase-9 activities for apoptosis execution. Collectively, the apoptosis pathway of melanoma cells B16-F10 may involve both mitochondria and death receptor. Keywords: coffee ground, coffee oil-algae oil nanoemulsion, DHA, melanoma cell apoptosis, mouse skin protection, GC-MS

Ping-Hui Wang,1 Cheng-Chang Yang,2 Wei-Ren Su,3 Po-Ting Wu,3 Shun-Chien Cheng,1 I-Ming Jou4 1Department of Orthopedics, Chi-Mei Medical Center, 2Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 3Department of Orthopedics, National Cheng Kung University Hospital, Tainan, 4Department of Orthopedics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan Purpose: To determine susceptibility to decompression surgery in diabetic and nondiabetic peripheral neuropathy using a chronic compression neuropathy model. Materials and methods: Twenty-four streptozotocin-induced diabetic rats were randomly divided into three groups: group I, chronic compression of the left sciatic nerve for 4 weeks with decompression; group II, similar without decompression; and group III, sham exposing the sciatic nerve only. The other 24 nondiabetic rats were assigned to groups IV–VI, which received compression–decompression, compression, and the sham operation, respectively. Mixed-nerve-elicited somatosensory evoked potentials (M-SSEPs) and compound muscle action potentials (CMAPs) were measured to verify the compression neuropathy in the posttreatment follow-up. Behavioral observations in thermal hyperalgesia tests were quantified before electrophysiologic examinations. Treated and contralateral nerves were harvested for histomorphologic analysis. Results: Chronic compression of sciatic nerve induced significant reduction of amplitude and increment of latency of M-SSEP and CMAP in both diabetic and nondiabetic rats. Diabetic group changes were more susceptible. Decompression surgery significantly improved both sensory and motor conduction, thermal hyperalgesia, and the mean myelin diameter of the rat sciatic nerve in both diabetic and nondiabetic groups. Near full recovery of motor and sensory function occurred in the nondiabetic rats, but not in the diabetic rats 8 weeks postdecompression. Conclusion: Behavioral, electrophysiologic, and histomorphologic findings indicate that decompression surgery is effective in both diabetic and nondiabetic peripheral neuropathy. Keywords: compression, decompression, streptozotocin, sciatic nerve, diabetes, rat

Yuan Ma,1,* Jujie Sun,2,* Cuicui Yang,1 Dandan Yuan,3 Jie Liu3 1Department of Oncology, Shandong Cancer Hospital & Institute, School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong Province, People’s Republic of China; 2Department of Pathology, 3Department of Oncology, Shandong Cancer Hospital & Institute, Jinan, Shandong Province, People’s Republic of China*These authors contributed equally to this work Abstract: Follicular dendritic cell sarcoma (FDCS) is a rare malignant tumor recognized in recent years. It accounts for only 0.4% of soft-tissue sarcomas, and its underlying causes are largely unknown. A correct diagnosis can be difficult to make. Diagnosis of FDCS depends on the combined clinical examination, histopathologic features, electron microscopic examination and confirmation with immunohistochemical studies. Here, we report two rare cases of FDCS: one case involving multiple bones, and the other involving extensive abdominal and pelvic cavities. Clinical, histopathological, and immunohistochemical aspects, therapeutic options, and a related literature review of the two cases are discussed. As the prevalence of FDCS is increasing, the details of these rare cases may highlight the importance and facilitate treatment of similar diseases. Keywords: FDCS, bone, abdominal cavity, pelvic cavity, diagnosis, therapy

Jie Cui,1,2 Ya-Huan Guo,3 Hong-Yi Zhang,4 Li-Li Jiang,1 Jie-Qun Ma,1 Wen-Juan Wang,1 Min-Cong Wang,1 Cheng-Cheng Yang,1 Ke-Jun Nan,1 Li-Ping Song5 1Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, 2Department of Oncology, Yan'an University Affiliated Hospital, Yan'an, 3Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, 4Department of Urology, Yan'an University Affiliated Hospital, Yan'an, 5Department of Radiotherapy, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China Purpose: Celecoxib, an inhibitor of cyclooxygenase-2 (COX2), was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs), as well as elucidate the underlying mechanisms. Methods: The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. Results: MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 µmol/L) plus 5-fluorouracil (8.1 × 10-3 g/L) or sorafenib (4.4 µmol/L) increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR) and phosphorylated (p)-AKT expression. Gefitinib (5 µmol/L), which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 µmol/L) plus celecoxib (21.8 µmol/L) increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. Conclusion: Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2 MCSs. Our results provided molecular evidence to support celecoxib combination-treatment strategies for patients with human hepatocellular carcinoma. MCSs provided a good model to evaluate the interaction of anticancer drugs. Keywords: hepatocellular carcinoma, celecoxib, multicellular spheroids, 5-fluorouracil, sorafenib, gefitinib

Chien-Hsi Chang,1 Zhi-Xian Lai,1 Hsiu-Li Lin,2 Che-Chuan Yang,3 Hsin-Hsien Chen,3,4 Shieh-Yueh Yang,5 Herng-Er Horng,3 Chin-Yih Hong,6 Hong-Chang Yang,4 Hsiu-Chen Lin1,71Department of Laboratory Medicine, Taipei Medical University Hospital, 2Department of Neurology, General Cathay Hospital, Sijhih Branch, 3Institute of Electro-optical Science and Technology, National Taiwan Normal University, 4Department of Physics, National Taiwan University, 5MagQu Co, Ltd, Sindian District, New Taipei City, 6Department of Mechanical Engineering, Nan-Kai University of Technology, Nan-tau County, 7Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanBackground: Magnetic nanoparticles biofunctionalized with antibodies are able to recognize and bind to the corresponding antigens. In this work, anti-C-reactive protein (CRP) antibody was covalently conjugated onto the surface of magnetic nanoparticles to label CRP specifically in serum.Methods: The level of serum CRP was detected by immunomagnetic reduction (IMR) assay, which identifies the changes in the magnetic signal representing the level of interaction between antibody-conjugated magnetic nanoparticles and CRP proteins. To investigate the feasibility of IMR for clinical application, pure CRP solutions and 40 human serum samples were tested for IMR detection of CRP to characterize sensitivity, specificity, and interference.Results: In comparison with the immunoturbidimetry assay, the results of the IMR assay indicated higher sensitivity and had a high correlation with those of the current immunoturbidimetry assay.Conclusion: We have developed a novel and promising way to assay CRP in human serum using immunomagnetic reduction in clinical diagnosis.Keywords: magnetic nanoparticles, immunomagnetic reduction, C-reactive protein

Kai-Wen Huang1, Shieh-Yueh Yang2,3, Yu-Wei Hong3, Jen-Jie Chieh3, Che-Chuan Yang3, Herng-Er Horng3, Chau-Chung Wu4, Chin-Yih Hong5, Hong-Chang Yang61Department of Surgery and Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University, Taipei, 2MagQu Co, Ltd, Sindian Dist, New Taipei City, 3Institute of Electro-optical Science and Technology, National Taiwan Normal University, Taipei, 4Departments of Internal Medicine and Primary Care Medicine, College of Medicine, National Taiwan University, Taipei, 5Graduate Institute of Bio-medical Engineering, National Chung Hsing University, Taichung, 6Department of Physics, National Taiwan University, Taipei, TaiwanAbstract: Some previous reports have already shown the characterizations of immunomagnetic reduction (IMR). The assay technology involves the utilities of biofunctionalized magnetic nanoparticles to label target biomolecules. However, the detection threshold and interference tests for IMR have not been investigated in detail. In this study, alpha-fetoprotein (AFP) was used as a target biomolecule. The signals for AFP solutions of various concentrations, or with interfering materials, were detected via IMR. These samples were also used for characterizing the detection threshold and interference with enzyme-linked immunosorbent assay (ELISA). The results of assaying AFP level with IMR and ELISA were compared. The detection threshold for assaying AFP with IMR was found to be 3 ng/mL, which is 15 times lower than that of ELISA, and definitely suppresses false negative. For the interfering materials noted commonly in serum such as hemoglobin, bilirubin, triglyceride, and vascular endothelial growth factor, there was no detectable interfering effect when assaying AFP with IMR. Several serum samples from normal people and liver-tumor-bearing patients were used for the detections of AFP concentration via IMR. These results reveal the feasibilities of assaying AFP in blood using IMR, as well as achieving high-sensitive and high-specific assay for AFP.Keywords: immunomagnetic reduction, ELISA, biofunctionalized magnetic nanoparticles

Hai-Hua Chuang,1– 3 Chi-Hung Liu,4 Chao-Yung Wang,5 Yu-Lun Lo,6 Guo-She Lee,7,8 Yi-Ping Chao,4,9 Hsueh-Yu Li,10 Terry BJ Kuo,11 Cheryl CH Yang,11 Liang-Yu Shyu,12 Li-Ang Lee10,11 1Department of Family Medicine, Chang Gung Memorial Hospital, Taipei Branch and Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 2Department of Industrial Engineering and Management, National Taipei University of Technology, Taipei, Taiwan; 3Genomic Medicine Institute & Obesity Institute, Geisinger Medical, Danville, PA, USA; 4Department of Neurology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 5Department of Cardiology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 6Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 7Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; 8Department of Otolaryngology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan; 9Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan, Taiwan; 10Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 11Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 12Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, TaiwanCorrespondence: Li-Ang LeeDepartments of Otorhinolaryngology-Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital, Linkou Main Branch, No. 5, Fu-Hsing Street, Guishan District, Taoyuan, 33305, TaiwanTel +886 33281200 ext. 3972Fax +886 33979361Email 5738@cgmh.org.twBackground: Obstructive sleep apnea (OSA) and snoring have been reported to be modifiable risk factors for thick carotid intima-media thickness (CIMT) and carotid atherosclerosis, which are closely linked to cardiovascular disease.Methods: This cross-sectional study prospectively recruited 70 participants with OSA and without a history of carotid artery disorder, who primarily sought surgical Intervention. OSA and snoring were assessed with the Epworth Sleepiness Scale, Snore Outcomes Survey, polysomnography, and snoring sound recording. The carotid arteries were evaluated with ultrasonography and divided into three types of carotid artery profiles (normal carotid artery, thick CIMT, or significant carotid atherosclerosis). Multivariate linear/logistic/categorical regressions were performed with the forward selection approaches/logistic least absolute shrinkage and selection operator, as appropriate.Results: Normalized snoring sound energy (301– 850 Hz) was independently associated with the carotid intima-media thickness (regression coefficient [β] = 0.01, standard error [SE] = 0.004, P = 0.03; R2 = 0.067) and type of carotid profile (β = 0.40, SE = 0.09, P < 0.001; R2 = 0.156). Normalized snoring sound energy (4– 300 Hz) (β = − 0.10, SE = 0.04, P = 0.01) and female sex (β = 1.90, SE = 0.94, P = 0.04) were independently related to the presence of carotid stenosis (R2 = 0.159). The optimal regression model of the type of carotid artery profile included normalized snoring sound energy (301– 850 Hz) (β = 0.33, SE = 0.14, P = 0.03), snoring time (β = 0.26, SE = 0.13, P = 0.047), female sex (β = 0.26, SE = 0.13, P = 0.047), and increased age (β = 0.20, SE = 0.10, P = 0.04) under the control of the Snore Outcomes Survey score, 3% oxygen desaturation index, snoring sound energy (4– 1500 Hz), normalized snoring sound energy (851– 1500 Hz), cigarette smoking, and hyperlipidemia (R2 = 0.427).Conclusion: Our findings suggested that snoring sound characteristics are associated with carotid artery profiles among early OSA patients who cannot be noticed by ultrasound because organic changes of the carotid artery have not yet started. Future studies are warranted to verify the clinical significance of the results.Keywords: atherosclerosis, common carotid artery, categorical regression, obstructive sleep apnea, snoring, ultrasound

Chuang HH, Liu CH, Wang CY, et al. Nat Sci Sleep. 2021;13:1243–1255. Page 1253, Acknowledgment section, second line, the text “CMRPG3F1091-3” should read “CMRPG3G1381-3”. The authors apologize for this error. Read the original article