Search

Yul Hee Kim,1 Han-Seul Kim,1 Hyeung Kyoo Kim,2 Soo Young Kim,2 Jeonghun Lee,2 You Chan Kim,1 Young Joon Park1 1Department of Dermatology, Ajou University School of Medicine, Suwon, Republic of Korea; 2Department of Surgery, Ajou University School of Medicine, Suwon, Republic of KoreaCorrespondence: Young Joon Park, Department of Dermatology, Ajou University Hospital, 164, World Cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-Do, Suwon, Republic of Korea, Tel +82-31-219-5187, Email aro@ajou.ac.krPurpose: Early intervention of surgical scars with a pulsed dye laser is known to effectively prevent pathologic scars. Despite multiple reports on the effectiveness of the treatment, very few studies have demonstrated its appropriate initiation timing. In this study, our objective was to determine the optimal timing for initiating laser treatment following thyroidectomy.Methods: This study retrospectively analyzed 91 patients undergoing pulsed dye laser treatment post-thyroidectomy, grouping them by treatment initiation timing. The patients underwent treatment at intervals of 3– 4 weeks with at least five sessions. Those with a high pliability score were injected with intralesional corticosteroids. The Antera 3D® skin imaging analyzer was used to assess biophysical parameters.Results: The total Vancouver Scar Scale score significantly reduced after treatment in all groups. The Vancouver Scar Scale score reduction rate was significantly higher after treatment in the group for which the treatment was initiated within 3 weeks of surgery. The pigmentation and erythema score analyzed by Antera 3D® was also lower in this group.Conclusion: Early intervention using a pulsed dye laser within 3 weeks of thyroidectomy can substantially inhibit pathological scar development, providing physicians with a guide for optimal treatment commencement.Keywords: hypertrophic scars, laser treatment of scar, scar, pulsed dye laser

Sohyeon Yu,1,2 Sangwoo Kim,1,3 Jisu Kim,1,3 Ji-Woong Kim,4 Su Young Kim,4 Bongjun Yeom,2 Hyungjun Kim,5 Won II Choi,1 Daekyung Sung1 1Center for Bio-Healthcare Materials, Bio-Convergence Materials R&D Division, Korea Institute of Ceramic Engineering and Technology, Cheongju, 28160, Republic of Korea; 2Department of Chemical Engineering, Hanyang University, Seoul, 04763, Republic of Korea; 3Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, 03722, Republic of Korea; 4Materials Science Research Institute, LABIO Co., Ltd, Seoul, 08501, Republic of Korea; 5Department of Chemistry and Bioscience, Kumoh National Institute of Technology, Gyeongbuk, 39177, Republic of KoreaCorrespondence: Won II Choi; Daekyung Sung, Center for Bio-Healthcare Materials, Bio-Convergence Materials R&D Division, Korea Institute of Ceramic Engineering and Technology, Cheongju, 28160, Republic of Korea, Tel +82-43-913-1513 ; +82-43-913-1511, Fax +82-43-913-1597, Email choi830509@kicet.re.kr; dksung@kicet.re.krIntroduction: Deinoxanthin (DX), a carotenoid, has excellent antioxidant and anti-inflammatory properties. However, owing to its lipophilicity, it is unfavorably dispersed in water and has low stability, limiting its application in cosmetics, food, and pharmaceuticals. Therefore, it is necessary to study nanoparticles to increase the loading capacity and stability of DX.Methods: In this study, DX-loaded nanocapsules (DX@NCs) were prepared by nanoprecipitation by loading DX into nanocapsules. The size, polydispersity index, surface charge, and morphology of DX@NCs were confirmed through dynamic light scattering and transmission electron microscopy. The loading content and loading efficiency of DX in DX@NCs were analyzed using high-performance liquid chromatography. The antioxidant activity of DX@NCs was evaluated by DPPH assay and in vitro ROS. The biocompatibility of DX@NCs was evaluated using an in vitro MTT assay. In vitro NO analysis was performed to determine the effective anti-inflammatory efficacy of DX@NCs.Results: DX@NCs exhibited increased stability and antioxidant efficacy owing to the improved water solubility of DX. The in situ and in vitro antioxidant activity of DX@NCs was higher than that of unloaded DX. In addition, it showed a strong anti-inflammatory effect by regulating the NO level in an in vitro cell model.Conclusion: This study presents a nanocarrier to improve the water-soluble dispersion and stability of DX. These results demonstrate that DX@NC is a carrier with excellent stability and has a high potential for use in cosmetic and pharmaceutical applications owing to its antioxidant and anti-inflammatory effects.Keywords: deinoxanthin, nanoprecipitation, reactive oxygen species scavenging, antioxidant activity, anti-inflammation

Ji-Yeon Park,1 Hae-Jin Ko,1,2 Ji-Eun Song,3 Sang-Min Ji,4 So-Yun Kim4 1Department of Family Medicine, Kyungpook National University Hospital, Daegu, Korea; 2Department of Family Medicine, School of Medicine, Kyungpook National University, Daegu, Korea; 3Department of Family Medicine, Kyungpook National University Chilgok Hospital, Daegu, Korea; 4Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju, KoreaCorrespondence: Hae-Jin Ko, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu, Korea, Tel +82-53-200-6578, Fax +82-53-200-5480, Email liveforme@knu.ac.krPurpose: Animal-assisted intervention (AAI) is an effective intervention that improves the mental and physical health. However, few have examined the efficacy of pet insects as a form of AAI for prefrail and frail elderly. This study aimed to ascertain the effects of pet insects on physical performance and psychological health in community-dwelling frail elderly individuals with a chronic disease.Patients and Methods: This study was an 8 week prospective single-arm interventional pilot study that enrolled prefrail and frail community-dwelling adults aged 70 years and older, all of whom had a chronic disease and attended a daycare facility. Pet insects and appropriate equipment were provided, and supporting programs were used to educate participants about how to rear the insects and how to get close to them. Pre- and post-interventional physical and psychological functions were evaluated.Results: A total of 23 subjects (mean age, 82.78 years) were enrolled in the final analysis. The timed up-and-go-test (TUG) was used to measure functional mobility, and grip strength was used as a measure of muscle strength; both showed significant changes after the 8-week intervention (Δ = − 0.35± 0.73 sec, P = 0.034; and Δ = 0.73± 0.99 kg, P = 0.002, respectively). In addition, the insomnia severity index (ISI) and average sleep duration improved significantly (Δ = − 2.91± 5.64, P = − 0.021; and Δ = 0.87± 1.98, P = 0.047, respectively). There were no significant changes in the results of other psychometric tests. Logistic regression analysis using the forward stepwise selection method revealed that the baseline ISI score and the absence of other comorbidities were significantly associated with the probability of positive changes in both the TUG and HS tests after the intervention.Conclusion: Pet insects may be an effective and easily applicable type of AAI, which improves physical function and sleep in prefrail and frail elderly individuals.Keywords: animal-assisted therapy, frail elderly, human-animal interaction, physical functional performance, sleep disorders

Seohyun Lee,1 Young-Ji Lee,2 SeYeon Kim,2 Wonil Choi,2 Yoojin Jeong,2 Nina Jinjoo Rhim,3 Ilwon Seo,4 Sun-Young Kim2,5 1Department of Global Public Administration, Yonsei University Mirae Campus, Wonju, Republic of Korea; 2Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea; 3Good Neighbors International, Seoul, Republic of Korea; 4Good Neighbors Ghana, Accra, Ghana; 5Institute of Health and Environment, Seoul National University, Seoul, Republic of KoreaCorrespondence: Sun-Young Kim, Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea, Tel +82-2-880-2768, Fax +82-2-762-2888, Email sykim22@snu.ac.krPurpose: An electronic health record (EHR) system known as the e-Tracker was introduced in community health facilities in Ghana and numerous advantages were expected for clinical staff, as evidenced by previous literature. However, little is known about public health officials’ views, specifically in low-resource settings. This study aimed to investigate the perceptions of district health officers on data quality, use, and management following the adoption of tablet-based electronic health records in Ghana.Methods: A pre- and post-survey was conducted in two regions of Ghana that adopted the e-Tracker for the entire districts during the early stages of the national rollout. Sociodemographic information, internet connection environment, and perceptions on data quality, use, and management were measured. McNemar’s test and Wilcoxon Signed-Rank test were performed to identify changes in perceptions. Chi-square test and Mann–Whitney U-test were used to find any statistical differences in demographic characteristics between the two regions.Results: Twenty-four out of 25 districts in Volta and 24 out of 26 districts in Eastern regions participated in both pre- and post-surveys, with a total of 73 participants. In terms of efficiency in data management, the district health officers reported reduced time commitment in data validation and aggregation. Within less than a year, however, no statistically significant improvement was found in data quality and the use of electronic data for relevant tasks.Conclusion: A new EHR system in low-resource settings can rapidly improve efficiency in data management from the public health officials’ perspectives. Further impact evaluation is warranted to assess the long-term effect of the EHR system.Keywords: mHealth, maternal and child health, Sub-Saharan Africa, LMIC

Minoxidil was originally introduced as a potent vasodilator, but is now widely used as a topical treatment for human alopecia. A 4-year-old neutered male Norwegian Forest cat presented with a 2-day history of anorexia, lethargy, and dyspnoea. A physical examination revealed hypothermia, tachypnoea, hypotension, and bilateral pulmonary crackles. The radiographs revealed pulmonary oedema and pleural effusions. The hypotension and pleural effusions exacerbated despite the supportive therapy, and the underlying cause remained undetermined. A further medical inquiry revealed the cat had been exposed to a topical minoxidil solution 3 days before admission. Accordingly, minoxidil toxicosis was managed using both i.v. fluids and vasopressors. Dopamine and norepinephrine were infused for 3 days to normalise the patient's blood pressure and related clinical signs. The cat recovered fully and was discharged 6 days after the minoxidil exposure. This is the first report on the successful management of minoxidil toxicosis in a cat. To broaden our knowledge of minoxidil toxicosis in cats, we have also described the serial changes in the clinical findings of this cat over the treatment period. Furthermore, on the basis of the experience gained from this case, we suggest an optimised management plan for future cases of feline minoxidil toxicosis.

Soyeon Jang,1 Soyoung Jang,1 Si-Yong Kim,1 Jiwon Ko,1 Eungyung Kim,2 Ji Yeong Park,1 Hyejin Hyung,1 Jin Hong Lee,1 Su-Geun Lim,3 Sijun Park,3 Junkoo Yi,4 Heon-Jin Lee,5 Myoung Ok Kim,2 Hyun-Shik Lee,1 Zae Young Ryoo1 1School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Korea; 2Department of Animal Science and Biotechnology, Kyungpook National University, Daegu, Korea; 3School of Life Science, Kyungpook National University, Daegu, Korea; 4Gyeongsangbukdo Livestock Research Institute, Yeongju, Korea; 5Department of Microbiology and Immunology, School of Dentistry, Kyungpook National University, Daegu, 41940, KoreaCorrespondence: Zae Young Ryoo; Hyun-Shik LeeSchool of Life Science, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, KoreaTel +82-53-950-7361; +82-53-950-7367Fax +82-53-943-6925; +82-53-943-2762Email jaewoong64@knu.ac.kr; leeh@knu.ac.krPurpose: Psoriasis is a common and well-studied autoimmune skin disease, which is characterized by plaques. The formation of psoriasis plaques occurs through the hyperproliferation and abnormal differentiation of keratinocytes, infiltration of numerous immune cells into the dermis, increased subepidermal angiogenesis, and various autoimmune-associated cytokines and chemokines. According to previous research, Lin28 regulates the let-7 family, and let-7b is associated with psoriasis. However, the link between Lin28 and psoriasis is unclear. In this study, an association was identified between Lin28a and psoriasis progression, which promoted the pathological characteristic of psoriasis in epidermal keratinocytes.Patients and Methods: This study aims to investigate the role of Lin28a and its underlying mechanism in psoriasis through in vivo and in vitro models, which include the Lin28a-overexpressing transgenic (TG) mice and Lin28a-overexpressing human keratinocyte (HaCaT) cell lines, respectively.Results: In vivo and in vitro results revealed that overexpression of Lin28a downregulated microRNA let-7 expression levels and caused hyperproliferation and abnormal differentiation in keratinocytes. In imiquimod (IMQ)-induced psoriasis-like inflammation, Lin28a overexpressing transgenic (TG) mice exhibited more severe symptoms of psoriasis.Conclusion: Mechanistically, Lin28a exacerbated psoriasis-like inflammation through the activation of the extracellular-signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 signaling (STAT 3) by targeting proinflammatory cytokine interleukin-6 (IL-6).Keywords: psoriasis, keratinocyte, Lin28a, let-7

Abigail C Burr,1,* Jalene V Velazquez,1,* Arzu Ulu,1 Rohan Kamath,1 Sang Yong Kim,1 Amanpreet K Bilg,1 Aileen Najera,1 Iman Sultan,1 Jon K Botthoff,2 Emma Aronson,3 Meera G Nair,1 Tara M Nordgren1 1Division of Biomedical Sciences, University of California Riverside, Riverside, CA, 92521, USA; 2Center for Conservation Biology, University of California Riverside, Riverside, CA, 92521, USA; 3Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, CA, 92521, USA*These authors contributed equally to this workCorrespondence: Tara M NordgrenDivision of Biomedical Sciences, University of California Riverside, 92521 University Avenue, Riverside, CA, 92521, USATel +1 951 827 3148Email tmnordgren@gmail.comPurpose: The Salton Sea, California’s largest lake, is designated as an agricultural drainage reservoir. In recent years, the lake has experienced shrinkage due to reduced water sources, increasing levels of aerosolized dusts in surrounding regions. Communities surrounding the Salton Sea have increased asthma prevalence versus the rest of California; however, a connection between dust inhalation and lung health impacts has not been defined.Methods: We used an established intranasal dust exposure murine model to study the lung inflammatory response following single or repetitive (7-day) exposure to extracts of dusts collected in regions surrounding the Salton Sea (SSDE), complemented with in vitro investigations assessing SSDE impacts on the airway epithelium.Results: In these investigations, single or repetitive SSDE exposure induced significant lung inflammatory cytokine release concomitant with neutrophil influx. Repetitive SSDE exposure led to significant lung eosinophil recruitment and altered expression of genes associated with allergen-mediated immune response, including Clec4e. SSDE treatment of human bronchial epithelial cells (BEAS-2B) induced inflammatory cytokine production at 5- and 24-hours post-treatment. When BEAS-2B were exposed to protease activity-depleted SSDE (PDSSDE) or treated with SSDE in the context of protease-activated receptor-1 and − 2 antagonism, inflammatory cytokine release was decreased. Furthermore, repetitive exposure to PDSSDE led to decreased neutrophil and eosinophilic influx and IL-6 release in mice compared to SSDE-challenged mice.Conclusion: These investigations demonstrate potent lung inflammatory responses and tissue remodeling in response to SSDE, in part due to environmental proteases found within the dusts. These studies provide the first evidence supporting a link between environmental dust exposure, protease-mediated immune activation, and respiratory disease in the Salton Sea region.Keywords: Salton Sea, dust exposure, lung inflammation, asthma, proteases, protease-activated receptors

Ho Tae Jeong,1 Young Chul Youn,1 Hyun-Ho Sung,2 Sang Yun Kim3 1Department of Neurology, Chung-Ang University of College of Medicine, Seoul, Korea; 2Department of Clinical Laboratory Science, Dongnam Health University, Suwon, Korea; 3Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, KoreaCorrespondence: Young Chul YounDepartment of Neurology, Chung-Ang University College of Medicine, 102, Heukseok-ro, Dongjak-gu, Seoul, 06973, KoreaTel +82 2 6299 1485Fax +82 2 6299 1493Email neudoc@cau.ac.krPurpose: The purpose of this study is to compare and analyze the power spectral changes between subjective cognitive decline (SCD) subjects and normal controls (NC) while checking the preclinical stage of AD in the SCD subjects and to use the derived data for biomarker research that can diagnose early-stage AD in the future.Methods: We recruited 23 SCD patients and 23 normal control subjects and QEEG analysis including power spectral density (PSD) and source-level analysis were performed. An automated preprocessing procedure and statistical analysis were performed by iSync Brain® (iMediSync Inc., Republic of Korea) (https://isyncbrain.com/) using the international standard 10– 20 system (19 electrodes).Results: Absolute PSD, there was no statistically significant difference in all of the EEG power measurements of the 19 channels. In the relative PSD analysis, the average delta band power of the SCD group was significantly higher in Fp2, F4, and F8 than NC. Alpha1 band power of the O1 channel was 22.56± 16.05 for the SCD group and 33.19± 19.05 for the NC (p-value < 0.05). Source-level analysis did not show a statistically significant difference.Conclusion: SCD subjects showed a partial increase of delta waves in the frontal lobe region and a partial decrease in alpha1, a fast wave in the occipital region, compared to the NC. SCD is considered one of the earliest clinical symptoms of AD and it is predicted to be related to minor nerve damage. We were able to observe the power spectral changes in SCD subjects in this cross-sectional study, a large number of subjects and longitudinal studies are needed to evaluate their predictability for future deterioration such as conversion to MCI.Keywords: Alzheimer, cognitive impairment, dementia, hypertension

Jung-Min Pyun,1 Ji Sun Ryu,2 Ryan Lee,2 Kyu Hawn Shim,3 Young Chul Youn,4 Nayoung Ryoo,5 Sang-Won Han,5 Young Ho Park,5 Sungmin Kang,2 Seong Soo A An,6 SangYun Kim5 1Department of Neurology, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu-si, Gyeonggi-do, Republic of Korea; 2Research and Development, PeopleBio Inc., Seongnam-si, Gyeonggi-do, Republic of Korea; 3Department of Neurology, Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea; 4Department of Neurology, Chung-Ang University College of Medicine, Seoul, Republic of Korea; 5Department of Neurology, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea; 6Department of Bionanotechnology, Gachon University, Seongnam-si, Gyeonggi-do, Republic of KoreaCorrespondence: SangYun KimDepartment of Neurology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of KoreaTel +82 31 787 7462 Fax +82 31 787 4059Email neuroksy@snu.ac.krPurpose: Among other emerging amyloid-targeting blood-based biomarkers, Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) measures dynamic changes in concentration of oligomeric amyloid-β (OAβ), which is considered the main pathogenic culprit of Alzheimer’s disease (AD), in plasma after spiking with synthetic amyloid-β (Aβ). We aimed to investigate the predictability of MDS-OAβ on amyloid positron emission tomography (PET) positivity.Patients and Methods: A total of 96 subjects who visited Seoul National University Bundang Hospital for medical check-up complaining of cognitive decline and had undergone extensive medical assessment were recruited. Amyloid statuses were dichotomized into positive or negative based on visual assessment of amyloid PET. Plasma OAβ concentration was measured by MDS-OAβ. In the previous validation study, 0.78ng/mL was established as the cut-off value and the plasma OAβ concentration higher than or equal to the cut-off value was defined as MDS-OAβ positive.Results: MDS-OAβ positivity could discriminate amyloid PET positivity with the AUC value of 0.855 (95% CI 0.776– 0.933). Adding MDS-OAβ positivity to prediction models including age, MMSE score, and APOE ϵ4 status improved performance up to the AUC value of 0.926 (95% CI 0.871– 0.980).Conclusion: The Aβ oligomerization tendency in plasma could predict amyloid PET positivity with high performance, and, when it is combined with age, MMSE score, and APOE ϵ4 status, predictability was improved substantially. This suggests the potential of MDS-OAβ as a useful initial stage test in the clinical and research fields of AD.Keywords: multimer detection system-oligomeric amyloid-β, Aβ oligomer, predictability, amyloidopathy, blood-based biomarker

Binh Thang Tran,1,2 Nhu Hiep Pham,3 Thanh Xuan Nguyen,3 Kui Son Choi,1,4 Dae Kyung Sohn,1,5 Sun-Young Kim,1 Jae Kyung Suh,6 Thuy Duyen Nguyen,1,7 Van Sang Phan,2 Dinh Trung Tran,8 The Thanh Nguyen,9 Thi Thanh Binh Nguyen,10 Minh Tu Nguyen,11 Jin-Kyoung Oh1,12 1Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea; 2Faculty of Public Health, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam; 3Department of Abdominal Emergency and Pediatric Surgery, Hue Central Hospital, Hue City, Vietnam; 4National Cancer Control Institute; National Cancer Center, Goyang, Republic of Korea; 5Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea; 6Division of Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea; 7Center for Population Health Sciences, Hanoi University of Public Health, Hanoi, Vietnam; 8Faculty of Public Health, Da Nang University of Medical Technology and Pharmacy, Da Nang City, Vietnam; 9Department of Endoscopy and Functional Exploration, Da Nang Oncology Hospital, Da Nang City, Vietnam; 10Department of Pediatrics, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam; 11Undergraduate Training Office, Hue University of Medicine and Pharmacy, Hue University, Hue City, Vietnam; 12Division of Cancer Prevention & Early Detection, National Cancer Center, Goyang, Republic of KoreaCorrespondence: Jin-Kyoung OhDepartment of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu, Goyang-si, Gyeonggi-do 410-769, Republic of KoreaTel +82-31-920-2921Fax +82-31-920-2929Email jkoh@ncc.re.krPurpose: Health-related quality of life (HRQoL) is an important construct in clinical settings, and it is crucial that it should be properly measured. As the EuroQol-5-dimensions-5 levels (EQ-5D-5L) is more effective for such measurement than the 3-level model, data on economic models, clinical studies, and public health evaluations previously collected through the EQ-5D-3L need to be revaluated using the EQ-5D-5L. This study evaluated colorectal cancer (CRC) patients’ HRQoL scores using the Vietnamese EQ-5D-5L value set.Patients and Methods: The cross-sectional study included CRC patients treated at a tertiary public hospital. HRQoL was assessed using the EQ-5D-5L, and HRQoL utility scores were calculated using the Vietnamese value set. Tobit regression examined factors associated with HRQoL.Results: The analysis included 197 CRC patients. Ages ranged from 20 to 87 years (M = 57.64, SD = 13.5); 42.2% and 57.8% were diagnosed with cancer of the colon or rectum/anus, respectively. Mean EQ-5D-5L was 0.561 (range, − 0.5115 to 1). Most participants experienced anxiety/depression (88%), followed by pain/discomfort (87%), mobility (71%), usual activity (69%), and self-care (67%). Advanced CRC stage (stage II: β − 0.303, se 0.08; stage III: β − 0.305, se 0.07; stage IV: β − 0.456, se 0.07) and surgery (β − 0.113, se 0.05) were negatively associated with EQ-5D-5L scores. Advanced education (high school: β 0.273, se 0.07); college/vocational: β 0.134se 0.05; university/higher: Coef 0.213, se 0.08;) and older age (age group 35− 44: β 0.253, se 0.10; 45− 54: β 0.327, se 0.09; 55− 64: β 0.355 se 0.09; 65+ β 0.204, se 0.09) were positively associated with EQ-5D-5L scores.Conclusion: Patients in advanced CRC stages or undergoing surgery experienced lower HRQoL and higher prevalence of anxiety/depression and pain/discomfort. Older age and high educational attainment predicted high HRQoL. This study provides information on CRC patients’ health utility based on various patient characteristics, which can be used in future economic evaluations.Keywords: HRQoL, EQ-5D-5L, utility, colorectal cancer, Vietnam

Soon Jun Hong,1,* Ki-Chul Sung,2,* Sang-Wook Lim,3 Seok-Yeon Kim,4 Weon Kim,5 Jinho Shin,6 Sungha Park,7 Hae-Young Kim,8 Moo-Yong Rhee9,10 On behalf of MH_APOLLO to read: HM_APOLLO1Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 2Department of Cardiology, Gangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea; 3Cardiology Division, Cardiac Center, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 4Department of Cardiology, Seoul Medical Center, Seoul, Republic of Korea; 5Department of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University, Seoul, Republic of Korea; 6Division of Cardiology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 7Department of Cardiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 8Department of Health Policy and Management, College of Health Science & Department of Health Care Science, Graduate School, Korea University, Seoul, Republic of Korea; 9Cardiovascular Center, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi, Republic of Korea; 10College of Medicine, Dongguk University, Gyeongju-si, Gyeongbuk, Republic of Korea*These authors contributed equally to this workCorrespondence: Moo-Yong RheeCardiovascular Center, Dongguk University Ilsan Hospital, 27 Dongguk-Ro, Ilsandong-Gu, Goyang-si, Gyeonggi-do 10326, Republic of KoreaTel +82 31 961 5775Fax +82 31 961 7786Email mooyong_rhee@dumc.or.krPurpose: We evaluated the dose-responsiveness, efficacy, and safety of low-dose triple antihypertensive combination therapies in patients with mild-to-moderate hypertension.Patients and Methods: After a 1 to 2-week placebo run-in period, 248 patients were randomized to the half-dose triple combination (amlodipine 2.5 mg + losartan 25 mg + chlorthalidone 6.25 mg), third-dose triple combination (amlodipine 1.67 mg + losartan 16.67 mg + chlorthalidone 4.17 mg), quarter-dose triple combination (amlodipine 1.25 mg + losartan 12.5 mg + chlorthalidone 3.13mg), amlodipine 10mg, amlodipine 5mg, losartan 100mg, and placebo groups for 8 weeks. The primary outcome was the mean change in systolic blood pressure (SBP) from baseline to week 8.Results: The placebo-corrected SBP reductions of the half-dose, third-dose, quarter-dose combination, amlodipine 10 mg, amlodipine 5 mg and losartan 100 mg treatments were − 17.2, − 19.5, − 14.9, − 18.5, − 11.3 and − 9.9 mmHg, respectively. The BP control and response rates were significantly higher in the half-dose, third-dose, and quarter-dose combination groups than in the placebo group (all p < 0.01). Despite no intergroup differences in study drug-related adverse events, ankle circumference increased significantly in the amlodipine group compared to those in the combination treatment groups. The quarter-dose combination, amlodipine 5 mg, and losartan 100 mg groups showed similar SBP reduction and BP response rates. The SBP reduction and BP response rate in the third-dose and half-dose combination groups were not significantly different from those in the amlodipine 10 mg group but superior to those in the losartan 100 mg group.Conclusion: Low-dose triple combination therapies could be effective as antihypertensive therapies.Trial Registration: ClinicalTrials.gov identifier NCT03897868.Keywords: hypertension, blood pressure, combination therapy, low-dose, amlodipine, losartan, chlorthalidone

Sun-Young Kim,1 Mi Hyun Lee,2 Weon-Jeong Lim,1 Soo In Kim,3 Yu Jin Lee2 1Department of Psychiatry, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea; 2Department of Psychiatry and Center for Sleep and Chronobiology, Seoul National University Hospital, Seoul University College of Medicine, Seoul, Republic of Korea; 3Department of Psychiatry, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Republic of KoreaCorrespondence: Yu Jin LeeDepartment of Psychiatry and Center for Sleep and Chronobiology, Seoul National University Hospital, Seoul National University College of Medicine, 103 Daehak-Ro, Jongno-Gu, Seoul 03080, Republic of KoreaTel +82-2-2072-2456Fax +82-2-744-7241Email ewpsyche@snu.ac.krPurpose: The mean sleep duration of Koreans is 7 hours 49 minutes, which is the lowest among Organization for Economic Cooperation and Development countries. Although vitamin D deficiency and arthritis are considered modifiable factors influencing restorative sleep, mean vitamin D levels are low (17.33 ng/mL) and arthritis is prevalent among Koreans. This study investigated whether vitamin D deficiency and arthritis increase the risk of short sleep duration.Patients and Methods: The current study used data from the Korean National Health and Nutrition Examination Survey (KNHANES) for 46,405 Korean adults. Vitamin D levels were measured using a radioimmunoassay kit. Sleep duration and arthritis history were assessed using a self-reported questionnaire. Sleep duration was categorized as optimal (7 to < 9 hours/day), short (< 7 hours/day), and long (≥ 9 hours/day). Vitamin D levels were grouped as vitamin D sufficiency (≥ 20 ng/mL), insufficiency (10– 19.99 ng/mL), and deficiency (< 10 ng/mL). Multiple imputation was used to compensate for missing data. Multinomial logistic regression was used to examine the associations of vitamin D and arthritis status with sleep duration. The regressions were adjusted for covariates, and each model was adjusted for vitamin D and arthritis.Results: Among these participants, 23,078 (49.73%) and 3518 (7.58%) had short and long sleep duration, respectively; 26,724 (57.59%) and 4349 (9.37%) exhibited vitamin D insufficiency and deficiency, respectively; and 4709 (10.15%) were arthritis patients. Compared with vitamin D sufficiency, vitamin D insufficiency and deficiency were associated with short sleep duration (vitamin D insufficiency group: OR = 1.07, 95% CI = 1.01– 1.13; vitamin D deficiency group: OR = 1.13, 95% CI = 1.03– 1.24). The presence of arthritis was associated with short sleep duration (OR = 1.14, 95% CI = 1.06– 1.22) compared with its absence. The interaction between vitamin D deficiency and the presence of arthritis was significantly associated with short sleep duration. However, long sleep duration was not significantly associated with vitamin D levels or arthritis status.Conclusion: Low vitamin D levels and the presence of arthritis were associated with an increased risk of short sleep duration. Additionally, there was a positive interaction effect between vitamin D deficiency and arthritis on short sleep duration.Keywords: vitamin D, arthritis, sleep duration, Korean National Health and Nutrition Examination Survey, KNHANES

Joon Young Choi,1,* Shin Young Kim,2,* Jae Ha Lee,3 Yong Bum Park,4 Yee Hyung Kim,5 Soo-Jung Um,6 Ki Suck Jung,7 Kwang Ha Yoo,8 Seoung Ju Park,9 Hyoung Kyu Yoon10 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 3Division of Pulmonology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea; 4Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul 134-701, Republic of Korea; 5Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea; 6Division of Respiratory Medicine, Department of Internal Medicine, Dong-A University College of Medicine, Dong-A University Medical Center, Busan, Republic of Korea; 7Division of Pulmonary Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang, Republic of Korea; 8Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea; 9Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, Republic of Korea; 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea*These authors contributed equally to this work.Correspondence: Hyoung Kyu YoonDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, #62 Youido-Dong Yeongdeungpo-Gu, Seoul, Republic of KoreaTel +82 2 3779 2213Fax +82 2 780 3132Email cmcyhg@gmail.comPurpose: The prevalence of chronic obstructive pulmonary disease (COPD) in females has increased, changing the concept of COPD as a disease mostly limited to males. In this study, the clinical characteristics of COPD in females were investigated.Patients and Methods: The study was based on a multicenter cohort of COPD patients recruited from 54 medical centers in South Korea. Sex-based differences in general characteristics, exposure risk factors, depression scores, results of pulmonary function tests, COPD exacerbation, symptom scores, and radiologic findings were evaluated. Sex-related differences in the annual FEV1 change over 5 years were analyzed in a linear mixed model.Results: Of the 2515 patients enrolled in this study, 8.1% were female. Female patients who had a higher BMI and a lower level of education were less likely to be smokers, were more exposed to passive smoking/biomass, and were more depressed compared to males. The rates of bronchiectasis, previous childhood respiratory infection, and asthma were higher in females. Female patients also had more symptoms and a poorer exercise capacity than males, but no significant differences were observed in terms of exacerbations. Radiologic findings revealed that male patients had worse emphysema, and female patients had worse bronchiectasis, as determined based on chest X-ray and computed tomography findings. On pulmonary function tests, female patients had less obstruction and less annual FEV1 loss over 5 years.Conclusion: This study revealed differences in the clinical parameters between male and female patients with COPD, including general characteristics, disease characteristics, and clinical outcomes.Keywords: COPD, gender difference, KOCOSS database, cohort study

Jeongsoo Kim,1 SuHwan Shin,2,3 YoungHyun Jeong,4 So Yoon Kim,5,6 Ho-Jin Lee4,7 1Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea; 2Department of Medical Law and Ethics, Graduate School, Yonsei University, Seoul, Republic of Korea; 3Blue Urology Clinic, Seoul, Republic of Korea; 4Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 5Division of Medical Law and Bioethics, Department of Medical Humanities and Social Sciences, Yonsei University College of Medicine, Seoul, Korea; 6Asian Institute for Bioethics and Health Law, Yonsei University, Seoul, Korea; 7Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Ho-Jin LeeDepartment of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaTel +82-2-2072-0039Fax +82-2-747-8363Email zenerdiode03@gmail.comPurpose: Although the use of opioids is increasing in South Korea, there have been no studies on the serious complications caused by the opioids. The aim of this study was to investigate the rare but serious complications through medicolegal analysis.Materials and Methods: From January 1994 to December 2019, we retrospectively reviewed the closed cases of lawsuits involving the complications of opioids using the database of judgments of the Supreme Court of Korea. General characteristics, opioid-induced complications, and judicial characteristics were analyzed.Results: Of the 46 cases, 31 cases of complications were finally included in the analysis. There were 28 (90.3%) cases of opioid administration for acute pain and 3 (9.7%) cases for chronic pain. The most commonly prescribed opioid was pethidine (n = 13, 41.9%), and the most common complication was respiratory depression (n = 17, 54.8%). All except two cases were associated with permanent injuries, including 18 (58%) deaths. Twelve (38.7%) cases were ruled in favor of the plaintiff in the claims for damages, with a median payment of United States dollar (USD) 126,346 (IQR: USD 77,275– 379,219). Of these cases, the most frequently admitted complaint by the court was the neglect of observation (n = 10, 32.3%), followed by the inappropriate drug choice (n = 4, 12.9%). Eleven (36.7%) cases were plaintiffs’ claims for violating explanation obligations, of which 2 (6.7%) were recognized in the court.Conclusion: Our results suggest that physicians must be aware of the serious complications related to opioids and health policies to prevent such complications and malpractice should be adopted.Keywords: acute pain, adverse drug events, complications, legislation and jurisprudence, medical liability, opioids

Kyoung Min Kim,1 Haebin Kim,2 Jae-Won Choi,3 Soo Yeon Kim,4 Jun Won Kim5 1Department of Psychiatry, College of Medicine, Dankook University, Cheonan, Republic of Korea; 2Department of Psychiatry, Kyung Hee University Hospital, Seoul, Republic of Korea; 3Department of Psychiatry, Gyeongsang National University Hospital, Jinju, Republic of Korea; 4Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea; 5Department of Psychiatry, Catholic University of Daegu School of Medicine, Daegu, Republic of KoreaCorrespondence: Jun Won KimDepartment of Psychiatry, Catholic University of Daegu School of Medicine, 3056-6 Daemyeong-4 Dong, Nam-gu, Daegu 705-718, Republic of KoreaTel +82 53 650 4332Fax +82 53 623 1694Email f_affection@naver.comPurpose: This study investigated the prevalence and correlates of problematic internet use (PIU) in a large sample of adolescents based on the type of internet service used.Materials and Methods: The study was conducted from 2008 to 2010, and 223,542 adolescents aged 12 to 18 years participated in the study. The participants responded to a self-report questionnaire including items for demographic factors, internet usage time, most used internet service and mental health. The PIU was assessed with the Internet Addiction Proneness Scale for Youth-Short Form.Results: The overall prevalence rate of PIU was 5.2%, and the prevalence rates stratified by sex were 7.7% in boys and 3.8% in girls. The distribution of most used internet services was significantly different across sexes. The most commonly used internet services were gaming (58.1%) in boys and blogging (22.1%) and messenger/chatting (20.3%) in girls. The odds ratio for PIU was significantly different according to the most used internet service; using the internet mostly for pornography compared to information searching had the highest odds ratio (4.526-fold higher). Depressive episodes, suicidal ideation, and suicidal attempts were significantly associated with higher odds ratios for PIU (1.725-, 1.747- and 1.361-fold, respectively).Conclusion: The present study identified clinically important information about PIU in adolescents. The distribution of PIU has different patterns based on sex and specific internet services. Studies of PIU with well-defined methodology and assessment tools for PIU of each specific internet service are needed.Keywords: addiction, adolescence, sex differences, internet usage

Ji-Eun Lee,1 Se Young Kim,2 Jae-Ho Yoo,3 Il Tae Hwang,4 Jung Sub Lim,5 Kyung Hee Yi,6 Young-Jun Rhie,7 Gyung Min Lee,8 Hyo-Kyoung Nam,9 Hyun Wook Chae,10 Eun Young Kim,11 Chong Kun Cheon,12 Jieun Lee,13 Young Suk Shim,14 YuJin Lee,15 Eun Young Kim,15 Jin Soon Hwang16 1Department of Pediatrics, Inha University Hospital, Inha University Graduate School of Medicine, Incheon, Republic of Korea; 2Department of Pediatrics & Adolescent Medicine, Bundang Jeseang General Hospital, Daejin Medical Center, Seongnam, Republic of Korea; 3Department of Pediatrics, Dong-a University Hospital, Dong-a University College of Medicine, Busan, Republic of Korea; 4Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University, College of Medicine, Seoul, Republic of Korea; 5Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Republic of Korea; 6Department of Pediatrics, Wonkwang University Sanbon Medical Center, Gunpo, Republic of Korea; 7Department of Pediatrics, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea; 8Department of Pediatrics, Konyang University Hospital, Daejeon, Republic of Korea; 9Department of Pediatrics, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 10Department of Pediatrics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 11Department of Pediatrics, Chosun University Hospital, Chosun University School of Medicine, Gwangju, Republic of Korea; 12Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea; 13Department of Pediatrics, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea; 14Department of Pediatrics & Adolescent Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Republic of Korea; 15Life Sciences, LG Chem, Ltd., Seoul, Republic of Korea; 16Department of Pediatrics & Adolescent Medicine, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of KoreaCorrespondence: Jin Soon HwangDepartment of Pediatrics & Adolescent Medicine, Ajou University Hospital, Ajou University School of Medicine, 164, World cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do 16499, Republic of KoreaTel +82 31 219 5166Fax +82 31 219 5169Email pedhwang@ajou.ac.krPurpose: To assess the usability and safety of the disposable pen compared to those of reusable devices in patients receiving recombinant human growth hormone (rhGH) treatment.Patients and methods: This study was a multicenter, single-arm, open-label, switch-over, prospective, Phase IV trial. After screening, eligible patients who were previously treated with rhGH using a reusable device were enrolled to receive treatment with the disposable pen for 8 weeks. The ease of use, preference, and tolerability of the disposable pen compared to those of the reusable device were assessed by the subjects and/or their caregivers using a questionnaire. Adverse events were evaluated by the investigators.Results: Of 116 subjects enrolled in this study, 115 received treatment with the disposable pen and 109 completed the study. The mean age of the subjects was 9.4 years. Compared to the previous reusable device, the disposable pen was assessed as significantly easier to use (mean value 7.88, 95% confidence interval (CI) [7.45–8.30] on a numerical scale ranging from 0 (far less easy) to 10 (far easier)). Furthermore, the percentage of subjects who preferred the disposable pen to the previously used reusable device was 75.7% (95% CI [67.6%–83.8%]). The percentages of subjects who rated pain and discomfort at the injection site as “not at all” were higher after using the disposable pen compared to the reusable device. No specific safety concerns were identified.Conclusion: The disposable pen is easier to use than the reusable devices and is preferred by approximately 75% of patients receiving rhGH treatment. Moreover, the disposable pen is safe and acceptable. Therefore, it could be a good alternative to reusable devices. The disposable pen is expected to provide benefits to patients receiving rhGH treatment.Clinicaltrials.gov identifier: NCT03015909.Keywords: growth hormone, disposable equipment, patient preference, usability, safety

Shukho Kim,1 Jung Hwa Woo,1 Nayeong Kim,1 Mi Hyun Kim,1 Se Yeon Kim,1 Joo Hee Son,1 Dong Chan Moon,2 Suk-Kyung Lim,2 Minsang Shin,1 Je Chul Lee1 1Department of Microbiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Bacterial Disease Division, Animal and Plant Quarantine Agency, Gimcheon-si, Gyeongsangbuk-do, Republic of KoreaCorrespondence: Je Chul LeeDepartment of Microbiology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of KoreaTel +82-53-420-4844Fax +82-53-427-5664Email leejc@knu.ac.krPurpose: Colistin resistance in gram-negative bacteria from humans and livestock has been increasingly reported worldwide. The aim of this study was to investigate the underlying mechanisms of chromosome-mediated colistin resistance in Escherichia coli isolates from livestock in Korea.Materials and methods: Thirty mcr-1-negative isolates were selected from a collection of colistin-resistant E. coli isolates collected from livestock in 2005 and 2015 in Korea. Amino acid alterations in PmrAB, PhoPQ, MgrB, and PmrD were investigated. Colistin-resistant derivatives were produced by serial passage of colistin-susceptible E. coli isolates in colistin-containing media.Results: Thirty colistin-resistant mcr-negative E. coli isolates were classified into 26 sequence types. Twenty-two isolates carried diverse amino acid alterations in PmrB, PhoP, PhoQ, MgrB, and/or PmrD, whereas no mutation in any of these genes was found in the remaining eight isolates. Sixteen out of the 22 isolates shared a total of nine polymorphic positions that were found in colistin-susceptible E. coli strains. Colistin-resistant derivatives from two colistin-susceptible isolates showed the same genetic alterations that were observed in colistin-resistant clinical isolates.Conclusion: Our results suggest that the mechanism underlying chromosome-mediated colistin resistance remain to be discovered in E. coli. Selective pressure of colistin in vitro induced the same genetic mutations associated with colistin resistance in vivo. Efforts to reduce colistin consumption in livestock should be redoubled, to prevent the occurrence of colistin-resistant E. coli strains.Keywords: colistin resistance, two-component system, livestock, genetic mutation, mcr gene

Ho Yub Yoon,1,* In Ho Chang,2,* Yoon Tae Goo,1 Chang Hyun Kim,1 Tae Hoon Kang,1 Soo-Yeon Kim,3 Sang Jin Lee,3 Seh Hyon Song,4 Young Mi Whang,2 Young Wook Choi1 1College of Pharmacy, Chung-ang University, Seoul, Korea; 2College of Medicine, Chung-ang University, Seoul, Korea; 3Research Institute, National Cancer Center, Goyang, Korea; 4College of Pharmacy, Kyungsung University, Busan, Korea*These authors contributed equally to this workPurpose: To develop an intravesical instillation system for the treatment of bladder cancer, rapamycin (Rap) was encapsulated into liposomes and then homogeneously dispersed throughout a poloxamer 407 (P407)-based hydrogel.Methods: Rap-loaded conventional liposomes (R-CL) and folate-modified liposomes (R-FL) were prepared using a film hydration method and pre-loading technique, and characterized by particle size, drug entrapment efficiency, and drug loading. The cellular uptake behavior in folate receptor-expressing bladder cancer cells was observed by flow cytometry and confocal laser scanning microscopy using a fluorescent probe. In vitro cytotoxic effects were evaluated using MTT assay, colony forming assay, and Western blot. For in vivo intravesical instillation, Rap-loaded liposomes were dispersed in P407-gel, generating R-CL/P407 and R-FL/P407. Gel-forming capacities and drug release were evaluated. Using the MBT2/Luc orthotopic bladder cancer mouse model, in vivo antitumor efficacy was evaluated according to regions of interest (ROI) measurement.Results: R-CL and R-FL were successfully prepared, at approximately 12 hrs, both R-CL/P407 and R-FL/P407 preparations transformed into gel immediately after instillation into the mouse bladder. Drug release from the liposomal gel was erosion controlled. In orthotopic bladder cancer mouse model, statistically significant differences in ROI values were found between R-CL/P407 and R-FL/P407 groups at day 11 (P=0.0273) and day 14 (P=0.0088), indicating the highest tumor growth inhibition by R-FL/P407.Conclusion: Intravesical instillation of R-FL/P407 might represent a good candidate for bladder cancer treatment, owing to its enhanced retention and FR-targeting.Keywords: bladder cancer, prolonged retention, enhanced uptake, antitumor efficacy, autophagy, mTOR signaling

Thu-Thi Pham,1 Minji Hwang,2 Eun-Sook Lee,1,3,4 Sun-Young Kong,1,3,4 So-Youn Jung,3,4 Seeyoun Lee,4 Jeongseon Kim,1,3 Mina Ha,5 Sun-Young Kim,1 Boyoung Park21National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Republic of Korea; 2Department of Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 3Research Institute, National Cancer Center, Goyang, Republic of Korea; 4Hospital, National Cancer Center, Goyang, Republic of Korea; 5Dankook University College of Medicine, Cheonan, Republic of KoreaCorrespondence: Boyoung ParkDepartment of Medicine, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of KoreaTel +82 22 220 0682Fax +82 312 220 0699Email hayejine@hanmail.netPurpose: This study evaluated the association between night-shift work (NSW) and breast cancer risk as well as subtypes of breast cancer in Korean women.Patients and methods: The study population included 1721 female breast cancer cases and 1721 female controls matched by age. The subtypes of breast cancer were determined based on estrogen, progesterone, and human epidermal growth factor receptor 2 statuses by reviewing pathology reports. Odds ratios (ORs) for NSW experience, age at commencement of NSW, frequency, and duration were estimated using conditional logistic regression and were adjusted for confounders such as parity and socioeconomic status–related factors.Results: Among 1721 pairs, 10.58% of cases and 9.59% of controls had ever engaged in NSW. NSW was not associated with breast cancer risk in terms of ever having night-shift exposure (adjusted OR was 1.11, 95% confidence interval [CI] =0.89–1.40), duration, frequency, or cumulative working time. The OR for >10 years of lifetime duration of NSW was 1.55 (95% CI 0.89–2.69, P=0.124). In addition, the OR for >35,000 hrs for cumulative frequency of night work was OR=1.42 (95% CI=0.73–2.74, P=0.304). There was no heterogeneity in ORs of ever having NSW and cumulative duration of NSW between four subtypes of breast cancer.Conclusion: NSW including long-term and heavy working exposure was not associated with breast cancer risk.Keywords: night-shift work, breast cancer, hormone receptor, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2

Vo Van Giau,1,* Vorapun Senanarong,2,* Eva Bagyinszky,1 Chanin Limwongse,2 Seong Soo A An,1 SangYun Kim3 1Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Seongnam, South Korea; 2Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 3Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea *These authors contributed equally to this work Introduction: Early-onset Alzheimer’s disease (AD) accounts for than less 1% of all AD cases, with large variation in the reported genetic contributions of known dementia genes. Mutations in the amyloid precursor protein (APP) gene were the first to be recognized as the cause of AD. Methods: Here, a male patient with probable early-onset AD at the age of 55 years from Thailand was investigated by next-generation sequencing. Results: A novel mutation in exon 14 of APP (c.1810C>T, p.V604M) was found. He initially illustrated the clinical manifestations of progressive nonfluent aphasia in 2011. However, he was finally diagnosed with AD presenting logopenic aphasia in 2013. The follow-up magnetic resonance imaging scan showed progression of hippocampal trophy compared with the initial image. A 3D protein structure model revealed that V604M exchange could result in significant changes in the APP protein due to the increased hydrophobicity of methionine in the helix, which could result in altering of the APP functions. Conclusion: Additional studies to characterize APP p.V604M are necessary to further understand the effects of this mutation. Keywords: APP, Alzheimer’s disease, Thailand, V604M

Young Chul Youn,1 Seong Hye Choi,2 Hae-Won Shin,1 Ko Woon Kim,3 Jae-Won Jang,4 Jason J Jung,5 Ging-Yuek Robin Hsiung,6 SangYun Kim7 1Department of Neurology, College of Medicine, Chung-Ang University, Seoul, South Korea; 2Department of Neurology, Inha University College of Medicine, Incheon, South Korea; 3Department of Neurology, Chonbuk National University Medical School and Hospital, Chonbuk, South Korea; 4Department of Neurology, Kangwon National University Hospital, Chuncheon, South Korea; 5Department of Computer Engineering, Chung-Ang University, Seoul, South Korea; 6Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada; 7Department of Neurology, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seoul, South Korea Purpose: The Mini-Mental State Examination (MMSE) is one of the most frequently used bedside screening measures of cognition. However, the Korean Dementia Screening Questionnaire (KDSQ) is an easier and more reliable screening method. Instead, other clinical variables and raw data were used for this study without the consideration of a cutoff value. The objective of this study was to develop a machine-learning algorithm for the detection of cognitive impairment (CI) based on the KDSQ and the MMSE.Patients and methods: The original dataset from the Clinical Research Center for Dementia of South Korea study was obtained. In total, 9,885 and 300 patients were randomly allocated to the training and test datasets, respectively. We selected up to 24 variables including sex, age, education duration, diabetes mellitus, and hypertension. We trained a machine-learning algorithm using TensorFlow based on the training dataset and then calculated its accuracy using the test dataset. The cost was calculated by conducting a logistic regression.Results: The accuracy of the model in predicting CI based on the KDSQ only, the MMSE only, and the combination of the KDSQ and MMSE was 84.3%, 88.3%, and 86.3%, respectively. For the KDSQ, the sensitivity for detecting CI was 91.50% and the specificity for detecting normal cognition (NL) was 59.60%. The sensitivity of the MMSE was 94.35%, and the specificity was 59.62%. When combining the KDSQ and the MMSE, the sensitivity for detecting CI was 91.5% and the specificity for detecting NL was 61.5%.Conclusion: The algorithm predicting CI based on the MMSE is superior. However, the KDSQ can be administered more easily in clinical practice and the algorithm using KDSQ is a comparable screening tool. Keywords: dementia, mild cognitive impairment, machine learning, TensorFlow, Mini-Mental State Examination, dementia questionnaire

Hong SJ, Sung KC, Lim SW, et al. Drug Des Devel Ther. 2020;14:5735–5746 Page 5735, the affiliation for Ki-Chul Sung should be “2Department of Cardiology, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea”. Page 5744, Acknowledgment section, 4th-6th lines, “....Hospital, Korea University College of Medicine), Ki- Chul Sung (Gangbuk Samsung Hospital, Sungkyunkwan University College of Medicine), Sang-Wook Lim (CHA.....” should read “......Hospital, Korea University College of Medicine), Ki- Chul Sung (Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine), Sang-Wook Lim (CHA......” The authors apologize for these errors. Read the original article

Eva Bagyinszky,1 Vo Van Giau,1 Young Chul Youn,2 Seong Soo A An,1 SangYun Kim3 1Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Gyeonggi-do, South Korea; 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea; 3Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea Abstract: Abnormal prion proteins are responsible for several fatal neurodegenerative diseases in humans and in animals, including Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. Genetics is important in prion diseases, but in the most cases, cause of diseases remained unknown. Several mutations were found to be causative for prion disorders, and the effect of mutations may be heterogeneous. In addition, different prion mutations were suggested to play a possible role in additional phenotypes, such as Alzheimer’s type pathology, spongiform encephalopathy, or frontotemporal dementia. Pathogenic nature of several prion mutations remained unclear, such as M129V and E219K. These two polymorphic sites were suggested as either risk factors for different disorders, such as Alzheimer’s disease (AD), variant CJD, or protease-sensitive prionopathy, and they can also be disease-modifying factors. Pathological overlap may also be possible with AD or progressive dementia, and several patients with prion mutations were initially diagnosed with AD. This review also introduces briefly the diagnosis of prion diseases and the issues with their diagnosis. Since prion diseases have quite heterogeneous phenotypes, a complex analysis, a combination of genetic screening, cerebrospinal fluid biomarker analysis and imaging technologies could improve the early disease diagnosis. Keywords: genetics, mutation, prion, PRNP gene, Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, fatal familial insomnia, Alzheimer’s disease, diagnosis

Sung Woo Moon,1 Song Yee Kim,1 Ji Ye Jung,1 Young Ae Kang,1 Moo Suk Park,1 Young Sam Kim,1 Joon Chang,1 Jun Soo Ro,2 Yong-Ho Lee,3 Sang Hoon Lee1,4 1Division of Pulmonary Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea; 2Center for Preventive Medicine and Public Health, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea; 3Division of Endocrinology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea; 4Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea Purpose: Previous studies have shown that progressive forms of non-alcoholic fatty liver disease (NAFLD) occur frequently in patients with obstructive lung disease (OLD). However, few studies have written about this relationship. This study aimed to investigate the relationship between OLD and NAFLD. Subjects and methods: The Korea National Health and Nutrition Examination Survey is a national population-based, cross-sectional surveillance program that was initiated to assess the health and nutritional status of the Korean population. From 2007 to 2010, 11,738 subjects were enrolled. The subjects were defined as having NAFLD when they had scores higher than -0.640 in a NAFLD liver fat score prediction model, which was a previously validated prediction score. Individuals with forced expiratory volume in one second/forced vital capacity

Vo Van Giau,1,* Jung-Min Pyun,2,* Eva Bagyinszky,2 Seong Soo A An,1 SangYun Kim2 1Department of BioNano Technology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea; 2Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea *These authors contributed equally to this work Background: Autosomal dominant early-onset Alzheimer’s disease (EOAD) is genetically heterogeneous and has been associated with mutations in 3 different genes, coding for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Most frequent cases are associated with mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. Methods: Patient who presented progressive memory decline in her 50s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using next-generation sequencing (NGS). The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs. Results: A pathogenic mutation in the PSEN2 gene in a Korean patient associated with EOAD was identified. Targeted Next-generation sequencing and Sanger sequencing revealed a heterozygous C to A transition at position 505 (c.505C>A), resulting in a probably missense mutation at codon 169 (p.His169Asn) in PSEN2. PolyPhen-2 and SIFT software analyses predicted this mutation to be a probable damaging variant. This hypothesis was supported by the results of 3D in silico modelling analyses that predicted the p.His169Asn may result in major helix torsion due to histidine to asparagine substitution. Mutation may cause additional stresses with hydrophobic residues on the surface that interact inside the transmembrane domain III, which is a conserved domain in PSEN2 His169. Conclusion: These findings revealed that the p.His169Asn might be an important residue in PSEN2, which may alter the functions of PSEN2, suggesting its potential involvement with AD phenotype. Future functional studies are needed to evaluate the role of PSEN2 p.His169Asn mutation in AD disease progression. Keywords: Alzheimer’s disease, p.His169Asn mutation, presenilin-2, next-generation sequencing

Youngmok Park, Ji Ye Jung, Young Sam Kim, Kyung Soo Chung, Joo Han Song, Song Yee Kim, Eun Young Kim, Young Ae Kang, Moo Suk Park, Joon Chang, Ah Young Leem Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea Background: Lung function and depression are closely related to many chronic lung diseases. However, few studies have evaluated this association in the general population. In this study, we evaluated the relationship between lung function and depression in the general population in Korea. Participants and methods: Data from the Ansung–Ansan cohort, a community-based cohort in Korea, were used to analyze the relationships between depression and lung function parameters. A total of 3,321 men and women aged 40–69 years were enrolled. Spirometry data included the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio. Depression was defined as a score of ≥16 by the Beck Depression Inventory (BDI). A propensity score analysis was conducted with the aim of reducing the bias of the retrospective study. Results: The overall prevalence of depression in the study population was 13.1% (434/3,321 participants). Depression was significantly more prevalent in women than in men (P

Soo-Yeon Kim,1,2 Sang-Jin Lee,2 Jin-Ki Kim,3 Han-Gon Choi,3 Soo-Jeong Lim1 1Department of Bioscience and Bioengineering, Sejong University, Seoul, Kwangjin-gu, Seoul, 2Immunotherapeutics Branch, Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, 3College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, Sangnok-gu, Ansan, Republic of Korea Abstract: Cationic lipid-based nanoparticles enhance viral gene transfer by forming electrostatic complexes with adenoviral vectors. We recently demonstrated the superior complexation capabilities of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) emulsion compared with a liposomal counterpart but the cytotoxicity of DOTAP emulsions remained a challenge. The present study is aimed at formulating an emulsion capable of acting as a highly effective viral gene transfer vehicle with reduced cytotoxicity and to physicochemically characterize the structures of virus-emulsion complexes in comparison with virus–liposome complexes when the only difference between emulsions and liposomes was the presence or absence of inner oil core. The emulsion formulation was performed by 1) reducing the content of DOTAP while increasing the content of zwitterionic lipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and 2) optimizing the oil content. The complexation capability of formulated DOTAP:DMPC mixed emulsions was similar to those of emulsions containing DOTAP alone while displaying significantly lower cytotoxicity. The complexation capabilities of the DOTAP:DMPC mixed emulsion were serum-compatible and were monitored in a variety of cell types, whereas its liposomal counterpart was totally ineffective. Characterization by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, and dynamic light scattering studies indicated that the optimized emulsions spontaneously surrounded the virus particles to generate emulsions that encapsulated the viral particles, whereas viral particles merely attached to the surfaces of the counterpart liposomes to form multiviral aggregates. Overall, these studies demonstrated that optimized DOTAP:DMPC mixed emulsions are potentially useful for adenoviral gene delivery due to less cytotoxicity and the unique ability to encapsulate the viral particle, highlighting the importance of nanoparticle formulation. Keywords: cationic lipid, oil, emulsion, adenovirus, gene delivery

Young Chul Youn,1,* Yong Kwan Lim,2,* Su-Hyun Han,1 Vo Van Giau,3 Mi-Kyung Lee,2 Kwang-Yeol Park,1 SangYun Kim,4,5 Eva Bagyinszky,3 Seong Soo A An,3 Hye Ryoun Kim2 1Department of Neurology, 2Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, 3College of BioNano Technology, Gachon BioNano Research Institute, Gachon University, 4Department of Neurology, Seoul National University Bundang Hospital, 5Department of Neurology, Seoul National University College of Medicine, Seongnam, South Korea *These authors contributed equally to this work Purpose: APOE ε7 gene is a rare mutant form of APOE ε3. The mutation occurs in the lipid-binding domain of APOE. Based on the protein’s structure, APOE ε7 is expected to function in lipid and β-amyloid metabolism, similar to APOE ε4. However, unlike that for APOE ε4, the mechanisms responsible for Alzheimer’s disease (AD) cases associated with APOE ε7 expression have not been elucidated. The present study aims to investigate the association between APOE ε7 expression and cognitive impairment. Methods: APOE was sequenced in DNA samples collected from 344 memory-complaint patients who visited the memory clinic, and from 345 non-memory-complaint individuals from the health promotion center. The protein structures of ApoE3, ApoE4, and ApoE7 were predicted. Results: Three ε3/ε7 heterozygote individuals who were all classified under the memory-complaint group were identified. Of these, two subjects were clinically diagnosed with AD with small vessel disease, and the remaining individual was diagnosed with subjective cognitive impairment. This study predicted the protein structures of ApoE3, ApoE4, and ApoE7 and determined the three-dimensional structure of the carboxy terminus of ApoE7, which participates in an electrostatic domain interaction similar to that of APOE ε4. APOE K244 or K245 mutations for APOE ε7 were not found in the Korean reference genome database, which contains information (http://152.99.75.168/KRGDB/browser/mainBrowser.jsp) from 622 healthy individuals. Conclusion: As verified by the results of structural prediction, APOE ε7 could serve as another risk factor for cognitive impairment and is particularly associated with vascular disease. However, additional studies are required to validate the pathogenic nature of APOE ε7. Keywords: apolipoprotein structure, Alzheimer’s disease, vascular cognitive impairment, small vessel disease

Young Chul Youn,1 Jae-Won Jang,2 Su-Hyun Han,1 HyeRyoun Kim,3 Ju-Won Seok,4 Jun Soo Byun,5 Kwang-Yeol Park,1 Seong Soo A An,6 In Kook Chun,7 SangYun Kim8 1Department of Neurology, Chung-Ang University College of Medicine, Seoul, 2Department of Neurology, Kangwon National University Hospital, 3Department of Laboratory Medicine, 4Department of Nuclear Medicine, 5Department of Radiology, Chung-Ang University College of Medicine, 6College of Bionano Technology, Gachon Bionano Research Institute, Gachon University, 7Department of Nuclear Medicine, Kangwon National University Hospital, 8Department of Neurology, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Gyeonggi-do, Republic of Korea Purpose: Early-onset Alzheimer’s disease (EOAD) has a different pathologic burden and clinical features compared with late-onset Alzheimer’s disease (LOAD). We examined the effects of age at onset on the burden and distribution of β-amyloid in patients with EOAD, in whom well-characterized mutations associated with Alzheimer’s disease were absent.Methods: We genotyped ApoE, APP, PSEN1 and PSEN2 in the patients with Alzheimer’s disease: 9 patients with EOAD (age 70) and 8 normal controls (NCs), all of whom had undergone 11C-labeled Pittsburgh compound B-positron emission tomography imaging.Results: Patients with EOAD exhibited higher z scores and larger cluster sizes, and retained higher levels of Pittsburgh compound B in the bilateral thalamus and in some parts of the globus pallidus (P

Jae Chul Koh, Young Song, So Yeon Kim, Sooyeun Park, Seo Hee Ko, Dong Woo Han Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, South Korea Abstract: In this retrospective study, data of 2,435 patients who received fentanyl and ropivacaine-based patient-controlled epidural analgesia (PCEA) for pain relief after elective surgery under general or spinal anesthesia were reviewed. Differences in postoperative pain, incidence of patient-controlled analgesia (PCA)-related adverse effects, and risk factors for the need for rescue analgesics for 48 hours postsurgery in young (age 20–39 years) and elderly (age ≥70 years) patients were evaluated. Although there were no significant differences in postoperative pain intensity between the two groups until 6 hours postsurgery, younger patients experienced greater postoperative pain intensity compared with older patients 6–48 hours postsurgery. While younger patients exhibited greater incidence of numbness, motor weakness, and discontinuation of PCA postsurgery, elderly patients exhibited greater incidence of hypotension, nausea/vomiting, rescue analgesia, and antiemetic administration. Upon multivariate analysis, low fentanyl dosage and history of smoking were found to be associated with an increased need for rescue analgesia among younger patients, while physical status classification III/IV and thoracic surgery were associated with a decreased need for rescue analgesia among the elderly. Discontinuation of PCA was more frequent among younger patients than the elderly (18.5% vs 13.5%, P=0.001). Reasons for discontinuation of PCA among young and elderly patients, respectively, were nausea and vomiting (6.8% vs 26.6%), numbness or motor weakness (67.8% vs 11.5%), urinary retention (7.4% vs 8.7%), dizziness (2.2% vs 5.2%), and hypotension (3.1% vs 20.3%). In conclusion, PCEA was more frequently associated with numbness, motor weakness, and discontinuation of PCA in younger patients and with hypotension, nausea/vomiting, and a greater need for rescue analgesics/antiemetics among elderly patients. Therefore, in order to minimize the adverse effects of PCEA and enhance pain relief, different PCEA regimens and administration/prevention strategies should be considered for young and elderly patients. Keywords: adverse effect, age, elderly, epidural analgesia, pain management, patient-controlled analgesia

Kyung Won Park,1,* Seong Soo An,1,2,* Eva Bagyinszky,2 SangYun Kim3 1Department of Neurology, Busan Metropolitan Dementia Center, Dong-A University College of Medicine, Busan, 2Department of BioNano Technology and Gachon BioNano Research Institute, Gachon University, 3Department of Neurology, Seoul National University College of Medicine and Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea *These authors contributed equally to this work Abstract: A 49-year-old Korean male patient with dementia was diagnosed with probable early-onset Alzheimer’s disease (AD). He presented with memory problems, personality changes, and disorientation. His family history of dementia was probably negative, since no family member with dementia was found or mentioned. Mild cortical atrophy was observed upon magnetic resonance imaging analyses of his brain, and the single-photon emission computed tomography analysis revealed hypoperfusion in the frontal, temporal, and limbic lobes. The patient was tested for mutations in APP, PSEN1, PSEN2, PGRN, MAPT, and PRNP genes. Genetic analysis revealed R62C mutation in PSEN2 gene. PSEN2 R62C mutation was previously reported in European populations, including Dutch and Belgian families with AD. Herein, we present the first case report of PSEN2 R62C mutation in Asia. PolyPhen-2 and SIFT software analyses predicted this mutation as “possibly damaging”, suggesting its potential involvement with AD. In silico protein structural prediction analyses of PSEN2 R62 and C62 revealed two divergent structures, suggesting that large perturbations of R62C mutation might cause dysfunctions of PSEN2, which may alter the normal amyloid production. Keywords: Alzheimer’s disease, PSEN2 mutation, dementia, PET, MRI, presenilin-2

Seong Soo An,1,* Sun Ah Park,2,* Eva Bagyinszky,1 Sun Oh Bae,1 Yoon-Jeong Kim,2 Ji Young Im,2 Kyung Won Park,3 Kee Hyung Park,4 Eun-Joo Kim,5 Jee Hyang Jeong,6 Jong Hun Kim,7 Hyun Jeong Han,8 Seong Hye Choi,9 SangYun Kim10 1Department of Bionano Technology, Gachon University, Seongnam-si, 2Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, 3Department of Neurology, Dong-A University College of Medicine and Institute of Convergence Bio-Health, Busan, 4Department of Neurology, Gachon University Gil Medical Center, Incheon, 5Department of Neurology, Pusan National University Hospital, Busan, 6Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, 7Department of Neurology, Ilsan Hospital, National Health Insurance Corporation, 8Department of Neurology, Myongii Hospital, Goyang, 9Department of Neurology, Inha University School of Medicine, Incheon, 10Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea *These authors contributed equally to this work Abstract: Early-onset Alzheimer’s disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer’s disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer’s disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April 2012 to February 2014. We checked the sequence of APP (exons 16-17), PSEN1 (exons 3-12), and PSEN2 (exons 3-12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE ε4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history in Korean EOAD population. Keywords: Alzheimer’s disease, mutation, presenilin, apolipoprotein-E, sequencing, early onset Alzheimer’s disease, genetics

Su Youn Kim, Falk R Ochsendorf Clinic for Dermatology, Venereology, and Allergology, University Hospital, Frankfurt/M, Germany Abstract: The fixed-dose combination adapalene 0.1%/benzoylperoxide 2.5% (A/BPO) was introduced as an acne vulgaris therapeutic in 2007. It combines anti-inflammatory, keratolytic, comedolytic, and antibacterial properties. Thus, it addresses several pathophysiological factors involved in the pathophysiology of acne. This review highlights the rationale for the use of this fixed-dose combination product, its therapeutic efficacy including effects on adherence and quality of life, its use for different forms of acne, and the side-effect profile. In summary, the fixed-dose combination of A/BPO gel can be regarded as a highly effective and safe formulation. It is not associated with antibiotic resistance. It reduces factors that cause nonadherence and has positive effects on the quality of life of affected patients. The tolerance is good. The initial mild irritation potential can be addressed by adequate counseling. A/BPO can be used for all forms of inflammatory acne, including severe forms, as part of a combination with systemic antibiotics. Finally, it can also be used for the long-term treatment of chronic acne. Thus, it is a very valuable therapeutic option in daily practice, which is reflected by its strong recommendation in the “European S3-guidelines”. Keywords: adapalene, benzoylperoxide, acne vulgaris, treatment

Eva Bagyinszky,1,* Sun Ah Park,2,* Hyung Jun Kim,2 Seong Hye Choi,3 Seong Soo A An,1 SangYun Kim4 1Department of BioNano Technology, Gachon University, Seongnam-si, 2Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, 3Department of Neurology, Inha University School of Medicine, Incheon, 4Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea *These authors contributed equally to this work Abstract: In this study, we report a first 226leucine (Leu) mutation to phenylalanine (Phe) in (PSEN1, CTC>TTC, L226F) in Asia from a Korean early-onset Alzheimer’s disease (EOAD) patient. Polymerase chain reaction (PCR)–single strand conformation polymorphism, sequencing, and in silico predictions were performed. Previously, L226F was reported in EOAD patients by Zekanowski et al and Gómez-Tortosa et al. Disease phenotypes appeared in their thirties, and family history was positive in both cases. In our patient, age of onset was similar (37 years of age), but the mutation seemed to be de novo, since no affected family member was found. This leucine to phenylalanine substitution may cause additional stresses inside the transmembrane region due to large aromatic side chain and increased hydrophobic interactions with hydrocarbon chains in the membrane and its binding partners. Clinical phenotype of the mutation was aggressive progression into neurodegeneration, resulting in rapid cognitive decline. One of the patients was initially diagnosed with frontotemporal dementia, but the diagnosis was revised to AD upon postmortem studies in which Aβ plaques were seen. A second mutation, L226R, was found for the L226 residue. Similar to L226F, the patient with L226R also developed the first symptoms in his 30s, but EOAD was diagnosed in his 40s. These findings suggested that L226 might be an important residue in PSEN1, since mutations could result in neurodegenerative disease phenotypes at relatively young ages. There are mutations, such as L226F, which may not present clear clinical symptoms for the definitive diagnosis between frontotemporal dementia and AD. In addition, the similarities in the phenotypes could also be possible between AD and frontotemporal dementia, suggesting difficulties in differential diagnosis of various neurodegenerative diseases. Keywords: Alzheimer’s disease, PSEN1 mutation, sequencing, frontotemporal dementia

Chungyoul Choe,1,* Yong-Sung Shin,1,* Changhoon Kim,2 So-Jung Choi,1 Jinseon Lee,1 So Young Kim,1 Yong Beom Cho,3 Jhingook Kim1,41Samsung Biomedical Research Institute, Samsung Medical Center Sungkyunkwan University, School of Medicine, 2Department of Biomedical Science, Graduate School of Biomedical & Engineering, Hanyang University, 3Department of Surgery, 4Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea*These authors contributed equally to this workAbstract: Although lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly sensitive to selective EGFR tyrosine kinase inhibitors (TKIs), these tumors invariably develop acquired drug resistance. Host stromal cells have been found to have a considerable effect on the sensitivity of cancer cells to EGFR TKIs. Little is known, however, about the signaling mechanisms through which stromal cells contribute to the response to EGFR TKI in non-small cell lung cancer. This work examined the role of hedgehog signaling in cancer-associated fibroblast (CAF)-mediated resistance of lung cancer cells to the EGFR TKI erlotinib. PC9 cells, non-small cell lung cancer cells with EGFR-activating mutations, became resistant to the EGFR TKI erlotinib when cocultured in vitro with CAFs. Polymerase chain reaction and immunocytochemical assays showed that CAFs induced epithelial to mesenchymal transition phenotype in PC9 cells, with an associated change in the expression of epithelial to mesenchymal transition marker proteins including vimentin. Importantly, CAFs induce upregulation of the 7-transmembrane protein smoothened, the central signal transducer of hedgehog, suggesting that the hedgehog signaling pathway is active in CAF-mediated drug resistance. Indeed, downregulation of smoothened activity with the smoothened antagonist cyclopamine induces remodeling of the actin cytoskeleton independently of Gli-mediated transcriptional activity in PC9 cells. These findings indicate that crosstalk with CAFs plays a critical role in resistance of lung cancer to EGFR TKIs through induction of the epithelial to mesenchymal transition and may be an ideal therapeutic target in lung cancer.Keywords: CAFs, lung cancer, NSCLC, direct coculture, hedgehog signaling, EMT, actin, EGFR TKIs

Sei Won Kim,1 Kyungdo Han,2 Shin Young Kim,3 Chan Kwon Park,3 Chin Kook Rhee,1 Hyoung Kyu Yoon3 1Department of Internal Medicine, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, 2Department of Medical Statistics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, 3Department of Internal Medicine, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Background: Potential associations between oral health and respiratory disease, including chronic obstructive pulmonary disease (COPD), have been suggested in several studies. Among the indicators reflecting oral health, the number of natural teeth is an integrated and simple index to assess in the clinic. In this study, we examined the relationship between the number of natural teeth and airflow obstruction, which is a central feature of COPD.Methods: A total of 3,089 participants over 40 years, who underwent reliable spirometry and oral health assessments were selected from the Korean National Health and Nutrition Examination Survey 2012, a cross-sectional and nationally representative survey. Spirometry results were classified as normal, restrictive, or obstructive pattern. Total number and pairs of natural teeth were counted after excluding third molars.Results: After adjusting for other variables, such as age, body mass index, socioeconomic factors, and oral health factors, the group with airflow obstruction showed significantly fewer natural teeth than the other groups in males (P=0.014 and 0.008 for total number and total pairs of natural teeth, respectively). Compared with participants with full dentition, the adjusted odds ratio for airflow obstruction in males with fewer than 20 natural teeth was 4.18 (95% confidence interval: 2.06–8.49) and with fewer than 10 pairs of natural teeth was 4.74 (95% confidence interval: 2.34–9.62). However, there was no significant association between the total number or pairs of natural teeth and airflow obstruction after adjustment in females.Conclusions: Loss of natural teeth was significantly associated with the presence of airflow obstruction in males. Our finding suggests that the number of natural teeth could be one of the available indices for obstructive lung diseases, including COPD. Keywords: tooth loss, oral health, airflow obstruction, chronic obstructive pulmonary disease

Youn YC, Choi SH, Shin HW, et al. Neuropsychiatr Dis Treat. 2018;14:2939–2945.On page 2944, under Supplementary materials section, the Table S2 was incorrect.Read the original article.

Kuntaek Lim,1 Su Yeon Kim,2 Byoungsub Lee,1 Christiane Segarra,3 Sungmin Kang,1 Youngran Ju,2 Mary Jo Schmerr,4 Joliette Coste,3 Sang Yun Kim,5 Takashi Yokoyama,6 Seong Soo A An7 1Department of Research and Development, PeopleBio Inc., 2Department of Arborbiology, Korean Center for Diseases and Control (KCDC), Seoul, Republic of Korea; 3Department of Blood Screening, Etablissement Français Du Sang (EFS), Montpellier, France; 4Ames Laboratories, US Department of Energy (USDOE), Iowa State University, Ames, IA, USA; 5Department of Neurology, Seoul National University Bundang Hospital, Sungnam-si, Republic of Korea; 6Department of Prion Research, National Institute of Animal Health, Tsukuba, Japan; 7Department of Bionano Technology, Gachon University, Sungnam-si, Republic of Korea Abstract: Transmissible spongiform encephalopathies (TSEs) are zoonotic fatal neurodegenerative diseases in animals and humans. TSEs are commonly known as bovine spongiform encephalopathy in cattle, scrapie in sheep and goats, chronic wasting disease in cervids, and Creutzfeldt–Jakob disease in humans. The putative transmissible agents are infectious prion proteins (PrPSc), which are formed by the conversion of the normal prion protein on the glycoprotein cell surface in the presence of other PrPSc. Reports of the transmission of TSEs through blood raised considerable concern about the safety of blood and blood products. To address this issue, many laboratories attempted to develop a sensitive and accurate blood diagnostic test to detect PrPSc. Previously, we reported that, compared to normal controls, the multimer detection system (MDS) was more efficient in detecting PrPSc in infected hamster brain homogenate, mouse plasma spiked with purified PrPSc from scrapie mouse brain, and scrapie-infected hamster plasmas. MDS differentiates prion multimers from the cellular monomer through the multimeric expression of epitopes on prion multimers, in contrast to the monomeric form. In this study, MDS detected PrPSc in plasma samples from scrapie-infected sheep expressing clinical symptoms, demonstrating 100% sensitivity and specificity in these samples. Plasma samples from asymptomatic lambs at the preclinical stage (8-month-old naturally infected offspring of scrapie-infected parents expressing a highly susceptible genotype) tested positive with 50% sensitivity and 100% specificity. In the first of two coded analyses using clinical scrapie-infected sheep and normal healthy samples, MDS successfully identified all but one of the clinical samples with 92% sensitivity and 100% specificity. Similar results were obtained in the second coded analysis using preclinical samples. MDS again successfully identified all but one of the samples with 87% sensitivity and 100% specificity. The false-negative sample was subjected to a protease pretreatment. In conclusion, MDS could accurately detect scrapie in plasma samples at both preclinical and clinical stages. From these studies, we conclude that MDS could be a promising tool for the early diagnosis of TSEs from blood samples. Keywords: transmissible spongiform encephalopathies, infectious prion proteins, normal prion protein, sensitivity, specificity, biomarker

Gaik-Siew Ch’ng,1,* Seong Soo A An,2,* Sun Oh Bae,2 Eva Bagyinszky,2 SangYun Kim3,41Department of Genetics, Kuala Lumpur Hospital, Malaysia; 2Department of Bionano Technology, Gachon University, 3Department of Neurology, Seoul National University College of Medicine, 4Seoul National University Bundang Hospital, South Korea*These authors contributed equally to this workAbstract: Alzheimer’s disease (AD) is the most common form of dementia, which can be categorized into two main forms: early onset AD and late onset AD. The genetic background of early onset AD is well understood, and three genes, the APP, PSEN1, and PSEN2 have been identified as causative genes. In the current study, we tested three siblings from Malaysia who were diagnosed with early onset dementia, as well as their available family members. The family history was positive as their deceased father was similarly affected. Patients were tested for mutations in APP, PSEN1, PSEN2, and PRNP. A novel variant, E280K, was discovered in exon 8 of PSEN1 in the three siblings. In silico analyses with SIFT, SNAP, and PolyPhen2 prediction tools and three-dimensional modeling were performed, and the results suggested that the mutation is probably a pathogenic variant. Two additional pathogenic mutations were previously been described for codon 280, E280A, and E280G, which could support the importance of the E280 residue in the PS1 protein contributing to the pathogenic nature of E280K. Additional ten family members were screened for the E280K mutation, and all of them were negative. Six of them presented with a variety of neuropsychiatric symptoms, including learning disabilities, epilepsy, and schizophrenia, while four family members were asymptomatic. A novel PRNP G127S mutation was found in a step-niece of the three siblings harboring the PSEN1 E280K mutation. In silico predictions for PRNP G127S mutation suggested that this might be possibly a damaging variant. Additional studies to characterize PRNP G127S would be necessary to further understand the effects of this mutation. Keywords: Alzheimer’s disease, presenilin-1, prion, mutation

Min Beom Heo,1,2 Sun-Young Kim,1 Wan Soo Yun,3 Yong Taik Lim1 1SKKU Advanced Institute of Nanotechnology (SAINT), School of Chemical Engineering, Sungkyunkwan University, Suwon, 2Center for Nanosafety Metrology, Division of Convergence Technology, Korea Research Institute of Standards and Science, Daejeon, 3Department of Chemistry, Sungkyunkwan University, Suwon, Republic of Korea Abstract: Chemoimmunotherapy combines chemotherapy based on anticancer drugs with immunotherapy based on immune activators to eliminate or inhibit the growth of cancer cells. In this study, water-insoluble paclitaxel (PTX) was dispersed in water using hyaluronic acid (HA) to generate a tumor-associated antigen in the tumor microenvironment. Cytosine–phosphate–guanosine oligodeoxynucleotides (CpG ODNs) were used to enhance the T helper (Th) 1 immune response. However, CpG ODNs also induced the secretion of interleukin-10 (IL-10) that reduces the Th1 response and enhances the T helper 2 (Th2) response. Therefore, RNA interference was used to downregulate IL-10 secretion from bone marrow-derived dendritic cells (BMDCs). For the combined immunomodulation of BMDCs, we fabricated two types of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing CpG ODNs to activate BMDCs via Toll-like receptor 9 (CpG ODN-encapsulated PLGA NPs, PCNs) or a small interfering RNA to silence IL-10 (IL-10 small interfering RNA-encapsulated PLGA NPs, PINs). Treatment of BMDCs with both types of PLGA NPs increased the Th1/Th2 cytokine (IL-12/IL-10) expression ratio, which is important for the effective induction of an antitumor immune response. After primary injection with the HA/PTX complex, the tumor-associated antigen was generated and taken up by tumor-recruited BMDCs. After a secondary injection with immunomodulating PCNs and PINs, the BMDCs became activated and migrated to the tumor-draining lymph nodes. As a result, the combination of chemotherapy using the HA/PTX complex and immunotherapy using PCNs and PINs not only efficiently inhibited tumor growth but also increased the animal survival rate. Taken together, our results suggest that the sequential treatment of cancer cells with a chemotherapeutic agent and immunomodulatory nanomaterials represents a promising strategy for efficient cancer therapy. Keywords: nanoparticles, chemoimmunotherapy, dendritic cells, cancer, siRNA

Ah Young Leem, Se Kyu Kim, Joon Chang, Young Ae Kang, Young Sam Kim, Moo Suk Park, Song Yee Kim, Eun Young Kim, Kyung Soo Chung, Ji Ye Jung Division of Pulmonology, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Background: Heavy metal exposure may contribute to inflammation in the lungs via increased oxidative stress, resulting in tissue destruction and obstructive lung function (OLF). In this study, we evaluated the relationship between lead and cadmium levels in blood, and lung function in the Korean population.Methods: Pooled cross-sectional data from 5,972 subjects who participated in the Korean National Health and Nutrition Examination Survey 2008–2012 were used for this study. OLF was defined as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC)

Vo Van Giau,1 Eva Bagyinszky,1 Seong Soo A An,1 SangYun Kim2 1Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea; 2Department of Neurology, Seoul National University College of Medicine in Seoul National Bundang Hospital, Seoul, South Korea Abstract: Apolipoprotein E (APOE) is a lipid-transport protein abundantly expressed in most neurons in the central nervous system. APOE-dependent alterations of the endocytic pathway can affect different functions. APOE binds to cell-surface receptors to deliver lipids and to the hydrophobic amyloid-β peptide, regulating amyloid-β aggregations and clearances in the brain. Several APOE isoforms with major structural differences were discovered and shown to influence the brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. This review will summarize the updated research progress on APOE functions and its role in Alzheimer’s disease, Parkinson’s disease, cardiovascular diseases, multiple sclerosis, type 2 diabetes mellitus, Type III hyperlipoproteinemia, vascular dementia, and ischemic stroke. Understanding the mutations in APOE, their structural properties, and their isoforms is important to determine its role in various diseases and to advance the development of therapeutic strategies. Targeting APOE may be a potential approach for diagnosis, risk assessment, prevention, and treatment of various neurodegenerative and cardiovascular diseases in humans. Keywords: apolipoprotein E, pathogenesis, diseases

Yan Cai,1 Seong Soo A An,1 SangYun Kim2 1Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, 2Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, South Korea Abstract: Alzheimer’s disease (AD) is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson’s disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders. Keywords: mutations in presenilin 2, Alzheimer’s disease

Keun Sang Oh,1 Ji Young Yhee,2 Dong-Eun Lee,3 Kwangmeyung Kim,2 Ick Chan Kwon,2 Jae Hong Seo,4 Sang Yoon Kim,5 Soon Hong Yuk1,4 1College of Pharmacy, Korea University, Sejong, 2Biomedical Research Center, Korea Institute of Science and Technology, Seoul, 3Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeonbuk, 4Biomedical Research Center, Korea University Guro Hospital, Seoul, 5Department of Otolaryngology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea Abstract: Primary tumor and tumor-associated metastatic lymphatics have emerged as new targets for anticancer therapy, given that these are difficult to treat using traditional chemotherapy. In this study, docetaxel-loaded Pluronic nanoparticles with Flamma™ (FPR-675, fluorescence molecular imaging dye; DTX/FPR-675 Pluronic NPs) were prepared using a temperature-induced phase transition for accurate detection of metastatic lymphatics. Significant accumulation was seen at the primary tumor and in metastatic lymph nodes within a short time. Particle size, maximum drug loading capacity, and drug encapsulation efficiency of the docetaxel-loaded Pluronic NPs were approximately 10.34±4.28 nm, 3.84 wt%, and 94±2.67 wt%, respectively. Lymphatic tracking after local and systemic delivery showed that DTX/FPR-675 Pluronic NPs were more potent in tumor-bearing mice than in normal mice, and excised mouse lymphatics showed stronger near-infrared fluorescence intensity on the tumor-bearing side than on the non-tumor-bearing side at 60 minutes post-injection. In vivo cytotoxicity and efficacy data for the NPs demonstrated that the systemically administered NPs caused little tissue damage and had minimal side effects in terms of slow renal excretion and prolonged circulation in tumor-bearing mice, and rapid renal excretion in non-tumor-bearing mice using an in vivo real-time near-infrared fluorescence imaging system. These results clearly indicate that docetaxel-loaded Pluronic NPs could provide a strategy to achieve effective cancer therapy by simultaneous delivery to primary tumors, tumor lymphatics, and tumor-associated metastatic lymphatics. Keywords: metastatic lymphatics, primary tumor targeting, lymphatic tracking, temperature-induced phase transition, Pluronic nanoparticles

Eva Bagyinszky,1 Young Chul Youn,2 Seong Soo A An,1,* SangYun Kim3,*1Department of BioNano Technology Gachon University, Gyeonggi-do, 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, 3Department of Neurology, Seoul National University Budang Hospital, Gyeonggi-do, South Korea*These authors contributed equally to this workAbstract: Alzheimer's disease (AD) is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age), or late onset (over 65 years of age). Three main genes are involved in early onset AD: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). The apolipoprotein E (APOE) E4 allele has been found to be a main risk factor for late-onset Alzheimer's disease. Additionally, genome-wide association studies (GWASs) have identified several genes that might be potential risk factors for AD, including clusterin (CLU), complement receptor 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM), and sortilin-related receptor (SORL1). Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2) and cluster of differentiation 33 (CD33). Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.Keywords: dementia, amyloid precursor protein, presenilin 1, presenilin 2, APOE, mutation, diagnosis, genetic testing

Sunhyae Jang1,*, Ji Won Park2,*, Hye Rim Cha1, Sun Young Jung1, Jeong Eun Lee1, Sung Soo Jung1, Ju Ock Kim1, Sun Young Kim1, Choong Sik Lee3, Hee Sun Park1 1Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Medical School, Daejeon, 2Division of Pulmonology, Department of Internal Medicine, Daejeon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, 3Department of Pathology, Chungnam National University Medical School, Daejeon, South Korea*These authors contributed equally to this workAbstract: The anti-inflammatory action of silver nanoparticles (NPs) has been reported in a murine model of asthma in a previous study. But more specific mechanisms of silver NPs in an attenuation of allergic airway inflammation have not yet been established. Vascular and mucous changes are believed to contribute largely in pathophysiology in asthma. Among various factors related to vascular changes, vascular endothelial growth factor (VEGF) plays a pivotal role in vascular changes in asthma. Mucin proteins MUC5AC and MUC5B have been implicated as markers of goblet cell metaplasia in lung pathologies. The aim of this study was to investigate the effects of silver NPs on VEGF signaling pathways and mucus hypersecretion. Ovalbumin (OVA)-inhaled female BALBc mice were used to evaluate the role of silver NPs and the related molecular mechanisms in allergic airway disease. In this study, with an OVA-induced murine model of allergic airway disease, it was found that the increased levels of hypoxia-inducible factor (HIF)-1α, VEGF, phosphatidylinositol-3 kinase (PI3K) and phosphorylated-Akt levels, and mucous glycoprotein expression (Muc5ac) in lung tissues were substantially decreased by the administration of silver NPs. In summary, silver NPs substantially suppressed mucus hypersecretion and PI3K/HIF-1α/VEGF signaling pathway in an allergic airway inflammation.Keywords: allergic airway disease, hypoxia inducible factor-1α, vascular endothelial growth factor

We model the ultraviolet spectra of the Seyfert 1 galaxy NGC 5548 obtained with the Hubble Space Telescope during the 6 month reverberation mapping campaign in 2014. Our model of the emission from NGC 5548 corrects for overlying absorption and deblends the individual emission lines. Using the modeled spectra, we measure the response to continuum variations for the deblended and absorption-corrected individual broad emission lines, the velocity-dependent profiles of Ly and C iv, and the narrow and broad intrinsic absorption features. We find that the time lags for the corrected emission lines are comparable to those for the original data. The velocity-binned lag profiles of Ly and C iv have a double-peaked structure indicative of a truncated Keplerian disk. The narrow absorption lines show a delayed response to continuum variations corresponding to recombination in gas with a density of ∼105 cm-3. The high-ionization narrow absorption lines decorrelate from continuum variations during the same period as the broad emission lines. Analyzing the response of these absorption lines during this period shows that the ionizing flux is diminished in strength relative to the far-ultraviolet continuum. The broad absorption lines associated with the X-ray obscurer decrease in strength during this same time interval. The appearance of X-ray obscuration in ∼2012 corresponds with an increase in the luminosity of NGC 5548 following an extended low state. We suggest that the obscurer is a disk wind triggered by the brightening of NGC 5548 following the decrease in size of the broad-line region during the preceding low-luminosity state.

High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.

Merging galaxy clusters have been touted as one of the best probes for constraining selfinteracting darkmatter, but fewsimulations exist to back up this claim. We simulate equal-mass mergers of 1015 M⊙ haloes, like the El Gordo and Sausage clusters, with cosmologically motivated halo and merger parameters, and with velocity-independent dark-matter self-interactions. Although the standard lore for merging clusters is that self-interactions lead to large separations between the galaxy and dark-matter distributions, we find that maximal galaxy-dark matter offsets of ≲20 kpc form for a self-interaction cross-section of σSI/mχ = 1 cm2 g-1. This is an order of magnitude smaller than those measured in observed equal-mass and near-equalmass mergers, and is likely to be even smaller for lower mass systems. While competitive cross-section constraints are thus unlikely to emerge from offsets, we find other signatures of self-interactions that are more promising. Intriguingly, we find that after dark-matter haloes coalesce, the collisionless galaxies [and especially the brightest cluster galaxy (BCG)] oscillate around the centre of the merger remnant on stable orbits of 100 kpc for σSI/mχ =1 cm2 g-1 for at least several Gyr, well after the clusters have relaxed. If BCG miscentring in relaxed clusters remains a robust prediction of self-interacting dark matter under the addition of gas physics, substructure, merger mass ratios (e.g. 10:1 like the Bullet Cluster) and complex cosmological merger histories, the observed BCG offsets may constrain σSI/mχ to ≲0.1 cm2 g-1 - the tightest constraint yet.

Rapid urbanization and economic development in East Asia in past decades has led to photochemical air pollution problems such as excess photochemical ozone and aerosol formation. Asian megacities such as Seoul, Tokyo, Shanghai, Guangzhou, and Beijing are surrounded by densely forested areas, and recent research has consistently demonstrated the importance of biogenic volatile organic compounds (VOCs) from vegetation in determining oxidation capacity in the suburban Asian megacity regions. Uncertainties in constraining tropospheric oxidation capacity, dominated by hydroxyl radical, undermine our ability to assess regional photochemical air pollution problems. We present an observational data set of CO, NOx, SO2, ozone, HONO, and VOCs (anthropogenic and biogenic) from Taehwa research forest (TRF) near the Seoul metropolitan area in early June 2012. The data show that TRF is influenced both by aged pollution and fresh biogenic volatile organic compound emissions. With the data set, we diagnose HOx (OH, HO2, and RO2) distributions calculated using the University of Washington chemical box model (UWCM v2.1) with near-explicit VOC oxidation mechanisms from MCM v3.2 (Master Chemical Mechanism). Uncertainty from unconstrained HONO sources and radical recycling processes highlighted in recent studies is examined using multiple model simulations with different model constraints. The results suggest that (1) different model simulation scenarios cause systematic differences in HOx distributions, especially OH levels (up to 2.5 times), and (2) radical destruction (HO2 + HO2 or HO2 + RO2) could be more efficient than radical recycling (RO2 + NO), especially in the afternoon. Implications of the uncertainties in radical chemistry are discussed with respect to ozone-VOC-NOx sensitivity and VOC oxidation product formation rates. Overall, the NOx limited regime is assessed except for the morning hours (8 a.m. to 12 p.m. local standard time), but the degree of sensitivity can significantly vary depending on the model scenarios. The model results also suggest that RO2 levels are positively correlated with oxygenated VOCs (OVOCs) production that is not routinely constrained by observations. These unconstrained OVOCs can cause higher-than-expected OH loss rates (missing OH reactivity) and secondary organic aerosol formation. The series of modeling experiments constrained by observations strongly urge observational constraint of the radical pool to enable precise understanding of regional photochemical pollution problems in the East Asian megacity region.