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Ah Yeong Chae,1 So Yeon Park,1 Jung Hyun Bae,1 So Yeon Jeong,1 Ji Su Kim,1 Jeong Soo Lee,2 Soo Jin Kim,2 Soo Jeong Lee,3 Sang Hun Lee3 1Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 2Department of Obstetrics and Gynecology, Eulji University, Nowon Eulji Medical Center, Seoul, Korea; 3Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, KoreaCorrespondence: Sang Hun Lee, Department of Obstetrics and Gynecology, Ulsan University Hospital, University of Ulsan College of Medicine, 290-3 Joenha-Dong, Dong-Gu, Ulsan, 682-714, Korea, Tel +82-052-250-8786, Fax +82-052-250-7163, Email shlee73@uuh.ulsan.krBackground: Bochdalek hernia (BH) of congenital diaphragm hernia is infrequently seen in adults. Strangulation of the diaphragm hernia has been recognized as a severe complication. Among several factors, pregnancy is an important cause of diaphragm hernia’s deterioration. However, nausea, vomiting, and upper abdominal pain are often considered non-specific pregnancy-related symptoms.Case Presentation: We report a case of a 39-year-old (gravida II, para I) multigravida woman with a delayed diagnosis of strangulated herniated viscera complicating total gastric gangrene at 26+1 weeks’ gestation. The preoperative diagnosis was confirmed by an X-ray examination and magnetic resonance imaging (MRI). After identifying the size and severity of the herniated contents through video-assisted thoracoscopy (VAT), we immediately converted to abdominal laparotomy. Antenatal corticosteroids were administered simultaneously with diagnosis to promote fetal maturity. The fetal condition was maintained well in the maternal uterus during the operation. Careful monitoring of the fetus and the mother’s clinical conditions should be performed during expectant management to achieve delayed delivery after maternal surgical correction. Delivery was completed through cesarean delivery at 27+1 weeks of gestation.Conclusion: Despite the rarity of maternal Bochdalek hernias during pregnancy, early diagnosis and appropriate treatment via multidisciplinary care are essential for maternal and fetal outcomes.Keywords: strangulation, Bochdalek hernia, pregnancy

Wan Seo,1 Hyung Woo Kim,2 Eung Gu Lee,3 Tai Joon An,4 Seunghoon Kim,5 Yun-Jeong Jeong,6 Sang Haak Lee,7 Yeonhee Park,8 Jeongha Mok,9 Jee Youn Oh,10 Yousang Ko,11 Sun-Hyung Kim,12 Sun Jung Kwon,13 Sung Soo Jung,14 Jin Woo Kim,1 Ju Sang Kim,2 Jinsoo Min15 1Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Pulmonology 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; 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 4Division of Pulmonology 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; 5Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, St. Vincent’s Hospital, College of Medici ne, The Catholic University of Korea, Seoul, Republic of Korea; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea; 7Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 8Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 9Department of Internal Medicine, Pusan National University Hospital, Busan, Republic of Korea; 10Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 11Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Republic of Korea; 12Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; 13Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Konyang University Hospital, Daejeon, Republic of Korea; 14Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea; 15Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Jinsoo Min, Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea, Tel +82-2-2258-6785, Email minjinsoo@gmail.comPurpose: Isoniazid-monoresistant tuberculosis (Hr-TB) has emerged as a global challenge, necessitating detailed guidelines for its diagnosis and treatment. We aim to consolidate the Korean guidelines for Hr-TB management by gathering expert opinions and reaching a consensus.Patients and Methods: A conventional Delphi method involving two rounds of surveys was conducted with 96 experts selected based on their clinical and research experience and involvement in nationwide tuberculosis studies and development of the Korean guidelines on tuberculosis. The survey consisted of three sections of questionnaires on diagnosis, treatment, and general opinions on Hr-TB.Results: Among the 96 experts, 72 (75%) participated in the two rounds of the survey. A majority of experts (96%) strongly agreed on the necessity of molecular drug susceptibility testing (DST) for isoniazid and rifampin resistance in all tuberculosis patients and emphasized the importance of interpreting mutation types (inhA or katG) and additional molecular DST for fluoroquinolones for confirmed isoniazid-resistant cases. Over 95.8% of experts recommended treating Hr-TB with a combination of rifampin, ethambutol, pyrazinamide, and levofloxacin for six months, without exceeding 12 months unless necessary. They also acknowledged the drawbacks of long-term pyrazinamide use due to its side effects and agreed on shortening its duration by extending the duration of the rest of the treatment with a modified combination of choice.Conclusion: This Delphi survey enabled Korean tuberculosis experts to reach a consensus on diagnosing and treating Hr-TB. These findings will be valuable for developing the upcoming revised Korean guidelines for Hr-TB management.Keywords: tuberculosis, isoniazid-resistance, delphi technique

Kwang Je Lee,1 Jae-Kean Ryu,2 Yun-Hyeong Cho,3 Won Yong Shin,4 Jeong Su Kim,5 Young Won Yoon,6 Ji Yong Jang,7 Won Ho Kim,8 Jong Wook Beom,9 Seok-Min Kang10 On behalf of LG-VROS001 STUDY INVESTIGATOR GROUP1Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea; 2Department of Internal Medicine, Daegu Catholic University Medical Center, Daegu, Korea; 3Cardiovascular Center, Myongji Hospital, Goyang, Korea; 4Department of Cardiology, Soon Chun Hyang University Hospital Cheonan, Cheonan, Korea; 5Cardiovascular Center, Pusan National University Yangsan Hospital, Yangsan, Korea; 6Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 7Department of Cardiology, National Health Insurance Service Ilsan Hospital, Ilsan, Korea; 8Eulji University School of Medicine, Daejeon, Korea; 9Department of Cardiology, Jeju National University Hospital, Jeju, Korea; 10Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Seok-Min Kang, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea, Tel +82 2-2647-3225, Email SMKANG@yuhs.acPurpose: This study aimed to assess the effectiveness and safety of a fixed-dose combination of rosuvastatin and valsartan (Rovatitan®) in Korean patients with concomitant hypertension and hyperlipidemia.Patients and Methods: A total of 1008 eligible patients with concomitant hypertension and hyperlipidemia were enrolled and treated for 12 weeks. Both upward and downward drug dose titrations were allowed based on the investigator’s discretion. This study evaluated the effectiveness of the study drug, defined by the percentage of patients achieving the blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) treatment targets. Additionally, regression analyses were conducted to evaluate the factors associated with the effectiveness and safety of the study drug. Of the 1008 patients enrolled in the study, 911 were analyzed for clinical effectiveness.Results: At 12 weeks, 84.6% and 75.9% of patients treated with the study drug achieved their BP and LDL-C targets, respectively, and 64.8% of patients achieved both targets simultaneously. Furthermore, the percentage of patients who achieved their BP and LDL-C treatment targets demonstrated a trend across the respective risk groups; the higher the risk group, the lower the success of attaining the respective target. This trend was also observed regardless of the prior antihypertensive and/or lipid-lowering treatments. According to regression analysis, poor metabolic profiles, including a higher body mass index (BMI) and higher BP and LDL-C levels at baseline, were significantly associated with treatment failure for BP. Among the 1005 patients included in the safety analysis, 17 patients (1.7%) experienced serious adverse events; however, none were considered related to the study drug.Conclusion: The study drug used for the treatment of concomitant hypertension and hyperlipidemia in a real-world setting was effective and was well tolerated. Therefore, the study drug is suggested as a good alternative to increase patient convenience and compliance, particularly in those taking multiple medications.Keywords: hypertension, hyperlipidemia, rosuvastatin, valsartan, effectiveness, safety

Jung Hee Lee,1,* Hyun-Jong Lee,1,* Sang Ha Woo,1 Yu-Kyeong Park,1 Ji Hoon Han,1 Ga-Young Choi,1 Eun Sil Heo,1 Jae Soo Kim,1 Chung A Park,2 Woo Dong Lee,3 Chang Sop Yang,4 Ae-Ran Kim,5 Chang-Hyun Han4,6 1Department of Acupuncture & Moxibustion, College of Korean Medicine, Daegu Haany University, Daegu, Republic of Korea; 2Department of Diagnostics, College of Korean Medicine, Daegu Haany University, Daegu, Republic of Korea; 3Pre-Major of Cosmetics and Pharmaceutics, College of Herbal Bio-Industry, Daegu Haany University, Daegu, Republic of Korea; 4KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 5Clinical Research Coordinating Team, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea; 6Korean Convergence Medicine, University of Science & Technology (UST), Campus of Korea Institute of Oriental Medicine, Daejeon, Republic of Korea*These authors contributed equally to this workCorrespondence: Chang-Hyun Han, KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, 34054, Republic of Korea, Tel +82 42 868 9498, Fax +82 42 869 2775, Email chhan@kiom.re.krPurpose: In Korea, complex treatments such as acupotomy, acupuncture, and physical therapy are performed for lumbar spinal stenosis (LSS). Although there are reports of acupotomy as monotherapy or acupuncture treatment for LSS, pragmatic studies are lacking. Therefore, this study aimed to determine the effectiveness and safety of acupotomy for LSS to provide baseline evidence for a large-scale study.Materials and Methods: This pragmatic randomized controlled pilot study enrolled 34 participants and randomly assigned them to two groups (n=17/group). The intervention was conducted for 8 weeks. Acupotomy plus and usual care groups received acupuncture (17 acupoints) and interferential current therapy (ICT) twice weekly; however, the acupotomy plus group received an additional acupotomy (7 acupoints) for treatment of the usual care group. The primary outcome was measured using visual analog scales (VAS), and secondary outcomes were assessed using the self-rated walking distance, short-form McGill Pain Questionnaire (SF-MPQ), and the Oswestry Disability Index (ODI). Outcome measurements were conducted at baseline and 4, 8, and 12 weeks after the commencement of the intervention. Adverse events were assessed at each visit. Hematological and biochemical examinations were performed at screening and week 8.Results: Overall, 33 of the 34 participants completed the study, and one participant in the usual care group dropped out. In both groups, VAS scores at weeks 4, 8, and 12 significantly improved compared to baseline. Also, self-rated walking distance, SF-MPQ, and ODI scores were significantly improved at weeks 4, 8, and 12 than at baseline. However, there were no significant differences in the time-dependent and group-to-time interactions between the two groups. In addition, no severe adverse reactions were reported, and there were no significant differences in hematological and biochemical results.Conclusion: This study provides baseline data for large-scale studies on the effectiveness and safety of acupotomy in LSS.Clinical Trial Number: KCT0006234.Keywords: complementary therapy, pragmatic clinical trial, low back pain, acupuncture therapy

Jee Youn Oh,1 Sung-Soon Lee,2 Hyung Woo Kim,3 Jinsoo Min,4 Yousang Ko,5 Hyeon-Kyoung Koo,2 Yun-Jeong Jeong,6 Hyeon Hui Kang,7 Ji Young Kang,8 Ju Sang Kim,3 Jae Seuk Park,9 Yunhyung Kwon,10 Jiyeon Yang,10 Jiyeon Han,10 You Jin Jang,10 Min Ki Lee,11 Yangjin Jegal,12 Young-Chul Kim,13 Yun Seong Kim14 1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea; 3Division 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; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea; 7Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 9Division of Pulmonary Medicine, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Republic of Korea; 10Division of Tuberculosis Prevention and Control, Korea Disease Control and Prevention Agency, Cheongju, Republic of Korea; 11Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Pusan, Republic of Korea; 12Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Ulsan University Hospital, Ulsan University College of Medicine, Ulsan, Republic of Korea; 13Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea; 14Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of KoreaCorrespondence: Sung-Soon Lee, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea, Tel +82-10-7173-6575, Fax +82-2-2626-1166, Email sungsoonlee@gmail.comPurpose: Bronchoscopy is widely used for microbiological diagnosis of patients with minimal sputum production. However, the usefulness of bronchoscopy in patient groups who benefit from subsequent microbiological confirmation has not been established.Patients and Methods: We retrospectively analyzed Korean tuberculosis (TB) cohort data from September 2018 to October 2019 to evaluate the usefulness of bronchoscopy in patients with microbiologically negative pulmonary TB (based on initial sputum polymerase chain reaction and culture results). The primary outcome was the proportion of microbiological diagnoses made after bronchoscopy. Secondary outcomes were the predictors of microbiological confirmation and the percentage of additional resistance detection after bronchoscopy.Results: A total of 5194 patients were diagnosed with pulmonary TB, 937 of whom were microbiologically negative for pulmonary TB based on the initial sputum findings. Of these, 319 patients underwent bronchoscopy, and further microbiological confirmation was achieved in 157 (49.1%) patients. The predictors of microbiological confirmation after bronchoscopy were age > 65 years, female sex, and low body mass index (BMI). The rate of additional resistance detection was 10.5% (multidrug resistant/rifampin-resistant 3.8%; isoniazid-resistant 5.7%).Conclusion: Bronchoscopy can be used for the detection of resistant pathogens. Bronchoscopy should be considered for microbiologically negative pulmonary TB in women aged > 65 years and with low BMI for subsequent microbiological confirmation.Keywords: tuberculosis, pulmonary, bronchoscopy, cohort studies

Han-sang Baek,1 Chai-ho Jeong,2 Jeonghoon Ha,1 Ja-Seong Bae,3 Jeong-soo Kim,3 Dong-Jun Lim,1 Chul-Min Kim4 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Republic of Korea; 3Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 4Department of Family Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Dong-Jun LimDivision of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of KoreaEmail ldj6026@catholic.ac.krChul-Min KimDepartment of Family Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of KoreaEmail musofm@catholic.ac.krAbstract: Papillary thyroid microcarcinoma (PTMC) has indolent features and low mortality. Recently, active surveillance (AS) instead of early surgery (ES) has been introduced as one treatment option but economical preference has not been established. The study objective was to systemically review the literature relating to cost-effectiveness of AS compared to ES for PTMC. Keywords were selected through PICO (Population, Intervention, Comparison, and Outcomes) tools. The search was conducted using PubMed, Cochrane, EMBASE, and Elsevier databases. Papers that had irrelevant titles were written in foreign languages, or had no original results were excluded. Out of the 62 papers extracted, five relevant to the subject matter of this study were identified. Three papers made their own decision models and proceeded with cost-effectiveness analysis (CEA), but the remaining two simply compared costs rather than cost-effectiveness. In terms of cost-effectiveness, three papers preferred AS, one preferred ES, and one preferred neither. The major differences in the CEA might arise from variations in each country’s medical insurance system, the utility score systems, and decision models used. In subgroup analysis, two papers preferred AS to ES for patients at a younger age at diagnosis in terms of cost-effectiveness as well as tumor biological characteristics. Although AS has been generally more cost-effective than ES in previous publications, younger age at diagnosis could be one factor contributing to preference for ES. The CEA of prospective cohorts based on the decision model and utility score for thyroid cancer should be undertaken to confirm the cost-effectiveness of AS.Keywords: cost-effectiveness analysis, papillary thyroid cancer, quality of life, active surveillance, endocrine surgical procedures

Jung Suk Kim,1,* Fakhar ud Din,2,* Sang Min Lee,1,* Dong Shik Kim,1 Mi Ran Woo,1 Seunghyun Cheon,1 Sang Hun Ji,1 Jong Oh Kim,3 Yu Seok Youn,4 Kyung Taek Oh,5 Soo-Jeong Lim,6 Sung Giu Jin,7 Han-Gon Choi1 1College of Pharmacy, Hanyang University, Ansan, South Korea; 2Department of Pharmacy, Quaid-I-Azam University, Islamabad, Pakistan; 3College of Pharmacy, Yeungnam University, Gyongsan, South Korea; 4School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; 5College of Pharmacy, Chung-Ang University, Seoul, South Korea; 6Department of Bioscience and biotechnology, Sejong University, Seoul, South Korea; 7Department of Pharmaceutical Engineering, Dankook University, Cheonan, South Korea*These authors contributed equally to this workCorrespondence: Sung Giu Jin; Han-Gon Choi Tel +82 41-550-3558; +82 31-400-5802Fax +82 41-559-7945; +82 31-400-5958Email sklover777@dankook.ac.kr; hangon@hanyang.ac.krBackground: The purpose of this study was to screen various drug delivery systems for improving the aqueous solubility and oral bioavailability of sildenafil. Three representative techniques, solid self-nanoemulsifying drug delivery systems (SNEDDS), amorphous microspheres and crystalline microspheres, were compared.Methods: Both microspheres systems contained sildenafil:Labrasol:PVP at a weight ratio of 1:1:6. The amorphous microspheres were manufactured using ethanol, while crystalline microspheres were generated using distilled water. Liquid SNEDDS was composed of sildenafil:Labrasol:Transcutol HP:Captex 300 in the ratio of 1:70:15:15 (w:w:w:w). The solidification process in SNEDDS was performed using HDK N20 Pharma as a solid carrier.Results: The amorphous microspheres appeared spherical with significantly decreased particle size compared to the drug powder. The crystalline microspheres exhibited a rough surface with no major particle-size difference compared with sildenafil powder, indicating that the hydrophilic excipients adhered to the sildenafil crystal. Solid SNEDDS presented a smooth surface, assuming that the oily liquid was adsorbed to the porous solid carrier. According to the physicochemical evaluation, the crystalline state maintained in crystalline microspheres, whereas the crystal state changed to amorphous state in other formulations. Amorphous microspheres, crystalline microspheres and solid SNEDDS produced about 79, 55, 82-fold increased solubility, compared to drug powder. Moreover, the prepared formulations provided a higher dissolution rate (%) and plasma concentration than did the drug powder (performance order; solid SNEDDS ≥ amorphous microspheres ≥ crystalline microspheres > drug powder). Among the formulations, solid SNEDDS demonstrated the highest improvement in oral bioavailability (AUC; 1508.78 ± 343.95 h·ng/mL).Conclusion: Therefore, solid SNEDDS could be recommended as an oral dosage form for enhancing the oral bioavailability of sildenafil.Keywords: sildenafil, amorphous microspheres, crystalline microspheres, solid self-nanoemulsifying drug delivery system, aqueous microenvironment, oral bioavailability

Hee Ji Shin,1,* Min Jeong Jo,1,* Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul, 04310, Republic of Korea*These authors contributed equally to this workCorrespondence: Dae Hwan ShinCollege of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, 28160, Republic of KoreaTel +82 43 261 2820Fax +82 43 268 2732Email dshin@chungbuk.ac.krPurpose: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles.Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles.Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration–time curve from 0 to 2 h (AUC0– 2 h) and 0 to 8 h (AUC0– 8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution.Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.Keywords: combination therapy, drug interaction, cytotoxicity, biodistribution, bioavailability

Focal myositis is a rare disease defined by an isolated inflammatory pseudotumour usually restricted to one skeletal muscle. Approximately, 250 cases of focal myositis have been described in the literature, and two recent large cohorts have been used to help in the diagnosis. Isolated gastrocnemius myositis, a rare immune-mediated condition, is a diagnostic entity used by internal medicine clinician in the gastrocnemius myalgia syndrome associated with Crohn’s disease (CD). However, focal myositis and isolated gastrocnemius myositis with Crohn's disease share clinical, haematological, pathological, and radiological similarities. We present a case of unilateral focal myositis of the gastrocnemius muscle in a patient with no underlying diseases, including Crohn’s disease. At clinical evaluation, we encountered a challenge in differentiating between focal myositis and the isolated gastrocnemius myositis of Crohn’s due to similarities in clinical manifestation. We attempt to clarify focal myositis and isolated gastrocnemius myositis through our case report and a review of literature.

Jeong Uk Lim,1 Hye Seon Kang,2 Chang Dong Yeo,3 Ju Sang Kim,4 Chan Kwon Park,1 Yong Hyun Kim,2 Jin Woo Kim,5 Seung Joon Kim,6,7 Sang Haak Lee3,7 1Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea; 3Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 4Division of Pulmonary, Critical Care and Sleep Allergy, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 5Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 6Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 7Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Yong Hyun KimDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327, Sosa-ro, Bucheon-si, Gyeonggi-do 14647, Republic of KoreaTel +82-32-340-7039Fax +82-32-340-2669Email kyh30med@catholic.ac.krBackground: In patients with non-small cell lung cancer (NSCLC), both chronic obstructive pulmonary disease (COPD) and systemic inflammatory biomarkers, such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), have significant association with prognosis. NLR and PLR also predict mortality in patients with COPD alone. A combination of the two parameters may be helpful in a more individualized approach for predicting prognosis in NSCLC.Methods: Medical records of patients with stage IIIB and IV NSCLC from January 2012 to January 2018 in seven university hospitals were reviewed. Patients were categorized into four subgroups based on pulmonary function test results and cutoffs for NLR or PLR.Results: A total of 277 patients were evaluated and categorized into non-COPD and COPD groups; 194 patients were in the non-COPD group and 83 patients were in the COPD group. The non-COPD group showed significantly longer overall survival (OS) compared with the COPD group (P = 0.019). Median survival was significantly different between high/low PLR groups (P < 0.001), between high/low NLR groups (P = 0.001), and between high/low c-reactive protein (CRP) groups (P < 0.001). PLR, NLR and CRP showed significant correlations with each other. PLR showed a significant negative linear correlation with FVC (absolute) (r = − 0.149, P = 0.015), FVC (%) (r = − 0.192, P = 0.002), DLCO (absolute) (r = − 0.271, P < 0.001), DLCO (%) (r = − 0.139, P = 0.032), and NLR (r = 0.718, P < 0.001). In the multivariate analysis, the high PLR, COPD sub-group showed significantly higher risk for mortality (HR 2.066 (1.175– 3.633), P = 0.012) compared with the low-PLR non-COPD group. However, COPD-NLR subtype was not an independent predictor for OS.Conclusion: A combination of COPD status and PLR may be a cost-effective and readily available prognostic marker in patients with advanced NSCLC.Keywords: chronic obstructive pulmonary disease, non-small cell lung cancer, survival, platelet, lymphocyte, inflammation, biomarker

Jong Geol Jang,1 Jee Seon Kim,2 Jin Hong Chung,1 Kyeong Cheol Shin,1 June Hong Ahn,1 Mi Sook Lee,3 So Hee Bang,3 Da Yeong Park,3 Mee Jung Nam,3 Hyun Jung Jin,1,* Kwan Ho Lee1,* 1Division of Pulmonology and Allergy, Department of Internal Medicine, Yeungnam University Medical Center, College of Medicine, Daegu, Republic of Korea; 2Department of Internal Medicine, Semyeong Christianity Hospital, Pohang, Republic of Korea; 3Department of Education and Management Services, Yeungnam University Medical Center,College of Medicine, Daegu, Republic of Korea*These authors contributed equally to this workCorrespondence: Hyun Jung JinDivision of Pulmonology and Allergy, Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Republic of KoreaTel +82-53-640-6578Fax +82-53-640-6449Email jhj0619@yu.ac.krBackground: Despite the increasing prevalence of chronic obstructive pulmonary disease (COPD) worldwide, knowledge and awareness of COPD remain extremely low. This prospective study aimed to demonstrate the effectiveness of organized educational intervention.Patients and methods: The study participants included patients diagnosed with COPD and receiving inhaler treatment. In this prospective study, the patients made three sequential visits to the hospital (baseline, 1 month, 3 months). On their first and second visits, patients received systematic education about COPD. On their first and third visits, each patient was evaluated using a COPD Assessment Test, COPD Knowledge Questionnaire, Hospital Anxiety and Depression Scale, and Rosenberg Self-Esteem Scale.Results: Fifty-five participants were enrolled in the study. The mean COPD knowledge score before and after education was 12.51±3.19 and 17.89±1.37, respectively, indicating a significant increase in the score post-education (P

JongSeo Kim Kim-Jongseo Plastic Surgery Clinic, Seoul, Republic of KoreaCorrespondence: JongSeo KimKim-JongSeo Plastic Surgery Clinic, 2F ApGuJung bd, 842-NonHyun-ro, GangNam-gu, Seoul 06025, Republic of KoreaTel +82 10-9026-0000Email plastic@surgery.co.krIntroduction: During a sitting position, the pressure distribution is located below the ischial tuberosity. Many women have skin atrophy on the ischial area. To treat atrophic changes on the skin above the ischium, volumization and improving skin texture are acquired simultaneously. Two methods of automatic and manual injections using a hard filler with a stitmulating effect were administered respectively to both the dermis and subdermis layers. A biopsy study using various straining evaluated histological tissue reactions after the filler injections.Methods: This study focused on rejuvenating soft tissue on the atrophic ischeal areas, as described by the author as the previous phase of chronic sitting pressure sore, by using the multi-layered injection of calcium-hydroxylapatite (CaHA) filler. Sixteen women (mean, 38.5 years) were treated from 2012 January to 2019 April. Prior to the injection, 1.5cc of Radiesse® (calcium hydroxylapatite filler; Merz, Germany) was diluted with 1cc of normal saline and 0.5cc of lidocaine, and 3cc of filler mixture (1:1 dilution) was made. All subjects received the intradermal injection and multi layered subdermal injection with 2.5cc of diluted CaHA filler. A second session for booster treatment was performed at 6 months using the same method. Photography was taken by a camera and a dermascope observation before and 7 months after. Before and 7 months after the first injection, soft tissue depression, skin discoloration, and roughness were assessed. Standard deviations and coefficients of variation were also calculated for changes in depression, discoloration and roughness after the treatment. Biopsy specimens (3×5 mm) were taken from three patients 7 months after the first session. The specimens were analyzed using various stainins.Results: The improvements of skin quality, skin fold, and roughness were visible at physical examination, medical photography and also at high-resolution dermascope examination in all patients. Post-treatment the depressed amounts on the ischial areas reduced with increased volume.Conclusion: Depressed soft tissue and skin folds on ischial areas were significantly improved by volumization of subdermal filler injection. The skin quality, roughness, and pigmentation on ischial areas improved, and these improvements may be caused by intradermal micro-droplet injections of CaHA filler which may be influenced by neocollagenesis by numerous fibroblasts and increased micro-blood circulation (neovascularization). This is the first article to show the scientific evidence of neocollagenesis and tissue reaction after an injection of CaHA filler in the dermis, especially using various histological staining and to show various stages of inflammation and foreign body reaction around CaHA particles. Numerous fibroblasts were present around CaHA particles, but plasma cells were not found. Interestingly a few eosinophils were found around CaHA filler. After a significant period of time, multi-layered injections of diluted CaHA tightened and remodeled atrophic ischial skin. The multi layered injection approach was safe and effectively treated ischial soft tissue atrophy without significant side effects, such as infection or delayed swelling or lumps.Keywords: calcium hydroxylapatite filler, ischial pressure sore, skin roughness, neocollagenesis, tissue reactions

Dong Shik Kim1,*, Jung Hyun Cho1,*, Jong Hyuck Park,1 Jung Suk Kim,1 Eon Soo Song,2 Jaewook Kwon,2 Bhupendra Raj Giri,2 Sung Giu Jin,3 Kyeong Soo Kim,4 Han-Gon Choi,1 Dong Wuk Kim21College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea; 2College of Pharmacy & Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea; 3Department of Pharmaceutical Engineering, Dankook University, Cheonan, South Korea; 4Department of Pharmaceutical Engineering, Gyeongnam National University of Science and Technology, Jinju, South Korea*These authors contributed equally to this workPurpose: The objective of this study was to exploit a novel methotrexate (MTX)-loaded solid self-microemulsifying drug delivery system (SMEDDS) with enhanced bioavailability and photostability.Materials and methods: The optimized liquid SMEDDS was composed of castor oil, Tween® 80, and Plurol® diisostearique at a voluminous ratio of 27:63:10. The solid SMEDDS was formulated by spray drying liquid SMEDDS with the solid carrier (calcium silicate). Particle size analyzer, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy experiments characterized the physiochemical properties of the MTX-loaded solid SMEDDS. These properties include a z-average diameter of emulsion around 127 nm and the amorphous form of the solid SMEDDS. Furthermore, their solubility, dissolution, and pharmacokinetics in Sprague-Dawley rats were analyzed in comparison with the MTX powder.Results: The final dissolution rate and required time for complete release of solid SMEDDS were 1.9-fold higher and 10 min shorter, respectively, than those of MTX powder. Pharmacokinetic analysis demonstrated 2.04- and 3.41-fold increments in AUC and Cmax, respectively in comparison to MTX powder. The AUC and Cmax were significantly increased in solid SMEDDS. Finally, the photostability studies revealed the substantially enhanced photostability of the MTX-loaded SMEDDS under the forced degradation and confirmatory conditions.Conclusion: This solid SMEDDS formulation could be an outstanding candidate for improving the oral bioavailability and photostability of MTX.Keywords: methotrexate, solid SMEDDS, solubility, bioavailability, photostability

Jeongwoo Lee,1,2,* Jeong Seob Kim,1 Sehrin Kang,1 Yu Seob Shin,2,3,* A Ram Doo1,2 1Department of Anesthesiology and Pain Medicine, Chonbuk National University Medical School, Jeonju, South Korea; 2Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea; 3Department of Urology, Chonbuk National University Medical School, Jeonju, South Korea *These authors contributed equally to this work Background: Retropharyngeal hematoma following cervical spine trauma may lead to life-threatening upper airway obstruction and difficult airway management. This retrospective study was performed to investigate whether the extension of retropharyngeal space (RPS) was associated with difficult intubation by direct laryngoscopy in traumatic cervical spine injury.Patients and methods: Sixty-two patients who had undergone direct endotracheal intubation under general anesthesia for cervical spine surgery were retrospectively identified. Laryngoscopic grade by Cormack–Lehane (C-L) classification was collected; grade 1 or 2 was categorized as easy laryngoscopy, whereas grade 3 or 4 was categorized as difficult laryngoscopy. In these patients, RPS thickness and the proportions of RPS to the vertebral bodies were measured at the 2nd, 5th and 7th cervical spine levels using magnetic resonance imaging (MRI) of the cervical spine. Measures of RPS were compared between easy and difficult laryngoscopy. Relationships between measures of RPS and difficult laryngoscopy were analyzed with logistic regression analysis.Results: RPS thickness at C2 was significantly greater in difficult laryngoscopy (median 14.29 mm, IQR: 9.75–18.04) than easy laryngoscopy (median 5.10, IQR: 4.33–5.94, p

Jeong Uk Lim, Chang Dong Yeo, Chin Kook Rhee, Hye Seon Kang, Chan Kwon Park, Ju Sang Kim, Jin Woo Kim, Seung Joon Kim, Hyoung Kyu Yoon, Sang Haak LeeDivision of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaObjectives: A significant proportion of non-small cell lung cancer (NSCLC) patients are never-smokers. However, the clinical impact of spirometrically diagnosed chronic obstructive pulmonary disease (COPD) on the prognosis of never-smoking NSCLC has not been evaluated in the context of treatment modalities and other cancer-related factors. In the present study, we evaluated the clinical impact of COPD in non-smoking NSCLC patients, and correlations between COPD and other previously unevaluated clinical variables.Materials and methods: Lung cancer patients (stages I to IV) diagnosed with NSCLC between January 2008 and December 2015 at six university hospitals were enrolled in the study cohort and retrospectively evaluated. Clinical parameters were compared between spirometrically diagnosed COPD and non-COPD groups. Correlations between COPD status and other variables were evaluated. In order to reduce the effect of potential confounders and selection bias, we performed adjustment for differences in baseline parameters by using propensity score matching (PSM). After PSM, clinical variables were evaluated for their effects on overall survival (OS).Results: Of the 345 patients enrolled in the study, 277 were categorized as non-COPD and 68 as COPD. Old age, male gender, and wild-type EGFR were significantly correlated with COPD. By univariate analysis of 218 patients in a propensity score matched cohort, not receiving active anticancer treatment, advanced stage, and COPD were significantly associated with shorter OS. Multivariate analysis showed that not receiving active anticancer treatment, advanced cancer stage, and COPD (P=0.044, HR: 1.526, 95% CI: 1.012–2.300) were significant predictors of shorter OS.Conclusion: In the present study, never-smoker NSCLC patients with COPD had shorter OS times, compared to non-COPD never-smoker NSCLC patients.Keywords: never smoker, overall survival, risk factor

Hye Sook Choi,1 Yong Bum Park,2,3 Kyeong Cheol Shin,4 Seung Hun Jang,3,5 Kang Hyeon Choe,6 Young Sam Kim,7 Sun Young Kyung,8 Sung Ho Yoon,9 Ju Sang Kim,10 Sung Soo Jung11 1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea; 2Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital-Kangdong, Seoul, Republic of Korea; 3Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea; 4Division of Pulmonology and Allergy, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea; 5Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea; 6Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; 7Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Yonsei University Health System, Seoul, Republic of Korea; 8Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea; 9Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Chosun University Hospital, Gwangju, Republic of Korea; 10Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, The Catholic University, Incheon St Mary’s Hospital, Incheon, Republic of Korea; 11Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea Background and objective: The Exacerbations of Chronic Obstructive Pulmonary Disease Tool-Patient-Reported Outcomes (EXACT-PRO) has been suggested as a reliable and valid measure for early assessment of COPD exacerbations and perceived recovery. However, there has been no evidence for EXACT-PRO efficacy in assessing recovery from treatment in a randomized controlled trial. The study evaluated the reliability, validity, and responsiveness of EXACT-PRO for the evaluation of the efficacy of acute treatment in patients with COPD exacerbation.Methods: In a Phase III randomized controlled study for assessing the efficacy of antibiotic treatment on COPD exacerbation, EXACT-PRO was evaluated in the responders and non-responders.Results: A total of 295 patients were analyzed (259 responders and 37 non-responders). Cronbach’s α was 0.96 for EXACT total, 0.96 for the breathlessness domain, 0.89 for the cough and sputum domain, and 0.93 for the chest symptoms domain. The EXACT score correlated with the COPD assessment test (CAT) score (r=0.8, P

Mi Seon Park,1,* Young-Mo Yang,2,* Ju-Sin Kim,1 Eun Joo Choi2 1Department of Pharmacy, Chonbuk National University Hospital, Jeonju, South Korea; 2Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea *These authors contributed equally to this work Background: With the advent of combination antiretroviral therapy (ART), people living with HIV have lived to older age. So they have experienced age-related illnesses and have taken non-antiretroviral (ARV) medications to manage these illnesses. The aims of this study were to investigate the use patterns of ARV agents in HIV-positive patients by age and to evaluate potential or contraindicated drug–drug interactions (DDIs) between ARV and non-ARV. Methods: This study was retrospectively conducted with HIV-infected patients receiving ART medications between October 2011 and September 2017 at Chonbuk National University Hospital in South Korea. Data were collected by reviewing patients’ electronic medical charts. Results: Among 207 patients diagnosed with HIV infection, 183 (86.9% males; 104 aged

Jung Seok Kim,1,* Min Woo Kim,1,* Seong Jae Kang,1,* Hwa Yeon Jeong,1 Sang Il Park,1 Yeon Kyung Lee,1 Hong Sung Kim,2 Keun Sik Kim,3 Yong Serk Park1 1Department of Biomedical Laboratory Science, Yonsei University, Wonju, Republic of Korea; 2Department of Biomedical Laboratory Science, Korea Nazarene University, Cheonan, Republic of Korea; 3Department of Biomedical Laboratory Science, Konyang University, Daejeon, Republic of Korea *These authors contributed equally to this work Background: Efficient target-specific siRNA delivery has always been a primary concern in the field of siRNA clinical application. Purpose: In this study, four different types of anti-epidermal growth factor receptor (EGFR) antibody-conjugated immunonanoparticles were prepared and tested for cancer cell-targeted therapeutic siRNA delivery. Materials and methods: The prepared nanoparticles encapsulating siRNAs were characterized by gel retardation and particle analysis using a Zetasizer. In vitro transfection and reduction of target genes, vimentin and JAK3, were determined using quantitative reverse transcription polymerase chain reaction. In vivo tumor targeting and antitumoral efficacies of the nanoparticles were evaluated in mice carrying tumors. Results: Among these immunonanoparticles, anti-EGFR immunolipoplexes and immunoviroplexes exhibited remarkable cell binding and siRNA delivery to EGFR-expressing tumor cells compared to immunoliposomes and immunovirosomes. Especially, the anti-EGFR immunoviroplexes exhibited the most efficient siRNA transfection to target tumor cells. Therefore, antitumoral vimentin and Janus kinase-3 siRNAs were loaded in the anti-EGFR immunolipoplexes and immunoviroplexes, which were tested in mice carrying SK-OV-3 tumor xenografts. In fact, the therapeutic siRNAs were efficiently delivered to the tumor tissues by both delivery vehicles, resulting in significant inhibition of tumor growth. Moreover, administration of doxorubicin in combination with anti-EGFR immunoviroplexes resulted in remarkable and synergistic tumor growth inhibition. Conclusion: This study provides experimental proof that cancer cell-targeted immunoviroplexes are an efficient siRNA delivery system for cancer therapy. Moreover, this study also suggests that a combination of conventional chemotherapy and tumor-directed anticancer siRNA therapy would be a better modality for cancer treatment. Keywords: EGFR, siRNA delivery, anti-EGFR immunonanoparticles, anti-EGFR immunoviroplexes, combinatorial therapy

Jeong Uk Lim, Chang Dong Yeo, Chin Kook Rhee, Yong Hyun Kim, Chan Kwon Park, Ju Sang Kim, Jin Woo Kim, Seung Joon Kim, Hyoung Kyu Yoon, Sang Haak Lee Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Objectives: Focusing on the advanced non-small cell lung cancer (NSCLC) patients without driver mutations can elucidate the clinical impact of COPD on treatment outcomes. The present study evaluated the effects of COPD on the overall survival of driver mutation-negative NSCLC patients undergoing conventional chemotherapy as the first-line treatment. Patients and methods: Medical records of stage IIIB and IV NSCLC patients from January 2008 to December 2015 from six university hospitals were reviewed. Results: The total study population consisted of 197 patients; 92 (46.7%) were COPD patients and 105 (53.3%) were non-COPD patients. The median survival in the non-COPD group was 11.5 months, compared to 9.2 months in the COPD group. Univariate analysis showed that old age (>70 years), high Eastern Cooperative Oncology Group status score (2–3), squamous cell histology, and COPD were risk factors for mortality. The presence of COPD was a significant prognostic factor in univariate analysis (hazard ratio [HR], 1.402; p=0.037), but not in multivariate analysis (HR, 1.275; p=0.144). Subgroup analysis of 143 smokers showed that COPD was a significant prognostic factor on multivariate analysis (HR, 1.726; p=0.006). In 154 stage IV patients, COPD was also a prognostic factor in multivariate analysis (HR, 1.479; p=0.039). Conclusion: COPD had a negative impact on overall survival in the stage IV NSCLC and smoker NSCLC patients who underwent conventional chemotherapy. Keywords: non-small cell lung cancer, chronic obstructive pulmonary disease, smoker, overall survival

Yates YY Chao,1 Jong Woo Kim,2 JongSeo Kim,3 Hyungseok Ko,4 Kate Goldie5 1Chao and Chiu Institute of Aesthetic Medicine, Taipei, Taiwan; 2IU Clinic, Seoul, Republic of Korea; 3Kim‑JongSeo Plastic Surgery Clinic, Seoul, Republic of Korea; 4Samsung Lohas Clinic, Jeonju, Republic of Korea; 5European Medical Aesthetics Ltd, London, UK Abstract: With their high elasticity and viscosity, calcium hydroxylapatite (CaHA) fillers are now widely used to treat age-related or hereditary facial soft tissue volume deficits. CaHA filler volume augmentation is further enhanced by its ability to stimulate neocollagenesis and improve skin quality. However, its high viscosity and cohesivity may hinder its spread and distribution, while its injection by cannula or needle may require moderate extrusion force and lead to uneven distribution or focal accumulation in tissues. Thus, new or modified delivery techniques and tools have emerged, particularly from East Asian physicians. One such technique is hyperdilution with diluents such as lidocaine or normal saline. CaHA hyperdilution appears to be more frequently used by experienced injectors who have varying methodologies. Here, we demonstrate the precise delivery of diluted filler to treat indications related to hereditary volume deficits, volume loss, or aging in the periorbital, nasolabial and submalar regions, marionette lines, and hollowed mid-facial areas. Regardless of age or indication, dilution eases filler delivery for the injector, while using lidocaine as the diluent decreases patient discomfort and minimizes pain. Increasing injection diluent volumes reduces filler thickness (viscosity) and facilitates its even spread, encouraging skin stimulation through more direct contact with tissues and minimizing unevenness. Our results effectively demonstrate that hyperdilution is an innovative and positive evolution in CaHA filler delivery. Keywords: CaHA, hyperdilution, skin regeneration, facial sculpting, facial volumization

Kyung Hoon Kim,1 Hye Seon Kang,2 Ju Sang Kim,3 Hyoung Kyu Yoon,4 Sung Kyoung Kim,5 Chin Kook Rhee1 1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 2Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, 3Division of Pulmonary Medicine, Department of Internal Medicine, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 5Division of Pulmonary Medicine, Department of Internal Medicine, St Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea Introduction: Roflumilast is a phosphodiesterase-4 inhibitor, which can decrease exacerbation in patients with chronic obstructive pulmonary disease (COPD). However, adverse effects are a major barrier to medication use, and little is known regarding the risk factors for discontinuation of roflumilast in COPD patients.Method: A search of the clinical databases identified all patients who were prescribed roflumilast between December 2012 and April 2015 in the four hospitals of The Catholic University of Korea, Korea. The study subjects were limited to patients who had taken 500 µg of roflumilast. We studied the factors associated with drug discontinuation and drug adverse events by univariate and multivariate analyses.Results: Among 154 eligible patients, 54 (35.1%) discontinued their roflumilast prescription. Most patients were elderly, male, current or former smokers, and had moderate-to-severe airflow limitation. Low–body mass index (BMI) patients were more likely to undergo drug discontinuation (1-unit decrease in BMI: odds ratio [OR] =1.165, p=0.006; BMI

Tae Won Kwak,1,* Hye Lim Lee,2,* Yeon Hui Song,2 Chan Kim,3 Jungsoo Kim,2 Sol-Ji Seo,2 Young-Il Jeong,2 Dae Hwan Kang2,4 1Medical Convergence Textile Center, Gyeongbuk, Republic of Korea; 2Biomedical Research Institute, Pusan National University Hospital, Pusan, Republic of Korea; 3Amogreentech Co. Ltd. Gyeonggi-do, Republic of Korea; 4Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Gyeongnam, Republic of Korea *These authors contributed equally to this work Purpose: The aim of this study was to fabricate a vorinostat (Zolinza™)-eluting nanofiber membrane-coated gastrointestinal (GI) stent and to study its antitumor activity against cholangiocarcinoma (CCA) cells in vitro and in vivo. Methods: Vorinostat and poly(DL-lactide-co-glycolide) dissolved in an organic solvent was sprayed onto a GI stent to make a nanofiber-coated stent using an electro-spinning machine. Intact vorinostat and vorinostat released from nanofibers was used to assess anticancer activity in vitro against various CCA cells. The antitumor activity of the vorinostat-eluting nanofiber membrane-coated stent was evaluated using HuCC-T1 bearing mice. Results: A vorinostat-incorporated polymer nanofiber membrane was formed on the surface of the GI stent. Vorinostat was continuously released from the nanofiber membrane over 10 days, and its release rate was higher in cell culture media than in phosphate-buffered saline. Released vorinostat showed similar anticancer activity against various CCA cells in vitro compared to that of vorinostat. Like vorinostat, vorinostat released from nanofibers induced acetylation of histone H4 and inhibited histone deacetylases 1·3·4/5/7 expression in vitro and in vivo. Furthermore, vorinostat nanofibers showed a higher tumor growth inhibition rate in HuCC-T1 bearing mice than vorinostat injections. Conclusion: Vorinostat-eluting nanofiber membranes showed significant antitumor activity against CCA cells in vitro and in vivo. We suggest the vorinostat nanofiber-coated stent may be a promising candidate for CCA treatment. Keywords: vorinostat, nanofiber, GI stent, cholangiocarcinoma, drug eluting

Jeong Uk Lim,1 Jae Ha Lee,2 Ju Sang Kim,3 Yong Il Hwang,4 Tae-Hyung Kim,5 Seong Yong Lim,6 Kwang Ha Yoo,7 Ki-Suck Jung,4 Young Kyoon Kim,8 Chin Kook Rhee8 1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, St Paul’s Hospital, College of Medicine, The Catholic University of Korea, 2Division of Pulmonology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, 3Division of Pulmonary Medicine, Department of Internal Medicine, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, 4Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 5Division of Pulmonary and Critical Care Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 7Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, 8Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Introduction: A low body mass index (BMI) is associated with increased mortality and low health-related quality of life in patients with COPD. The Asia-Pacific classification of BMI has a lower cutoff for overweight and obese categories compared to the World Health Organization (WHO) classification. The present study assessed patients with COPD among different BMI categories according to two BMI classification systems: WHO and Asia-Pacific. Patients and methods: Patients with COPD aged 40 years or older from the Korean COPD Subtype Study cohort were selected for evaluation. We enrolled 1,462 patients. Medical history including age, sex, St George’s Respiratory Questionnaire (SGRQ-C), the modified Medical Research Council (mMRC) dyspnea scale, and post-bronchodilator forced expiratory volume in 1 second (FEV1) were evaluated. Patients were categorized into different BMI groups according to the two BMI classification systems. Result: FEV1 and the diffusing capacity of the lung for carbon monoxide (DLCO) percentage revealed an inverse “U”-shaped pattern as the BMI groups changed from underweight to obese when WHO cutoffs were applied. When Asia-Pacific cutoffs were applied, FEV1 and DLCO (%) exhibited a linearly ascending relationship as the BMI increased, and the percentage of patients in the overweight and obese groups linearly decreased with increasing severity of the Global Initiative for Chronic Obstructive Lung Disease criteria. From the underweight to the overweight groups, SGRQ-C and mMRC had a decreasing relationship in both the WHO and Asia-Pacific classifications. The prevalence of comorbidities in the different BMI groups showed similar trends in both BMI classifications systems. Conclusion: The present study demonstrated that patients with COPD who have a high BMI have better pulmonary function and health-related quality of life and reduced dyspnea symptoms. Furthermore, the Asia-Pacific BMI classification more appropriately reflects the correlation of obesity and disease manifestation in Asian COPD patients than the WHO classification. Keywords: body mass index, COPD, comorbidity

Bu Ki Kim, Su Joung Mun, Hyun Tae Choi, Young Hoon Yang, Ji Sun Kim, Jun Hyung Moon, Young Taek Chung Onnuri Smile Eye Clinic, Seoul, Korea Abstract: This study describes a new one-handed revolving technique for soft cataract extraction. Following hydrodissection, the endonucleus is removed piecemeal while the lens is rotated using a phaco tip. A peripheral groove is created in the 6 o’clock direction and, after lens rotation through 180° using the phaco tip, another 6 o’clock groove is created. After a further 90° of lens rotation, the residual plate is readily flipped over and emulsified. The entire procedure requires only a phaco tip; it is not necessary to create a corneal side port or use any instrument. Keywords: cataract, phacoemulsification, one-handed technique, revolving technique, soft cataract

Jeong Soo Kim,1 Kwang Ho Cha,1 Seung Yeob Kang,1 Donghan Won,1 Sun Woo Jang,1 Miwon Son,1 Moon Ho Son,1 Ho Jung Choi,2 Young Won Lee,2 Myung Joo Kang3 1Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin, Gyeonggi, 2College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, 3College of Pharmacy, Dankook University, Dongnam-gu, Cheonan, Chungnam, South Korea Objective: DA-9601, an extract of Artemisia asiatica containing eupatilin and jaceosidin as active compounds, has been prescribed to treat gastritis in Asia. In recent times, sustained-release, floating gastroretentive (GR) tablets of DA-9601 are available on the market. In the present study, the physical properties and in vitro drug release profile, in vivo gastric residence time, and gastroprotective effect of GR tablet were compared to those of immediate release (IR) tablets of DA-9601.Method: In vitro buoyancy behavior (floating lag time and duration) and release profile of eupatilin were assessed in acidic medium. The in vivo intragastric behaviors of the barium sulfate-loaded IR and GR tablets were evaluated in beagle dogs by radiographic studies. Local gastroprotective effect was compared in an experimentally induced gastric lesion in beagle dogs after oral administration of IR (three times per day) or GR (twice daily) tablets for 15 days.Results: Upon contact with gastric juice, a low-density floating tablet (apparent density of 0.93 g/cm3) was buoyant on the medium and was upheld for 14 hours, providing sustained drug release profile, whereas the IR tablet disintegrated within 10 minutes, showing complete drug release within 2 hours. In vivo radiographic studies showed that the GR tablet was retained for >4 hours in the stomach. Both DA-9601 formulations remarkably alleviated gastric mucosal injury compared to placebo group, when observed by gastric endoscopy.Conclusion: Twice-daily GR tablets exhibited a prolonged gastric residence time and a remarkable mucosal restoration effect in animal models. Therefore, the GR system of DA-9601 could be a substitute dosage form for the treatment of gastritis, while reducing the dosing frequency and thus improving patient compliance. Keywords: DA-9601, gastroretentive tablet, controlled release, radiographic studies, gastroprotective effects

Na-Kyung Han,1,* Dae Hwan Shin,1,* Jung Seok Kim,1 Kwon Yeon Weon,2 Chang-Young Jang,1 Jin-Seok Kim1 1Research Center for Cell Fate Control (RCCFC) and College of Pharmacy, Sookmyung Women’s University, Seoul, 2College of Pharmacy, Catholic University of Daegu, Gyeongbuk, Korea *These authors contributed equally to this work Abstract: Investigation of potential therapeutics for targeting breast cancer stem cells (BCSCs) is important because these cells are regarded as culprit of breast cancer relapse. Accomplishing this kind of strategy requires a specific drug-delivery system using the distinct features of liposomes. Studies on targeted liposomal delivery systems have indicated the conjugation of hyaluronan (HA), a primary ligand for CD44 surface markers, as an appropriate method for targeting BCSCs. For this study, enriched BCSCs were obtained by culturing MCF-7 breast cancer cells in nonadherent conditions. The enriched BCSCs were challenged with HA-conjugated liposomes encapsulating gemcitabine (2, 2-difluoro-2-deoxycytidine, GEM). In vitro study showed that the HA-conjugated liposomes significantly enhanced the cytotoxicity, anti-migration, and anti-colony formation abilities of GEM through targeting of CD44 expressed on BCSCs. In pharmacokinetic study, area under the drug concentration vs time curve (AUC) of the immunoliposomal GEM was 3.5 times higher than that of free GEM, indicating that the HA-conjugated liposomes enhanced the stability of GEM in the bloodstream and therefore prolonged its half-life time. The antitumor effect of the immunoliposomal GEM was 3.3 times higher than that of free GEM in a xenograft mouse model, probably reflecting the unique targeting of the CD44 receptor by HA and the increased cytotoxicity and stability through the liposomal formulation. Furthermore, marginal change in body weight demonstrated that the use of liposomes considerably reduced the systemic toxicity of GEM on normal healthy cells. Taken together, this study demonstrates that HA-conjugated liposomes encapsulating GEM show promise for the therapy of breast cancer in vitro and in a xenograft model by targeting the BCSCs. Keywords: breast cancer stem cells, targeting, CD44 surface marker, EPR effect, drug delivery system

Tae-Eon Kim,1–3,* Chang Gun Kim,1–3,* Jin Soo Kim,4 Songwan Jin,4 Sik Yoon,5 Hae-Rahn Bae,6 Jeong-Hwa Kim,7,8 Young Hun Jeong,7,8 Jong-Young Kwak1–3 1Department of Pharmacology, School of Medicine, 2Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon, South Korea; 3Immune Network Pioneer Research Center, Ajou University Medical Center, Suwon, South Korea; 4Department of Mechanical Engineering, Korea Polytechnic University, Gyeonggi, South Korea; 5Department of Anatomy, School of Medicine, Pusan National University, Yangsan, South Korea; 6Department of Physiology, College of Medicine, Dong-A University, Busan, South Korea; 7School of Mechanical Engineering, 8Department of Mechanical Engineering, Graduate School, Kyungpook National University, Daegu, South Korea *These authors contributed equally to this work Abstract: An artificial three-dimensional (3D) culture system that mimics the tumor microenvironment in vitro is an essential tool for investigating the cross-talk between immune and cancer cells in tumors. In this study, we developed a 3D culture system using an electrospun poly(ε-caprolactone) (PCL) nanofibrous scaffold (NFS). A hybrid NFS containing an uninterrupted network of nano- and submicron-scale fibers (400 nm to 2 µm) was generated by deposition onto a stainless steel mesh instead of an aluminum plate. The hybrid NFS contained multiplanar pores in a 3D structure. Surface-seeded mouse CT26 colon cancer cells and bone marrow-derived dendritic cells (BM-DCs) were able to infiltrate the hybrid NFS within several hours. BM-DCs cultured on PCL nanofibers showed a baseline inactive form, and lipopolysaccharide (LPS)-activated BM-DCs showed increased expression of CD86 and major histocompatibility complex Class II. Actin and phosphorylated FAK were enriched where unstimulated and LPS-stimulated BM-DCs contacted the fibers in the 3D hybrid NFS. When BM-DCs were cocultured with mitoxantrone-treated CT26 cells in a 3D hybrid NFS, BM-DCs sprouted cytoplasm to, migrated to, synapsed with, and engulfed mitoxantrone-treated CT26 cancer cells, which were similar to the naturally occurring cross-talk between these two types of cells. The 3D hybrid NFS developed here provides a 3D structure for coculture of cancer and immune cells. Keywords: 3D cell culture, electrospinning, nanofibrous scaffold, dendritic cell, colon cancer cell

Myong Ki Baeg, Myung-Gyu Choi, Sun-Hye Ko, Chul-Hyun Lim, Jin Su Kim, Yu Kyung Cho, Jae Myung Park, Young-Seok Cho, Bo-In Lee, In-Seok LeeDepartment of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Republic of KoreaBackground: Sarcopenia is associated with adverse outcomes such as physical disability, poorer quality of life, and death. Helicobacter pylori (HP) eradication increases ghrelin secretion, which may be a possible treatment for sarcopenia. We investigated whether HP eradication reduces the risk of low muscle mass (LMM), which is an integral component of sarcopenia.Materials and methods: Healthy, asymptomatic women aged ≥60 years who participated in a health screening program were enrolled. Subjects with a history of HP eradication were compared with those who were HP IgG+, but had not received HP-eradicating therapy. Body composition was measured by multifrequency bioelectrical impedance analysis. LMM was defined as body muscle mass 2 standard deviations below the mean muscle mass of healthy women aged 20–39 years from the same program. Multivariable analysis was used to identify sarcopenia risk factors.Results: Three hundred seventy-two women had received HP eradication, while 689 HP IgG+ women had not. The prevalence of LMM was significantly lower in those who received HP eradication (13.7% vs 21.6%, P=0.002). Multivariable analysis identified risk factors for LMM as age, white blood cell count, serum total protein concentration, and the metabolic syndrome. HP eradication (odds ratio: 0.632, 95% confidence interval: 0.440–0.824, P=0.013) was a significant preventive factor, and exercise (odds ratio: 0.710, 95% confidence interval: 0.504–1.002, P=0.051) had a preventive tendency.Conclusion: HP eradication might reduce LMM risk. This finding should be confirmed in prospective longitudinal studies to determine the long-term effects of HP eradication on sarcopenia.Keywords: sarcopenia, Helicobacter pylori, eradication, bioelectrical impedance analysis

Eun-Sol Ha,1 Jeong-Soo Kim,2 In-hwan Baek,3 Jin-Wook Yoo,1 Yunjin Jung,1 Hyung Ryong Moon,1 Min-Soo Kim1 1College of Pharmacy, Pusan National University, 2Dong-A ST Co Ltd, Yongin, 3College of Pharmacy, Kyungsung University, Busan, South Korea Abstract: In the present study, solid dispersion nanoparticles with a hydrophilic polymer and surfactant were developed using the supercritical antisolvent (SAS) process to improve the dissolution and oral absorption of megestrol acetate. The physicochemical properties of the megestrol acetate solid dispersion nanoparticles were characterized using scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction, and a particle-size analyzer. The dissolution and oral bioavailability of the nanoparticles were also evaluated in rats. The mean particle size of all solid dispersion nanoparticles that were prepared was 95% rapid dissolution within 30 minutes, in addition to good oral bioavailability, with approximately 4.0- and 5.5-fold higher area under the curve (0–24 hours) and maximum concentration, respectively, than raw megestrol acetate powder. These results suggest that the preparation of megestrol acetate solid dispersion nanoparticles using the supercritical antisolvent process is a promising approach to improve the dissolution and absorption properties of megestrol acetate. Keywords: bioavailability, megestrol acetate, dissolution, supercritical technology

Jee Young Kwon,1,* Hye Lim Kim,1,* Jong Yun Lee,2 Yo Han Ju,2 Ji Soo Kim,2 Seung Hun Kang,1 Yu-Ri Kim,3 Jong-Kwon Lee,4 Jayoung Jeong,4 Meyoung-Kon Kim,3 Eun Ho Maeng,2 Young Rok Seo1 1Department of Life Science, Institute of Environmental Medicine, Dongguk University, Seoul, 2Korea Testing and Research Institute, 3Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea *These authors contributed equally to this work and should be considered co-first authors Background: Silica dioxide (SiO2) has been used in various industrial products, including paints and coatings, plastics, synthetic rubbers, and adhesives. Several studies have investigated the genotoxic effects of SiO2; however, the results remain controversial due to variations in the evaluation methods applied in determining its physicochemical properties. Thus, well characterized chemicals and standardized methods are needed for better assessment of the genotoxicity of nanoparticles.Methods: The genotoxicity of SiO2 was evaluated using two types of well characterized SiO2, ie, 20 nm (-) charge (SiO2EN20(-)) and 100 nm (-) charge (SiO2EN100(-)). Four end point genotoxicity tests, ie, the bacterial mutation assay, in vitro chromosomal aberration test, in vivo comet assay, and in vivo micronucleus test, were conducted following the test guidelines of the Organization for Economic Cooperation and Development (OECD) with application of Good Laboratory Practice.Results: No statistically significant differences were found in the bacterial mutation assay, in vitro chromosomal aberration test, in vivo comet assay, and in vivo micronucleus test when tested for induction of genotoxicity in both two types of SiO2 nanoparticles.Conclusion: These results suggest that SiO2 nanoparticles, in particular SiO2EN20(-) and SiO2EN100(-), are not genotoxic in both in vitro and in vivo systems under OECD guidelines. Further, the results were generated in accordance with OECD test guidelines, and Good Laboratory Practice application; it can be accepted as reliable information regarding SiO2-induced genotoxicity. Keywords: genotoxicity test, Organization for Economic Cooperation and Development test guideline, Good Laboratory Practice, silica dioxide

Jae-Young Lee,1 Jung Sun Kim,2 Hyun-Jong Cho,3 Dae-Duk Kim1 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; 2Division of Health Sciences, Dongseo University, Busan, Republic of Korea; 3College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea Abstract: Poly(styrene)-b-poly(DL-lactide) (PS-PDLLA) copolymer-based nanoparticles (NPs) of a narrow size distribution, negative zeta potential, and spherical shape were fabricated for the delivery of docetaxel (DCT). The particle size was consistently maintained in serum for 24 hours and a sustained drug release pattern was observed for 10 days in the tested formulations. The cytotoxicity of the developed blank NPs was negligible in prostate cancer (PC-3) cells. Cellular uptake and distribution of the constructed NPs containing a hydrophobic fluorescent dye was monitored by confocal laser scanning microscopy (CLSM) for 24 hours. Anti-tumor efficacy of the PS-PDLLA/DCT NPs in PC-3 cells was significantly more potent than that of the group treated with commercially available DCT, Taxotere® (P

Jin Hyun Kim,1,* Hyun Hoon Chung,2,* Min Sook Jeong,1 Mi Ryoung Song,1 Keon Wook Kang,3,4 Jun Sung Kim1 1R&D Center, Biterials Co, Ltd, Seoul, Republic of Korea; 2Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 4Cancer Research Institute, Seoul National University, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: Ovarian cancer is the fifth-leading cause of cancer-related deaths among women as a result of late diagnosis. For survival rates to improve, more sensitive and specific methods for earlier detection of ovarian cancer are needed. This study presents the development of rapid and specific one-step circulating tumor cell (CTC) detection using flow cytometry in a whole-blood sample with fluorescent silica nanoparticles. We prepared magnetic nanoparticle (MNP)-SiO2(rhodamine B isothiocyanate [RITC]) (MNP-SiO2[RITC] incorporating organic dyes [RITC, λmax(ex/em) = 543/580 nm]) in the silica shell. We then controlled the amount of organic dye in the silica shell of MNP-SiO2(RITC) for increased fluorescence intensity to overcome the autofluorescence of whole blood and increase the sensitivity of CTC detection in whole blood. Next, we modified the surface function group of MNP-SiO2(RITC) from –OH to polyethylene glycol (PEG)/COOH and conjugated a mucin 1 cell surface-associated (MUC1) antibody on the surface of MNP-SiO2(RITC) for CTC detection. To study the specific targeting efficiency of MUC1-MNP-SiO2(RITC), we used immunocytochemistry with a MUC1-positive human ovarian cancer cell line and a negative human embryonic kidney cell line. This technology was capable of detecting 100 ovarian cancer cells in 50 µL of whole blood. In conclusion, we developed a one-step CTC detection technology in ovarian cancer based on multifunctional silica nanoparticles and the use of flow cytometry. Keywords: circulating tumor cells, CTCs, fluorescent nanoprobe, MUC1, ovarian cancer

Wonkyung Cho,1,2 Min-Soo Kim,3 Jeong-Soo Kim,2 Junsung Park,1,2 Hee Jun Park,1,2 Kwang-Ho Cha,1,2 Jeong-Sook Park,2 Sung-Joo Hwang1,4 1Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea; 2College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; 3Department of Pharmaceutical Engineering, Inje University, Gimhae, Republic of Korea; 4College of Pharmacy, Yonsei University, Incheon, Republic of Korea Background: The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability. Methods: Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. Results: In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocaprylate (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune® oral solution). Conclusion: The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration. Keywords: sirolimus, solubility, stability, bioavailability, self-emulsifying drug delivery systems, microemulsion

Kwang-Ho Cha,1,3 Kyung-Jin Cho,3 Min-Soo Kim,4 Jeong-Soo Kim,3 Hee Jun Park,1,3 Junsung Park,1,3 Wonkyung Cho,1,3 Jeong-Sook Park,3 Sung-Joo Hwang1,21Yonsei Institute of Pharmaceutical Sciences, 2College of Pharmacy, Yonsei University, Incheon, Republic of Korea; 3College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; 4Department of Pharmaceutical Engineering, Inje University, Gimhae, Republic of KoreaBackground: The aim of this study was to enhance the bioavailability of fenofibrate, a poorly water-soluble drug, using a melt-adsorption method with supercritical CO2.Methods: Fenofibrate was loaded onto Neusilin® UFL2 at different weight ratios of fenofibrate to Neusilin UFL2 by melt-adsorption using supercritical CO2. For comparison, fenofibrate-loaded Neusilin UFL2 was prepared by solvent evaporation and hot melt-adsorption methods. The fenofibrate formulations prepared were characterized by differential scanning calorimetry, powder x-ray diffractometry, specific surface area, pore size distribution, scanning electron microscopy, and energy-dispersive x-ray spectrometry. In vitro dissolution and in vivo bioavailability were also investigated.Results: Fenofibrate was distributed into the pores of Neusilin UFL2 and showed reduced crystal formation following adsorption. Supercritical CO2 facilitated the introduction of fenofibrate into the pores of Neusilin UFL2. Compared with raw fenofibrate, fenofibrate from the prepared powders showed a significantly increased dissolution rate and better bioavailability. In particular, the area under the drug concentration-time curve and maximal serum concentration of the powders prepared using supercritical CO2 were 4.62-fold and 4.52-fold greater than the corresponding values for raw fenofibrate.Conclusion: The results of this study highlight the usefulness of the melt-adsorption method using supercritical CO2 for improving the bioavailability of fenofibrate.Keywords: fenofibrate, melt adsorption, supercritical CO2, bioavailability

Min-Soo Kim1, Jeong-Soo Kim1, Hee Jun Park1, Won Kyung Cho1,3, Kwang-Ho Cha1,3, Sung-Joo Hwang2,31College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea, 2College of Pharmacy, 3Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of KoreaBackground: The aim of this study was to improve the physicochemical properties and bioavailability of poorly water-soluble sirolimus via preparation of a solid dispersion of nanoparticles using a supercritical antisolvent (SAS) process.Methods: First, excipients for enhancing the stability and solubility of sirolimus were screened. Second, using the SAS process, solid dispersions of sirolimus-polyvinylpyrrolidone (PVP) K30 nanoparticles were prepared with or without surfactants such as sodium lauryl sulfate (SLS), tocopheryl propylene glycol succinate, Sucroester 15, Gelucire 50/13, and Myrj 52. A mean particle size of approximately 250 nm was obtained for PVP K30-sirolimus nanoparticles. Solid state characterization, kinetic solubility, powder dissolution, stability, and pharmacokinetics were analyzed in rats.Results: X-ray diffraction, differential scanning calorimetry, and high-pressure liquid chromatography indicated that sirolimus existed in an anhydrous amorphous form within a solid dispersion of nanoparticles and that no degradation occurred after SAS processing. The improved supersaturation and dissolution of sirolimus as a solid dispersion of nanoparticles appeared to be well correlated with enhanced bioavailability of oral sirolimus in rats. With oral administration of a solid dispersion of PVP K30-SLS-sirolimus nanoparticles, the peak concentration and AUC0→12h of sirolimus were increased by approximately 18.3-fold and 15.2-fold, respectively.Conclusion: The results of this study suggest that preparation of PVP K30-sirolimus-surfactant nanoparticles using the SAS process may be a promising approach for improving the bioavailability of sirolimus.Keywords: sirolimus, solubility, bioavailability, supercritical antisolvent, nanoparticles

Kwon JY, Kim HL, Lee JY, et al. Int J Nanomedicine. 2014;9(Suppl 2):173–181.The title of the paper “Undetactable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests” should read “Undetectable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests”.Read the original article

The FeSe nematic phase has been the focus of recent research on iron-based superconductors (IBSs) due to its unusual properties, which are distinct from those of the pnictides. A series of theoretical/experimental studies were performed to determine the origin of the nematic phase. However, they yielded conflicting results and caused additional controversies. Here, we report the results of angle-resolved photoemission and X-ray absorption spectroscopy studies on FeSe detwinned by a piezo stack. We fully resolved band dispersions with orbital characters near the Brillouin zone (BZ) corner, and revealed an absence of any Fermi pocket at the Y point in the 1-Fe BZ. In addition, the occupation imbalance between dxz and dyz orbitals was the opposite of that of iron pnictides, consistent with the identified band characters. These results resolve issues associated with the FeSe nematic phase and shed light on the origin of the nematic phase in IBSs.

The nematic phase in iron based superconductors (IBSs) has attracted attention with a notion that it may provide important clue to the superconductivity. A series of angle-resolved photoemission spectroscopy (ARPES) studies were performed to understand the origin of the nematic phase. However, there is lack of ARPES study on LaFeAsO nematic phase. Here, we report the results of ARPES studies of the nematic phase in LaFeAsO. Degeneracy breaking between the [Formula: see text] and [Formula: see text] hole bands near the [Formula: see text] and M point is observed in the nematic phase. Different temperature dependent band splitting behaviors are observed at the [Formula: see text] and M points. The energy of the band splitting near the M point decreases as the temperature decreases while it has little temperature dependence near the [Formula: see text] point. The nematic nature of the band shift near the M point is confirmed through a detwin experiment using a piezo device. Since a momentum dependent splitting behavior has been observed in other iron based superconductors, our observation confirms that the behavior is a universal one among iron based superconductors.

The nematic phase in iron based superconductors (IBSs) has attracted attention with a notion that it may provide important clue to the superconductivity. A series of angle-resolved photoemission spectroscopy (ARPES) studies were performed to understand the origin of the nematic phase. However, there is lack of ARPES study on LaFeAsO nematic phase. Here, we report the results of ARPES studies of the nematic phase in LaFeAsO. Degeneracy breaking between the [Formula: see text] and [Formula: see text] hole bands near the [Formula: see text] and M point is observed in the nematic phase. Different temperature dependent band splitting behaviors are observed at the [Formula: see text] and M points. The energy of the band splitting near the M point decreases as the temperature decreases while it has little temperature dependence near the [Formula: see text] point. The nematic nature of the band shift near the M point is confirmed through a detwin experiment using a piezo device. Since a momentum dependent splitting behavior has been observed in other iron based superconductors, our observation confirms that the behavior is a universal one among iron based superconductors.

This article reviews the advancements and prospects of liquid cell transmission electron microscopy (TEM) imaging and analysis methods in understanding the nucleation, growth, etching, and assembly dynamics of nanocrystals. The bonding of atoms into nanoscale crystallites produces materials with nonadditive properties unique to their size and geometry. The recent application of in situ liquid cell TEM to nanocrystal development has initiated a paradigm shift, (1) from trial-And-error synthesis to a mechanistic understanding of the synthetic reactions responsible for the emergence of crystallites from a disordered soup of reactive species (e.g., ions, atoms, molecules) and shape-defined growth or etching; and (2)A from post-processing characterization of the nanocrystals' superlattice assemblies to inA situ imaging and mapping of the fundamental interactions and energy landscape governing their collective phase behaviors. Imaging nanocrystal formation and assembly processes on the single-particle level in solution immediately impacts many existing fields, including materials science, nanochemistry, colloidal science, biology, environmental science, electrochemistry, mineralization, soft condensed-matter physics, and device fabrication.

Background and purposeThe progression pattern of brain structural changes in patients with isolated cerebrovascular disease (CVD) remains unclear. To investigate the role of isolated CVD in cognitive impairment patients, patterns of cortical thinning and hippocampal atrophy in pure subcortical vascular mild cognitive impairment (svMCI) and pure subcortical vascular dementia (SVaD) patients were characterized.MethodsForty-five patients with svMCI and 46 patients with SVaD who were negative on Pittsburgh compound B (PiB) positron emission tomography imaging and 75 individuals with normal cognition (NC) were recruited.ResultsCompared with NC, patients with PiB(-) svMCI exhibited frontal, language and retrieval type memory dysfunctions, which in patients with PiB(-) SVaD were further impaired and accompanied by visuospatial and recognition memory dysfunctions. Compared with NC, patients with PiB(-) svMCI exhibited cortical thinning in the frontal, perisylvian, basal temporal and posterior cingulate regions. This atrophy was more prominent and extended further toward the lateral parietal and medial temporal regions in patients with PiB(-) SVaD. Compared with NC subjects, patients with PiB(-) svMCI exhibited hippocampal shape deformities in the lateral body, whilst patients with PiB(-) SVaD exhibited additional deformities within the lateral head and inferior body.ConclusionsOur findings suggest that patients with CVD in the absence of Alzheimer's disease pathology can be demented, showing cognitive impairment in multiple domains, which is consistent with the topography of cortical thinning and hippocampal shape deformity.

Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas