Nam Kyung Je

Epithelial-mesenchymal Transition is Associated with Acquired Resistance to 5-Fluorocuracil in HT-29 Colon Cancer Cells

5-Fluorouracil (5-FU) is commonly used for the therapy of colon cancer; however, acquired resistance to 5-FU is a critical barrier to successful treatment and the primary cause of chemotherapy failure. Epithelialmesenchymal transition (EMT) is a process whereby cells undergo alterations in morphology and molecular characteristics promoting tumor progression and metastasis. Accumulating evidence shows that transition from epithelial to mesenchymal phenotype in cancer cells is associated with their resistance to chemotherapy. However, it is still poorly understood whether EMT is involved in acquired resistance to 5-FU. In this study, we developed an in vitro cell model, 5-FU-resistant HT-29 colon cancer cells, and characterized the differences in cellular morphology and molecular alterations between parental and resistant cells. In accord with mesenchymal-like morphology of 5-FU-resistant HT-29 cells, the expression of the mesenchymal marker fibronectin was significantly increased in these cells in comparision with that in the parental cells. Of interest, we also found a marked increase in the expression of EMT-inducing transcription factors Twist, Zeb1, and Zeb2. Finally, 5-FU-resistant cells showed enhanced migration in comparison with parental HT-29. Taken together, these results indicate that EMT could be associated with 5-FU resistance acquired by HT-29 cells. A specific role of each transcription factor found in this study will require further investigation.

Oligonol Ameliorates CCl4-Induced Liver Injury in Rats via the NF-Kappa B and MAPK Signaling Pathways

Oxidative stress is thought to be a key risk factor in the development of hepatic diseases. Blocking or retarding the reactions of oxidation and the inflammatory process by antioxidants could be a promising therapeutic intervention for prevention or treatment of liver injuries. Oligonol is a low molecular weight polyphenol containing catechin-type monomers and oligomers derived from lychee fruit. In this study, we investigated the anti-inflammatory effect of oligonol on carbon tetrachloride- (CCl4-) induced acute hepatic injury in rats. Oral administration of oligonol (10 or 50 mg/kg) reduced CCl4-induced abnormalities in liver histology and serum AST and serum ALT levels. Oligonol treatment attenuated the CCl4-induced production of inflammatory mediators, including TNF-α, IL-1β, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA levels. Western blot analysis showed that oligonol suppressed proinflammatory nuclear factor-kappa B (NF-κB) p65 activation, phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) as well as Akt. Oligonol exhibited strong antioxidative activity in vitro and in vivo, and hepatoprotective activity against t-butyl hydroperoxide-induced HepG2 cells. Taken together, oligonol showed antioxidative and anti-inflammatory effects in CCl4-intoxicated rats by inhibiting oxidative stress and NF-κB activation via blockade of the activation of upstream kinases including MAPKs and Akt.

Underutilization of warfarin for stroke prophylaxis in patients with atrial fibrillation or atrial flutter in Korea

OBJECTIVE Anticoagulation therapy with warfarin is recommended for stroke prevention in patients with atrial fibrillation (AF) or atrial flutter (AFL) whose risks for stroke are high. However, previous studies suggest that warfarin is markedly underused. This study aims to investigate the incidence and risk factors of warfarin underutilization in patients with high risk of stroke in Korea. METHODS This was a cross-sectional study using the data of 2009 from National Patients Sample compiled by the Health Insurance Review and Assessment Service. Patients with high risk of thromboembolism were identified with congestive heart failure, hypertension, age ≥75 years, diabetes, and prior stroke (CHADS2) score ≥2. High-risk patients of bleeding were excluded using Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) score >4. Warfarin and antithrombotic therapy underutilization were defined and estimated in high-risk patients. Any demographic and clinical factors associated with warfarin and antithrombotic therapy underutilization were explored using a logistic regression model. RESULTS Of the national patient sample, 15,885 patients were identified with AF or AFL. Among them, a total of 8475 patients who had an admission history, CHADS2 ≥2, and ATRIA score ≤4 were included in the analysis. From the study sample, warfarin underutilization and antithrombotic therapy underutilization were estimated to be 64.0% and 20.4%, respectively. Predictors of warfarin underutilization include female sex, age ≥80 years, lower CHADS2 score, and insurance type (Medical Aid program). CONCLUSIONS A high portion of AF/AFL patients with CHADS2 score ≥2 were undertreated with warfarin. As ischemic stroke is one of the leading causes of death in Korea, a more aggressive approach to prevent stroke in patients with AF/AFL is required.

Therapeutic Effects of S-Petasin on Disease Models of Asthma and Peritonitis

To explore the anti-allergic and anti-inflammatory effects of extracts of Petasites genus, we studied the effects of s-petasin, a major sesquiterpene from Petasites formosanus (a butterbur species) on asthma and peritonitis models. In an ovalbumin-induced mouse asthma model, s-petasin significantly inhibited the accumulations of eosinophils, macrophages, and lymphocytes in bronchoalveolar fluids. S-petasin inhibited the antigen-induced degranulation of β-hexosamidase but did not inhibit intracellular Ca2+ increase in RBL-2H3 mast cells. S-petasin inhibited the LPS induction of iNOS at the RNA and protein levels in mouse peritoneal macrophages. Furthermore, s-petasin inhibited the production of NO (the product of iNOS) in a concentration-dependent manner in the macrophages. Furthermore, in an LPS-induced mouse model of peritonitis, s-petasin significantly inhibited the accumulation of polymorpho nuclear and mononuclear leukocytes in peritoneal cavity. This study shows that s-petasin in Petasites genus has therapeutic effects on allergic and inflammatory diseases, such as, asthma and peritonitis through degranulation inhibition in mast cells, suppression of iNOS induction and production of NO in macrophages, and suppression of inflammatory cell accumulation.

Satisfaction and expressed needs of pharmaceutical care services and challenges recognized by patients in South Korea

Purpose To assess the degree of satisfaction and expressed needs of pharmaceutical care services in patients with chronic diseases and explore the factors related to the needs from patients’ perspectives for the further development of pharmaceutical care service models. Patients and methods A cross-sectional survey of 220 patients (mean age ± SD: 61.3±13.1, male:female: 104:116) was conducted. The questionnaire was structured to measure patients’ degree of satisfaction and expressed needs using a 5-point Likert scale. Additionally, preferred duration, methods of service delivery, and willingness to pay were surveyed. Responses were analyzed using an ordinal regression method to predict factors that were related to pharmaceutical care services. Results Sixty-seven patients had experienced pharmaceutical care services. Their satisfaction levels were high in all categories; however, there were no significant differences between categories. The levels of expressed needs were similar among categories without significant differences. The preferred delivery method was a face-to-face conversation combined with being provided with written information (53.2%). The preferred duration was ≤10 min (70.5%). About 48% of the patients showed willingness to pay for the service. Education level and region influenced patients’ needs. Conclusion The satisfaction and needs of pharmaceutical care services was very positive; however, noticing only a third of patients experienced pharmaceutical care services, this may indicate a lack of awareness and less appreciation of pharmacists by patients. Details concerning patients’ awareness and the value of pharmaceutical care services require further investigation.

Perceived needs of pharmaceutical care services among healthcare professionals in South Korea: a qualitative study

Purpose To explore the need for pharmaceutical care services, key features of desirable pharmacy services, and perceived barriers for advancing the services in hospital environments with doctors and nurses who are key co-workers of the interdisciplinary team care services.Methods Semi-structured, in-depth interviews with eighteen doctors and fifteen nurses employing purposive and snowballing sampling strategies were conducted in ten hospitals in South Korea. Results The level of pharmaceutical care was varied across regions or institutions in South Korea. The concept of pharmaceutical care was insufficiently defined, and tended to be limited to some parts of medication counseling. Through pharmaceutical care services, doctors desired to acquire comprehensive drug information from and to share clinical responsibilities with pharmacists. Nurses wished to lower their burdens of medication counseling services from their daily practices. Doctors and nurses asked for pharmacists providing essential and carefully selected medication information to their patients in a patient-centered manner. The listed barriers to pharmaceutical care included the lack of appropriate systems for reward, insufficient accessibility to patient records by pharmacists, ambiguous role descriptions of pharmacist, and absence of effective communication among professionals. Conclusion A successful pharmaceutical care service model should allow efficient exchange of information among healthcare professionals to build inter-professional trust and to provide a continuity of care both in terms of time and setting. As prerequisites of such system, it was warranted to develop clinical evidence and an appropriate reward system for pharmaceutical care services.

Inadequate stroke prevention in Korean atrial fibrillation patients in the post-warfarin era

BACKGROUND Anticoagulation therapy with warfarin or direct oral anticoagulants (DOACs) is recommended for atrial fibrillation (AF) patients who are at a high risk for stroke. This study aimed to investigate the utilization of anticoagulants since the introduction of DOACs in South Korea. METHODS This was a cross-sectional study using claim-based national data from 2011 to 2014 derived from the Aged Patient Sample (APS) compiled by the Health Insurance Review & Assessment Service (HIRA). Patients with a high risk for thromboembolism were identified as those having a CHA2DS2-VASc (congestive heart failure, hypertension, age≥75, diabetes mellitus, stroke (or transient ischemic attack), vascular disease, sex) score of ≥2. Patients at a high risk for bleeding with an ATRIA (anticoagulation and risk factors in atrial fibrillation) bleeding score of >4 were excluded. Anticoagulant underutilization was estimated in these high-risk patients. Demographic and clinical factors associated with warfarin and DOAC underutilization were explored using a logistic regression model. RESULTS Anticoagulant underutilization among high-risk patients for stroke decreased from 68% to 62.5% between 2011 and 2014; however, there was further scope for improvement. The risk factors for underutilization were identified as follows: female sex, old age, having medical aid insurance, presence of vascular disease, and limited anticoagulant options. CONCLUSIONS Our study demonstrates that a large population of AF patients in South Korea failed to obtain adequate stroke prevention treatment, even in the era of DOAC usage. A more aggressive approach to provide optimal antithrombotic therapy is warranted.

Transformation of Mouse Liver Cells by Methylcholanthrene Leads to Phenotypic Changes Associated with Epithelial-mesenchymal Transition

Environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) have been implicated in cancer development and progression. However, the effects of PAHs on carcinogenesis are still poorly understood. Here, we characterized a mouse cancer cell line BNL 1ME A. 7R.1 (1MEA) derived by transformation of non-tumorigenic liver cell line BNL CL.2 (BNL) using 3-methylcholanthrene (3MC), a carcinogenic PAH. RT-PCR and immunoblot analysis were used to determine the expression level of mRNA and proteins, respectively. To determine functionality, cell motility was assessed in vitro using a transwell migration assay. Both mRNA and protein levels of E-cadherin were significantly decreased in 1MEA cells in comparison with BNL cells. While the expression levels of mesenchymal markers and related transcription factors were enhanced in 1MEA cells, which could lead to increase in cell motility. Indeed, we found that 7-day exposure of BNL cells to 3-MC reduced the level of the adhesion molecule and epithelial marker Ecadherin and increased reciprocally the level of the mesenchymal marker vimentin in a dose-dependent manner. Taken together, these results indicate that the process of epithelial-mesenchymal transition (EMT) may be activated during premalignant transformation induced by 3-MC. A mechanism study to elucidate the relation between 3-MC exposure and EMT is underway in our laboratory.

Adherence with renal dosing recommendations in outpatients undergoing haemodialysis

Adjustment of drug dosage in patients with end‐stage renal disease prevents serious adverse effects, which occur due to the accumulation of drugs or other toxic metabolites. Nevertheless, dosing errors occur most commonly among patients with end‐stage renal disease. The aim of this study was to assess the quality of care for end‐stage renal disease outpatients using their renal dosing adjustment status.

Physicians' and pharmacists' acceptance of online, real-time "drug combinations to avoid" messages.

UNLABELLED Drug-induced prolongation of the electrocardiogram QT interval, a risk factor for ventricular arrhythmia and death, has been observed for some small drugs with masses < 1 kDa. Over the last two decades, patient exposure to large molecule monoclonal antibody drugs with masses > 40 kDa has increased dramatically; hence, the aim of this study was to systematically review the scientific literature for evidence of QT prolongation induced by these drugs. METHODS The PubMed and Embase databases were searched for cases indicative of drug-induced QT prolongation for 28 pre-identified monoclonal antibody drugs authorized in Europe. Cases were identified by applying a standardized search string and a subsequent text search and manual review. In parallel, the public European Medicines Agency (EMA) database was searched for reported frequencies of adverse events indicative of QT prolongation. RESULTS A valid case of drug-induced QT prolongation, caused indirectly by hypocalcaemia, could be identified for only 1 out of 28 monoclonal antibody drugs (denosumab) from the PubMed and Embase search. The EMA database showed no hits for denosumab. Considering that hypocalcaemia-mediated QT prolongation is an already-identified and labelled risk for denosumab, the current study did not identify any additional evidence of QT prolongation caused by monoclonal antibody drugs.