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Lily G Bessette,1 Daniel E Singer,2 Ajinkya Pawar,1 Vincent Wong,1 Dae Hyun Kim,1,3,* Kueiyu Joshua Lin1,2,* 1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Marcus Institute for Aging Research, Hebrew Rehabilitation Center, Harvard Medical School, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Kueiyu Joshua Lin, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 1620 Tremont St. Suite 3030, Boston, MA, 02120, USA, Tel +1 (617) 278-0930, Fax +1 (617) 232-8602, Email jklin@bwh.harvard.eduBackground: High risk of intracranial hemorrhage (ICH) is a leading reason for withholding anticoagulation in patients with atrial fibrillation (AF). We aimed to develop a claims-based ICH risk prediction model in older adults with AF initiating oral anticoagulation (OAC).Methods: We used US Medicare claims data to identify new users of OAC aged ≥ 65 years with AF in 2010– 2017. We used regularized Cox regression to select predictors of ICH. We compared our AF ICH risk score with the HAS-BLED bleed risk and Homer fall risk scores by area under the receiver operating characteristic curve (AUC) and assessed net reclassification improvement (NRI) when predicting 1-year risk of ICH.Results: Our study cohort comprised 840,020 patients (mean [SD] age 77.5 [7.4] years and female 52.2%) split geographically into training (3963 ICH events [0.6%] in 629,804 patients) and validation (1397 ICH events [0.7%] in 210,216 patients) sets. Our AF ICH risk score, including 50 predictors, had superior AUCs of 0.653 and 0.650 in the training and validation sets than the HAS-BLED score of 0.580 and 0.567 (p< 0.001) and the Homer score of 0.624 and 0.623 (p< 0.001). In the validation set, our AF ICH risk score reclassified 57.8%, 42.5%, and 43.9% of low, intermediate, and high-risk patients, respectively, by HAS-BLED score (NRI: 15.3%, p< 0.001). Similarly, it reclassified 0.0, 44.1, and 19.4% of low, intermediate, and high-risk patients, respectively, by the Homer score (NRI: 21.9%, p< 0.001).Conclusion: Our novel claims-based ICH risk prediction model outperformed the standard HAS-BLED score and can inform OAC prescribing decisions.Keywords: atrial fibrillation, anticoagulants, prediction modeling, prescriber decisions, AF

Hamin Kim,1,&ast; Tae-Jin Song,2,&ast; Jeong Yee,1 Dong-Hyeok Kim,3 Junbeom Park,4 Hye Sun Gwak1 1College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea; 2Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Korea; 3Department of Cardiology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Korea; 4Department of Cardiology, Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Korea&ast;These authors contributed equally to this workCorrespondence: Hye Sun Gwak, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Korea, Tel +82-2-3277-4376, Email hsgwak@ewha.ac.kr Junbeom Park, Department of Cardiology, Mokdong Hospital, Ewha Womans University College of Medicine, 1071, Annyangcheon-Ro, Yangcheon-Gu, Seoul, 07985, Korea, Tel +82-2-2650-5826, Email parkjb@ewha.ac.krPurpose: Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by ABCG2, is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban).Patients and Methods: Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of ABCG2 were selected. Previously studied genes (ABCB1, CYP3A4, and CYP3A5) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case–control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis.Results: Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210– 17.442), 2.385 (1.064– 5.349), 2.188 (1.156– 4.142), and 3.243 (1.371– 7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with bleeding complications.Conclusion: The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, ABCG2 rs3114018, and ABCB1 rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.Keywords: ABCG2, apixaban, bleeding complications, polymorphism, rivaroxaban

Jae Geun Song,&ast; Da Hyun Kim,&ast; Hyo-Kyung Han BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Korea&ast;These authors contributed equally to this workCorrespondence: Hyo-Kyung Han, BK21 FOUR Team, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, 10326, Korea, Tel +82-31-961-5217, Fax +82-31-961-5206, Email hkhan@dongguk.eduPurpose: Oral administration of liraglutide, a protein drug, suffers from low intestinal absorption and instability in the gastrointestinal tract, resulting in low bioavailability. The present study aimed to develop a pH-responsive nanocomposite based-colonic delivery system to improve the oral efficacy of liraglutide.Methods: Nanocomplex (AC-Lira) between aminoclay and liraglutide was prepared by a spontaneous self-assembly. After surface charge reversal using citric acid, AC-Lira was coated with poly(methacrylic acid-co-methyl methacrylate) (1:2). The fabricated nanocomplex underwent various in vitro studies to characterize its physicochemical properties, drug release, and cellular transport. In vivo efficacy studies were also conducted using streptozotocin-induced diabetic rats.Results: Both uncoated (AC-Lira) and coated nanocomplex (EAC-Lira) achieved high entrapment efficiency (> 90%) and showed a narrow size distribution. While exhibiting low drug release at pH 1.2 (approximately 30%), EAC-Lira achieved rapid and extensive drug release (~90%) at pH 7.4, displaying pH-dependent drug release. EAC-Lira showed significant size reduction and surface charge reversal during dissolution at pH 7.4, probably due to the removal of the outer coating layer. Furthermore, EAC-Lira was effective at protecting the entrapped proteins against enzymatic degradation. EAC-Lira also increased the membrane transport of liraglutide by 3.5 folds in Caco-2 cells. Owing to enhanced membrane transport and metabolic stability, EAC-Lira improved in vivo efficacy of orally administered liraglutide, significantly reducing blood glucose concentrations, intake of food and water, and body weight in type 2 diabetes rats.Conclusion: These results suggest EAC-Lira is a promising approach to improving the oral bioavailability and efficacy of liraglutide.Keywords: liraglutide, aminoclay, GLP-1 agonist, type 2 diabetes, nanocomposite

An 11-year-old spayed female Toy Poodle presented with acute tetraparesis. A small subcutaneous mass was found in the right trunk region, and the magnetic resonance revealed a compressive spinal cord lesion due to an irregular bone proliferation at the third cervical vertebra. After surgical resection of the vertebral lesion, the neurological symptoms improved, and the patient could walk on her own. The excised vertebral and subcutaneous masses were diagnosed as a mammary adenocarcinoma on the histopathological examination, with Ki-67 and HER-2 immunohistochemistry staining. This case report highlights the importance of defining the primary tumours of metastatic vertebral tumours and the necessity of palliative surgery to improve the patient's quality of life.

Virendra Kumar Yadav,1,* Parth Malik,2,* Vineet Tirth,3,4 Samreen Heena Khan,5 Krishna Kumar Yadav,6 Saiful Islam,7 Nisha Choudhary,8 Gajendra Kumar Inwati,9 Amir Arabi,3 Do-Hyeon Kim,10 Byong-Hun Jeon10 1Department of Microbiology, School of Sciences, PP Savani University, Surat, Gujarat, 394125, India; 2School of Chemical Sciences, Central University of Gujarat, Gandhinagar, 382030, Gujarat, India; 3Mechanical Engineering Department, College of Engineering, King Khalid University, Abha, 61411, Asir, Kingdom of Saudi Arabia; 4Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, 61413, Asir, Kingdom of Saudi Arabia; 5Research and Development Centre, YNC Envis, New Delhi, 110059, India; 6Faculty of Science and Technology, Madhyanchal Professional University, Bhopal, 462044, India; 7Civil Engineering Department, College of Engineering, King Khalid University, Abha, 61411, Asir, Kingdom of Saudi Arabia; 8Department of Environment Science, School of Sciences, PP Savani University, Kosamba, Surat, Gujarat, 394125, India; 9Department of Chemistry, DP Chaturvedi College, Rani Durgavati University, Seoni, Madhya Pradesh, 480661, India; 10Department of Earth Resources and Environmental Engineering, Hanyang University, Seoul, 04763, South Korea*These authors contributed equally to this workCorrespondence: Byong-Hun Jeon, Email bhjeon@Hanyang.ac.krAbstract: Incense burning is practiced alongside many sacred rituals across different regions of the world. Invariable constituents of incense brands are 21% (by weight) herbal and wood powder, 33% bamboo stick, 35% fragrance material, and 11% adhesive powder. Major incense-combustion outputs include particulate matter (PM), volatile organic content, and polyaromatic hydrocarbons. The relative toxicity of these products is an implicit function of particle size and incomplete combustion, which in turn vary for a specific incense brand. Lately, the attention given to the Air Quality Index by international regulatory bodies has created concern about mounting PM toxicity. The uncharacteristically small physical dimensions of these entities complicates their detection, and with no effect of gravity PM fractions rapidly contribute to oxidative stress, enhancing random biochemical reactions upon being inhaled. Incense burning generates four times the PM extent (45 mg•g− 1) of cigarettes (∼ 10 mg•g− 1). Several poisonous gases, such as CO, CO2, NO2, and SO2, and the unavoidable challenge of disposing of the burnt incense ash further add to the toxicity. Taken together, these issues demonstrate that incense burning warrants prompt attention. The aim of this article is to highlight the toxicity of incense-combustion materials on the environment and human health. This discussion could be significant in framing future policy regarding ecofriendly incense manufacture and reduced usage.Keywords: incense combustion, particulate matter, polyaromatic hydrocarbons, volatile organic content, oxidative stress, burnt incense ash

Ye Eun Kim,1,&ast; Dong Hwan Kim,1,&ast; Ami Choi,1,&ast; Seoul Jang,1 Kwiwan Jeong,2 Young-mi Kim,1 Tae-gyu Nam1 1Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, 15588, Republic of Korea; 2Gyeonggi Bio-Center, Gyeonggido Business & Science Accelerater, Suwon, Gyeonggi-do, 16229, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Young-mi Kim; Tae-gyu Nam Tel +82-31-400-5815; +82-31-400-5807Fax +82-31-400-5958Email ymikim12@hanyang.ac.kr ; tnam@hanyang.ac.krIntroduction: Endoplasmic reticulum (ER) stress condition is characterized as the accumulation of misfolded or unfolded proteins in lumen of ER. This condition has been implicated in various diseases and pathologies including β-cell apoptosis, Alzheimer’s disease and atherosclerosis. We have reported that hydroxynaphthoic acids (HNA), naphthalene analogues of salicylic acid (SA), reduced ER stress. In this study, we explored structural modification to bi-aryl analogues of SA.Methods: Palladium-catalyzed cross-coupling was applied to synthesize bi-aryl analogues of SA. Anti-ER stress activity was monitored by using our cell-based assay system where ER stress is induced by tunicamycin. To monitor ER stress markers, ER stress was induced physiologically relevant palmitate system.Results: Many analogues decreased ER stress signal induced by tunicamycin. Compounds creating dihedral angle between Ar group and SA moiety generally increased the activity but gave some cytotoxicity to indicate the crucial role of flat conformation of aromatic region. The best compound (16e) showed up to almost 6-fold and 90-fold better activity than 3-HNA and tauro-ursodeoxycholic acid, positive controls, respectively. ER stress markers such as p-PERK and p-JNK were accordingly decreased in Western blotting upon treatment of 16e under palmitate-induced condition.Conclusion: Anti-ER stress activity and toxicity profile of bi-aryl analogues of SA could provide a novel platform for potential therapy for protein misfolding diseases.Keywords: endoplasmic reticulum stress, aryl-substituted salicylate, protein misfolding, biaryl group

Eun Joo Choi,1 Dong-Hyun Kim,1 Woong Ki Han,1 Ho-Jin Lee,2 Imhong Kang,3 Francis Sahngun Nahm,1,4 Pyung-Bok Lee1,4 1Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; 2Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Korea; 3Department of Anesthesiology and Pain Medicine, Bundang Chuk Hospital, Seongnam, Korea; 4Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Pyung-Bok LeeDepartment of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, 82, Gumi-Ro 173 Beon-Gil, Bundang-Gu, Seongnam, 13620, KoreaTel +82-31- 787-7499Fax +82-31- 787-4063Email painfree@snubh.orgPurpose: Particulate steroids used in epidural steroid injections have been suspected as a cause of post-procedural embolic events. Some particulate steroids have been suspended only when the transforaminal approach is used for an epidural block of the spine. In contrast, non-particulate steroids are generally accepted for safety during epidural steroid injections. However, the safety of using a mixture of non-particulate steroids and local anesthetics is unknown. This study analyzed whether mixtures of commonly used non-particulate steroids and local anesthetics form crystals in solution.Methods: We mixed non-particulate steroids (betamethasone sodium phosphate, dexamethasone sodium phosphate, and dexamethasone palmitate) and local anesthetics (ropivacaine, levobupivacaine, bupivacaine, and lidocaine) at different ratios. We used fluorescence microscopy to observe whether crystals formed in mixed solutions; we also measured the pH of each steroid, local anesthetic, and the mixtures.Results: Ropivacaine or levobupivacaine and betamethasone sodium phosphate produced large crystals (> 50 μm). Ropivacaine or levobupivacaine and dexamethasone sodium phosphate produced small crystals (< 10 μm). Lidocaine and all non-particulate steroids produced no identifiable crystals; dexamethasone palmitate and all local anesthetics did not form significant particulates. Betamethasone sodium phosphate and dexamethasone sodium phosphate demonstrated basic pH, while all local anesthetics demonstrated acidic pH. Mixtures showed a wide pH range.Conclusion: Non-particulate steroids can form crystals upon combination with local anesthetics. Crystal formation may be caused by alkalinization of steroids. The mixing of ropivacaine or levobupivacaine and betamethasone sodium phosphate may require caution during an epidural steroid injection. Lidocaine or bupivacaine is recommended as a local anesthetic. Dexamethasone palmitate is a candidate for a mixture, but additional studies on its safety and effectiveness are needed.Keywords: epidural space, injections, lidocaine, local anesthetics, particle size, steroids

Kyung Jae Ryu,1 Seunghoon Kim,2 Mee Kum Kim,3 Hae Jung Paik,1 Dong Hyun Kim1 1Department of Ophthalmology, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea; 2RudaCure Co., LTD, Incheon, Korea; 3Department of Ophthalmology, Seoul National University College of Medicine, Seoul, KoreaCorrespondence: Dong Hyun KimDepartment of Ophthalmology, Gachon University College of Medicine, Gil Medical Center, 1198, Guwol-dong, Namdong-Gu, Incheon, 21565, KoreaEmail amidfree@gmail.comPurpose: To compare the short-term therapeutic effects of topical corticosteroids in patients with refractory dry eye disease (DED) according to the tear matrix metalloproteinase 9 (MMP-9) point-of-care positivity.Methods: This study was conducted on 137 patients who were referred from other eye clinics, complaining of irresponsive DED or acute DED flares despite routine treatment with topical cyclosporin or diquafosol. The patients received treatment with topical corticosteroids for 1 month. DED was evaluated by SANDE (Symptom Assessment in Dry Eye) questionnaire, tear film breakup time, ocular surface staining score, and meibomian gland dysfunction stage. The InflammaDry MMP-9 immunoassay was conducted in more symptomatic eyes of all patients. The changes in the subjective symptoms were additionally surveyed as symptom improvement score.Results: The mean age of the patients was 57.8± 13.4 years, and the tear MMP-9 positivity was 73.0%. Topical corticosteroids treatment showed significant improvement of symptoms and signs in the patients with refractory DED irrespective of the positivity of MMP-9 (each p< 0.001). The changes in SANDE score and OSS, and symptom improvement score were higher in the MMP-9 positive group than in the MMP-9 negative group (p=0.002/0.010/0.011). The overall rates of subjective symptoms improvement and SANDE reduction were 73.0% and 90.6% after topical corticosteroids treatment, respectively.Conclusion: Short-term topical corticosteroids had excellent therapeutic effects in patients with refractory DED or acute DED flares, irrespective of the tear MMP-9 level. Tear MMP-9 positivity may serve as a reliable response predictor of topical corticosteroids treatment in DED.Keywords: dry eye disease, ocular surface inflammation, tear MMP-9 positivity, corticosteroid

Aarti Rao,1 Sandra M Shi,2,3 Jonathan Afilalo,4 Jeffrey J Popma,5 Kamal R Khabbaz,6 Roger J Laham,5 Kimberly Guibone,5 Edward R Marcantonio,2,7,* Dae Hyun Kim2,3,* 1Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 3Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA; 4Division of Cardiology and Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; 5Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 6Division of Cardiac Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA; 7Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Dae Hyun KimHinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA 02131, USATel +1 617-971-8320Fax +1 617-971-5339Email daehyunkim@hsl.harvard.eduBackground: Delirium is a major risk factor for poor recovery after surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). It is unclear whether preoperative physical performance tests improve delirium prediction.Objective: To examine whether physical performance tests can predict delirium after SAVR and TAVR, and adapt an existing delirium prediction rule for cardiac surgery, which includes Mini-Mental State Examination (MMSE), depression, prior stroke, and albumin level.Design: Prospective cohort, 2014– 2017.Setting: Single academic center.Subjects: A total of 187 patients undergoing SAVR (n=77) or TAVR (n=110).Methods: The Short Physical Performance Battery (SPPB) score was calculated based on gait speed, balance, and chair stands (range: 0– 12 points, lower scores indicate poor performance). Delirium was assessed using the Confusion Assessment Method. We fitted logistic regression to predict delirium using SPPB components and risk factors of delirium.Results: Delirium occurred in 35.8% (50.7% in SAVR and 25.5% in TAVR). The risk of delirium increased for lower SPPB scores: 10– 12 (28.2%), 7– 9 (34.5%), 4– 6 (37.5%) and 0– 3 (44.1%) (p-for-trend=0.001). A model that included gait speed < 0.46 meter/second (OR, 2.7; 95% CI, 1.2– 6.4), chair stands time ≥ 11.2 seconds (OR, 3.5; 95% CI, 1.0– 12.4), MMSE < 24 points (OR, 2.9; 95% CI, 1.3– 6.4), isolated SAVR (OR, 5.4; 95% CI, 2.1– 13.8), and SAVR and coronary artery bypass grafting (OR, 15.8; 95% CI, 5.5– 45.7) predicted delirium better than the existing prediction rule (C statistics: 0.71 vs 0.61; p=0.035).Conclusion: Assessing physical performance, in addition to cognitive function, can help identify high-risk patients for delirium after SAVR and TAVR.Keywords: delirium, physical performance, aortic valve replacement, prediction

Yun Jeong Chae,* Dae Hee Kim,* Eun Jeong Park, Juyeon Oh, In Kyong Yi Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon 16499, South Korea*These authors contributed equally to this workCorrespondence: In Kyong YiDepartment of Anaesthesiology and Pain Medicine, Ajou University School of Medicine, 164 World Cup-ro, Yeongtong-gu, Suwon 16499, South KoreaTel +82 219 7522Fax +82 219 5579Email lyrin01@gmail.comPurpose: Videolaryngoscopy in nasotracheal intubation has been reported to be better than direct laryngoscopy. The most suitable type of videolaryngoscope remains unknown. This study aimed to compare two videolaryngoscopes (McGrath MAC and Pentax AWS) with a Macintosh laryngoscope during nasotracheal intubation.Methods: Overall, 123 patients older than 18 with normal airways who needed nasotracheal intubation were randomly allocated into three groups: Macintosh (n=41), McGrath (n=41), and Pentax (n=41). Intubation time was the primary outcome and subdivided into three steps: nose to oropharynx, oropharynx to laryngeal inlet, and laryngeal inlet to trachea. Time required, ease of each step, glottic view grade, modified nasal intubation–difficulty score, and subjective difficulty were evaluated.Results: Intubation time among the three groups was not significantly different (Macintosh 34.6±8.1 seconds, McGrath 35.2±7.9 seconds, Pentax 36.2±9.7 seconds; p=0.727). While the glottal view was better with videolaryngoscopes (I/IIa/IIb/III 36.6%/36.6%/19.5%/7.3% vs 82.9%/9.8%/7.3%/0%, vs 63.4%/29.3%/4.9%/2.4%, p=0.000), modified nasal intubation–difficulty score and subjective difficulty and ease of each step were not significantly different. However, the Pentax took longest for the second step (11.8±6.3 vs 10.3±3.5 vs 15.1±7.6 seconds, p=0.001) but was shortest for the third step (2.9±2.6 vs 4.4±5.6 vs 1.7±0.7 seconds, p=0.001).Conclusion: The McGrath MAC and Pentax AWS showed no benefits in intubation time or difficulty, despite better glottal views, compared to the Macintosh laryngoscope in nasotracheal intubation. Additionally, videolaryngoscopes had variable performance at different steps of nasotracheal intubation.Keywords: laryngoscopes, laryngoscopy, intubation, trachea, nose

Dae Hun Kim,1,* Jae Yeol Kim,1,* Rae Man Kim,1 Pooja Maharjan,1 Yu-Geun Ji,2 Dong-Jin Jang,3 Kyoung Ah Min,1 Tae-Sung Koo,2 Kwan Hyung Cho1 1Department of Pharmacy, Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Republic of Korea; 2Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea; 3Department of Pharmaceutical Engineering, Inje University, Gimhae, Republic of Korea *These authors contributed equally to this work Background: The present study aimed to develop orlistat-loaded solid self-nanoemulsifying drug delivery system preconcentrate (SSP) with the minimum use of lipid excipients for the enhanced solubility, in vitro dissolution, lipase inhibition, and in vivo performance. Materials and methods: In the screening of solubilizing vehicles, Solutol HS15 and Lauroglycol 90 were selected as the surfactant and oil phase, respectively. A pseudo-ternary phase diagram composed of Solutol HS15, Lauroglycol 90, and orlistat as an anti-obesity agent and lipid component was constructed, and the SSP regions were confirmed in terms of the particle size distribution in water, melting point by differential scanning calorimetry, and crystallinity by X-ray diffraction. Results: Physicochemical interaction between Solutol HS15 and orlistat resulted in SSP with various melting points in the range of 26°C~33°C. The representative maximum orlistat-loaded SSP (orlistat/Solutol HS15/Lauroglycol 90=55/40/5, weight ratio) showed the melting point of 32.23°C and constructed uniform nanoemulsion with the particle size of 141.7±1.1 nm dispersed in water. In the dissolution test at pH 1.2 without any detergent, the SSP reached 98.12%±0.83% until 45 minutes, whereas raw orlistat showed no significant dissolution rate. The dissolution samples containing SSP showed a lipase inhibition of 90.42%±1.58% within 45 minutes. In terms of the reduction level of fat absorption in rats, the intake group of SSP gave a significantly higher fat excretion into stool than the one observed in the raw orlistat group (P

Sun Jeong Kim,1 Philip D Tatman,2 Da-Hyun Song,1 Albert O Gee,3 Deok-Ho Kim,2 Sang Jun Kim1 1Department of Physical and Rehabilitation Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea; 2Department of Bioengineering, University of Washington, Seattle, WA, USA; 3Department of Orthopedic Surgery and Sports Medicine, University of Washington, Seattle, WA, USA Background: Tendon-derived stem cells (TDSCs) are key factors associated with regeneration and healing in tendinopathy. The aim of this study was to investigate the effects of mechanical stiffness and topographic signals on the differentiation of TDSCs depending on age and pathological conditions. Materials and methods: We compared TDSCs extracted from normal tendon tissues with TDSCs from tendinopathic Achilles tendon tissues of Sprague Dawley rats in vitro and TDSCs cultured on nanotopographic cues and substrate stiffness to determine how to control the TDSCs. The tendinopathy model was created using a chemical induction method, and the tendon injury model was created via an injury-and-overuse method. Norland Optical Adhesive 86 (NOA86) substrate with 2.48 GPa stiffness with and without 800 nm-wide nanogrooves and a polyurethane substrate with 800 nm-wide nanogrooves were used. Results: TDSCs from 5-week-old normal tendon showed high expression of type III collagen on the flat NOA86 substrate. In the 15-week normal tendon model, expression of type III collagen was high in TDSCs cultured on the 800 nm NOA86 substrates. However, in the 15-week tendon injury model, expression of type III collagen was similar irrespective of nanotopographic cues or substrate stiffness. The expression of type I collagen was also independent of nanotopographic cues and substrate stiffness in the 15-week normal and tendon injury models. Gene expression of scleraxis was increased in TDSCs cultured on the flat NOA86 substrate in the 5-week normal tendon model (P=0.001). In the 15-week normal tendon model, scleraxis was highly expressed in TDSCs cultured on the 800 nm and flat NOA86 substrate (P=0.043). However, this gene expression was not significantly different between the substrates in the 5-week tendinopathy and 15-week tendon injury models. Conclusion: Development and maturation of tendon are enhanced when TDSCs from normal tendons were cultured on stiff surface, but not when the TDSCs came from pathologic models. Therapeutic applications of TDSCs need to be flexible based on tendon age and tendinopathy. Keywords: gene expression, differentiation, animal models, tendon-derived stem cells

Seung Hyun Kim,1 Do-Hyeong Kim,2 Eungjin Kim,1 Hyun Jung Kim,3,* Yong Seon Choi2,* 1Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 2Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 3Department of Preventive Medicine, College of Medicine, Institute for Evidence-based Medicine, Korea University, Seoul, Korea *These authors contributed equally to this work Purpose: Perioperative dextrose-containing fluid administration has been used as a non-pharmacologic preventive measure against postoperative nausea and vomiting (PONV), a common and distressing complication of anesthesia. However, its efficacy remains unclear as previous studies reported inconsistent results. Our objective was to compare dextrose-containing fluid with non-dextrose-containing fluid in terms of PONV for 24 hours after surgery under general anesthesia. The effects of dextrose according to different types of surgery and the fluid volume were also examined.Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing dextrose-containing fluid with non-dextrose-containing fluids after general anesthesia in terms of PONV incidence and the need for rescue anti-emetic therapies for 24 hours after surgery. A literature search was performed, using Medline, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus, up to February 2018.Results: We included seven RCTs. Compared with the control group, perioperative dextrose administration did not reduce the risk for PONV, with a relative risk (RR) of 0.72 (95% CI: 0.50–1.03). However, perioperative dextrose reduced the requirement for anti-emetics, compared with the control group, with a RR of 0.60 (95% CI: 0.44–0.83). The quality of evidence in this meta-analysis was poor due to high risks of selection and performance biases and substantial statistical heterogeneity. After subgroup analysis, the risk for PONV was reduced in patients who had undergone laparoscopic cholecystectomy, but not other surgeries, and the effects of dextrose on the risk for PONV did not differ according to the fluid volume administered.Conclusion: Perioperative intravenous (i.v.) dextrose did not reduce the risk for PONV. However, it did reduce the need for anti-emetics after general anesthesia. Furthermore, the effects of dextrose varied according to the surgery type. Further studies are needed to determine the benefits of perioperative i.v. dextrose administration as a preventive measure against PONV. Keywords: general anesthesia, PONV, dextrose, laparoscopic cholecystectomy

Il-Young Jang,1,2 Hee-Won Jung,3 Hyelim Park,1,2 Chang Ki Lee,4 Sang Soo Yu,2 Young Soo Lee,1 Eunju Lee,1 Robert J Glynn,5,6 Dae Hyun Kim6,7 1Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2PyeongChang Health Center & County Hospital, Pyeongchang, Gangwon-Do, Republic of Korea; 3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea; 4Goldman Urology Clinic, Seoul, Republic of Korea; 5Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; 6Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; 7Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA Purpose: The primary aim of this study was to evaluate the effectiveness of a 6-month multicomponent intervention on physical function in socioeconomically vulnerable older adults in rural communities. As secondary aims, we evaluated the effectiveness of the intervention on frailty and other geriatric syndromes, sustained benefit at 12 months, and baseline characteristics associated with poor response. Patients and methods: This designed-delay study was conducted in 187 adults (mean age: 77 years; 75% women) who were living alone or on a low income in three rural regions of Korea. A 24-week multicomponent program that consisted of group exercise, nutritional supplementation, depression management, deprescribing medications, and home hazard reduction was implemented with a planned 6-month interval from August 2015 through January 2017. The primary outcome was physical function, measured using the Short Physical Performance Battery (SPPB) score (range: 0–12; minimum clinically important difference ≥1) at 6 months. Secondary outcomes included frailty phenotype, sarcopenia, Mini Nutritional Assessment-Short Form score (range: 0–14), Center for Epidemiologic Studies-Depression Scale score (range: 0–60), and falls. Results: At 6 months, the SPPB score increased by 3.18 points (95% CI: 2.89, 3.48) from baseline. The program improved frailty (odds ratio: 0.06; 95% CI: 0.02, 0.16), sarcopenia (odds ratio: 0.32; 95% CI: 0.15, 0.68), Mini Nutritional Assessment-Short Form score by 1.67 points (95% CI: 1.28, 2.06), and Center for Epidemiologic Studies-Depression Scale score by -3.83 points (95% CI: -5.26, -2.39), except for fall (rate ratio: 0.99; 95% CI: 0.69, 1.43). These beneficial effects were sustained at 12 months. Body mass index ≥27 kg/m2 and instrumental activities of daily living disability at baseline were associated with poor improvement in the SPPB score. Conclusion: This 24-week multicomponent program had sustained beneficial effects up to 1 year on physical function, frailty, sarcopenia, depressive symptoms, and nutritional status in socioeconomically vulnerable older adults in rural communities. (ClinicalTrials.gov, NCT 02554994) Keywords: clinical trial, exercise, frailty, geriatric assessment, malnutrition, public health practice

Do-Hyeong Kim, Namo Kim, Jae Hoon Lee, Minju Jo, Yong Seon Choi Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea Background: Children undergoing major orthopedic surgery of the lower extremities can experience severe postoperative pain; yet, the ideal postoperative pain management strategy is unknown. Thus, in this patient population, we investigated the effect of intraoperative epidural infusion of local anesthetic on acute postoperative pain and analgesic consumption. Patients and methods: Patients (N=50, 3–12 years) randomly received either ropivacaine 0.15% (preemptive group) or normal saline (control group) as an initial bolus of 0.2 mL/kg, followed by continuous infusion of 0.15 mL/kg/h throughout surgery. Following surgery, patient-controlled epidural analgesia with ropivacaine 0.1% was provided. The main study outcomes were the revised Face, Legs, Activity, Cry, and Consolability pain scores, epidural ropivacaine consumption, and additional analgesic requirements during the first 48 hours postoperatively. Results: Forty-seven patients completed the study, 23 in the preemptive group and 24 in the control group, respectively. The revised Face, Legs, Activity, Cry, and Consolability pain scores were significantly lower in the preemptive group only at 30 minutes after postanesthesia care unit arrival and 6 hours after surgery (median difference –1.0, 95% CI –2.0 to –1.0, P=0.001 and median difference –2.0, 95% CI –3.0 to –1.0, P=0.005, respectively). However, they were not significantly different between the groups at 12, 24, and 48 hours postoperatively. Epidural ropivacaine consumption and additional analgesic requirements throughout 48 hours postoperatively were not significantly different between the groups. Conclusion: Intraoperative epidural infusion of ropivacaine did not demonstrate preemptive analgesic efficacy within 48 hours postoperatively in children undergoing extensive lower limb orthopedic surgery. Keywords: epidural analgesia, postoperative analgesia, orthopedics, pediatrics

Do-Hyeong Kim,1 Seokyung Shin,1 Ji Young Kim,1 Seung Hyun Kim,2 Minju Jo,2 Yong Seon Choi1 1Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Background: This study investigated the ability of pulse pressure variation (PPV) and pleth variability index (PVI) to predict fluid responsiveness of patients undergoing spinal surgery in the prone position.Patients and methods: A total of 53 patients undergoing posterior lumbar spinal fusion in the prone position on a Jackson table were studied. PPV, PVI, and hemodynamic and respiratory variables were measured both before and after the administration of 6 mL/kg colloid in both the supine and prone positions. Fluid responsiveness was defined as a 15% or greater increase in stroke volume index, as assessed by esophageal Doppler monitor after fluid loading.Results: In the supine position, 40 patients were responders. The areas under the receiver operating characteristic (ROC) curves for PPV and PVI were 0.783 [95% CI 0.648–0.884, P

Il-Young Jang,1,2 Chang Ki Lee,3 Hee-Won Jung,4,5 Sang Soo Yu,2 Young Soo Lee,1 Eunju Lee,1 Dae Hyun Kim6,7 1Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2PyeongChang Health Center & County Hospital, PyeongChang, Gangwon-Do, Republic of Korea; 3Goldman Urology Clinic, Seoul, Republic of Korea; 4Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea; 5Geriatric Center, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-Do, Republic of Korea; 6Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 7Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA Purpose: Frailty is an important consideration in the management of lower urinary tract symptoms and erectile dysfunction in older men; frailty increases vulnerability to treatment-related adverse outcomes, but its burden is not known. The authors aimed to examine the burden of frailty and associated geriatric conditions in community-dwelling older men.Patients and methods: A cross-sectional study was conducted with 492 community-dwelling older men (mean age, 74.2 years; standard deviation, 5.6 years). All the participants were administered the International Prostate Symptom Score (IPSS) (range: 0–35) and a five-item version of the International Index of Erectile Function (IIEF-5) (range: 5–25). Frailty phenotype was assessed based on exhaustion, inactivity, slowness, weakness, and weight loss. Prevalence of frailty phenotype and geriatric conditions were assessed by the IPSS severity category (mild, 0–7; moderate, 8–19; severe, 20–35 points) and the first IIEF-5 question, which assesses the confidence in erectile function (low, 1–2; moderate, 3; high, 4–5 points).Results: Older men with severe urologic symptoms had a high prevalence of frailty. According to the IPSS questionnaire, the prevalence of frailty was 7.3% (21/288) in the mild category, 16.3% (26/160) in the moderate category, and 43.2% (19/44) in the severe category. Participants in the severe IPSS category showed high prevalence of dismobility (45.5%), multimorbidity (43.2%), malnutrition risk (40.9%), sarcopenia (40.9%), and polypharmacy (31.8%). According to erectile confidence based on the first IIEF-5 question, the prevalence of frailty was 18.7% (56/300) for low confidence, 5.3% (6/114) for moderate confidence, and 5.1% (4/78) for high confidence. Participants with low confidence in erectile function showed high prevalence of sarcopenia (39.0%), multimorbidity (37.7%), dismobility (35.7%), malnutrition risk (33.3%), and polypharmacy (23.0%).Conclusion: The prevalence of frailty and geriatric conditions was higher in older men with severe urologic symptoms. A frailty screening should be routinely administered in urology practices to identify older men who are vulnerable to treatment-related adverse events. Keywords: erectile dysfunction, frailty, geriatric assessment, lower urinary tract symptoms, risk management

Dae Hee Kim,1 Go Un Roh,2 Young Bok Lee,3 Chang Ik Choi,3 Jae Moon Lee,3 Yun Jeong Chae1 1Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon, 2Department of Anesthesiology and Pain Medicine, CHA Bundang Medical Center, CHA University, Seongnam, 3Department of Anesthesiology and Pain Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea Purpose: The development of emergence agitation (EA) is associated with several factors including age, preoperative anxiety, postoperative pain, anesthesia method, and surgery type. No studies have investigated whether the withdrawal reaction following rocuronium injection can predict the occurrence of EA. Therefore, we investigated this relationship in preschool-aged children undergoing inguinal herniorrhaphy, and which grade of withdrawal reaction is appropriate for identifying patients at risk of experiencing EA. Methods: A total of 40 patients were enrolled in this study. During anesthesia induction, the withdrawal reaction after loss of consciousness following rocuronium injection was assessed using a 4-point scale. After surgery, EA was assessed using the Watcha scale. Results: There was a correlation between withdrawal reaction and EA on admission to the postanesthesia care unit (PACU). Patients with a severe withdrawal reaction (grade 3) showed a significantly higher incidence of severe EA requiring medication on admission to the PACU. Conclusion: The findings of this preliminary exploratory observational study suggest that it is possible for withdrawal movement following rocuronium injection during anesthesia induction to reflect pain sensitivity of pediatric patients, which in turn may be useful in identifying those at risk of severe EA on admission to the PACU among preschool children undergoing inguinal herniorrhaphy. Further studies with a larger sample size are required to validate these findings. The exact correlation between pain reaction following rocuronium injection and postoperative pain or pain-related phenomenon should be elucidated. Keywords: emergence agitation, prediction, rocuronium, withdrawal movement

Yi-Hwa Choi,1 Dae-Hwan Kim,2 Tae-Young Kim,2 Tae-Wan Lim,1 Seok-Woo Kim,2 Je-Hyun Yoo2 1Department of Anesthesiology and Pain Medicine, Hallym Sacred Heart Hospital, Hallym University College of Medicine, 2Department of Orthopaedic Surgery, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea Purpose: Postoperative delirium is a risk factor for worse outcome after hip fracture surgery in elderly patients. Postoperative delirium is associated with anesthesia, postoperative pain, and patient factors. We investigated the incidence, predictors, and prognostic implications of postoperative delirium after hemiarthroplasty (HA) in elderly patients with femoral neck fracture.Patients and methods: A total of 356 consecutive patients aged >70 years who underwent HA for femoral neck fracture were enrolled. Diagnosis of delirium was made by a psychiatrist based on patient status and an objective scoring system. The patients were divided into 2 categories according to the HA onset time (immediate [≤24 h after surgery] vs delayed delirium [>24 h after surgery]) and its incidence, predictors and mortality were evaluated.Results: Postoperative delirium was diagnosed in 110 patients (30.9%) during hospitalization. Immediate and delayed delirium occurred in 59 (53.6%), and 51 (46.4%) patients, respectively. The independent predictors of immediate delirium included age (odds ratio [OR] 1.47, 95% CI 0.98–2.23, p=0.066), and general anesthesia (OR 2.25, 95% CI 1.17–4.43, p=0.015). The independent predictors of delayed delirium were parkinsonism (OR 5.75, 95% CI 1.66–19.96, p=0.006), intensive care unit stay (OR 1.85, 95% CI 0.97–3.56, p=0.064), and higher American Society of Anesthesiologists grade (OR 2.33, 95% CI 0.90–6.07, p=0.083). On Kaplan–Meier survival analysis, the 2-year survival rate was significantly lower in the immediate delirium group than those in the delayed and control groups (71.0% vs 83.6% vs 87.8%, respectively; p=0.031).Conclusion: Immediate and delayed delirium after HA for femoral neck fracture had different predictors and immediate delirium was associated with worse prognosis. Keywords: delirium, elderly patients, femoral neck fracture, hemiarthroplasty

Jong Ho Ahn,1 Yoon-Hyeong Choi,2 Hae Jung Paik,1 Mee Kum Kim,3 Won Ryang Wee,3 Dong Hyun Kim1 1Department of Ophthalmology, Gachon University Gil Medical Center, 2Department of Preventive Medicine, Gachon University College of Medicine, Incheon, 3Department of Ophthalmology, Seoul National University College of Medicine, Seoul, South Korea Purpose: Aging is a major risk factor in dry eye disease (DED), and understanding sexual differences is very important in biomedical research. However, there is little information about sex differences in the effect of aging on DED. We investigated sex differences in the effect of aging and other risk factors for DED.Methods: This study included data of 16,824 adults from the Korea National Health and Nutrition Examination Survey (2010–2012), which is a population-based cross-sectional survey. DED was defined as the presence of frequent ocular dryness or a previous diagnosis by an ophthalmologist. Basic sociodemographic factors and previously known risk factors for DED were included in the analyses. Linear regression modeling and multivariate logistic regression modeling were used to compare the sex differences in the effect of risk factors for DED; we additionally performed tests for interactions between sex and other risk factors for DED in logistic regression models.Results: In our linear regression models, the prevalence of DED symptoms in men increased with age (R=0.311, P=0.012); however, there was no association between aging and DED in women (P>0.05). Multivariate logistic regression analyses showed that aging in men was not associated with DED (DED symptoms/diagnosis: odds ratio [OR] =1.01/1.04, each P>0.05), while aging in women was protectively associated with DED (DED symptoms/diagnosis: OR =0.94/0.91, P=0.011/0.003). Previous ocular surgery was significantly associated with DED in both men and women (men/women: OR =2.45/1.77 [DED symptoms] and 3.17/2.05 [DED diagnosis], each P

Do Hyun Kim,1 Su Jeong Kim,1 Sultan Ullah,1 Hwi Young Yun,1 Pusoon Chun,2 Hyung Ryong Moon1 1College of Pharmacy, Pusan National University, Busan, 2College of Pharmacy, Inje University, Gimhae, South Korea Abstract: The authors designed and synthesized 17 (2-substituted phenyl-1,3-dithiolan-4-yl) methanol (PDTM) derivatives to find a new chemical scaffold, showing excellent tyrosinase-inhibitory activity. Their tyrosinase-inhibitory activities were evaluated against mushroom tyrosinase at 50 µM, and five of the PDTM derivatives (PDTM3, PDTM7–PDTM9, and PDTM13) were found to inhibit mushroom tyrosinase more than kojic acid or arbutin, the positive controls. Of seventeen PDTMs, PDTM3 (half-maximal inhibitory concentration 13.94±1.76 µM), with a 2,4-dihydroxyphenyl moiety, exhibited greatest inhibitory effects (kojic acid half-maximal inhibitory concentration 18.86±2.14 µM). Interestingly, PDTM compounds with no hydroxyl group, PDTM7–PDTM9, also had stronger inhibitory activities than kojic acid. In silico studies of interactions between tyrosinase and the five PDTMs suggested their binding affinities were closely related to their tyrosinase-inhibitory activities. Cell-based experiments performed using B16F10 mouse-skin melanoma cells showed that PDTM3 effectively inhibited melanogenesis and cellular tyrosinase activity. A cell-viability study conducted using B16F10 cells indicated that the antimelanogenic effect of PDTM3 was not attributable to its cytotoxicity. Kinetic studies showed PDTM3 competitively inhibited tyrosinase, indicating binding to the tyrosinase-active site. We found that PDTM3 with a new chemical scaffold could be a promising candidate for skin-whitening agents, and that the 1,3-dithiolane ring could be used as a chemical scaffold for potent tyrosinase inhibition. Keywords: tyrosinase inhibitor, melanogenesis, 1,3-dithiolane, PDTM

Jong-Hyun Jeong,1 Won-Myong Bahk,1 Young Sup Woo,1 Kyung-Uk Lee,1 Do Hoon Kim,2 Moon-Doo Kim,3 Won Kim,4 Jong-Chul Yang,5 Kwang Heun Lee6 1Department of Psychiatry, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 2Department of Psychiatry, Chuncheon Sacred Heart Hospital, Hallym University, Chuncheon, 3Department of Psychiatry, Jeju National University Hospital, Jeju, 4Department of Psychiatry, Stress Research Institute, Seoul Paik Hospital, College of Medicine, Inje University, Seoul, 5Department of Psychiatry, Chonbuk National University Medical School, Jeonju, 6Department of Psychiatry, College of Medicine, Dongguk University, Gyeongju, South Korea Objectives: The primary aim of this non-inferiority study was to investigate the clinical effectiveness and safety of generic escitalopram (Lexacure®) versus branded escitalopram (Lexapro®) for patients with major depressive disorder (MDD).Methods: The present study included 158 patients, who were randomized (1:1) to receive a flexible dose of generic escitalopram (n=78) or branded escitalopram (n=80) over a 6-week single-blind treatment period. The clinical benefits in the two groups were evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS), the 17-item Hamilton Depression Rating Scale (HDRS), the Clinical Global Impressions-Severity scale (CGI-S), and the Clinical Global Impressions-Improvement scale (CGI-I) at baseline, week 1, week 2, week 4, and week 6. The frequency of adverse events (AEs) was also assessed to determine safety at each follow-up visit.Results: During the 6-week study period, 30 patients (38.5%) from the generic escitalopram group and 28 patients (30.0%) from the branded escitalopram group dropped out of the study (P=0.727). The MADRS, HDRS, CGI-S, and CGI-I scores significantly decreased in both groups, and there were no significant differences between the groups. At week 6, 28 patients (57.1%) in the generic escitalopram group and 35 patients (67.3%) in the branded escitalopram group had responded to treatment (as indicated by a ≥50% decrease from the baseline MADRS score; P=0.126), and the remission rates (MADRS score: ≤10) were 42.9% (n=21) in generic escitalopram group and 53.8% (n=28) in the branded escitalopram group (P=0.135). The most frequently reported AEs were nausea (17.9%), sleepiness/somnolence (7.7%), weight gain (3.8%), and dry mouth (2.6%) in the generic escitalopram group and nausea (20.0%), sleepiness/somnolence (3.8%), weight gain (2.5%), and dry mouth (2.5%) in the branded escitalopram group.Conclusion: The present non-inferiority study demonstrated that generic escitalopram is a safe and an effective initial treatment for patients with MDD and may also be considered as an additional therapeutic option for this population. Keywords: depression, branded escitalopram, Lexapro®, generic escitalopram, Lexacure®

Hwi Young Yun,1 Do Hyun Kim,1 Sujin Son,1 Sultan Ullah,1 Seong Jin Kim,1 Yeon-Jeong Kim,2 Jin-Wook Yoo,1 Yunjin Jung,1 Pusoon Chun,2 Hyung Ryong Moon1 1College of Pharmacy, Pusan National University, Busan, 2College of Pharmacy, Inje University, Gimhae, Republic of Korea Background: Tyrosinase is the most prominent target for inhibitors of hyperpigmentation because it plays a critical role in melaninogenesis. Although many tyrosinase inhibitors have been identified, from both natural and synthetic sources, there remains a considerable demand for novel tyrosinase inhibitors that are safer and more effective. Methods: (E)-2-Benzoyl-3-(substituted phenyl)acrylonitriles (BPA analogs) with a linear β-phenyl-α,β-unsaturated carbonyl scaffold were designed and synthesized as potential tyrosinase inhibitors. We evaluated their effects on cellular tyrosinase activity and melanin biosynthesis in murine B16F10 melanoma cells and their ability to inhibit mushroom tyrosinase activity. Results: BPA analogs exhibited inhibitory activity against mushroom tyrosinase. In particular, BPA13 significantly suppressed melanin biosynthesis and inhibited cellular tyrosinase activity in B16F10 cells in a dose-dependent manner. A docking study revealed that BPA13 had higher binding affinity for tyrosinase than kojic acid. Conclusion: BPA13, which possesses a linear β-phenyl-α,β-unsaturated carbonyl scaffold, is a potential candidate skin-whitening agent and treatment for diseases associated with hyperpigmentation. Keywords: (E)-2-benzoyl-3-(substituted phenyl)acrylonitriles, melanogenesis, tyrosinase inhibitor

Tae Won Kwak,1,* Hee Jae Shin,2,* Young-Il Jeong,1 Myoung-Eun Han,3 Sae-Ock Oh,3 Hyun-Jung Kim,4 Do Hyung Kim,5 Dae Hwan Kang1 1Biomedical Research Institute, Pusan National University Hospital, Busan, 2Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science and Technology, Ansan, 3Department of Anatomy, School of Medicine, Pusan National University, Gyeongnam, 4Genewel Co Ltd. Gyeonggi-do, 5School of Medicine, Pusan National University, Yangsan, Gyeongnam, Republic of Korea *These authors contributed equally to this work Background: The aim of this study is to investigate the anticancer activity of streptochlorin, a novel antineoplastic agent, in cholangiocarcinoma. Methods: The anticancer activity of streptochlorin was evaluated in vitro in various cholangiocarcinoma cell lines for apoptosis, proliferation, invasiveness, and expression of various protein levels. A liver metastasis model was prepared by splenic injection of HuCC-T1 cholangiocarcinoma cells using a BALB/c nude mouse model to study the systemic antimetastatic efficacy of streptochlorin 5 mg/kg at 8 weeks. The antitumor efficacy of subcutaneously injected streptochlorin was also assessed using a solid tumor xenograft model of SNU478 cells for 22 days in the BALB/c nude mouse. Results: Streptochlorin inhibited growth and secretion of vascular endothelial growth factor by cholangiocarcinoma cells in a dose-dependent manner and induced apoptosis in vitro. In addition, streptochlorin effectively inhibited invasion and migration of cholangiocarcinoma cells. Secretion of vascular endothelial growth factor and activity of matrix metalloproteinase-9 in cholangiocarcinoma cells were also suppressed by treatment with streptochlorin. Streptochlorin effectively regulated metastasis of HuCC-T1 cells in a mouse model of liver metastasis. In a tumor xenograft study using SNU478 cells, streptochlorin significantly inhibited tumor growth without changes in body weight when compared with the control. Conclusion: These results reveal that streptochlorin is a promising chemotherapeutic agent to the treatment of cholangiocarcinoma. Keywords: streptochlorin, cholangiocarcinoma, chemotherapeutic agent, invasion, metastasis

Dong-Hwan Kim,1 Ubonvan Termsarasab,1 Hyun-Jong Cho,2 In-Soo Yoon,3 Jae-Young Lee,1 Hyun Tae Moon,1 Dae-Duk Kim1 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; 2College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea; 3College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea Abstract: Low-molecular-weight heparin (LMWH)–stearylamine (SA) conjugates (LHSA)-based self-assembled nanoparticles were prepared for intravenous delivery of docetaxel (DCT). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide were used as coupling agents for synthesis of LHSA conjugates. The physicochemical properties, in vitro antitumor efficacy, in vitro cellular uptake efficiency, in vivo antitumor efficacy, and in vivo pharmacokinetics of LHSA nanoparticles were investigated. The LHSA nanoparticles exhibited a spherical shape with a mean diameter of 140–180 nm and a negative surface charge. According to in vitro release and in vivo pharmacokinetic test results, the docetaxel-loaded LHSA5 (LMWH:SA =1:5) nanoparticles exhibited sustained drug release profiles. The blank LHSA nanoparticles demonstrated only an insignificant cytotoxicity in MCF-7 and MDAMB 231 human breast cancer cells; additionally, higher cellular uptake of coumarin 6 (C6) in MCF-7 and MDAMB 231 cells was observed in the LHSA5 nanoparticles group than that in the C6 solution group. The in vivo tumor growth inhibition efficacy of docetaxel-loaded LHSA5 nanoparticles was also significantly higher than the Taxotere®-treated group in the MDAMB 231 tumor-xenografted mouse model. These results indicated that the LHSA5-based nanoparticles could be a promising anticancer drug delivery system. Keywords: amphiphilic polymer, docetaxel, drug delivery, low-molecular-weight heparin, self-assembled nanoparticle

Jae-Hyun Kim,1,* Cheol-Su Kim,1,* Rosa Mistica Coles Ignacio,2,* Dong-Heui Kim,2 Ma Easter Joy Sajo,2 Eun Ho Maeng,3 Xu-Feng Qi,4 Seong-Eun Park,5 Yu-Ri Kim,7 Meyoung-Kon Kim,7 Kyu-Jae Lee,2 Soo-Ki Kim1,5,6 1Department of Microbiology, 2Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju-si, Gangwon-do, Republic of Korea; 3Healthcare Laboratory, Medical Device Evaluation, Korea Testing and Research Institute, Wonju-si, Gangwon-do, Republic of Korea; 4Key Laboratory for Regenerative Medicine of Ministry of Education and Department of Developmental and Regenerative Biology, School of Life Science and Technology, Ji Nan University, Guangzhou, People’s Republic of China; 5Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju-si, Gangwon-do, Republic of Korea; 6Institute of Biomaterials, Yonsei University, Wonju Campus, Wonju-si, Gangwon-do, Republic of Korea; 7Department of Biochemistry and Molecular Biology, Medical School and College, Korea University, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: Silicon dioxide (SiO2) nanoparticles (NPs) have been widely used in the biomedical field, such as in drug delivery and gene therapy. However, little is known about the biological effects and potential hazards of SiO2. Herein, the colloidal SiO2 NPs with two different sizes (20 nm and 100 nm) and different charges (L-arginine modified: SiO2EN20[R], SiO2EN100[R]; and negative: SiO2EN20[-], SiO2EN100[-]) were orally administered (750 mg/kg/day) in female C57BL/6 mice for 14 days. Assessments of immunotoxicity include hematology profiling, reactive oxygen species generation and their antioxidant effect, stimulation assays for B- and T-lymphocytes, the activity of natural killer (NK) cells, and cytokine profiling. In vitro toxicity was also investigated in the RAW 264.7 cell line. When the cellularity of mouse spleen was evaluated, there was an overall decrease in the proliferation of B- and T-cells for all the groups fed with SiO2 NPs. Specifically, the SiO2EN20(-) NPs showed the most pronounced reduction. In addition, the nitric oxide production and NK cell activity in SiO2 NP-fed mice were significantly suppressed. Moreover, there was a decrease in the serum concentration of inflammatory cytokines such as interleukin (IL)-1Β, IL-12 (p70), IL-6, tumor necrosis factor-α, and interferon-γ. To elucidate the cytotoxicity mechanism of SiO2 in vivo, an in vitro study using the RAW 264.7 cell line was performed. Both the size and charge of SiO2 using murine macrophage RAW 264.7 cells decreased cell viability dose-dependently. Collectively, our data indicate that different sized and charged SiO2 NPs would cause differential immunotoxicity. Interestingly, the small-sized and negatively charged SiO2 NPs showed the most potent in vivo immunotoxicity by way of suppressing the proliferation of lymphocytes, depressing the killing activity of NK cells, and decreasing proinflammatory cytokine production, thus leading to immunosuppression. Keywords: silicon dioxide, nanoparticle, immunotoxicity, oxidative stress, cytokines, immunosuppression

Hye Myeong Lee,1,* Chung-Wook Chung,2,* Cy Hyun Kim,1,3 Do Hyung Kim,1,3 Tae Won Kwak,1 Young-Il Jeong,1 Dae Hwan Kang1,3 1National Research and Development Center for Hepatobiliary Cancer, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Republic of Korea; 2Department of Biological Sciences, Andong National University, Andong, Republic of Korea; 3School of Medicine, Pusan National University, Yangsan, Republic of Korea *Both authors contributed equally to this work Abstract: In this study, the effect of chlorin e6-based photodynamic therapy (Ce6-PDT) was investigated in human intrahepatic (HuCC-T1) and extrahepatic (SNU1196) cholangiocarcinoma (CCA) cells. The amount of intracellular Ce6 increased with increasing Ce6 concentration administered, or with incubation time, in both cell lines. The ability to take up Ce6 and generate reactive oxygen species after irradiation at 1.0 J/cm2 did not significantly differ between the two CCA cell types. However, after irradiation, marked differences were observed for photodamage and apoptotic/necrotic signals. HuCC-T1 cells are more sensitive to Ce6-PDT than SNU1196 cells. Total glutathione (GSH) levels, glutathione peroxidase and glutathione reductase activities in SNU1196 cells were significantly higher than in HuCC-T1 cells. With inhibition of enzyme activity or addition of GSH, the phototoxic effect could be controlled in CCA cells. The intracellular level of GSH is the most important determining factor in the curative action of Ce6-PDT against tumor cells. Keywords: cholangiocarcinoma, chlorin e6, photodynamic therapy, reactive oxygen species, glutathione, heme oxygenase-1

Ji Eun Kim,1 Sang Mok Lee,2 Soo Hyun Kim,1 Phil Tatman,3 Albert O Gee,4 Deok-Ho Kim,3,5 Kyung Eun Lee,6 Youngmee Jung,1 Sang Jun Kim21Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, South Korea; 2Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Seoul, South Korea; 3Department of Bioengineering, 4Department of Orthopaedics and Sports Medicine, 5Institute for Stem Cell and Regenerative Medicine and Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA; 6Advanced Analysis Center, Korea Institute of Science and Technology, Seoul, South KoreaPurpose: To evaluate the efficacy of mesenchymal stem cells (MSCs) encapsulated in self-assembled peptide (SAP) hydrogels in a rat knee model for the prevention of osteoarthritis (OA) progression.Materials and methods: Nanostructured KLD-12 SAPs were used as the injectable hydrogels. Thirty-three Sprague Dawley rats were used for the OA model. Ten rats were used for the evaluation of biotin-tagged SAP disappearance. Twenty-three rats were divided into four groups: MSC (n=6), SAP (n=6), SAP-MSC (n=6), and no treatment (n=5). MSCs, SAPs, and SAP-MSCs were injected into the knee joints 3 weeks postsurgery. Histologic examination, immunofluorescent staining, measurement of cytokine levels, and micro-computed tomography analysis were conducted 6 weeks after injections. Behavioral studies were done to establish baseline measurements before treatment, and repeated 3 and 6 weeks after treatment to measure the efficacy of SAP-MSCs.Results: Concentration of biotinylated SAP at week 1 was not significantly different from those at week 3 and week 6 (P=0.565). Bone mineral density was significantly lower in SAP-MSC groups than controls (P=0.002). Significant differences in terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining between the control group and all other groups were observed. Caspase-8, tissue inhibitor of metalloproteinases 1, and matrix metalloproteinase 9 were diffusely stained in controls, whereas localized or minimal staining was observed in other groups. Modified Mankin scores were significantly lower in the SAP and SAP-MSC groups than in controls (P=0.001 and 0.013). Although not statistically significant, synovial inflammation scores were lower in the SAP (1.3±0.3) and SAP-MSC (1.3±0.2) groups than in controls (2.6±0.2). However, neither the cytokine level nor the behavioral score was significantly different between groups.Conclusion: Injection of SAP-MSC hydrogels showed evidence of chondroprotection, as measured by the histologic grading and decreased expression of biochemical markers of inflammation and apoptosis. It also lowered subchondral bone mineral density, which can be increased by OA. This suggests that the SAP-MSC complex may have clinical potential to inhibit OA progression.Keywords: self-assembled peptide, mesenchymal stem cell, osteoarthritis, apoptosis, chondrogenesis

Eung-Sam Kim,1,2 Eun Hyun Ahn,3,4 Tal Dvir,5,6 Deok-Ho Kim1,4,71Department of Bioengineering, University of Washington, Seattle, WA, USA; 2Department of Biological Sciences, Chonnam National University, Gwangju, Korea; 3Department of Pathology, 4Institute of Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA, USA; 5Department of Molecular Microbiology and Biotechnology, 6Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; 7Center for Cardiovascular Biology, University of Washington, Seattle, WA, USAThe history of human kind suggests that there has been a correlation between global population growth and major events in science and technology over the last three centuries. Sharp increases in the world’s population have been triggered by the industrial revolution and scientific and technological breakthroughs including: the advent of the railways, discovery of penicillin and deoxyribonucleic acid (DNA), and the invention of the computer.1 Since the 20th century, interdisciplinary areas in the physical and biological sciences have accelerated the progress of biomedical applications. The recent integration of emerging nanotechnology into biology and biomedicine has resulted in a range of innovative nanoengineering efforts for the repair and regeneration of tissues and organs.2 Thus, it is expected that nanoengineering approaches to biomedical applications can contribute to addressing the present issue of personal and global health care and its economic burden for more than 7 billion people.Why are we paying attention to nanoengineering for biomedical applications? The size of most biomolecules ranges from 0.2 nm to 200 nm (Figure 1). Research has focused on control of the interaction and localization of biomolecules even at the single-molecule level using ever-evolving nanotechnology.3 The evidence indicates that cells can respond to nanoscale changes in the dynamic extracellular matrix and vice versa. Biomimetic nanopatterns alone can direct the differentiation of stem cells without involvement of exogenous soluble biochemical factors.4,5 This regulation of cellular behavior by nanotechnology is one of many examples demonstrating the significant applications of nanoengineering in biomedicine. This special issue includes four review papers and seven research articles that provide an insight into current nanoengineering approaches to the repair or regeneration of tissues and organs.

Yang Guo,1 Zhuoli Zhang,1 Dong-Hyun Kim,1,5 Weiguo Li,1 Jodi Nicolai,1 Daniel Procissi,1 Yi Huan,2 Guohong Han,3 Reed A Omary,1,4,5 Andrew C Larson1,4,5 1Department of Radiology, Northwestern University, Chicago, IL, USA; 2Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China; 3Department of Digestive Interventional Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China; 4Department of Biomedical Engineering, Northwestern University, Chicago, IL, USA; 5Robert H Lurie Comprehensive Cancer Center, Chicago, IL, USA Purpose: Photothermal ablation is a minimally invasive approach, which typically involves delivery of photothermal sensitizers to targeted tissues. The purpose of our study was to demonstrate that gold nanoparticles are phagocytosed by pancreatic cancer cells, thus permitting magnetic resonance imaging (MRI) of sensitizer delivery and photothermal ablation. Patients and methods: Iron-oxide core/gold-shell nanoparticles (GoldMag®, 30 nm diameter; Xi'an GoldMag Biotechnology Co, Xi'an, People's Republic of China) were used. In a 96-well plate, 3 × 104 PANC-1 (human pancreatic cancer cell line) cells were placed. GoldMag (0, 25, or 50 µg/mL) was added to each well and 24 hours allowed for cellular uptake. Samples were then divided into two groups: one treated with photothermal ablation (7.9 W/cm2) for 5 minutes, the other not treated. Photothermal ablation was performed using laser system (BWF5; B&W Tek, Inc, Newark, DE, USA). Intraprocedural temperature changes were measured using a fiber optic temperature probe (FTP-LN2; Photon Control Inc, Burnaby, BC, Canada). After 24 hours, the remaining number of viable cells was counted using trypan blue staining; cell proliferation percentage was calculated based on the total number of viable cells after treatment compared with control. MRI of GoldMag uptake was performed using a 7.0T ClinScan system (Bruker BioSpin, Ettlingen, Germany). Results: Temperature curves demonstrated that with increased GoldMag uptake, laser irradiation produced higher temperature elevations in the corresponding samples; temperature elevations of 12.89°C, 35.16°C, and 79.51°C were achieved for 0, 25, and 50 µg/mL GoldMag. Without photothermal ablation, the cell proliferation percentage changed from 100% to 71.3% and 47.0% for cells treated with 25 and 50 µg/mL GoldMag. Photothermal ablation of PANC-1 cells demonstrated an effective treatment response, specifically a reduction to only 61%, 21.9%, and 2.3% cell proliferation for cells treated with 0, 25, and 50 µg/mL GoldMag. MRI was able to visualize GoldMag uptake within PANC-1 cells. Conclusion: Our findings suggest that photothermal ablation may be effective in the treatment of pancreatic cancer. GoldMag nanoparticles could serve as photothermal sensitizers, and MRI is feasible to quantify delivery. Keywords: photothermal ablation therapy, hybrid nanoparticles, magnetic resonance imaging

Jong-Ho Hwang,1,2 Cheol Woong Choi,1 Hyung-Wook Kim,1 Do Hyung Kim,3 Tae Won Kwak,3 Hye Myeong Lee,3 Cy Hyun Kim,3 Chung Wook Chung,3 Young-Il Jeong,3 Dae Hwan Kang1,3 1Department of Internal Medicine, Medical Research Institute, Pusan National University School of Medicine, Yangsan, Republic of Korea; 2Department of Internal Medicine, Busan Medical Center, Yeonje-gu, Busan, Republic of Korea; 3National Research and Development Center for Hepatobiliary Disease, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea Purpose: Nanoparticles based on stimuli-sensitive drug delivery have been extensively investigated for tumor targeting. Among them, pH-responsive drug targeting using pH-sensitive polymers has attracted attention because solid tumors have an acidic environment. A dextran-b-poly(L-histidine) (DexPHS) copolymer was synthesized and pH-responsive nanoparticles were fabricated for drug targeting. Methods and results: A DexPHS block copolymer was synthesized by attaching the reductive end of dextran to the amine groups of poly(L-histidine). pH-responsive nanoparticles incorporating doxorubicin were fabricated and studied in HuCC-T1 cholangiocarcinoma cells. Synthesis of DexPHS was confirmed by 1H nuclear magnetic resonance spectroscopy, with specific peaks of dextran and PHS observed at 2–5 ppm and 7.4–9.0 ppm, respectively. DexPHS nanoparticles showed changes in particle size with pH sensitivity, ie, the size of the nanoparticles increased at an acidic pH and decreased at a basic pH. DexPHS block copolymer nanoparticles incorporating doxorubicin were prepared using the nanoprecipitation dialysis method. The doxorubicin release rate was increased at acidic pH compared with basic pH, indicating that DexPHS nanoparticles have pH-sensitive properties and that drug release can be controlled by variations in pH. The antitumor activity of DexPHS nanoparticles incorporating doxorubicin were studied using HuCC-T1 cholangiocarcinoma cells. Viability was decreased in cells treated with nanoparticles at acidic pH, whereas cell viability in response to treatment with doxorubicin did not vary according to changes of pH. Conclusion: Our results indicated that DexPHS polymeric micelles are promising candidates for antitumor drug targeting. Keywords: pH-responsive drug targeting, nanoparticles, block copolymer, poly(L-histidine), dextran

Kyung Dong Lee,1,* Young-Il Jeong,2,* Da Hye Kim,3,4 Gyun-Taek Lim,2 Ki-Choon Choi5 1Department of Oriental Medicine Materials, Dongshin University, Naju, South Korea; 2Department of Polymer Engineering, Chonnam National University, Gwangju, South Korea; 3Faculty of Life and Environmental Science, Shimane University, Matsue, Japan; 4United Graduate School of Agricultural Sciences, Tottori University, Tottori, Japan; 5Grassland and Forages Division, National Institute of Animal Science, Rural Development Administration, Cheonan, South Korea *These authors contributed equally to this work Background: Although cisplatin is extensively used in the clinical field, its intrinsic toxicity limits its clinical use. We investigated nanoparticle formations of poly(acrylic acid-co-methyl methacrylate) (PAA-MMA) incorporating cisplatin and their antitumor activity in vitro and in vivo. Methods: Cisplatin-incorporated nanoparticles were prepared through the ion-complex formation between acrylic acid and cisplatin. The anticancer activity of cisplatin-incorporated nanoparticles was assessed with CT26 colorectal carcinoma cells. Results: Cisplatin-incorporated nanoparticles have small particle sizes of less than 200 nm with spherical shapes. Drug content was increased according to the increase of the feeding amount of cisplatin and acrylic acid content in the copolymer. The higher acrylic acid content in the copolymer induced increase of particle size and decrease of zeta potential. Cisplatin-incorporated nanoparticles showed a similar growth-inhibitory effect against CT26 tumor cells in vitro. However, cisplatin-incorporated nanoparticles showed improved antitumor activity against an animal tumor xenograft model. Conclusion: We suggest that PAA-MMA nanoparticles incorporating cisplatin are promising carriers for an antitumor drug-delivery system. Keywords: cisplatin, nanoparticle, poly(acrylic acid-co-methyl methacrylate), ion complexes

Cy Hyun Kim,1,2,* Chung-Wook Chung,1,* Hye Myeong Lee,1 Do Hyung Kim,1,2 Tae Won Kwak,1 Young-IL Jeong,1 Dae Hwan Kang1,21National Research and Development Center for Hepatobiliary Cancer, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Republic of Korea; 2School of Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea*These authors contributed equally to this workAbstract: 5-Aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has the potential to kill cancer cells via apoptotic or necrotic signals that are dependent on the generation of intracellular reactive oxygen species (ROS). Celecoxib is an anti-inflammatory drug that induces intracellular ROS generation. We investigated whether the combined application of celecoxib and ALA-PDT improved the efficacy of PDT in human cholangiocarcinoma cells and in tumor bearing mice. In vitro, combined treatment of celecoxib and ALA-PDT increased phototoxicity and intracellular ROS levels after irradiation with 0.75 J/cm2 when compared to ALA-PDT alone. Even though ROS levels increased with 0.25 J/cm2 of irradiation, it did not influence phototoxicity. When heme oxygenase-1, a defensive protein induced by oxidative stress, was inhibited in the combined treatment group, phototoxicity was increased at both 0.25 J/cm2 and 0.75 J/cm2 of irradiation. We identified the combined effect of ALA-PDT and celecoxib through the increase of oxidative stress such as ROS. In vivo, about 40% tumor growth inhibition was observed with combined application of ALA-PDT and celecoxib when compared to ALA-PDT alone. The combined application of ALA-PDT and celecoxib could be an effective therapy for human cholangiocarcinoma. Moreover, use of a heme oxygenase-1 inhibitor with PDT could play an important role for management of various tumors involving oxidative stress.Keywords: celecoxib, aminolevulinic acid, reactive oxygen species, photodynamic therapy, human cholangiocarcinoma

Do Hyung Kim,1,2,* Young-Il Jeong,1,* Chung-Wook Chung,1 Cy Hyun Kim,1,2 Tae Won Kwak,1 Hye Myeong Lee,1 Dae Hwan Kang1,21National Research and Development Center for Hepatobiliary Cancer, Pusan National University Yangsan Hospital, 2School of Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, South Korea *These authors equally contributed to this work. Background: Cholangiocarcinoma is a malignant tumor arising from the epithelium of the bile ducts. In this study, we prepared sorafenib-loaded biliary stents for potential application as drug-delivery systems for localized treatment of extrahepatic cholangiocarcinoma. Methods: A sorafenib-coated metal stent was prepared using an electrospray system with the aid of poly(ε-caprolactone) (PCL), and then its anticancer activity was investigated using human cholangiocellular carcinoma (HuCC)-T1 cells in vitro and a mouse tumor xenograft model in vivo. Anticancer activity of sorafenib against HuCC-T1 cells was evaluated by the proliferation test, matrix metalloproteinase (MMP) activity, cancer cell invasion, and angiogenesis assay in vitro and in vivo. Results: The drug-release study showed that the increased drug content on the PCL film induced a faster drug-release rate. The growth of cancer cells on the sorafenib-loaded PCL film surfaces decreased in a dose-dependent manner. MMP-2 expression of HuCC-T1 cells gradually decreased according to sorafenib concentration. Furthermore, cancer cell invasion and tube formation of human umbilical vein endothelial cells significantly decreased at sorafenib concentrations higher than 10 mM. In the mouse tumor xenograft model with HuCC-T1 cells, sorafenib-eluting PCL films significantly inhibited the growth of tumor mass and induced apoptosis of tumor cells. Various molecular signals, such as B-cell lymphoma (Bcl)-2, Bcl-2-associated death promoter, Bcl-x, caspase-3, cleaved caspase-3, Fas, signal transducer and activator of transcription 5, extracellular signal-regulated kinases, MMP-9 and pan-janus kinase/stress-activated protein kinase 1, indicated that apoptosis, inhibition of growth and invasion was cleared on sorafenib-eluting PCL films. Conclusion: These sorafenib-loaded PCL films are effective in inhibiting angiogenesis, proliferation and invasion of cancer cells. We suggest that sorafenib-loaded PCL film is a promising candidate for the local treatment of cholangiocarcinoma. Keywords: sorafenib, polycaprolactone, biliary stent, human cholangiocarcinoma cells, angiogenesis

Young Il Jeong,1,* Kyu Don Chung,2,* Da Hye Kim,3 Yoon Hyuk Kim,4 Yeon Soo Lee,5 Ki Choon Choi31Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea; 2Department of Anesthesiology and Pain Medicine, Catholic University, Seoul, South Korea; 3Grassland and Forage Research Center, Rural Development Administration, Cheonan, South Korea; 4Department of Mechanical Engineering, Kyung Hee University, Seoul, South Korea; 5Department of Biomedical Engineering, Catholic University of Daegu, Daegu, South Korea*These authors equally contributed to this workPurpose: All-trans retinoic acid (RA)-incorporated nanoparticles were prepared using deoxycholic acid-conjugated dextran (DexDA). Anticancer activity of RA-incorporated DexDA nanoparticles were tested in vitro and in vivo.Methods: RA-incorporated nanoparticles were prepared by dialysis. Antiproliferative and anti-invasive potential of RA-incorporated nanoparticles were studied using CT26 colorectal carcinoma cells.Results: RA-incorporated nanoparticles have small particle sizes of around 70–300 nm and spherical shapes. The higher drug-feeding ratio and higher substitution degree of deoxycholic acid in the conjugates resulted in higher drug contents, lower loading efficiency, and larger particle size. RA release rate became slower at higher drug contents and higher substitution degree of deoxycholic acid in the DexDA conjugates. The antiproliferation activity, anti-invasive activity, and matrix metalloproteinase 2 expression of RA-incorporated nanoparticles against CT26 cells in vitro was similar to RA. However, RA-incorporated nanoparticles had superior antimetastatic activity in an animal pulmonary metastatic model of CT26 cells compared to RA itself.Conclusion: RA-incorporated nanoparticles showed similar anticancer activity in vitro and superior antimetastatic activity in vivo in a pulmonary metastatic model of CT26 cells. We suggest that RA-incorporated nanoparticles are promising vehicles for efficient delivery of RA.Keywords: nanoparticle, dextran, deoxycholic acid, retinoic acid, cancer cell invasion

Young-Il Jeong1,*, Do Hyung Kim1,2,*, Chung-Wook Chung1, Jin-Ju Yoo1, Kyung Ha Choi1, Cy Hyun Kim1,2, Seung Hee Ha1, Dae Hwan Kang1,2 1National Research and Development Center for Hepatobiliary Cancer, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea, Research Institute for Convergence of Biomedical Science and Technology, 2School of Medicine, Pusan National University, Yangsan, Republic of Korea*These authors contributed equally to this work.Background: Polymeric micelles using amphiphilic macromolecules are promising vehicles for antitumor targeting. In this study, we prepared anticancer agent-incorporated polymeric micelles using novel block copolymer.Methods: We synthesized a block copolymer composed of dextran and poly (DL-lactide-co-glycolide) (DexbLG) for antitumor drug delivery. Doxorubicin was selected as the anticancer drug, and was incorporated into polymeric micelles by dialysis. Polymeric micelles were observed by transmission electron microscopy to be spherical and smaller than 100 nm, with a narrow size distribution. The particle size of doxorubicin-incorporated polymeric micelles increased with increasing drug content. Higher initial drug feeding also increased the drug content. Results: During the drug-release study, an initial burst release of doxorubicin was observed for 10 hours, and doxorubicin was continuously released over 4 days. To investigate the in vitro anticancer effects of the polymeric micelles, doxorubicin-resistant HuCC-T1 cells were treated with a very high concentration of doxorubicin. In an antiproliferation study, the polymeric micelles showed higher cytotoxicity to doxorubicin-resistant HuCC-T1 cells than free doxorubicin, indicating that the polymeric micelles were effectively engulfed by tumor cells, while free doxorubicin hardly penetrated the tumor cell membrane. On confocal laser scanning microscopy, free doxorubicin expressed very weak fluorescence intensity, while the polymeric micelles expressed strong red fluorescence. Furthermore, in flow cytometric analysis, fluorescence intensity of polymeric micelles was almost twice as high than with free doxorubicin.Conclusion: DexbLG polymeric micelles incorporating doxorubicin are promising vehicles for antitumor drug targeting.Keywords: dextran, polymeric micelle, block copolymer, poly(DL-lactide-co-glycolide)

Cy Hyun Kim1,2, Chung-Wook Chung1, Kyung Ha Choi1, Jin-Ju Yoo1, Do Hyung Kim1,2, Young-IL Jeong1, Dae Hwan Kang1,21National Research and Development Center for Hepatobiliary Cancer, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea; 2School of Medicine, Pusan National University, Yangsan, Republic of Korea The first two authors contributed equally to this work.Abstract: Cancer cells have been reported to exhibit an enhanced capacity for protoporphyrin IX (PpIX) synthesis facilitated by the administration of 5-aminolevulinic acid (ALA). We investigated the effect of ALA-based photodynamic therapy (PDT) on human cholangiocarcinoma cells (HuCC-T1). Since protoporphyrin IX (PpIX), a metabolite of ALA, can produce reactive oxygen species (ROS) under irradiation and then induce phototoxicity, ALA-based PDT is a promising candidate for the treatment of cholangiocarcinoma. When various concentrations of ALA (0.05–2 mM) were used to treat HuCC-T1 cells for 6 or 24 hours, the intracellular PpIX level increased according to the ALA concentration and treatment time. Furthermore, an increased amount of PpIX in HuCC-T1 cells induced increased production of ROS by irradiation, resulting in increased phototoxicity.Keywords: ALA-based photodynamic therapy, HuCC-T1, protoporphyrin IX, ROS

BackgroundFrailty is associated with mortality in older adults hospitalized with COVID-19, yet few studies have quantified healthcare utilization and spending following COVID-19 hospitalization.ObjectiveTo evaluate whether survival and follow-up healthcare utilization and expenditures varied as a function of claims-based frailty status for older adults hospitalized with COVID-19.DesignRetrospective cohort study.Participants136 patients aged 65 and older enrolled in an Accountable Care Organization (ACO) risk contract at an academic medical center and hospitalized for COVID-19 between March 11, 2020 - June 3, 2020.MeasurementsWe linked a COVID-19 Registry with administrative claims data to quantify a frailty index and its relationship to mortality, healthcare utilization, and expenditures over 6 months following hospital discharge. Kaplan Meier curves and Cox Proportional Hazards models were used to evaluate survival by frailty. Kruskal-Wallis tests were used to compare utilization. A generalized linear model with a gamma distribution was used to evaluate differences in monthly Medicare expenditures.ResultsMuch of the cohort was classified as moderate to severely frail (65.4%), 24.3% mildly frail, and 10.3% robust or pre-frail. Overall, 27.2% (n=37) of the cohort died (n=26 during hospitalization, n=11 after discharge) and survival did not significantly differ by frailty. Among survivors, inpatient hospitalizations during the 6-month follow-up period varied significantly by frailty (p=0.02). Mean cost over follow-up was $856.37 for the mild and $4914.16 for the moderate to severe frailty group, and monthly expenditures increased with higher frailty classification (p

Self-Assembly, a process in which molecules, polymers, and particles are driven by local interactions to organize into patterns and functional structures, is being exploited in advancing silicon electronics and in emerging, unconventional electronics. Silicon electronics has relied on lithographic patterning of polymer resists at progressively smaller lengths to scale down device dimensions. Yet, this has become increasingly difficult and costly. Assembly of block copolymers and colloidal nanoparticles allows resolution enhancement and the definition of essential shapes to pattern circuits and memory devices. As we look to a future in which electronics are integrated at large numbers and in new forms for the Internet of Things and wearable and implantable technologies, we also explore a broader material set. Semiconductor nanoparticles and biomolecules are prized for their size-, shape-, and composition-dependent properties and for their solution-based assembly and integration into devices that are enabling unconventional manufacturing and new device functions.

A three-dimensional breakdown behavior of the magnetic Bloch-point domain wall (BP-DW) propagation was investigated in a ferromagnetic nanowire with the variation of the external magnetic field by means of micromagnetic simulation. As magnetic field strength increases up to a threshold value, the BP-DW velocity approaches a critical phase velocity of the spontaneously emitting spin wave (SW), where a Cherenkov-type DW breakdown phenomenon is observed originating from an interaction between the spontaneously emitting SW and the BP-DW. It is found that the velocity of the BP-DW approaches a maximum value (∼2000 m/s) due to the intrinsic reversal time of a BP spin texture. This suggests that although cylindrical ferromagnetic nanowires might be free from the two-dimensional Walker breakdown phenomenon, there exists a Cherenkov-type three-dimensional breakdown behavior.

With increasing global uptake of variable-speed (inverter-driven) air conditioners (ACs), the globally uniform energy-efficiency ratio (EER) metric has given way to various region-specific part-load and seasonal performance AC metrics in many markets. As a result, policymakers around the world lack comparative data that might help them create more effective AC efficiency market-transformation programs. To help fill this gap, this paper explores relationships between the room AC efficiency performance metrics of different regions—including China, the European Union, India, Japan, South Korea, and the United States—using performance data for split room AC models. We use these interregional conversion relationships to estimate the performance of >6000 AC models, including reversible heat pumps, in efficiency metrics used in the six economies as well as the International Organization for Standardization (ISO) 16,358 metric. Our results suggest a way to identify the potential for improving AC efficiency policies in regional markets. The most efficient models sold in each region and worldwide typically are more efficient than the most efficient level recognized by regional energy standards and labeling programs. This information could help policymakers evaluate and improve their AC efficiency market-transformation programs to align with the globally best-available technology.

The electronic structure of a charge density wave (CDW) system PrTe3 and its modulated structure in the CDW phase have been investigated by employing ARPES, XAS, Pr 4 f RPES, and first-principles band structure calculation. Pr ions are found to be nearly trivalent, supporting the CDW instability in the metallic Te sheets through partial filling. Finite Pr 4 f spectral weight is observed near the Fermi level, suggesting the non-negligible Pr 4 f contribution to the CDW formation through the Pr 4 f -Te 5p hybridization. The two-fold symmetric features in the measured Fermi surface (FS) of PrTe3 are explained by the calculated FS for the assumed 7 × 1 CDW supercell formation in Te sheets. The shadow bands and the corresponding very weak FSs are observed, which originate from both the band folding due to the 3D interaction of Te sheets with neighboring Pr-Te layers and that due to the CDW-induced FS reconstruction. The straight vertical FSs are observed along kz, demonstrating the nearly 2D character for the near-EF states. The observed linear dichroism reveals the in-plane orbital character of the near-EF Te 5p states.

© 2015 Vossel et al.Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid β (Aβ) peptides and pathological forms of the microtubuleassociated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transpo

Background/objectivesThe accuracy of dietary recalls might be enhanced by providing participants with photo images of foods they consumed during the test period.Subjects/methodsWe examined the feasibility of a system (Image-Diet Day) that is a user-initiated camera-equipped mobile phone that is programmed to automatically capture and transmit images to a secure website in conjunction with computer-assisted, multipass, 24-h dietary recalls in 14 participants during 2007. Participants used the device during eating periods on each of the three independent days. Image processing filters successfully eliminated underexposed, overexposed and blurry images. The captured images were accessed by the participants using the ImageViewer software while completing the 24-h dietary recall on the following day.ResultsNone of the participants reported difficulty using the ImageViewer. Images were deemed 'helpful' or 'sort of helpful' by 93% of participants. A majority (79%) of users reported having no technical problems, but 71% rated the burden of wearing the device as somewhat to very difficult, owing to issues such as limited battery life, self-consciousness about wearing the device in public and concerns about the field of view of the camera.ConclusionOverall, these findings suggest that automated imaging is a promising technology to facilitate dietary recall. The challenge of managing the thousands of images generated can be met. Smaller devices with a broader field of view may aid in overcoming self-consciousness of the user with using or wearing the device.

Ureteral-iliac artery fistula (UIAF) is a rare life threatening cause of hematuria. The increasing frequency is attributed to increasing use of ureteral stents. A 68-year-old female presented with gross hematuria. She had prior low anterior resection for rectal cancer and a retained ureteral stent. CT abdomen and pelvis showed a large recurrent pelvic mass and a retained stent. The patient underwent cystoscopy which showed a normal bladder. Upon removal of the stent, brisk bleeding was noted coming from the ureteral orifice. Antegrade pyelogram was done which revealed a UIAF. Angiography was done and a covered stent was placed. Multiple treatment options are available. All must consider management of the arterial and ureteral side. The arterial side may be addressed by primary open repair, embolization with extra-anatomic vascular reconstruction, or endovascular stenting. The ureter can be managed with nephroureterectomy, ureteral reconstruction, placement of a nephrostomy tube, or ureteral stenting. Being minimally invasive, we believe that endovascular stenting should be the preferred therapeutic option as it also corrects the source of bleeding while preserving distal blood flow.