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Seho Kweon,1,2 Seong Jin Park,3 Ha Kyeong Lee,1 Seo Hee Kang,4 Kwan-Young Chang,4 Jeong Uk Choi,5 Jooho Park,6 Jung-Hyun Shim,7 Jin Woo Park,7 Youngro Byun1,3 1Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea; 2College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea; 3College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; 4Global R&D Center, IcureBNP, Seoul, 06170, Republic of Korea; 5College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea; 6Department of Biomedical & Health Science, Konkuk University, Chungju, 27478, Republic of Korea; 7College of Pharmacy and Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, 58554, Republic of KoreaCorrespondence: Jin Woo Park; Youngro Byun, Tel +82 61 450 2704, Email jwpark@mokpo.ac.kr; yrbyun@snu.ac.krBackground: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog’s poor cellular permeability and gastrointestinal (GI) stability.Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic (db/db) mouse model were evaluated.Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10− 6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day.Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.Keywords: nanoformulation of GLP-1A, oral liraglutide, ASBT-mediated endocytosis, EGFR

Ji Won Park,1,&ast; Yoonki Hong,2,&ast; Chin Kook Rhee,3 Hye Sook Choi,4 Kyungjoo Kim,3 Kwang Ha Yoo,5 Ki-Suck Jung,6 Joo Hun Park1 1Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea; 2Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea; 3Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea; 4Department of Internal Medicine, Kyung Hee University Medical Center, Seoul, South Korea; 5Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea; 6Department of Pulmonary, Allergy and Critical Care Medicine, Hallym University Sacred Heart Hospital, Anyang, South Korea&ast;These authors contributed equally to this workCorrespondence: Joo Hun Park, Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Worldcup road 164, Suwon, Gyeonggi-do, 16499, South Korea, Tel +82-31-219-5116 ; +82-10-8379-8299, Fax +82-31-219-5124, Email jhpamc@naver.com; jhpamc@hanmail.netBackground: A comprehensive analysis of the effects of inhaled corticosteroids (ICS) on COPD in a real-world setting is required due to safety concerns regarding ICS in COPD. This study aimed to explore the impact of ICS on the prognosis of Asian COPD patients in the real-life world.Methods: We examined 978 COPD patients registered in the Korean National Health and Nutrition Examination Survey (KNHANES) database and with their data linked to Health Insurance and Review Assessment (HIRA) data. The outcome measures were ascertained by HIRA from January 1, 2009, to December 31, 2012. This study enrolled two arms; ICS users (N = 85, mean age = 66.7 ± 8.9 years) and non-ICS users (N = 893, mean age = 63.7 ± 9.7 years).Results: Compared to the non-ICS users, the ICS users had a higher rate of pneumonia, tuberculosis, and acute exacerbations (P< 0.05). Hospitalization due to respiratory causes was also higher among ICS users (P< 0.05). Multivariate analysis showed that acute exacerbation was independently associated with the development of pneumonia (P< 0.05), whereas ICS therapy had a tendency to be associated with pneumonia. Another multivariate analysis demonstrated that old age, FEV1, ICS therapy, and pneumonia were independently associated with the occurrence of acute exacerbation (P< 0.05). The concomitant pneumonia (HR = 3.353, P = 0.004) was independently associated with higher mortality (P< 0.05).Conclusion: Our data demonstrated that the ICS users had a higher rate of pneumonia and tuberculosis and the concomitant pneumonia was independently associated with higher mortality, highlighting the importance of cautious and targeted administration of ICS in COPD.Keywords: COPD, inhaled corticosteroids, pneumonia, mortality

Hye Jung Park,1 Soyoung Jeon,2 Hye Sun Lee,2 Bo Yeon Kim,3 Yu Jin Chae,3 Gui Ok Kim,3 Jung-Won Park,4,5 Jae-Hyun Lee4,5 1Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Healthcare Insurance Review & Assessment Service, Wonju, Republic of Korea; 4Division of Allergy and Immunology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 5Institute of Allergy, Yonsei University College of Medicine, Seoul, Republic of KoreaCorrespondence: Jae-Hyun Lee, Division of Allergy and Immunology, Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea, Tel +82-2-2228-1977, Fax +82-2-393-6884, Email jhleemd@yuhs.acBackground: Although a wide variety of asthma medications have been developed and are used in clinical practice, there is limited evidence of their comparative effects on asthma exacerbations.Methods: We used claims data provided by the Health Insurance Review and Assessment Service. We selected subjects commencing asthma treatment between July 1, 2017 and June 30, 2018, with no change in drug regimen. The primary outcome was asthma exacerbation requiring systemic corticosteroids. Cox regression analysis was used to assess outcomes considering the exacerbation-free period.Results: Of the 254,951 asthma subjects, 107,694 subjects (42.2%) experienced asthma exacerbation. Inhaled corticosteroids (ICSs) (hazard ratio [HR], 0.378– 0.508), ICS-long-acting β2-agonist (LABAs) (HR, 0.284– 0.479), long-acting muscarine antagonists (LAMAs) (HR, 0.432– 0.572), leukotriene receptor antagonists (LTRAs) (HR, 0.371– 0.419), and xanthines (HR, 0.326– 0.482) significantly reduced the rate of first and second exacerbation of asthma (all P-values, < 0.001). The clinical effectiveness of asthma medications varied according to the active ingredient (HR 0.164– 0.670) and was significant for all active ingredients (all P-values, < 0.001). The effectiveness of combination treatment using ICS-LABA and LTRA varied (HR, 0.159– 0.670); however, all combination treatment options evaluated were effective in preventing asthma exacerbations (all P-values, < 0.001). Long-term use of ICS-LABA (HR, 0.278– 0.653), LTRA (HR, 0.259– 0.628), and xanthines (HR, 0.351– 0.783) showed consistent effectiveness (all P-values, < 0.001).Conclusion: This real-world study showed that the effectiveness of asthma medications varied according to drug type, active ingredient, combination, and period of use, although effectiveness was significant in all cases studied.Keywords: asthma, medication, exacerbation, real-world data, drug, combination

A Young Kim, Jun Young Do, Kyu Hyang Cho, Jong Won Park, Seok Hui Kang Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of KoreaCorrespondence: Seok Hui Kang, Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea, Tel +82-53-620-3836, Fax +82-53-654-8386, Email kangkang@ynu.ac.krPurpose: As the number of patients with chronic kidney disease increases, nephrologist activities are gradually expanding. This study evaluated the safety and success of peripherally inserted central catheter (PICC) performed by nephrologists.Patients and Methods: We retrospectively analyzed the medical records of a medical center. All patients underwent a PICC procedure by two nephrologists. The reasons for catheter removal were classified as accidental removal; treatment termination; catheter occlusion; vessel thrombosis; catheter-related infection, or patient death. Overall catheter complications were defined as catheter occlusion, vessel thrombosis, or catheter-related infection.Results: A total of 335 catheterizations among 286 patients were performed. Overall, catheter removal was required during follow-up in 251 of 335 cases. The catheter was removed in 48 out of 251 (19.1%) cases with catheter-related complications. In univariate and multivariate analyses, diabetes mellitus was associated with catheter-related infection. The catheter survival rates were 85.3% at 1 month. In univariate and multivariate analyses, diabetes mellitus and fluoroscopy-guided insertion were associated with favorable catheter survival.Conclusion: The results of our study showed high success and low complication rates for PICC insertion by nephrologists. These findings indicate that interventional nephrologists already skilled in other procedures can expand their field of activity and profit.Keywords: catheter-related complication, catheter survival, fluoroscopy, interventional nephrology, peripheral inserted central catheter

Hyewon Seo,1 Yun Su Sim,2 Kyung Hoon Min,3 Jae Ha Lee,4 Byung-Keun Kim,5 Yeon Mok Oh,6 Seung Won Ra,7 Tae-Hyung Kim,8 Yong Il Hwang,9 Jeong-Woong Park10 1Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Division of Pulmonary, Allergy and Critical Care Medicine, Kangnam Sacred Heart Hospital, Seoul, Republic of Korea; 3Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 4Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea; 5Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea; 6Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 7Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea; 9Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea; 10Department of Allergy, Pulmonary and Critical Care Medicine, Gachon University Gil Medical Center, Incheon, Republic of KoreaCorrespondence: Jeong-Woong Park, Department of Allergy, Pulmonary and Critical Care Medicine, Gachon University Gil Medical Center, Namdong-daero 774 beon-gil, Namdong, Incheon, 21565, Republic of Korea, Tel +82-10-5574-0164, Fax +82-32-469-4320, Email jwpark@gilhospital.comPurpose: Data regarding the relationship between microbiologic features and comorbidities in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are limited. The aim of this study was to correlate microbiologic findings with comorbidities in patients with moderate to severe AECOPD.Patients and Methods: This multicenter observational study included patients with AECOPD seen at 28 hospitals in South Korea between January 2015 and December 2018, and the data were retrospectively collected. Pathogens were examined in patients with either pulmonary or extrapulmonary comorbidities, and compared to those of patients without comorbidities. The relationship between pathogen type and the number of comorbidities was also evaluated.Results: Bacterial infections (178 [37.2%] vs 203 [28.7%], p = 0.002) and co-infections with bacteria and viruses (65 [13.6%] vs 57 [8.1%], p = 0.002) were more prevalent in patients with pulmonary comorbidities. Bacterial pathogens (280 [34.7%] vs 101 [26.7%], p=0.006) were detected at a higher rate in patients with extrapulmonary comorbidities. Previous pulmonary tuberculosis (PTB), bronchiectasis, and diabetes mellitus were risk factors for bacterial infection, and congestive heart failure was a risk factor for bacterial and viral co-infection. As the number of comorbidities increased, the risk of bacterial infection increased considerably. Pseudomonas aeruginosa was more frequently identified in patients with previous PTB (57 [15.3%] vs 59 [7.4%], p < 0.001) and bronchiectasis (33 [19.6%] vs 83 [8.3%], p < 0.001).Conclusion: AECOPD patients with comorbidities were more likely to experience infection-related exacerbations compared to those without comorbidities. As the overall number of comorbidities increased, the risk of bacterial infection increased significantly.Keywords: chronic obstructive pulmonary disease, acute exacerbation, comorbidity, bacteria, virus

Seon-Jip Kim,1,2 Sang Min Park,3,4 Hyun-Jae Cho,1,2,&ast; Ji Woon Park2,5,6,&ast; 1Department of Preventive Dentistry and Public Oral Health, School of Dentistry, Seoul National University, Seoul, Republic of Korea; 2Dental Research Institute, Seoul National University, Seoul, Republic of Korea; 3Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 4Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea; 5Department of Oral Medicine and Oral Diagnosis, School of Dentistry, Seoul National University, Seoul, Republic of Korea; 6Department of Oral Medicine, Seoul National University Dental Hospital, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Ji Woon ParkDepartment of Oral Medicine and Oral Diagnosis, School of Dentistry, Seoul National University, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of KoreaTel +82 2-2072-4912Email ankara01@snu.ac.krHyun-Jae ChoDepartment of Preventive Dentistry and Public Oral Health, School of Dentistry, Seoul National University, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of KoreaTel +82 2-740-8677Email stbluewi@snu.ac.krBackground: While evidence is accumulating to propose a specific contribution of sleep disorders and low quality sleep in the pathogenesis of temporomandibular disorders (TMD), management of primary sleep disorders in the process of preventing and treating TMD still remains scientifically unsupported.Objective: To investigate the association of primary sleep disorders with TMD risk in South Korea.Patients and Methods: This study was based on the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) of South Korea with 468,882 participants. After excluding participants diagnosed in 2002, those with a diagnosis of a primary sleep disorder in 2003– 2005 were recruited. All participants diagnosed with TMD between January 1, 2006 and December 31, 2013 received follow-up. Cox proportional hazards regression was performed to determine the adjusted hazard ratios (aHR) and 95% confidence interval (CI) for TMD according to the presence or absence of a primary sleep disorder diagnosis.Results: After adjusting for all covariates, primary sleep disorder patients had a 44% higher risk for TMD compared with non-sleep disorder participants (aHR 1.44, 95% CI 1.02– 2.04). The incidence rate of TMD was nearly twice as high in participants with sleep disorders compared with those without (6.08 vs 3.27, per 104 person-years). In subgroup analysis, an association was observed with those over 60 years old or who frequently exercised physically.Conclusion: Primary sleep disorders could be an important independent risk factor for the initiation and maintenance of TMD. Patients with sleep disorders should be monitored for possible co-occurrence of TMD-related symptoms that could aggravate sleep disorders in turn.Keywords: sleep disorders, temporomandibular disorders, cohort studies, epidemiology

Rudra Pangeni,1,* Laxman Subedi,2,* Saurav Kumar Jha,2 Seho Kweon,3 Seo-Hee Kang,4 Kwan-Young Chang,4 Jeong Uk Choi,5 Youngro Byun,3 Jin Woo Park1,2 1College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 2Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Mokpo National University, Muan-gun, Jeonnam, 58554, Republic of Korea; 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 4Global R&D Center, IcureBNP, Seoul 08511, Republic of Korea; 5College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea*These authors contributed equally to this workCorrespondence: Youngro ByunCollege of Pharmacy, Seoul National University, 1 Gwanak-Ro, Seoul 08826, Republic of KoreaTel +82 2 880 7866Fax +82 2 872 7864Email yrbyun@snu.ac.krJin Woo ParkCollege of Pharmacy and Natural Medicine Research Institute, Mokpo National University, 1666 Youngsan-Ro, Muan-gun, Jeonnam 58554, Republic of KoreaTel +82 61 450 2704Fax +82 61 450 2689Email jwpark@mokpo.ac.krObjective: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy.Methods: An ion-pairing complex of OP with a permeation enhancer, Nα-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF).Results: The optimized powder formulation was sized in the nanoscale range (133± 1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls.Conclusion: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.Keywords: oxaliplatin, bile acid transporter-mediated permeation, oral bioavailability, metronomic dosing, colorectal cancer

Rudra Pangeni,1,* Saurav Kumar Jha,1,* Ruby Maharjan,2 Jeong Uk Choi,2 Kwan-Young Chang,3 Young Kweon Choi,3 Youngro Byun,4 Jin Woo Park11Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; 2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; 3Global R&D Center, Icure BNP, Seoul 06170, Republic of Korea; 4Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea*These authors contributed equally to this workObjective: The rational combination of immunotherapy with standard chemotherapy shows synergistic clinical activities in cancer treatment. In the present study, an oral powder formulation of pemetrexed (PMX) was developed to enhance intestinal membrane permeability and investigate its application in metronomic chemotherapy in combination with immunotherapy.Methods: PMX was ionically complexed with a bile acid derivative (Nα-deoxycholyl-l-lysyl-methylester; DCK) as a permeation enhancer and mixed with dispersing agents, such as poloxamer 188 (P188) and Labrasol, to form an amorphous oral powder formulation of PMX/DCK (PMX/DCK-OP).Results: The apparent permeability (Papp) of PMX/DCK-OP across a Caco-2 cell monolayer was 2.46- and 8.26-fold greater than that of PMX/DCK and free PMX, respectively, which may have been due to the specific interaction of DCK with bile acid transporters, as well as the alteration of membrane fluidity due to Labrasol and P188. Furthermore, inhibition of bile acid transporters by actinomycin D in Caco-2 cell monolayers decreased the Papp of PMX/DCK-OP by 75.4%, suggesting a predominant role of bile acid transporters in the intestinal absorption of PMX/DCK-OP. In addition, caveola/lipid raft-dependent endocytosis, macropinocytosis, passive diffusion, and paracellular transport mechanisms significantly influenced the permeation of PMX/DCK-OP through the intestinal membrane. Therefore, the oral bioavailability of PMX/DCK-OP in rats was 19.8%±6.93%, which was 294% higher than that of oral PMX. Moreover, an in vivo anticancer efficacy study in B16F10 cell-bearing mice treated with a combination of oral PMX/DCK-OP and intraperitoneal anti-PD1 exhibited significant suppression of tumor growth, and the tumor volume was maximally inhibited by 2.03- and 3.16-fold compared to the oral PMX/DCK-OP and control groups, respectively.Conclusion: These findings indicated the therapeutic potential of a combination of low-dose oral chemotherapy and immunotherapy for synergistic anticancer efficacy.Keywords: pemetrexed, bile acid derivative, oral powder formulation, intestinal membrane permeability, oral delivery, oral metronomic chemotherapy

Jin-Woo Park,1 Takao Hanawa,2 Jong-Hyuk Chung31Department of Periodontology, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea; 2Department of Metallic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; 3Department of Periodontology, School of Dentistry, Kyung Hee University, Seoul, Republic of KoreaPurpose: Calcium (Ca) and magnesium (Mg) ions have been used as promising bioactive ions in the surface chemistry modification of titanium (Ti) bone implants to increase bone regeneration capacity. However, it is not clear which (Ca or Mg) plays the more important role in the early osteogenic differentiation of mesenchymal stem cells (MSCs) when applied to the surface of commercially available microstructured Ti implants. This study investigated the relative effect of these two ions on the early osteogenic functionality of primary mouse bone marrow MSCs in order to obtain insights into the surface design of Ti implants with enhanced early osteogenic capacity.Methods and results: Wet chemical treatment was performed to modify a microrough Ti implant surface using Ca or Mg ions. Both the Ca and Mg-incorporated surfaces accelerated early cellular events and the subsequent osteogenic differentiation of MSCs compared with an unmodified microrough Ti surface. Surface Mg modification exhibited a more potent osteoblast differentiation-promoting effect than the Ca modification. Surface Mg incorporation markedly inhibited the phosphorylation of β-catenin.Conclusion: These results indicate that alteration of the surface chemistry of microstructured Ti implants by wet chemical treatment with Mg ions exerts a more effect on promoting the early osteogenic differentiation of MSCs than Ca ions by enhancing early cellular functions, including focal adhesion development and stabilization of intracellular β-catenin.Keywords: divalent cations, surface chemistry, nanotopography, bone implant

Jun-Pil Jee1,*, Rudra Pangeni2,*, Saurav Kumar Jha,2 Youngro Byun,3 Jin Woo Park21College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea; 2College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam 58554, Republic of Korea; 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea*These authors contributed equally to this workPurpose: We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site.Methods: To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model.Results: The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively.Conclusion: LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.Keywords: diabetic wound-healing, topical hydrogel, highly skin-permeable growth factors, quercetin, 1-bromoperfluorooctane, oxygen delivery

Rudra Pangeni,1,* Jeong Uk Choi,2,* Vijay Kumar Panthi,1 Youngro Byun,3 Jin Woo Park1 1College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea; 2College of Pharmacy, Seoul National University, Seoul, Republic of Korea; 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea *These authors contributed equally to this work Objective: The current study sought to design an oral delivery system of pemetrexed (PMX), a multitargeted antifolate antimetabolite, by enhancing its intestinal membrane permeability. Materials and methods: PMX was ionically complexed with a permeation enhancer such as Nα-deoxycholyl-l-lysyl-methylester (DCK) and prepared as an amorphous solid dispersion by mixing with dispersants such as 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and poloxamer 188 (P188), forming an HP-beta-CD/PMX/DCK/P188; the complex was incorporated into multiple water-in-oil-in-water nanoemulsions in a supersaturated state (HP-beta-CD/PMX/DCK/P188-NE). Results: After complex formation, the partition coefficient and in vitro membrane permeability of PMX were markedly increased, but it showed similar cytotoxic and inhibitory effects on cancer cell proliferation/migration. Furthermore, the intestinal membrane permeability and epithelial cell uptake of PMX were synergistically improved after HP-beta-CD/PMX/DCK/P188 was incorporated into a nanoemulsion with a size of 14.5±0.45 nm. The in vitro permeability of HP-beta-CD/PMX/DCK/P188-NE across a Caco-2 cell monolayer was 9.82-fold greater than that of free PMX, which might be attributable to the partitioning of PMX to the epithelial cells being facilitated via specific interaction of DCK with bile acid transporters, as well as the enhanced lipophilicity accompanied by surfactant-induced changes in the intestinal membrane structure and fluidity. Therefore, the oral bioavailability of HP-beta-CD/PMX/DCK/P188-NE in rats was evaluated as 26.8%±2.98% which was 223% higher than that of oral PMX. Moreover, oral HP-beta-CD/PMX/DCK/P188-NE significantly suppressed tumor growth in Lewis lung carcinoma cell-bearing mice, and the tumor volume was maximally inhibited by 61% compared with that in the control group. Conclusion: These results imply that HP-beta-CD/PMX/DCK/P188-NE is an effective and promising delivery system for enhancing the oral absorption of PMX. Thus, there is the potential for new medical applications, including applications in metronomic cancer treatment. Keywords: pemetrexed, deoxycholic acid derivative, multiple nanoemulsions, permeability, oral absorption, oral anticancer therapy

Hyeon-Kyoung Koo,1 Sung-Woo Park,2 Jeong-Woong Park,3 Hye Sook Choi,4 Tae-Hyung Kim,5 Hyoung Kyu Yoon,6 Kwang Ha Yoo,7 Ki-Suck Jung,8 Deog Kyeom Kim9 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Republic of Korea; 2Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soon Chun Hyang University Bucheon Hospital, Bucheon, Republic of Korea; 3Department of Pulmonary and Critical Care Medicine, Gachon University, Gil Medical Center, Incheon, Republic of Korea; 4Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea; 6Department of Internal Medicine, The Catholic University of Korea, Yeouido St Mary’s Hospital, Seoul, Republic of Korea; 7Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea; 8Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea; 9Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea Background and purpose: Chronic cough can be a dominant symptom of chronic obstructive pulmonary disease (COPD), although its clinical impact remains unclear. The aim of our study was to identify phenotypic differences according to the presence of chronic cough or sputum and evaluate the impact of chronic cough on the risk of acute exacerbation of COPD (AECOPD). Methods: In a nationwide COPD cohort including 1,613 COPD patients, patients with chronic cough only, those with sputum only, those with chronic bronchitis (CB), and those without cough and sputum were compared with regard to dyspnea, lung function, quality of life (QoL), and risk of AECOPD. Results: The rates of chronic cough, chronic sputum, and both were 23.4%, 32.4%, and 18.2%, respectively. Compared with patients without chronic cough, those with chronic cough exhibited a lower forced expiratory volume in 1 second (% predicted) and diffusing capacity of the lungs for carbon monoxide (% predicted), more frequent AECOPD, more severe dyspnea, and worse QoL. Pulmonary function, dyspnea severity, and QoL worsened in the following order: without cough or sputum, with sputum only, with cough only, and with CB. Multivariate analyses revealed chronic cough as an independent risk factor for a lower lung function, more severe dyspnea, and a poor QoL. Moreover, the risk of future AECOPD was significantly associated with chronic cough (odds ratio 1.56, 95% CI 1.08–2.24), but not with chronic sputum. Conclusion: Our results suggest that chronic cough should be considered as an important phenotype during the determination of high-risk groups of COPD patients. Keywords: pulmonary disease, chronic obstructive, cough, exacerbation, severity

Cheong-Ju Kim,1 Hyoung-Kyu Yoon,2 Myung-Jae Park,3 Kwang-Ha Yoo,4 Ki-Suck Jung,5 Jeong-Woong Park,6 Seong Yong Lim,7 Jae Jeong Shim,8 Yong Chul Lee,9 Young-Sam Kim,10 Yeon-Mok Oh,11 Song Kim,12 Chul-Gyu Yoo13 1Department of Internal Medicine, National Health Insurance System Ilsan Hospital, Koyang, 2Division of Pulmonology, Department of Internal Medicine, St Mary’s Hospital, College of Medicine, The Catholic University of Korea, 3Division of Respiratory and Critical Care Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul, 4Department of Internal Medicine, Konkuk University School of Medicine, Gwangjin-gu, 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang-si, 6Division of Pulmonary and Allergy Medicine, Gachon University Gil Medical Center, Incheon, 7Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 8Department of Internal Medicine, Korea University College of Medicine, Seoul, 9Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonbuk, 10Department of Internal Medicine, Yonsei University College of Medicine, 11Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 12Clinical Development and Medical Affairs, Novartis Korea Ltd., Seoul, 13Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Background and objective: Pulmonary tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD); however, few clinical studies have investigated treatment effectiveness in COPD patients with destroyed lung by TB. The Indacaterol effectiveness in COPD patients with Tuberculosis history (INFINITY) study assessed the efficacy and safety of once-daily inhaled indacaterol 150 µg for the treatment of Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation. Methods: This was a multicenter, double-blind, parallel-group study, in which eligible patients were randomized (1:1) to receive either once-daily indacaterol 150 µg or placebo for 8 weeks. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s at Week 8; the secondary endpoints included changes in transition dyspnea index score and St George’s Respiratory Questionnaire for COPD score at Week 8. Safety was evaluated over 8 weeks. Results: Of the 136 patients randomized, 119 (87.5%) completed the study treatment. At Week 8, indacaterol significantly improved trough forced expiratory volume in 1 s versus placebo (treatment difference [TD] 140 mL, P

Rudra Pangeni,1,* Sang Won Choi,1,* Ok-Cheol Jeon,2 Youngro Byun,3 Jin Woo Park1 1Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, 2Pharosgen R&D Center, Asan Institute for Life Sciences, 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: Oxaliplatin (OXA) is a third-generation cisplatin analog that has been approved as first-line chemotherapy in combination with 5-fluorouracil (5-FU) for the treatment of resectable and advanced colorectal cancer. However, the therapeutic efficacy of oral OXA and 5-FU is limited by their low bioavailability due to poor membrane permeability. The aim of the present study was to develop an oral delivery system for OXA and 5-FU. We constructed an ion-pairing complex of OXA with a deoxycholic acid derivative (Nα-deoxycholyl-L-lysyl-methylester, DCK) (OXA/DCK) as a permeation enhancer. Next, we prepared multiple water-in-oil-in-water nanoemulsions incorporating OXA/DCK and 5-FU to enhance their oral absorption. To evaluate their membrane permeability, we assessed in vitro permeabilities of OXA/DCK and 5-FU through an artificial intestinal membrane and Caco-2 cell monolayer. Finally, oral bioavailability in rats and tumor growth inhibition in the colorectal adenocarcinoma cell (CT26)-bearing mouse model were investigated after oral administration of nanoemulsion containing OXA/DCK and 5-FU. The droplet size of the optimized nanoemulsion was 20.3±0.22 nm with a zeta potential of -4.65±1.68 mV. In vitro permeabilities of OXA/DCK and 5-FU from the nanoemulsion through a Caco-2 cell monolayer were 4.80- and 4.30-fold greater than those of OXA and 5-FU, respectively. The oral absorption of OXA/DCK and 5-FU from the nanoemulsion also increased significantly, and the resulting oral bioavailability values of OXA/DCK and 5-FU in the nanoemulsive system were 9.19- and 1.39-fold higher than those of free OXA and 5-FU, respectively. Furthermore, tumor growth in CT26 tumor-bearing mice given the oral OXA/DCK- and 5-FU-loaded nanoemulsion was maximally inhibited by 73.9%, 48.5%, and 38.1%, compared with tumor volumes in the control group and the oral OXA and 5-FU groups, respectively. These findings demonstrate the therapeutic potential of a nanoemulsion incorporating OXA/DCK and 5-FU as an oral combination therapy for colorectal cancer. Keywords: oxaliplatin, 5-fluorouracil, deoxycholic acid derivative, ion-pairing complex, nanoemulsion, oral delivery

Seung Rim Hwang,1 Dong-Hyun Seo,2 Youngro Byun,3 Jin Woo Park4 1Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, 2Department of Biomedical Engineering, College of Health Science, Yonsei University, Wonju, Gangwon, 3Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul, 4Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea Abstract: The N-terminal 34-amino-acid peptide fragment of human parathyroid hormone PTH (1-34), is used clinically to treat osteoporosis; however, it is currently administered by a once-daily subcutaneous injection, resulting in poor patient compliance. We have developed enteric microcapsules containing an ionic nanocomplex between PTH (1-34) and lysine-linked deoxycholic acid (LysDOCA) for the oral delivery of PTH (1-34). We measured the particle size of the PTH/LysDOCA complex and assessed its biological activity by determining the cAMP content in MC3T3-E1 cells. We also assessed its permeability across a Caco-2 cell monolayer and the bioavailability of the intrajejunally administered PTH/LysDOCA complex compared with PTH (1-34) in rats. In addition, the antiosteoporotic activity of the PTH/LysDOCA complex, encapsulated in an enteric carrier by coaxial ultrasonic atomization, was evaluated after it was orally administered to ovariectomized (OVX) rats. The formation of an ionic complex between PTH (1-34) and LysDOCA produced nanoparticles of diameter 33.0±3.36 nm, and the bioactivity of the complex was comparable with that of PTH (1-34). The Caco-2 cell permeability and AUClast value of the PTH/LysDOCA (1:10) nanocomplex increased by 2.87- and 16.3-fold, respectively, compared with PTH (1-34) alone. Furthermore, the OVX rats treated with oral PTH/LysDOCA-loaded enteric microcapsules showed an increase in bone mineral density (159%), bone volume fraction (175%), and trabecular number (174%) compared with those in the OVX control group. Therefore, the PTH/LysDOCA nanocomplex oral delivery system is a promising treatment modality for osteoporosis because it improves osteogenesis and trabecular connectivity. Keywords: oral delivery, parathyroid hormone, nanocomplex, deoxycholic acid, coaxial ultrasonic atomization, osteoporosis

Il-Hong Bae,1 Jin Woo Park,2 Dae-Yong Kim1 1College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea; 2College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam, Republic of Korea Abstract: Exogenous administration of growth factors has potential benefits in wound ­healing; however, limited percutaneous absorption, inconsistent efficacy, and the need for high doses have hampered successful clinical use. To overcome these restrictions, we focused on the development of a topical formulation composed of highly skin-permeable multimeric nanocomplex of growth factors. In the present study, we fused low-molecular-weight protamine (LMWP) with epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-I), and platelet-derived growth factor A ligand (PDGF-A) (producing recombinant [r]LMWP-EGF, rLMWP-IGF-I, and rLMWP-PDGF-A, respectively) via genetic modification. Then, we used in vitro cell proliferation studies to assess the biological activity and the benefits of the combination. The LMWP-conjugated growth factors were complexed with low-molecular-weight heparin (LMWH) and formulated with Poloxamer 188 as a delivery vehicle. After confirming the enhanced skin permeability, in vivo studies were performed to assess whether the LMWP-conjugated growth factor nanocomplex formulations accelerated the healing of full-thickness wounds in mice. The LMWP-conjugated growth factors were biologically equivalent to their native forms, and their combination induced greater fibroblast proliferation. rLMWP-EGF showed significantly enhanced permeability and cumulative permeation, and the rates for rLMWP-IGF-I and rLMWP-PDGF-A, across excised mouse skin, were 124% and 164% higher, respectively, than for the native forms. The LMWP-fused growth factors resulted in formation of nanocomplexes (23.51±1.12 nm in diameter) in combination with LMWH. Topical delivery of growth factors fused with LMWP accelerated wound re-epithelialization significantly, accompanied by the formation of healthy granulation tissue within 9 days compared with a free–growth factor complex or vehicle. Thus, the LMWP-conjugated growth factor nanocomplex can induce rapid, comprehensive healing and may be a candidate wound-healing therapeutic. Keywords: epidermal growth factor, insulin-like growth factor, platelet-derived growth factor

Hyun-Jong Cho1, Jin Woo Park2, In-Soo Yoon2, Dae-Duk Kim31College of Pharmacy, Kangwon National University, Chuncheon, 2College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, 3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of KoreaAbstract: Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel.Keywords: solid lipid nanoparticles, vitamin E TPGS, docetaxel, lymphatic uptake, bioavailability, toxicity

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

Ji-Hee Lee1,*, Goeun Choi1,*, Yeon-Ji Oh1, Je Won Park1, Young Bin Choy3, Mung Chul Park1, Yeo Joon Yoon1, Hwa Jeong Lee2, Hee Chul Chang4, Jin-Ho Choy1 1Center for Intelligent Nano-Bio Materials (CINBM), Department of Bioinspired Science and Department of Chemistry and Nano Science, 2Division of Life and Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul, Korea; 3Department of Biomedical Engineering, College of Medicine and Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University, Seoul, Korea; 4Global Strategy Center and Pharmaceutical Research Institute, Daewoong Pharmaceutical Co., Ltd., Seoul, Korea*These authors contributed equally to this workAbstract: A nanohybrid was prepared with an inorganic clay material, montmorillonite (MMT), for taste masking of sildenafil (SDN). To further improve the taste-masking efficiency and enhance the drug-release rate, we coated the nanohybrid of SDN–MMT with a basic polymer, polyvinylacetal diethylaminoacetate (AEA). Powder X-ray diffraction and Fourier transform infrared experiments showed that SDN was successfully intercalated into the interlayer space of MMT. The AEA-coated SDN–MMT nanohybrid showed drug release was much suppressed at neutral pH (release rate, 4.70 ± 0.53%), suggesting a potential for drug taste masking at the buccal cavity. We also performed in vitro drug release experiments in a simulated gastric fluid (pH = 1.2) and compared the drug-release profiles of AEA-coated SDN–MMT and Viagra®, an approved dosage form of SDN. As a result, about 90% of SDN was released from the AEA-coated SDN–MMT during the first 2 hours while almost 100% of drug was released from Viagra®. However, an in vivo experiment showed that the AEA-coated SDN–MMT exhibited higher drug exposure than Viagra®. For the AEA-coated SDN–MMT, the area under the plasma concentration–time curve from 0 hours to infinity (AUC0-∞) and maximum concentration (Cmax) were 78.8 ± 2.32 µg • hour/mL and 12.4 ± 0.673 µg/mL, respectively, both of which were larger than those obtained with Viagra® (AUC0-∞ = 69.2 ± 3.19 µg • hour/mL; Cmax = 10.5 ± 0.641 µg/mL). Therefore, we concluded that the MMT-based nanohybrid is a promising delivery system for taste masking of SDN with possibly improved drug exposure.Keywords: montmorillonite, nanohybrids, polyvinylacetal diethylaminoacetate, sildenafil citrate, taste masking

Large-scale astronomical surveys have the potential to capture data on large numbers of strongly gravitationally lensed supernovae (LSNe). To facilitate timely analysis and spectroscopic follow-up before the supernova fades, an LSN needs to be identified soon after it begins. To quickly identify LSNe in optical survey data sets, we designed ZipperNet, a multibranch deep neural network that combines convolutional layers (traditionally used for images) with long short-term memory layers (traditionally used for time series). We tested ZipperNet on the task of classifying objects from four categories - no lens, galaxy-galaxy lens, lensed Type-Ia supernova, lensed core-collapse supernova - within high-fidelity simulations of three cosmic survey data sets: the Dark Energy Survey, Rubin Observatory's Legacy Survey of Space and Time (LSST), and a Dark Energy Spectroscopic Instrument (DESI) imaging survey. Among our results, we find that for the LSST-like data set, ZipperNet classifies LSNe with a receiver operating characteristic area under the curve of 0.97, predicts the spectroscopic type of the lensed supernovae with 79% accuracy, and demonstrates similarly high performance for LSNe 1-2 epochs after first detection. We anticipate that a model like ZipperNet, which simultaneously incorporates spatial and temporal information, can play a significant role in the rapid identification of lensed transient systems in cosmic survey experiments.

We present results from an international model comparison study involving a series of controlled fault activation experiments in Opalinus Clay at the Mont Terri Laboratory, Switzerland. The fault activation experiments were conducted in situ by water injection at variable pressure from boreholes targeting different parts of the Main Fault crossing several tunnels and galleries of the Mont Terri Laboratory. The model simulations focused on (1) an experiment activating a discontinuity (fracture or minor fault) within the damage zone of the main fault, and (2) an experiment activating discontinuities close to the core of the Main Fault. The experimental data consist of coupled hydraulic and mechanical responses monitored at an injection borehole and a monitoring borehole located a few meters away. After overcoming several modeling issues along with necessary model developments, a reasonably good agreement was achieved between the modeling results and the field observations. The fault activation experiments displayed an abrupt flow rate increase associated with a sudden fracture opening and rupture propagation after the injection pressure reached above the estimated normal stress on the fracture. This was followed by an abrupt flow rate decrease, indicating hydraulic closing, once the injection pressure decreases to an estimated 1–2 MPa below the stress normal to the opened fracture. The models were able to capture this abrupt hydromechanical behavior, including an observed dominant opening behavior along with the rupture propagation, while the spatial extent of the shear rupture and the quantity of peak injection flow were the most challenging to predict.

The present study is aimed at developing a numerical model to reproduce coupled hydro-mechanical processes associated with fault reactivation by fluid injection in low permeability rock, as part of the DECOVALEX-2019 project Task B. We proposed a modeling approach for simulating the processes using the TOUGH-FLAC simulator, and modeled a fault reactivation experiment conducted at Mont Terri Rock Laboratory in Switzerland. The first step of the study involved benchmark calculations considering a simplified fault plane and geometry. Fluid flow along a fault was modeled using elements of aperture-sized thickness on the basis of Darcy's law and the cubic law in TOUGH2, whereas the mechanical behavior of a single fault was represented by zero-thickness interface elements in FLAC3D upon which a slip and/or separation is allowed. A methodology to connect a TOUGH2 volume element to a FLAC3D interface element was developed for handling the hydro-mechanical interactions on the fault during fluid injection. Two different fault models for describing the evolutions of hydraulic aperture by elastic fracture opening and failure-induced aperture increase were considered in the benchmark calculations. In the coupling process, the changes in geometrical features and hydrological properties induced by mechanical deformation were continuously updated. The transient responses of the fault and host rock to stepwise pressurization were examined during the simulation. The hydro-mechanical behavior, including the injection flow rate, pressure distribution around the borehole, stress conditions, and displacements in normal and shear directions were monitored in the surrounding rock and along the fault. The results of benchmark calculations suggest that the developed model reasonably represents the hydro-mechanical behavior of a fault and the surrounding rock. This modeling approach was applied to the fault reactivation experiment of the Mont Terri Rock Laboratory. In this interpretive modeling, a parametric study was conducted to examine the effects of input parameters regarding in situ stress and fault properties on the hydro-mechanical responses of the fault to water injection. Then, an optimal parameter set to reproduce the field experiment results was chosen by trial-and-error. The injection flow rate and pressure response during fault reactivation closely matched those obtained at the site, which indicates the capability of the model to appropriately capture the progressive pathway evolution during fault reactivation tests at the site. The anchor displacements were overestimated by the model, but a fair agreement was obtained in terms of the order of magnitude and the variation tendency.

We numerically model the thermal-hydrological-mechanical (THM) processes within the rock mass surrounding a cavern used for thermal energy storage (TES). We consider a cylindrical rock cavern with a height of 50 m and a radius of 10 m storing thermal energy of 350 °C as a conceptual TES model, and simulate its operation for thirty years. At first, the insulator performance are not considered for the purpose of investigating the possible coupled THM behavior of the surrounding rock mass; then, the effects of an insulator are examined for different insulator thicknesses. The key concerns are hydro-thermal multiphase flow and heat transport in the rock mass around the thermal storage cavern, the effect of evaporation of rock mass, thermal impact on near the ground surface and the mechanical behavior of the surrounding rock mass. It is shown that the rock temperature around the cavern rapidly increases in the early stage and, consequently, evaporation of groundwater occurs, raising the fluid pressure. However, evaporation and multiphase flow does not have a significant effect on the heat transfer and mechanical behavior in spite of the high-temperature (350 °C) heat source. The simulations showed that large-scale heat flow around a cavern is expected to be conduction-dominated for a reasonable value of rock mass permeability. Thermal expansion as a result of the heating of the rock mass from the storage cavern leads to a ground surface uplift on the order of a few centimeters, and to the development of tensile stress above the storage cavern, increasing the potentials for shear and tensile failures after a few years of the operation. Finally, the analysis shows that high tangential stress in proximity of the storage cavern can some shear failure and local damage, although large rock wall failure could likely be controlled with appropriate insulators and reinforcement.

Abstract Liquid-water management in polymer-electrolyte fuel cells (PEFCs) remains an area of ongoing research. To enhance water removal, certain flow-fields induce cross-flow, or flow through the gas-diffusion layer (GDL) via channel-to-channel pressure differences. While beneficial to water removal, cross-flow comes at the cost of higher pumping pressures and may lead to membrane dehydration and other deleterious issues. This paper examines the impact of cross-flow on component saturation levels as determined through in-plane high-resolution neutron radiography. Various humidities and operating conditions are examined, and the results demonstrate that cell saturation levels correlate strongly with the level of cross-flow rate, and lower GDL saturation levels are found to correlate with an increase in permeability at higher flow rates. Effective water removal is found to occur at channel-to-channel pressure gradients greater than the measured breakthrough pressure of the GDL, evidence that similar liquid-water transport mechanisms exist for under-land area transport as in transverse GDL flow.

Micrometastatic cells in the bone marrow, now usually referred to as "disseminated tumor cells (DTCs)", can be detected in early stage cancer patients. It has been hypothesized that DTCs represent key intermediates in the metastatic process as possible pre

BackgroundThis phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC).MethodsPatients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured.ResultsThirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival.ConclusionThe combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

We show that strong edge magnetic shear, which is generic to divertor plasmas, makes the E × B shearing of turbulence eddys in toroidal geometry more effective. From calculations of the E × B shearing rates for KSTAR edge parameters, we conclude that the enhanced magnetic shear at the diverted KSTAR plasma edge facilitates E × B shear suppression of turbulence and ensuing H-mode transition. © 2013 IAEA, Vienna.

Preclinical data have demonstrated that the combination of antihuman epidermal growth factor receptor-2 (anti-HER2) and antivascular endothelial growth factor (anti-VEGF)-targeted agents has antitumor activity; these data indicate certain patients with HER