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1.  Gentamicin-Loaded Wound Dressing With Polyvinyl Alcohol/Dextran Hydrogel: Gel Characterization and In Vivo Healing Evaluation 
AAPS PharmSciTech  2010;11(3):1092-1103.
To develop a gentamicin-loaded wound dressing, cross-linked hydrogel films were prepared with polyvinyl alcohol (PVA) and dextran using the freezing–thawing method. Their gel properties such as gel fraction, swelling, water vapor transmission test, morphology, tensile strength, and thermal property were investigated. In vitro protein adsorption test, in vivo wound healing test, and histopathology were performed. Dextran decreased the gel fraction, maximum strength, and thermal stability of hydrogels. However, it increased the swelling ability, water vapor transmission rate, elasticity, porosity, and protein adsorption. The drug gave a little positive effect on the gel properties of hydrogels. The gentamicin-loaded wound dressing composed of 2.5% PVA, 1.13% dextran, and 0.1% drug was more swellable, flexible, and elastic than that with only PVA because of its cross-linking interaction with PVA. In particular, it could provide an adequate level of moisture and build up the exudates on the wound area. From the in vivo wound healing and histological results, this gentamicin-loaded wound dressing enhanced the healing effect more compared to conventional product because of the potential healing effect of gentamicin. Thus, this gentamicin-loaded wound dressing would be used as a potential wound dressing with excellent forming and improved healing effect in wound care.
doi:10.1208/s12249-010-9474-0
PMCID: PMC2974132  PMID: 20607628
dextran; gentamicin; histological examination; wound dressing; wound healing effect
2.  A Micro-Preconcentrator Combined Olfactory Sensing System with a Micromechanical Cantilever Sensor for Detecting 2,4-Dinitrotoluene Gas Vapor 
Sensors (Basel, Switzerland)  2015;15(8):18167-18177.
Preventing unexpected explosive attacks and tracing explosion-related molecules require the development of highly sensitive gas-vapor detection systems. For that purpose, a micromechanical cantilever-based olfactory sensing system including a sample preconcentrator was developed to detect 2,4-dinitrotoluene (2,4-DNT), which is a well-known by-product of the explosive molecule trinitrotoluene (TNT) and exists in concentrations on the order of parts per billion in the atmosphere at room temperature. A peptide receptor (His-Pro-Asn-Phe-Ser-Lys-Tyr-Ile-Leu-His-Gln-Arg) that has high binding affinity for 2,4-DNT was immobilized on the surface of the cantilever sensors to detect 2,4-DNT vapor for highly selective detection. A micro-preconcentrator (µPC) was developed using Tenax-TA adsorbent to produce higher concentrations of 2,4-DNT molecules. The preconcentration was achieved via adsorption and thermal desorption phenomena occurring between target molecules and the adsorbent. The µPC directly integrated with a cantilever sensor and enhanced the sensitivity of the cantilever sensor as a pretreatment tool for the target vapor. The response was rapidly saturated within 5 min and sustained for more than 10 min when the concentrated vapor was introduced. By calculating preconcentration factor values, we verified that the cantilever sensor provides up to an eightfold improvement in sensing performance.
doi:10.3390/s150818167
PMCID: PMC4570313  PMID: 26213944
DNT; gas sensor; cantilever; micro-preconcentrator
3.  Tenofovir Monotherapy versus Tenofovir plus Lamivudine or Telbivudine Combination Therapy in Treatment of Lamivudine-Resistant Chronic Hepatitis B 
Tenofovir disoproxil fumarate (TDF) monotherapy is a therapeutic option for chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV) variants resistant to lamivudine (LAM). We evaluated the antiviral efficacy and safety of TDF alone compared to those of TDF plus LAM or telbivudine (LdT) combination in patients harboring HBV variants with genotypic resistance to LAM. This multicenter retrospective study included consecutive patients who had LAM-resistant HBV variants and were treated with TDF alone (monotherapy group) or TDF combined with LAM or LdT (combination therapy group) for at least 6 months. Inverse probability of treatment weighting (IPTW) for the entire cohort was applied to control for treatment selection bias. Overall, 153 patients (33 in the monotherapy group and 120 in the combination therapy group) were analyzed. The overall probability of achieving complete virologic suppression at month 12 was 91.6%: 88.6% in the monotherapy group and 92.6% in the combination therapy group. Combination therapy was not superior to monotherapy in viral suppression before and after IPTW (P = 0.562 and P = 0.194, respectively). Hepatitis B e antigen (HBeAg) loss, biochemical response, and virologic breakthrough did not differ between treatment groups. The probabilities of complete virologic suppression were comparable between treatment groups in the subsets according to HBeAg status and HBV DNA levels at baseline. No patient experienced any significant renal dysfunction during the treatment period. In conclusion, TDF monotherapy has antiviral efficacy comparable to that of TDF plus LAM or LdT combination therapy, with a favorable safety profile in CHB patients with LAM-resistant HBV variants.
doi:10.1128/AAC.04454-14
PMCID: PMC4335865  PMID: 25421484
4.  Thermoregulatory Responses to Graded Exercise Differ among Sasang Types 
We compared sweat rate and variables such as workload (We), metabolic heat production (Hprod), and temperature increment load (Tinc) across Sasang types. 304 apparently healthy participants aged 20–49 years with their Sasang type determined were enrolled. Local sweat rates on the chest (LSRchest) and back (LSRback) were measured using a perspiration meter during a maximum treadmill exercise test. Oxygen uptake was measured continuously using a breath-by-breath mode indirect calorimeter. The TaeEum (TE) type had a larger body size, a higher percent body fat, and a lower body area surface area (BSA) to body mass compared with the other Sasang types, particularly the SoEum (SE) type. The TE type tended to have a shorter exercise time to exhaustion and lower maximal oxygen uptake (mL·kg−1·min−1) than the other types. LSRchest in TE types was greater than that of the SE and SoYang (SY) types in men, whereas LSRback was higher in the TE type than that of the other types in women. After normalizing LSR for We, Hprod, Tinc, and BSA, this tendency still remained. Our findings suggest that the thermoregulatory response to graded exercise may differ across Sasang types such that the TE type was the most susceptible to heat stress.
doi:10.1155/2015/879272
PMCID: PMC4468316  PMID: 26136810
5.  Efficacy of Entecavir-Tenofovir Combination Therapy for Chronic Hepatitis B Patients with Multidrug-Resistant Strains 
Antimicrobial Agents and Chemotherapy  2014;58(11):6710-6716.
The emergence of multidrug-resistant (MDR) strains of hepatitis B virus (HBV) is a major concern. This study aimed to investigate the efficacy and safety of combination therapy with entecavir (ETV) plus tenofovir disoproxil fumarate (TDF) against MDR HBV. To adjust for differences in baseline characteristics, inverse probability weighting (IPW) using propensity scores for the entire cohort and weighted Cox proportional hazards models were applied. Ninety-three consecutive patients who were treated with ETV-TDF combination therapy for >6 months were included; at baseline, 45 were infected with HBV strains with genotypic resistance to lamivudine (LAM) and ETV (the LAM/ETV-R group), 28 with strains resistant to LAM and adefovir (ADV) (the LAM/ADV-R group), and 20 with strains resistant to LAM, ETV, and ADV (the LAM/ETV/ADV-R group). The median duration of rescue therapy was 13.0 (range, 6.7 to 31.7) months. Seventy-four of 93 patients (79.6%) achieved complete virologic suppression, after a median of 4.5 (95% confidence interval, 3.0 to 6.0) months. The cumulative probability of complete virologic suppression at month 6 was 63.6% (55.7%, 75.0%, and 65.0% in the LAM/ETV-R, LAM/ADV-R, and LAM/ETV/ADV-R groups, respectively). During the treatment period, these probabilities were not significantly different across the resistance profiles before and after IPW (P = 0.072 and P = 0.510, respectively). In multivariate analysis, a lower baseline HBV DNA level, but not resistance profiles, was an independent predictor of complete virologic suppression. Renal dysfunction was not observed during the treatment period. In conclusion, rescue therapy with ETV-TDF combination is efficient and safe in patients infected with MDR HBV strains regardless of the antiviral drug resistance profiles.
doi:10.1128/AAC.03845-14
PMCID: PMC4249402  PMID: 25155601
6.  Hepatitis B Virus-Related Glomerulonephritis: Not a Predominant Cause of Proteinuria in Korean Patients with Chronic Hepatitis B 
Background/Aims. Hepatitis B virus (HBV) can form immune complexes which may result in various types of glomerulonephritis (GN). However, proteinuria can occur because of other kidney diseases besides HBV-related GN (HBV-GN). The aim of this study is to elucidate the causes of proteinuria and report on the clinical outcomes of HBV-GN. Methods. We reviewed the medical records of patients positive for serum hepatitis B surface antigen who underwent renal biopsies due to proteinuria at a tertiary medical center in Korea. Results. A total of 55 patients were included. HBV-GN was diagnosed in 20 (36.4%) of the patients by confirming the presence of immune complexes (12 of 13 membranoproliferative glomerulonephritis, 7 of 8 membranous glomerulonephritis, and 1 of 13 immunoglobulin A nephropathy). Twenty-one patients had other types of GN. A total of 13 (65%) HBV-GN patients were treated with antiviral agents for a median of 11 months. However, the degrees of proteinuria were not significantly reduced in the antiviral intervention group when compared to the control group. Conclusions. Proteinuria can be caused by various glomerular diseases and HBV-GN accounts for one-third of total GN cases. Well-designed prospective study is needed to assess whether antiviral therapy against HBV infection may improve the prognosis of HBV-GN.
doi:10.1155/2015/126532
PMCID: PMC4348579  PMID: 25788940
7.  Reduction of Oxidative Stress Attenuates Lipoapoptosis Exacerbated by Hypoxia in Human Hepatocytes 
Chronic intermittent hypoxia, a characteristic of obstructive sleep apnea (OSA), is associated with the progression of simple hepatic steatosis to necroinflammatory hepatitis. We determined whether inhibition of a hypoxia-induced signaling pathway could attenuate hypoxia-exacerbated lipoapoptosis in human hepatocytes. The human hepatocellular carcinoma cell line (HepG2) was used in this study. Palmitic acid (PA)-treated groups were used for two environmental conditions: Hypoxia (1% O2) and normoxia (20% O2). Following the treatment, the cell viability was determined by the 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay, and the mechanism of lipoapoptosis was evaluated by Western blotting. Hypoxia exacerbated the suppression of hepatocyte growth induced by palmitic acid via activation of mitochondrial apoptotic pathways as a result of endoplasmic reticulum (ER) and oxidative stresses. Ammonium pyrrolidine dithiocarbamate, a scavenger of reactive oxygen species, attenuated the hypoxia-exacerbated lipoapoptosis in hepatocytes, whereas glycerol, which reduces ER stress, did not. This may have been because inhibition of oxidative stress decreases the expression of pro-apoptotic proteins, such as caspase 9 and cytochrome c. These results suggested that modulation of apoptotic signaling pathways activated by oxidative stress can aid in identifying novel therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) with OSA. Further in vivo studies are necessary to understand the pathophysiologic mechanism of NASH with OSA and to prove the therapeutic effect of the modulation of the signaling pathways.
doi:10.3390/ijms16023323
PMCID: PMC4346898  PMID: 25654228
obstructive sleep apnea; nonalcoholic steatohepatitis; lipoapoptosis; hypoxia; endoplasmic reticulum stress; oxidative stress
8.  A Micro-Fabricated Force Sensor Using an All Thin Film Piezoelectric Active Sensor 
Sensors (Basel, Switzerland)  2014;14(12):22199-22207.
The ability to measure pressure and force is essential in biomedical applications such as minimally invasive surgery (MIS) and palpation for detecting cancer cysts. Here, we report a force sensor for measuring a shear and normal force by combining an arrayed piezoelectric sensors layer with a precut glass top plate connected by four stress concentrating legs. We designed and fabricated a thin film piezoelectric force sensor and proposed an enhanced sensing tool to be used for analyzing gentle touches without the external voltage source used in FET sensors. Both the linear sensor response from 3 kPa to 30 kPa and the exact signal responses from the moving direction illustrate the strong feasibility of the described thin film miniaturized piezoelectric force sensor.
doi:10.3390/s141222199
PMCID: PMC4299009  PMID: 25429407
force sensor; tactile sensor; piezoelectric; thin film; MEMS
9.  Comparison of Clinical Outcomes Associated with Pull-Type and Introducer-Type Percutaneous Endoscopic Gastrostomies 
Clinical Endoscopy  2014;47(6):530-537.
Background/Aims
Percutaneous endoscopic gastrostomy (PEG) is a method of providing enteral nutrition using endoscopy. The PEG techniques differ according to the insertion method, and include the pull type, push type, and introducer type. The aim of this study was to compare the clinical outcomes associated with the pull-type and introducer-type PEG insertion techniques, which included the adverse events, at our tertiary care center in Korea.
Methods
We retrospectively reviewed 141 cases that had undergone PEG insertion at our center from January 2009 to June 2012. The indications for PEG insertion and the acute and chronic complications caused by each type of PEG insertion were analyzed.
Results
The indications for PEG insertion in our cohort included neurologic disease (58.7%), malignancy (21.7%), and other indications (19.6%). Successful PEG insertions were performed on 136 cases (96.5%), and there were no PEG-associated deaths. Bleeding was the most frequent acute complication (12.8%), and wound problems were the most frequent chronic complications (8.8%). There were no statistically significant differences between the pull-type and introducer-type PEG insertion techniques in relation to complication rates in our study population.
Conclusions
PEG insertion is considered a safe procedure. The pull-type and introducer-type PEG insertion techniques produce comparable outcomes, and physicians may choose either of these approaches according to the circumstances.
doi:10.5946/ce.2014.47.6.530
PMCID: PMC4260101  PMID: 25505719
Percutaneous endoscopic gastrostomy; Pull type; Introducer type; Complication; Indication for PEG
10.  Does antiviral therapy reduce complications of cirrhosis? 
Chronic hepatitis B infection is associated with the development of cirrhosis, hepatocellular carcinoma, and finally liver-related mortality. Each year, approximately, 2%-5% of patients with hepatitis B virus (HBV)-related compensated cirrhosis develop decompensation, with additional clinical manifestations, such as ascites, jaundice, hepatic encephalopathy, and gastrointestinal bleeding. The outcome of decompensated HBV-related cirrhosis is poor, with a 5-year survival of 14%-35% compared to 84% in patients with compensated cirrhosis. Because the risk of disease progression is closely linked to a patient’s serum HBV DNA level, antiviral therapy may suppress viral replication, stabilize liver function and improve survival. This article briefly reviews the role that antiviral therapy plays in cirrhosis complications, particularly, in decompensation and acute-on-chronic liver failure.
doi:10.3748/wjg.v20.i23.7306
PMCID: PMC4064076  PMID: 24966601
Antiviral therapy; Cirrhosis; Complication; Hepatitis B; Decompensation
11.  Efficacy of Adefovir-Based Combination Therapy for Patients with Lamivudine- and Entecavir-Resistant Chronic Hepatitis B Virus Infection 
Antimicrobial Agents and Chemotherapy  2013;57(12):6325-6332.
Treatment strategies for entecavir (ETV)-resistant chronic hepatitis B (CHB) patients are not yet well established. The aim of this study was to evaluate overall antiviral efficacy and to compare the efficacy of combination therapy with adefovir (ADV) plus nucleoside analogues (lamivudine [LAM], telbivudine [LdT], or ETV) in patients infected with LAM- and ETV-resistant hepatitis B virus (HBV) variants. Virologic, biochemical, and serologic responses during combination therapy with ADV plus nucleoside analogues were assessed. Propensity score analysis was used to select a matched group of patients for the comparison of rescue therapy regimens. A total of 67 consecutive patients were analyzed. Complete virologic suppression was achieved in 27 patients. The overall cumulative incidence of complete virologic suppression at month 24 was 47.4%: 44.3% in the LAM or LdT plus ADV group and 51.4% in the group given ETV and ADV. There was no significant difference between these two groups (P = 0.234). The cumulative incidences of complete virologic suppression were still comparable between the two groups selected and matched using the propensity score model (P = 0.419). Virologic breakthrough was observed in 9 patients, and rtA181V substitution was newly detected in one patient. Hepatitis B e antigen (HBeAg) negativity and lower baseline HBV DNA level were associated with complete virologic suppression in univariate analysis. In multivariate analysis, lower baseline HBV DNA level remained an independent predictor. In conclusion, combination therapy with ADV plus nucleoside analogues fails to show sufficient antiviral efficacy in CHB patients with resistance to both LAM and ETV. Further study is warranted to evaluate the efficacy of a more potent tenofovir-based regimen in such patients.
doi:10.1128/AAC.01742-13
PMCID: PMC3837850  PMID: 24100506
12.  Inhibition of hypoxia-inducible carbonic anhydrase-IX enhances hexokinase II inhibitor-induced hepatocellular carcinoma cell apoptosis 
Acta Pharmacologica Sinica  2011;32(7):912-920.
Aim:
The hypoxic condition within large or infiltrative hypovascular tumors produces intracellular acidification, which could activate many signaling pathways and augment cancer cell growth and invasion. Carbonic anhydrase-IX (CA-IX) is an enzyme lowering pH. This study is to examine whether hypoxia induces CA-IX in hepatocellular carcinoma (HCC) cells, and to evaluate its clinical implication in HCC patients.
Methods:
Human HCC cell lines (Huh-7 and HepG2 cells) were used, and cell growth was assessed using MTS assay. CA-IX expression and apoptotic/kinase signaling were evaluated using immunoblotting. The cells were transfected with CA-IX-specific siRNA, or treated with its inhibitor 4-(2-aminoethyl) benzenesulfonamide (CAI#1), and/or the hexokinase II inhibitor, 3-bromopyruvate (3-BP). A clinic pathological analysis of 69 patients who underwent an HCC resection was performed using a tissue array.
Results:
Incubation of HCC cells under hypoxia (1% O2, 5% CO2, 94% N2) for 36 h significantly increased CA-IX expression level. CAI#1 (400 μmol/L) or CA-IX siRNA (100 μmol/L) did not influence HCC cell growth and induce apoptosis. However, CAI#1 or CA-IX siRNA at these concentrations enhanced the apoptosis induced by 3-BP (100 μmol/L). This enhancement was attributed to increased ER stress and JNK activation, as compared with 3-BP alone. Furthermore, a clinic pathological analysis of 69 HCC patients revealed that tumor CA-IX intensity was inversely related to E-cadherin intensity.
Conclusion:
Inhibition of hypoxia-induced CA-IX enhances hexokinase II inhibitor-induced HCC apoptosis. Furthermore, CA-IX expression profiles may have prognostic implications in HCC patients. Thus, the inhibition of CA-IX, in combination with a hexokinase II inhibitor, may be therapeutically useful in patients with HCCs that are aggressively growing in a hypoxic environment.
doi:10.1038/aps.2011.24
PMCID: PMC4003119  PMID: 21666701
hepatocellular carcinoma; hypoxia; intracellular acidification; carbonic anhydrase-IX; hexokinase II; apoptosis
13.  Validation of P2/MS for reflecting hepatic fibrosis in patients with hepatocellular carcinoma 
The Korean Journal of Hepatology  2010;16(4):389-396.
Background/Aims
P2/MS is known as a simple, accurate, and noninvasive marker for determination of the degree of hepatic fibrosis in patients with viral hepatitis. We aimed to validate P2/MS in patients with HCC.
Methods
Consecutive HCC patients who underwent surgical resection between June 2007 and March 2009 at Seoul National University Hospital were enrolled. Fibrosis stage was reviewed and assessed according to METAVIR scoring. P2/MS values [platelet count (109/L)]2/[monocyte fraction (%)×segmented neutrophil fraction (%)] and other noninvasive fibrosis scoring systems were calculated.
Results
A total of 171 patients were included; seven patients with METAVIR F1, 31 with F2, 41 with F3, and 92 with F4. The area under the receiver-operating characteristic curve of P2/MS was 0.804 [95% confidence interval (CI), 0.681~0.927] for detection of significant fibrosis (F2-F4) and 0.769 (95% CI, 0.698~0.839) for detection of histological cirrhosis (F4). At a value < 62, P2/MS detected significant fibrosis with a specificity of 85.7% (95% CI, 42.0~99.2) and a positive likelihood ratio of 4.268 (95% CI, 0.692~26.309); and at a value > 115, P2/MS ruled out significant fibrosis with a sensitivity of 90.2% (95% CI, 84.4~94.1) and a negative likelihood ratio of 0.34 (95% CI, 0.106~0.095). P2/MS had a superior efficacy for detection of hepatic fibrosis in patients with HCC compared to the other noninvasive panels.
Conclusions
P2/MS can accurately detect fibrosis in patients with HCC. Thus, P2/MS might be utilized as a noninvasive index reflecting the degree of hepatic fibrosis in HCC patients.
doi:10.3350/kjhep.2010.16.4.389
PMCID: PMC3304609  PMID: 21415583
P2/MS; Fibrosis; Hepatocellular carcinoma
14.  Estimating Clothing Thermal Insulation Using an Infrared Camera 
In this paper, a novel algorithm for estimating clothing insulation is proposed to assess thermal comfort, based on the non-contact and real-time measurements of the face and clothing temperatures by an infrared camera. The proposed method can accurately measure the clothing insulation of various garments under different clothing fit and sitting postures. The proposed estimation method is investigated to be effective to measure its clothing insulation significantly in different seasonal clothing conditions using a paired t-test in 99% confidence interval. Temperatures simulated with the proposed estimated insulation value show closer to the values of actual temperature than those with individual clothing insulation values. Upper clothing’s temperature is more accurate within 3% error and lower clothing’s temperature is more accurate by 3.7%~6.2% error in indoor working scenarios. The proposed algorithm can reflect the effect of air layer which makes insulation different in the calculation to estimate clothing insulation using the temperature of the face and clothing. In future, the proposed method is expected to be applied to evaluate the customized passenger comfort effectively.
doi:10.3390/s16030341
PMCID: PMC4813916  PMID: 27005625
clothing insulation; thermal comfort; PMV; infrared camera
15.  Covered Metallic Stents With an Anti-Migration Design vs. Uncovered Stents for the Palliation of Malignant Gastric Outlet Obstruction: A Multicenter, Randomized Trial 
OBJECTIVES:
Previous studies reported comparable stent patency between covered self-expandable metallic stents (SEMS) and uncovered SEMS (UCS) for palliation of malignant gastric outlet obstruction (GOO). The aim of this study was to evaluate the efficacy and safety of the newly developed WAVE-covered SEMS (WCS), which has an anti-migration design, compared with UCS in gastric cancer patients with symptomatic GOO.
METHODS:
A total of 102 inoperable gastric cancer patients with symptomatic GOO were prospectively enrolled from five referral centers and randomized to undergo UCS or WCS placement. Stent patency and recurrence of obstructive symptoms were assessed at 8 weeks and 16 weeks after stent placement.
RESULTS:
At the 8-week follow-up, both stent patency rates (72.5% vs. 62.7%) and re-intervention rates (19.6% vs. 19.6%) were comparable between the WCS and the UCS groups. Both stent stenosis (2.4% vs. 8.1%) and migration rates (9.5% vs. 5.4%) were comparable between WCS and UCS groups. At the 16-week follow-up, however, the WCS group had a significantly higher stent patency rate than the UCS group (68.6% vs. 41.2%). Re-intervention rates in the WCS and UCS groups were 23.5% and 39.2%, respectively. Compared with the UCS group, the WCS group had a significantly lower stent restenosis rate (7.1% vs. 37.8%) and a comparable migration rate (9.5% vs. 5.4%). Overall stent patency was significantly longer in the WCS group than in the UCS group. No stent-associated significant adverse events occurred in either the WCS or UCS groups. In the multivariate analysis, WCS placement and chemotherapy were identified as independent predictors of 16-week stent patency.
CONCLUSIONS:
WCS group showed comparable migration rate and significantly more durable long-term stent patency compared with UCS group for the palliation of GOO in patients with inoperable gastric cancer.
doi:10.1038/ajg.2015.286
PMCID: PMC4697131  PMID: 26372507
16.  Visceral Obesity Predicts Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Disease 
Medicine  2015;94(48):e2159.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with visceral obesity. However, the association between visceral adipose tissue (VAT) area and fibrosis in NAFLD patients has not been completely established. This study was aimed to determine the relationship between the computed tomography-measured VAT area and significant fibrosis in NAFLD patients. A total of 324 NAFLD patients and 132 controls were evaluated by liver biopsy. NAFLD was diagnosed based on histological examinations and alcohol consumption <20 g/day. The NAFLD patients showed a higher age and gender-adjusted VAT area than the control group (86.1 ± 2.3 vs 56.7 ± 3.7, P < 0.001). The VAT area increased across the control, NAFLD without significant fibrosis, and NAFLD with significant fibrosis groups (54.9 ± 3.5, 80.6 ± 2.4, and 123.4 ± 6.4, P < 0.001). This association persisted after adjusting for multiple confounders (P for trend = 0.028). A multivariate regression analysis demonstrated the VAT area was independently associated with NAFLD with significant fibrosis (F2–F4) (odds ratio [OR] 1.21 95% confidence interval [CI] 1.07–1.37 per 10 cm2 increase of VAT area; OR 2.62 [per 1 – standard deviation (SD)] 95% CI 1.41–4.86). Moreover, a multivariate logistic regression analysis revealed the VAT area was independently associated with nonalcoholic steatohepatitis (NASH) in NAFLD (OR 1.17 95% CI 1.05–1.32 per 10 cm2 increase of VAT area; OR 2.21 [per 1 – SD] 95% CI 1.25–3.89). Increased VAT area is independently associated with NASH or significant fibrosis and VAT might be a central target for lifestyle modifications in NAFLD patients.
doi:10.1097/MD.0000000000002159
PMCID: PMC4674200  PMID: 26632897
17.  Sofosbuvir-based therapy for patients with chronic hepatitis C: Early experience of its efficacy and safety in Korea 
Clinical and Molecular Hepatology  2015;21(4):358-364.
Background/Aims
The previous standard treatment for chronic hepatitis C (CHC) patients, comprising a combination of pegylated interferon (IFN) and ribavirin, was associated with suboptimal efficacy and severe adverse reactions. A new era of direct-acting antivirals is now dawning in Korea. Early experience of applying sofosbuvir-based therapy to CHC patients in Korea is reported herein.
Methods
Data on efficacy and safety were collected for CHC patients treated with a combination of sofosbuvir plus ribavirin or sofosbuvir/ledipasvir with or without ribavirin.
Results
This retrospective study included 25 consecutive patients who received sofosbuvir-based therapy (19 with genotype 1b and 6 with genotype 2) at Seoul National University Hospital from May 2014 to April 2015. A virologic response was achieved at week 4 by 85.7% and 80% of the patients with genotypes 1b and 2, respectively. The HCV-RNA level decreased more slowly in IFN-experienced than in treatment-naïve patients with genotype 1b. However, the sustained virologic response at week 12 (SVR12) rate did not differ among these patients, and was as high as 100%. The presence of cirrhosis significantly increased the risk of a virologic response failure at week 4 (OR, 11.0; P=0.011) among patients with HCV genotype 1b. Only five patients (20%) experienced minor adverse events, including grade 1 fatigue and headache. The hemoglobin level decreased slightly after sofosbuvir-based therapy, but there was no case of premature discontinuation of this therapy.
Conclusions
In a real clinical practice, sofosbuvir-based therapy for CHC patients in Korea achieved optimal antiviral efficacy with insignificant adverse events. Long-term follow-up data are warranted to ensure the sustained antiviral efficacy and long-term safety of sofosbuvir-based IFN-free therapy.
doi:10.3350/cmh.2015.21.4.358
PMCID: PMC4712163  PMID: 26770924
Chronic hepatitis C; Direct-acting antiviral; Korea
18.  Fucoidan protects hepatocytes from apoptosis and inhibits invasion of hepatocellular carcinoma by up-regulating p42/44 MAPK-dependent NDRG-1/CAP43 
Acta Pharmaceutica Sinica. B  2015;5(6):544-553.
Fucoidan is a traditional Chinese medicine suggested to possess anti-tumor effects. In this study the anti-metastatic effects of fucoidan were investigated in vitro in human hepatocellular carcinoma (HCC) cells (Huh-7 and SNU-761) under normoxic and hypoxic conditions and in vivo using a distant liver metastasis model involving injection of MH134 cells into spleen via the portal vein. Its ability to protect hepatocytes against bile acid (BA)-induced apoptosis was investigated in primary hepatocytes. Fucoidan was found to suppress the invasion of HCC cells through up-regulation of p42/44 MAPK-dependent NDRG-1/CAP43 and partly, under normoxic conditions, through up-regulation of p42/44 MAPK-dependent VMP-1 expression. It also significantly decreased liver metastasis in vivo. As regards its hepatoprotective effect, fucoidan decreased BA-induced hepatocyte apoptosis as shown by the attenuation of caspase-8, and -7 cleavages and suppression of the mobilization of caspase-8 and Fas associated death domain (FADD) into the death-inducing signaling complex. In summary, fucoidan displays inhibitory effects on proliferation of HCC cells and protective effects on hepatocytes. The results suggest fucoidan is a potent suppressor of tumor invasion with hepatoprotective effects.
Graphical abstract
Fucoidan protected hepatocytes from BA-induced apoptosis and preferentially inhibited invasion of HCC cells by up-regulating p42/44 MAPK-dependent NDRG-1/CAP43, suggesting it may be a potent suppressor of tumor invasion with hepatoprotective effects.
fx1
doi:10.1016/j.apsb.2015.09.004
PMCID: PMC4675821  PMID: 26713269
BA, bile acid; cDNA, complementary DNA; CXCL, chemokine ligand; DISC, death-inducing signaling complex; DMEM, Dulbecco׳s modified Eagle׳s medium; DNA, deoxyribonucleic acid; ELISA, enzyme-linked immunosorbent assay; FADD, Fas associated death domain; FBS, fetal bovine serum; FCS, fetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GP, glypican; HCC, hepatocellular carcinoma; IHC, immunohistochemistry; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MTS, 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt; NDRG, N-myc downstream-regulated gene; PCR, polymerase chain reaction; RNA, ribonucleic acid; SD, standard deviation; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; siRNA, small interfering RNA; VMP, vacuole membrane protein; WME, William's medium E; Fucoidan; Hepatocellular carcinoma; Invasion; Hypoxia; Hepatoprotective; Cultured hepatocyte; NDRG-1/CAP43; VMP-1
19.  Novel Anthropometry-Based Calculation of the Body Heat Capacity in the Korean Population 
PLoS ONE  2015;10(11):e0141498.
Heat capacity (HC) has an important role in the temperature regulation process, particularly in dealing with the heat load. The actual measurement of the body HC is complicated and is generally estimated by body-composition-specific data. This study compared the previously known HC estimating equations and sought how to define HC using simple anthropometric indices such as weight and body surface area (BSA) in the Korean population. Six hundred participants were randomly selected from a pool of 902 healthy volunteers aged 20 to 70 years for the training set. The remaining 302 participants were used for the test set. Body composition analysis using multi-frequency bioelectrical impedance analysis was used to access body components including body fat, water, protein, and mineral mass. Four different HCs were calculated and compared using a weight-based HC (HC_Eq1), two HCs estimated from fat and fat-free mass (HC_Eq2 and HC_Eq3), and an HC calculated from fat, protein, water, and mineral mass (HC_Eq4). HC_Eq1 generally produced a larger HC than the other HC equations and had a poorer correlation with the other HC equations. HC equations using body composition data were well-correlated to each other. If HC estimated with HC_Eq4 was regarded as a standard, interestingly, the BSA and weight independently contributed to the variation of HC. The model composed of weight, BSA, and gender was able to predict more than a 99% variation of HC_Eq4. Validation analysis on the test set showed a very high satisfactory level of the predictive model. In conclusion, our results suggest that gender, BSA, and weight are the independent factors for calculating HC. For the first time, a predictive equation based on anthropometry data was developed and this equation could be useful for estimating HC in the general Korean population without body-composition measurement.
doi:10.1371/journal.pone.0141498
PMCID: PMC4631517  PMID: 26529594
20.  The Safety and Clinical Outcomes of Chemoembolization in Child-Pugh Class C Patients with Hepatocellular Carcinomas 
Korean Journal of Radiology  2015;16(6):1283-1293.
Objective
To evaluate the safety and clinical outcomes of chemoembolization in Child-Pugh class C patients with hepatocellular carcinomas (HCC).
Materials and Methods
The study comprised 55 patients with HCC who were classified as Child-Pugh class C and who underwent initial chemoembolization between January 2003 and December 2012. Selective chemoembolization was performed in all technically feasible cases to minimize procedure-related complications. All adverse events within 30 days were recorded using the Common Terminology Criteria for Adverse Events (CTCAE). The tumor response to chemoembolization was evaluated using the modified Response Evaluation Criteria In Solid Tumors.
Results
Thirty (54.5%) patients were within the Milan criteria, and 25 (45.5%) were beyond. The mortality of study subjects at 30 days was 5.5%. Major complications were observed in five (9.1%) patients who were all beyond the Milan criteria: two hepatic failures, one hepatic encephalopathy, and two CTCAE grade 3 increases in aspartate aminotransferase/alanine aminotransferase abnormality. The mean length of hospitalization was 6.3 ± 8.3 days (standard deviation), and 18 (32.7%) patients were discharged on the next day after chemoembolization. The tumor responses of the patients who met the Milan criteria were significantly higher (p = 0.014) than those of the patients who did not. The overall median survival was 7.1 months (95% confidence interval: 4.4-9.8 months).
Conclusion
Even in patients with Child-Pugh class C, chemoembolization can be performed safely with a selective technique in selected cases with a small tumor burden.
doi:10.3348/kjr.2015.16.6.1283
PMCID: PMC4644750  PMID: 26576118
Hepatocellular carcinoma; Chemoembolization; Liver cirrhosis; Liver failure; Safety
21.  Clinical and Endoscopic Features of Metastatic Tumors in the Stomach 
Gut and Liver  2014;9(5):615-622.
Background/Aims
Metastasis to the stomach is rare. The aim of this study was to describe and analyze the clinical outcomes of cancers that metastasized to the stomach.
Methods
We reviewed the clinicopathological aspects of patients with gastric metastases from solid organ tumors. Thirty-seven cases were identified, and we evaluated the histology, initial presentation, imaging findings, lesion locations, treatment courses, and overall patient survival.
Results
Endoscopic findings indicated that solitary lesions presented more frequently than multiple lesions and submucosal tumor-like tumors were the most common appearance. Malignant melanoma was the tumor that most frequently metastasized to the stomach. Twelve patients received treatments after the diagnosis of gastric metastasis. The median survival period from the diagnosis of gastric metastasis was 3.0 months (interquartile range, 1.0 to 11.0 months). Patients with solitary lesions and patients who received any treatments survived longer after the diagnosis of metastatic cancer than patients with multiple lesions and patients who did not any receive any treatments.
Conclusions
Proper treatment with careful consideration of the primary tumor characteristics can increase the survival period in patients with tumors that metastasize to the stomach, especially in cases with solitary metastatic lesions in endoscopic findings.
doi:10.5009/gnl14032
PMCID: PMC4562778  PMID: 25473071
Stomach; Endoscopy; Metastasis
22.  Diagnostic and Prognostic Values of Noninvasive Predictors of Portal Hypertension in Patients with Alcoholic Cirrhosis 
PLoS ONE  2015;10(7):e0133935.
Portal hypertension is a direct consequence of hepatic fibrosis, and several hepatic fibrosis markers have been evaluated as a noninvasive alternative to the detection of portal hypertension and esophageal varices. In the present study, we compared the diagnostic and prognostic values of the noninvasive fibrosis markers in patients with alcoholic cirrhosis. A total of 219 consecutive alcoholic cirrhosis patients were included. Biochemical scores and liver stiffness (LS) were compared with hepatic venous pressure gradient (HVPG). For the detection of clinically significant portal hypertension (CSPH; HVPG≥10 mmHg) in compensated patients, LS and LS–spleen diameter to platelet ratio score (LSPS) showed significantly better performance with area under the curves (AUCs) of 0.85 and 0.82, respectively, than aspartate aminotransferase-to-platelet ratio index, FIB-4, Forns’ index, Lok index, (platelet count)2/[monocyte fraction (%) × segmented neutrophil fraction (%)], and platelet count-to-spleen diameter ratio (all P<0.001). However, for the detection of high-risk varices, none of the non-invasive tests showed reliable performance (AUCs of all investigated tests < 0.70). During a median follow-up period of 42.6 months, 46 patients with decompensated cirrhosis died. Lok index (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.05–1.22; P = 0.001) and FIB-4 (HR, 1.06; 95% CI, 1.01–1.10; P = 0.009) were independently associated with all-cause death in decompensated patients. Among the tested noninvasive markers, only Lok index significantly improved discrimination function of MELD score in predicting overall survival. In conclusion, LS and LSPS most accurately predict CSPH in patients with compensated alcoholic cirrhosis. In the prediction of overall survival in decompensated patients, however, Lok index is an independent prognostic factor and improves the predictive performance of MELD score.
doi:10.1371/journal.pone.0133935
PMCID: PMC4511411  PMID: 26196942
23.  Endoscopic and Oncologic Outcomes of Endoscopic Resection for Superficial Esophageal Neoplasm 
Gut and Liver  2014;9(4):470-477.
Background/Aims
Endoscopic resection (ER) of superficial esophageal neoplasm (SEN) is a technically difficult procedure. We investigated the clinical outcomes of ER for SEN to determine its feasibility and effectiveness.
Methods
Subjects who underwent ER for SEN at Asan Medical Center between December 1996 and December 2010 were eligible. The clinical features of patients and tumors, histopathological characteristics, adverse events, ER results and survival were investigated.
Results
A total of 129 patients underwent ER for 147 SENs. En bloc resection (EnR) was performed in 118 lesions (80.3%). Complete resection (CR) was accomplished in 128 lesions (86.5%), and curative resection (CuR) was performed in 118 lesions (79.7%). The EnR, CR, and CuR rates were significantly greater in the endoscopic submucosal dissection group when compared to those in the endoscopic resection group. Adverse events occurred in 22 patients (17.1%), including bleeding (n=2, 1.6%), perforation (n=12, 9.3%), and stricture (n=8, 6.2%). Local tumor recurrence occurred in 2.0% of patients during a median follow-up of 34.8 months. The 5-year overall and disease-specific survival rates were 94.0% and 97.5%, respectively.
Conclusions
ER is a feasible and effective method for the treatment of SEN as indicated by favorable clinical outcomes.
doi:10.5009/gnl13263
PMCID: PMC4477990  PMID: 25473069
Esophageal neoplasms; Treatment outcome; Endoscopic resection
24.  A Novel Nicotinamide Adenine Dinucleotide Correction Method for Mitochondrial Ca2+ Measurement with FURA-2-FF in Single Permeabilized Ventricular Myocytes of Rat 
Fura-2 analogs are ratiometric fluoroprobes that are widely used for the quantitative measurement of [Ca2+]. However, the dye usage is intrinsically limited, as the dyes require ultraviolet (UV) excitation, which can also generate great interference, mainly from nicotinamide adenine dinucleotide (NADH) autofluorescence. Specifically, this limitation causes serious problems for the quantitative measurement of mitochondrial [Ca2+], as no available ratiometric dyes are excited in the visible range. Thus, NADH interference cannot be avoided during quantitative measurement of [Ca2+] because the majority of NADH is located in the mitochondria. The emission intensity ratio of two different excitation wavelengths must be constant when the fluorescent dye concentration is the same. In accordance with this principle, we developed a novel online method that corrected NADH and Fura-2-FF interference. We simultaneously measured multiple parameters, including NADH, [Ca2+], and pH/mitochondrial membrane potential; Fura-2-FF for mitochondrial [Ca2+] and TMRE for Ψm or carboxy-SNARF-1 for pH were used. With this novel method, we found that the resting mitochondrial [Ca2+] concentration was 1.03 µM. This 1 µM cytosolic Ca2+ could theoretically increase to more than 100 mM in mitochondria. However, the mitochondrial [Ca2+] increase was limited to ~30 µM in the presence of 1 µM cytosolic Ca2+. Our method solved the problem of NADH signal contamination during the use of Fura-2 analogs, and therefore the method may be useful when NADH interference is expected.
doi:10.4196/kjpp.2015.19.4.373
PMCID: PMC4499650  PMID: 26170742
Calcium; Fura-2-FF; Mitochondrial membrane potential; NADH; pH
25.  Comparison of the Efficacy of Entecavir and Tenofovir in Nucleos(T)ide Analogue-Experienced Chronic Hepatitis B Patients 
PLoS ONE  2015;10(6):e0130392.
The efficacy of entecavir (ETV) and tenofovir (TDF) for the treatment of nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients has been little studied. Here, we compare the efficacy of both ETV and TDF in NA-experienced CHB patients without detectable genotypic resistance. This retrospective cohort study included consecutive NA-experienced patients who had neither current nor previous genotypic resistance and had received ETV or TDF for at least 6 months. Overall, 202 patients (146 patients in the ETV group and 56 in the TDF group) were analyzed. The cumulative probabilities of complete virologic suppression (CVS) at month 12 were 76.1% in the ETV group and 95.0% in the TDF group (P<0.001), respectively. The TDF-treated group achieved CVS more rapidly than the ETV group for both Hepatitis B e antigen (HBeAg)-negative and -positive patients (P = 0.006 and < 0.001, respectively), and for those with both low (< 2,000 IU/mL) and high (≥ 2,000 IU/mL) HBV DNA levels (P = 0.01 and 0.002, respectively). TDF group had an increased probability of achieving CVS (hazard ratio, 2.242; 95% confidence interval, 1.587–3.165; P = 0.001), after adjustment for HBV DNA level, the presence of HBeAg, and a history of CVS during prior treatment. During the treatment period, 23 patients (15.8%) in the ETV group developed virologic breakthrough, compared to none in the TDF group. The cumulative probabilities of developing virologic breakthrough and ETV-resistance at month 24 were 9.7% and 5.3%, respectively. In conclusion, TDF is preferable to ETV for achieving CVS in NA-experienced CHB patients without genotypic resistance.
doi:10.1371/journal.pone.0130392
PMCID: PMC4488001  PMID: 26121361

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