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Chi-Han Lin,1,2,&ast; Yung-Chia Kuo,1– 3,&ast; Hsuan-Chih Kuo,1– 3,&ast; Ching-Ting Wang,4 Shi-Ming Lin,1,5 Alan Chao-Wei Lee,1,6 Ming-Chin Yu,1,6,7 Wei-Chen Lee,1,6 Cherry Chiao-Erh Chen,2,3 Jason Chia-Hsun Hsieh1– 3 1College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 2Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 3Division of Hematology-Oncology, Department of Internal Medicine, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan; 4Registered Nurse, Case Manager of Nursing Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, 333, Taiwan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 6Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan; 7Department of Surgery, New Taipei City Municipal TuCheng Hospital, New Taipei City, 236, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jason Chia-Hsun Hsieh, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, No. 5, Fu-Hsin Street, Gueishan District, Taoyuan City, 333, Taiwan, Tel +886-3-3281200 Ext 8825, Email wisdom5000@gmail.comBackground: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear.Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns.Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses.Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.Keywords: hepatitis, immune checkpoint inhibitor, advanced hepatocellular carcinoma, liver enzymes, overall survival

Bashir Lawal,1,2,&ast; Yu-Cheng Kuo,3,4,&ast; Maryam Rachmawati Sumitra,1,2 Alexander TH Wu,5– 8 Hsu-Shan Huang1,2,8– 10 1PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, 11031, Taiwan; 2Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; 3Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; 4School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan; 5The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; 6Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan; 7TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan; 8Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 11490, Taiwan; 9School of Pharmacy, National Defense Medical Center, Taipei, 11490, Taiwan; 10PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan&ast;These authors contributed equally to this workCorrespondence: Alexander TH Wu; Hsu-Shan Huang Email chaw1211@tmu.edu.tw; huanghs99@tmu.edu.twPurpose: Breast cancer is the most frequently diagnosed cancer globally, and the leading cause of cancer-associated mortality among women. The efficacy of most clinical chemotherapies is often limited by poor pharmacokinetics and the development of drug resistance by tumors. In a continuing effort to explore small molecules as alternative therapies, we herein evaluated the therapeutic potential of HH-N25, a novel nitrogen-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivative.Methods: We evaluated the in vivo pharmacokinetic properties and maximum tolerated dose (MTD) of HH-N25 in rats. We also characterized the compound for in vitro and in vivo anticancer activities and its inhibitory effects against DNA topoisomerases and hormonal signaling in breast cancer. Furthermore, we used molecular docking to analyse the ligand–receptor interactions between the compound and the targets.Results: The maximum serum concentration (Cmax), half-life (t1/2 beta), mean residence time (MRT), oral clearance (CL/f), and apparent volume of distribution (VD/f) of HH-N25 were 1446.67 ± 312.05 ng/mL, 4.51 ± 0.27 h, 2.56 ± 0.16 h, 8.32 ± 1.45 mL/kg/h, and 1.26 ± 0.15 mL/kg, respectively, after single-dose iv administration at 3 mg/kg body weight. HH-N25 had potent anticancer activity against a panel of human breast cancer cell lines with 50% inhibitory concentrations (IC50) ranging 0.045± 0.01∼ 4.21± 0.05 μM. The drug also demonstrated marked in vivo anticancer activity at a tolerated dose and prolonged the survival duration of mice without unacceptable toxicities based on body weight changes in human tumor xenograft models. In addition, HH-N25 exhibited a dose-dependent inhibition of topoisomerase I and ligand-mediated activities of progesterone and androgen receptors.Conclusion: HH-N25 represents a new molecular entity that selective suppressed TOP1 and hormonal signaling, and shows potent antitumor activities in human breast cancer cells in vitro and in vivo. HH-N25 thus represents a promising anticancer agent that warrants further preclinical and clinical exploration.Keywords: pharmacokinetic, anticancer activities, HH-N25, topoisomerase inhibition, hormonal signaling

Ya-Chi Cheng,1,&ast; Yi-Chun Kuo,2,&ast; Pei-Chi Chang,2 Ya-Ching Li,2 Wan-Ting Huang,3 Wei Chen,4 Che-Yi Chou5– 7 1Division of Family Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City, Taiwan; 2Community Nursing Room, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City, Taiwan; 3Clinical Medicine Research Center, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City, Taiwan; 4Division of Pulmonary and Critical Care Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City, Taiwan; 5Division of Nephrology, Asia University Hospital, Wufeng, Taichung, Taiwan; 6Department of Post-baccalaureate Veterinary Medicine, Asia University, Wufeng, Taichung, Taiwan; 7Division of Nephrology, China Medical University Hospital, Taichung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Che-Yi Chou No. 222, Fuxin Road, Wufeng Dist, Taichung, 413, TaiwanTel +886-4-37061668-1878Fax +886-4-37061668-1337Email cychou.chou@gmail.comBackground: The World Health Organization (WHO) proposed the integrated care for older people (ICOPE) screening tool to identify functional impairment. We explore the association of geriatric functional impairment and hypertension, diabetes, dyslipidemia in the community-dwelling elderly.Methods: We enrolled individuals aged at least 65 with hypertension, diabetes, or dyslipidemia; or those aged at least 75 from May to July 2019. We applied ICOPE tools to evaluate six function assessments: cognitive decline, limited mobility, malnutrition, visual impairment, hearing loss, and depressive symptoms. Factors were analyzed using stepwise multivariable linear regression for ICOPE scores and logistic regression for geriatric functional impairment. All analyses were adjusted for age and glomerular filtration rate.Results: We enrolled 457 participants including 303 (66.3%) participants with hypertension, 296 (64.8%) diabetes, and 221 (48.4%) dyslipidemia. Seventy-eight (17.1%) participants have at least one geriatric functional impairment, including 41 (25.9%) participants aged ≥ 75 and 37 (12.4%) aged 65– 74. The ICOPE score (0.4 ± 0.6) of participants aged at least 75 was higher than that (0.1 ± 0.4) of the participants aged 65– 74 (p < 0.001). Dyslipidemia (p = 0.002) was positively associated with ICOPE score. Dyslipidemia (odds ratio: 2.15, 95% confidence interval: 1.27– 3.70, p = 0.005), not hypertension (p = 0.3) and diabetes (p = 0.9), was associated with geriatric functional impairment. Visual impairment was the most common function impairment. Female was linked to limited mobility, renal function was associated with mobility (p < 0.001) and nutrition (p = 0.02).Conclusion: Dyslipidemia but not hypertension, diabetes is linked to geriatric functional impairment in community-dwelling elderly. Lower renal function is associated with decreased mobility and nutrition. More studies are needed to determine if treatment of dyslipidemia reduces geriatric functional impairment.Keywords: aging, elderly, function impairment, geriatric functional impairment, ICOPE, renal function

Ji-An Liang,1,2,* Po-Chang Lee,3,* Chun-Ping Ku,3,* William Tzu-Liang Chen,2,3,* Chih-Yuan Chung,4 Yu-Cheng Kuo,1,2 Szu-Hsien Chou,5 Chia-Chin Li,6 Chun-Ru Chien1,2,6 1Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; 3Department of Surgery, China Medical University Hsinchu Hospital, Hsinchu, Taiwan; 4Department of Medical Oncology, China Medical University Hsinchu Hospital, Hsinchu, Taiwan; 5Department of Medical Imaging, China Medical University Hsinchu Hospital, Hsinchu, Taiwan; 6Department of Radiation Oncology, China Medical University Hsinchu Hospital, Hsinchu, Taiwan*These authors contributed equally to this workCorrespondence: Chun-Ru ChienSchool of Medicine, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, North District, Taichung, 40402, TaiwanTel +886-4-22052121-7450Fax +886-4-22052121-7460Email d16181@gmail.comPurpose: Image-guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the radiotherapy delivery. We aimed to compare the overall survival (OS) for localized breast cancer (LBC) patient treated with adjuvant conventional fractionated radiotherapy (CFRT) using IGRT vs those without IGRT via a population-based analysis.Patients and Methods: Eligible LBC patients diagnosed between 2011 and 2013 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders between groups. The hazard ratio (HR) of death and other outcomes were compared between IGRT and non-IGRT. We also evaluated OS in various supplementary analyses.Results: Our primary analysis included 6490 patients in whom covariates were well balanced after PS weighing. The HR for death when IGRT was compared with non-IGRT was 1.02 (95% confidence interval 0.80– 1.31, P = 0.86). There were also no significant differences in the supplementary analyses.Conclusion: We found that OS of LBC patients treated with adjuvant CFRT was not statistically different between those treated with IGRT versus without IGRT. This was the first study in this regard to our knowledge but randomized controlled trials were needed to confirm our finding.Keywords: breast cancer, effectiveness, image-guided radiotherapy

Hsien-Te Peng,1 Chueh-Ho Lin,2,3 Yu-Chi Kuo,4 Chen-Yi Song5 1Department of Physical Education, Chinese Culture University, Taipei, Taiwan; 2Master Program in Long-Term Care, College of Nursing, Taipei Medical University, Taipei, Taiwan; 3Center for Nursing and Healthcare Research in Clinical Practice Application, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 4Department of Exercise and Health Science, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; 5Department of Long-Term Care, National Taipei University of Nursing and Health Sciences, Taipei, TaiwanCorrespondence: Chen-Yi SongDepartment of Long-Term Care, National Taipei University of Nursing and Health Sciences, 365 Ming-Te Road, Taipei 11219, TaiwanTel +886 2 28227101 Ext 6136Fax +886 2 23891464Email cysong@ntunhs.edu.twPurpose: To explore the immediate and prolonged effects of arch support insoles on single- and dual-task gait performance among community-dwelling older adults.Methods: Twenty women performed single- and dual-task walking for 10 m at self-selected comfortable and fast paces while performing serial subtractions (cognitive interference) or carrying a tray (motor interference). Spatiotemporal gait parameters were measured and compared with measurements without arch support immediately after the insertion of the insoles and at 1-week follow-up.Results: Some effects were noted, with small-to-medium effect sizes. During comfortable-paced single-task walking, stride length and walk ratio (step length/cadence) increased after arch support use. During comfortable-paced motor dual-task walking, arch support use increased cadence, stride length, and speed and decreased dual-task costs (DTCs) on cadence and speed. During fast-paced motor dual-task walking, cadence increased and the DTC on cadence decreased after arch support use at the 1-week follow-up. During comfortable-paced cognitive dual-task walking, cadence increased and the walk ratio decreased following arch support use. At the 1-week follow-up, DTCs on cadence reduced, but those on stride length and speed increased. During fast-paced cognitive dual-task walking, the speed and stride length demonstrated immediate decreases followed by increases at the 1-week follow-up.Conclusion: The study results indicate that the use of arch support improves single- and motor dual-task gait performance, which may contribute to gait and balance training in older adults.Keywords: gait, dual-task, insole, elderly

Yung-Chih Kuo,1 Che-Yu Lin,1 Jay-Shake Li,2 Yung-I Lou3 1Department of Chemical Engineering, 2Department of Psychology, National Chung Cheng University, Chia-Yi, 3Department of Accounting, Providence University, Taichung, Taiwan, Republic of China Abstract: Curcumin (CRM) and nerve growth factor (NGF) were entrapped in liposomes (LIP) with surface wheat germ agglutinin (WGA) to downregulate the phosphorylation of kinases in Alzheimer’s disease (AD) therapy. Cardiolipin (CL)-conjugated LIP carrying CRM (CRM-CL/LIP) and also carrying NGF (NGF-CL/LIP) were used with AD models of SK-N-MC cells and Wistar rats after an insult with β-amyloid peptide (Aβ). We found that CRM-CL/LIP inhibited the expression of phosphorylated p38 (p-p38), phosphorylated c-Jun N-terminal kinase (p-JNK), and p-tau protein at serine 202 and prevented neurodegeneration of SK-N-MC cells. In addition, NGF-CL/LIP could enhance the quantities of p-neurotrophic tyrosine kinase receptor type 1 and p-extracellular signal-regulated kinase 5 for neuronal rescue. Moreover, WGA-grafted CRM-CL/LIP and WGA-grafted NGF-CL/LIP significantly improved the permeation of CRM and NGF across the blood–brain barrier, reduced Aβ plaque deposition and the malondialdehyde level, and increased the percentage of normal neurons and cholinergic activity in the hippocampus of AD rats. Based on the marker expressions and in vivo evidence, current LIP carriers can be promising drug delivery systems to protect nervous tissue against Aβ-induced apoptosis in the brain during the clinical management of AD. Keywords: liposome, Alzheimer’s disease, β-amyloid, neurodegeneration, blood–brain barrier, wheat germ agglutinin

Yung-Chih Kuo, Yin-Jung Lee Department of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China Abstract: β-Amyloid (Aβ)-targeting liposomes (LIP) with surface serotonin modulator (SM) and apolipoprotein E (ApoE) were utilized to facilitate the delivery of nerve growth factor (NGF) across the blood–brain barrier (BBB) for neuroprotection in the hippocampus. The therapeutic efficacy of SM- and ApoE-grafted LIP carrying NGF (NGF-SM-ApoE-LIP) was assessed by an in vitro Alzheimer’s disease (AD) model of degenerated SK-N-MC cells and an in vivo AD model of Aβ-insulted Wistar rats. The experimental evidences revealed that the modified SM and ApoE on the surface of LIP increased the permeation of NGF across the BBB without serious damage to structural integrity of tight junction. When compared with free NGF, NGF-SM-ApoE-LIP upregulated the expression of phosphorylated neurotrophic tyrosine kinase receptor type 1 on cholinergic neurons and significantly improved their survival. In addition, NGF-SM-ApoE-LIP could reduce the secretion of acetylcholinesterase and malondialdehyde and rescue hippocampal neurons from apoptosis in rat brains. The synergistic effect of SM and ApoE is promising in the induction of NGF to inhibit the neurotoxicity of Aβ and NGF-SM-ApoE-LIP can be a potent antiapoptotic pharmacotherapy for clinical care of patients with AD. Keywords: Alzheimer’s disease, blood–brain barrier, serotonin modulator, apolipoprotein E, nerve growth factor, liposome

Yung-Chih Kuo, Ching-Chun Lin Department of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China Abstract: Liposomes with cardiolipin (CL) and wheat germ agglutinin (WGA) were developed to permeate the blood–brain barrier and treat Alzheimer’s disease. WGA-conjugated and CL-incorporated liposomes (WGA-CL-liposomes) were used to transport nerve growth factor (NGF) and curcumin (CUR) across a monolayer of human brain-microvascular endothelial cells regulated by human astrocytes and to protect SK-N-MC cells against apoptosis induced by ß-amyloid1–42 (Aß1–42) fibrils. An increase in the CL mole percentage in lipids increased the liposomal diameter, absolute zeta potential value, entrapment efficiency of NGF and CUR, release of NGF, biocompatibility, and viability of SK-N-MC cells with Aß1–42, but decreased the atomic ratio of nitrogen to phosphorus and release of CUR. In addition, an increase in the WGA concentration for grafting enhanced the liposomal diameter, atomic ratio of nitrogen to phosphorus, and permeability of NGF and CUR across the blood–brain barrier, but reduced the absolute zeta potential value and biocompatibility. WGA-CL-liposomes carrying NGF and CUR could be promising colloidal delivery carriers for future clinical application in targeting the blood–brain barrier and inhibiting neurotoxicity. Keywords: Alzheimer’s disease, nerve growth factor, curcumin, wheat germ agglutinin, cardiolipin, liposome