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Moon Hee Lee,1 Seok-Kyu Yoon,1 Hyungsub Kim,2 Yong-Soon Cho,3 Sungpil Han,4 Shi Hyang Lee,1 Kyun-Seop Bae,1 Jina Jung,5 Sung Hee Hong,5 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; 2Department of Emergency Medical Services, College of Health Sciences, Eulji University, Seongnam, Republic of Korea; 3Department of Pharmacology and Clinical Pharmacology, Inje University College of Medicine, Busan, Republic of Korea; 4Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 5Hanmi Pharmaceutical Co. Ltd., Seoul, Republic of KoreaCorrespondence: Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea, Tel +82-2-3010-4613, Fax +82-2-3010-4623, Email mdlhs@amc.seoul.krPurpose: The combined administration of bazedoxifene, a tissue-selective estrogen receptor modulator, and cholecalciferol can be a promising therapeutic option for postmenopausal osteoporosis patients. This study aimed to examine the pharmacokinetic interactions between these two drugs and the tolerability of their combined administration in healthy male subjects.Patients and Methods: Thirty male volunteers were randomly assigned to one of the six sequences comprised of three treatments: bazedoxifene 20 mg monotherapy, cholecalciferol 1600 IU monotherapy, and combined bazedoxifene and cholecalciferol therapy. For each treatment, a single dose of the investigational drug(s) was administered orally, and serial blood samples were collected to measure the plasma concentrations of bazedoxifene and cholecalciferol. Pharmacokinetic parameters were calculated using the non-compartmental method. The point estimate and 90% confidence interval (CI) of the geometric mean ratio (GMR) were obtained to compare the exposures of combined therapy and monotherapy. The pharmacokinetic parameters compared were the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast). The safety and tolerability of the combined therapy were assessed in terms of the frequency and severity of adverse events (AEs).Results: For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.9263– 1.1765) for Cmax and 1.1329 (1.0232– 1.2544) for AUClast. For baseline-adjusted cholecalciferol, the GMR (90% CI) of the combined therapy to monotherapy was 0.8543 (0.8005– 0.9117) for Cmax and 0.8056 (0.7445– 0.8717) for AUClast. The frequency of AEs observed was not significantly different between the combined therapy and monotherapy, and their severity was mild in all cases.Conclusion: A mild degree of pharmacokinetic interaction was observed when bazedoxifene and cholecalciferol were administered concomitantly to healthy male volunteers. This combined therapy was well tolerated at the dose levels used in the present study.Keywords: bazedoxifene, cholecalciferol, drug-drug interaction, pharmacokinetics, tolerability

Hyun Chul Kim,1,2 Eunsol Yang,1,3 Mu Seong Ban,1 Yu Kyong Kim,4 Sung Hee Hong,5 Jina Jung,5 In-Jin Jang,1 SeungHwan Lee1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; 3Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Chungbuk National University College of Medicine and Hospital, Cheongju, Republic of Korea; 5Hanmi Pharmaceutical Co., Ltd., Seoul, Republic of KoreaCorrespondence: SeungHwan Lee, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, Tel +82-2-2072-2343, Fax +82-2-742-9252, Email leejh413@snu.ac.krBackground: Esomeprazole, a proton pump inhibitor (PPI), is widely used to treat acid-related disorders, but it has short plasma half-life which can cause insufficient gastric acid suppression, such as nocturnal acid breakthrough. A new dual delayed-release (DR) formulation of esomeprazole (Esomezol DR), was developed to extend the duration of gastric acid suppression.Purpose: This study aimed to evaluate the pharmacokinetics (PKs) and pharmacodynamics (PDs) of esomeprazole for the DR formulation compared to a conventional enteric-coated (EC) formulation (Nexium) in healthy male subjects.Methods: Two randomized, open-label, multiple-dose, two-way crossover studies with esomeprazole 20 mg and 40 mg were conducted. Subjects received the DR formulation or the EC formulation once daily for 7 days in each period with a 7-day washout. Serial blood samples were collected up to 24 hours after the 1st dose, and 24-hour intragastric pH was continuously monitored before the 1st dose as baseline and after the 1st and the 7th dose.Results: In 20 mg and 40 mg dose groups, 38 and 44 subjects completed the study, respectively. The DR formulation exhibited the dual-release pattern of esomeprazole, resulting in more sustained plasma concentration–time profiles compared to the EC formulation. The systemic exposure of esomeprazole for the DR formulation was comparable to that for the EC formulation, showing the similar area under the plasma concentration–time curve. The 24-hour gastric acid suppression was also similar between the two formulations, while the inhibition during night-time (22:00– 06:00) showed a better tendency in the DR formulation.Conclusion: The sustained exposure of esomeprazole in the DR formulation led to well-maintained and higher acid inhibition compared to the EC formulation, especially during the night-time. These results suggest that the DR formulation can be an alternative formulation to the conventional EC formulation, expecting the potential of relieving nocturnal acid-related symptoms.Keywords: proton pump inhibitors, esomeprazole, dual delayed-release formulation, gastro-esophageal reflux disease, GERD, nocturnal acid breakthrough

The diversity of health contexts in which members of the US Latinx population establish residence may provide insights into the variety of health challenges they face. We investigated differences in health professional shortages, general health services, health care safety-net supply, health access, and population health rankings across 3,113 US counties classified as established, new, or other Latinx population destinations. Compared with new destinations, established destinations had more health professional shortages, as well as higher rates of child and adult health uninsurance. New destinations had fewer health care safety-net services per 100,000 county residents than established destinations. Health contexts thus differ in significant ways across new and established Latinx destinations, and these differences have key implications for Latinx immigrant health.

Despite the common usage of radiotherapy for the treatment of human non-small-cell lung cancer (NSCLC), cancer therapeutic efficacy and outcome with ionizing radiation remains a challenge. Here, we report the antitumor effects and mechanism of a novel benzothiazole derivative PB01 (4-methoxy-cyclohexane carboxylic acid [2-(3,5-dimethyl-isoxazole-4-yl) sulpanil-benzothiazole-6-yl]-amide) in radiation-resistant human NSCLC cells. PB01 treatment is cytotoxic because it induces reactive oxygen species, ER stress, Bax, cytochrome c expression, the ATR-p53-GADD45ɑ axis, and cleavage of caspase-3 and -9. Additionally, we found that radio-resistant A549 and H460 subclones, named A549R and H460R, respectively, show enhanced epithelial-to-mesenchymal transition (EMT), whereas PB01 treatment inhibits EMT and mediates cell death through ER stress and the ATR axis under radiation exposure in radio-resistant A549R and H460R cells. Together, these results suggest that PB01 treatment can overcome radio-resistance during radiotherapy of NSCLC.

Peroxisome proliferator-activated receptor gamma (PPARɣ) agonists exert powerful anticancer effects by suppressing tumor growth. In this study, we developed PPZ023 (1-(2-(ethylthio)benzyl)-4-(2-methoxyphenyl)piperazine), a novel PPAR ligand candidate, and investigated the underlying signaling pathways in both non-small-cell lung cancer (NSCLC) and radio-resistant NSCLC cells. To identify whether PPZ023 has anticancer effects in NSCLC and radioresistant NSCLC cells, we performed WST-1, LDH, Western blot, and caspase-3 and -9 activity assays. Furthermore, we isolated exosomes from PPZ023-treated NSCLC cells and studied cell death signaling. PPZ023 reduces cell viability and increases LDH cytotoxicity and caspase-3 activity in NSCLC cells. PPZ023 induces cell death by generating reactive oxygen species (ROS) and triggering mitochondrial cytochrome c release. PPZ023 treatment causes cell death via the PERK–eIF2α–CHOP axis in both NSCLC cell lysates and exosomes, and PERK and CHOP knockdown significantly blocks ER stress-mediated apoptosis by reducing cleaved caspase-3. Interestingly, diphenyleneiodonium (DPI, a Nox inhibitor) inhibits PPZ023-induced cell death via ER stress, and PPARɣ knockdown inhibits PPZ023-induced ROS, ER stress, and cell death. Moreover, PPZ023, in combination with radiation, causes synergic cell death via exosomal ER stress in radioresistant NSCLC cells, indicating that PPZ023/radiation overcomes radioresistance. Taken together, our results suggest that PPZ023 is a powerful anticancer reagent for overcoming radioresistance., Cancer: Reversing resistance to radiotherapy A novel small molecule drug candidate known as PPZ023 could be a powerful anti-cancer agent due to its ability to overcome the resistance of tumors to radiation therapy. Sung Hee Hong and colleagues at the Korea Institute of Radiological and Medical Sciences in Seoul, South Korea, investigated the effects of the molecule on lung cancer cells, including cells that that had acquired resistance to radiotherapy. PPZ023 induces the death of cancer cells by binding to a protein in a known signaling pathway, which generates damaging chemicals known as reactive oxygen species. The researchers identified additional molecular details of the anti-cancer activity. They found the radiotherapy resistance of cancer cells is reversed when PPZ023 promotes cell death via a pathway interfering with the folding of newly formed proteins in a cell structure called the endoplasmic reticulum.

The study attempted to propose refined question items used for eight types of lectures practiced in college settings (i.e., theory-based learning, flipped learning, discussion-based lectures, problem-based learning, co-teaching, Capstone Design, e-learning, and laboratory lectures). Its purpose was to help students objectively and accurately evaluate the lectures so that the instructors could use the data to improve their teaching effectiveness and to heighten student satisfaction. Extracting data from 15 journal publishers, the study investigated 34 articles published since 2013 in relation to lecture evaluations. Results entail different lecture evaluation question items that well match distinct features each lecture type entails. Further implications for future studies are proposed based on the findings.

Objectives This study aims to examine the effect of adolescent suicide survivors' experience on suicide death risk, and the effect of referral to mental health services (hereafter referral) in this regard. Methods This study used the data of 878 suicide-deceased and suicide-attempted adolescents aged 8-19 years, managed by the Suicide and School Mental Health Institute from 2016 to 2018. Results Regression analysis for main effects showed that although suicide experience had no direct effect on suicide death, non-referral status was associated with a greater risk of death by suicide. While the "non-suicide survivor with non-referral" and "suicide survivor with non-referral" groups showed 1.87 [adjusted odds ratio=1.87, 95% confidence interval (CI)=1.21-2.89] and 4.59 (adjusted odds ratio= 4.59, 95% CI=2.02-10.42) times higher odds of suicide death, respectively, the "suicide survivor with referral" group showed no difference compared to the "non-suicide survivor with referral" group. Conclusion From these findings, there is a need to strengthen referral to mental health services and apply complicated grief treatment to improve the mental health of adolescent suicide survivors.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a well-known therapeutic target for type 2 diabetes as well as is a potential target for effective anti-cancer drug, since PPARγ ligands such as ciglitazone (Cig) frequently cause cell death in many types of cancer cells and suppress tumor growth. However, many cancer patients acquire chemo-resistance or radio-resistance after chemo or radiotherapy, and it is still unclear. In the difficulty of well-known anti-cancer drugs, we developed a novel PPARγ agonist CB13 (1-benzyl-5-(4-methylphenyl) pyrido [2,3-d]pyrimidine-2,4(1H,3H)-dione) and investigated the anti-cancer effect and cell death mechanism on human non-small cell lung cancer (NSCLC) cells. With anti-cancer effect of Cig, CB13 also causes inhibition of cell growth by decreasing cell viability, increasing the release of LDH, and increasing caspase-3, and caspase-9 activities. CB13 generates reactive oxygen species (ROS) and causes cell death via ER stress in NSCLC and radio-resistant NSCLC cells (A549R and H460R), and a combination of CB13 and radiation induces greater ER stress and cell death when compared to CB13 alone. Taken together, our results suggest that a combination of CB13 and radiation may overcome radio-resistance caused by radiotherapy.

Background Peroxisome proliferator-activated receptor γ (PPARγ) agonists frequently induce cell death in human non-small-cell lung cancer (NSCLC) cells. However, majority of NSCLC patients acquire resistance after cancer therapy, and it is still unclear. Methods In this study we investigated the apoptotic mechanism and the anti-cancer effects of a novel purine-based PPARγ agonist, CB11 (8-(2-aminophenyl)-3-butyl-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), on human NSCLC cells. CB11 mediates PPARγ-dependent cell death, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, cell cycle arrest, lactate dehydrogenase (LDH) cytotoxicity, and caspase-3 activity in human NSCLC cells. Results CB11 causes cell death via ROS-mediated ATM-p53-GADD45α signalling in human NSCLC cells, and diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, decreases cell death by inhibiting CB11-mediated ATM signalling. In a xenograft experiment, CB11 dramatically reduced tumour volume when compared to a control group. Furthermore, CB11 induced cell death by inhibiting epithelial-to-mesenchymal transition (EMT) under radiation exposure in radiation-resistant human NSCLC cells. However, PPARγ deficiency inhibited cell death by blocking the ATM-p53 axis in radiation/CB11-induced radiation-resistant human NSCLC cells. Conclusions Taken together, our results suggest that CB11, a novel PPARγ agonist, may be a novel anti-cancer agent, and it could be useful in a therapeutic strategy to overcome radio-resistance in radiation-exposed NSCLC.

Pluripotent stem cell-derived cerebral organoids have the potential to recapitulate the pathophysiology of in vivo human brain tissue, constituting a valuable resource for modelling brain disorders, including infectious diseases. Toxoplasma gondii, an intracellular protozoan parasite, infects most warm-blooded animals, including humans, causing toxoplasmosis. In immunodeficient patients and pregnant women, infection often results in severe central nervous system disease and fetal miscarriage. However, understanding the molecular pathophysiology of the disease has been challenging due to limited in vitro model systems. Here, we developed a new in vitro model system of T. gondii infection using human brain organoids. We observed that tachyzoites can infect human cerebral organoids and are transformed to bradyzoites and replicate in parasitophorous vacuoles to form cysts, indicating that the T. gondii asexual life cycle is efficiently simulated in the brain organoids. Transcriptomic analysis of T. gondii-infected organoids revealed the activation of the type I interferon immune response against infection. In addition, in brain organoids, T. gondii exhibited a changed transcriptome related to protozoan invasion and replication. This study shows cerebral organoids as physiologically relevant in vitro model systems useful for advancing the understanding of T. gondii infections and host interactions.

Cryptosporidium parvum and Giardia duodenalis are the main diarrhea-causing parasitic pathogens; however, their prevalence in Korea is unknown. Here, we conducted a survey to determine the prevalence and genotype distribution of these 2 pathogens causing acute diarrhea in 8,571 patients hospitalized in 17 Regional Institute of Health Environment sites in Korea, during 2013-2016. C. parvum and G. duodenalis were detected and genotyped by nested PCR, and the isolate were molecularly characterized by sequencing the glycoprotein 60 (Gp60) and β-giardin genes, respectively. The overall prevalence of C. parvum and G. duodenalis was 0.37% (n=32) and 0.55% (n=47), respectively, and both pathogens were more prevalent in children under 9 years old. Molecular epidemiological analysis showed that the C. parvum isolates belonged to the IIa family and were subtyped as IIaA13G2R1, IIaA14G2R1, IIaA15G2R1, and IIaA18G3R1. Analysis of the β-giardin gene fragment from G. duodenalis showed that all positive strains belong to assemblage A. This is the first report on the molecular epidemiology and subtyping of C. parvum and G. duodenalis in such a large number of diarrheal patients in Korea. These results highlight the need for continuous monitoring of these zoonotic pathogens and provide a basis for implementing control and prevention strategies. Further, the results might be useful for epidemiological investigation of the source of outbreak.

Among several anti-cancer therapies, chemotherapy can be used regardless of the stage of the disease. However, development of anti-cancer agents from potential chemicals must be executed very cautiously because of several problems, such as safety, drug resistance, and continuous administration. Most chemotherapeutics selectively cause cancer cells to undergo apoptosis. In this study, we tested the effects of a novel chemical, the benzothiazole derivative N-[2-[(3,5-dimethyl-1,2-oxazol-4-yl)methylsulfanyl]-1,3-benzothiazol-6-yl]-4-oxocyclohexane-1-carboxamide (PB11) on the human cell lines U87 (glioblastoma), and HeLa (cervix cancer). It was observed that this chemical was highly cytotoxic for these cells (IC50s < 50 nM). In addition, even 40 nM PB11 induced the classical apoptotic symptoms of DNA fragmentation and nuclear condensation. The increase of caspase-3 and -9 activities also indicated an increased rate of apoptosis, which was further confirmed via Western blotting analysis of apoptosis-associated proteins. Accordingly, PB11 treatment up-regulated the cellular levels of caspase-3 and cytochrome-c, whereas it down-regulated PI3K and AKT. These results suggest that PB11 induces cytotoxicity and apoptosis in cancer cells by suppressing the PI3K/AKT signaling pathways and, thus, may serve as an anti-cancer therapeutic.

Objectives Our study aimed to analyze the demographic and clinical characteristics of children and adolescents during their first visit to psychiatric outpatient departments for the management of suicidal ideation and behavior, and to compare the changes before and in 2012 or later. Methods This multicenter study was conducted at five university hospitals in a metropolitan area in South Korea. Medical records of patients aged 6-18 years were retrospectively reviewed from January 2009 to December 2016. Patients were analyzed by classifying them into suicidal and non-suicidal groups based on their visit to the hospital for management of suicidal ideation or suicide attempt and other mental problems, respectively. Results There were differences in the year of visit, diagnosis, education level, and referral sources between patients in the suicidal and non-suicidal groups. Multiple regression analysis was conducted based on the sex, education level, referral by school, and diagnosis of depression in patients in the suicidal group, which revealed significant association. Conclusion Suicide-related problems were significantly associated with the sex, education level, referral by school, and a diagnosis of depression in the patients. A well-connected referral system would be necessary for professional mental health management of high-risk children and adolescents.

Babesiosis is a tick-transmitted intraerythrocytic zoonosis. In Korea, the first mortalities were reported in 2005 due to Babesia sp. detection in sheep; herein we report epidemiological and genetic characteristics of a second case of babesiosis. Microscopic analysis of patient blood revealed polymorphic merozoites. To detect Babesia spp., PCR was performed using Babesia specific primers for β-tubulin, 18S rDNA, COB, and COX3 gene fragments. 18S rDNA analysis for Babesia sp., showed 98% homology with ovine Babesia sp. and with Babesia infections in Korea in 2005. Moreover, phylogenetic analysis of 18S rDNA, COB, and COX3 revealed close associations with B. motasi. For identifying the infectious agent, Haemaphysalis longicornis (296) and Haemaphysalis flava (301) were collected around the previous residence of the babesiosis patient. Babesia genes were identified in three H. longicornis: one sample was identified as B. microti and two samples were 98% homologous to B. motasi. Our study is the first direct confirmation of the infectious agent for human babesiosis. This case most likely resulted from tick bites from ticks near the patient house of the babesiosis patient. H. longicornis has been implicated as a vector of B. microti and other Babesia sp. infections.

Background Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. Methods To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. Results We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Conclusions Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.

Objectives Korea was an endemic area for lymphatic filariasis (LF), caused by the nematode parasite Brugia malayi, until the 1970s. The World Health Organization recognized Korea as LF-free in June 2008. However, it is necessary to confirm that patients that have had LF in the past still test negative, to prevent the re-emergence of LF in Korea. Methods We followed up a total of 83 patients who had been diagnosed with LF between 2002 and 2010 in endemic LF areas. Results Fifty-two of the 83 subjects were negative for LF, whereas 31 subjects had re-located to a different city or province, were dead, or were unaccounted for. Most subjects with negative test results still exhibited edema in the legs or the arms, and some complained of redness and swelling in the legs or ankle joints. However, we found that these symptoms were due to diseases other than LF. Conclusion In this follow-up study, we did not find any evidence indicating the potential re-emergence of LF in Korea.