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1.  Red Ginseng (Panax ginseng) Decreases Isoproterenol-Induced Cardiac Injury via Antioxidant Properties in Porcine 
Journal of Medicinal Food  2014;17(1):111-118.
Red ginseng (RG, Panax ginseng) has been shown to possess various ginsenosides. These ginsenosides are widely used for treating cardiovascular diseases in Asian communities. The present study was designed to evaluate the cardioprotective potential of RG against isoproterenol (ISO)-induced myocardial infarction (MI), by assessing electrocardiographic, hemodynamic, and biochemical parameters. Male porcines were orally administered with RG (250 and 500 mg/kg) or with vehicle for 9 days, with concurrent intraperitoneal injections of ISO (20 mg/kg) on the 8th and 9th day. RG significantly attenuated ISO-induced cardiac dysfunctions as evidenced by improved ventricular hemodynamic functions and reduced ST segment and QRS complex intervals. Also, RG significantly ameliorated myocardial injury parameters such as antioxidants. Malonaldialdehyde formation was also inhibited by RG. Based on the results, it is concluded that RG possesses significant cardioprotective potential through the inhibition of oxidative stress and may serve as an adjunct in the treatment and prophylaxis of MI.
PMCID: PMC3901382  PMID: 24456361
antioxidant; hemodynamic function; myocardial infarction; myocardial protection; red ginseng
2.  Gastroprotective Activity of Violacein Isolated from Chromobacterium violaceum on Indomethacin-Induced Gastric Lesions in Rats: Investigation of Potential Mechanisms of Action 
The Scientific World Journal  2014;2014:616432.
Chromobacterium violaceum, Gram-negative bacteria species found in tropical regions of the world, produces a distinct deep violet-colored pigment called violacein. In the present study, we investigated whether violacein can promote a gastroprotective effect and verified the possible mechanisms involved in this action. For this study, an indomethacin-induced gastric ulcer rat model was used. The roles of biomolecules such as MPO, PGE2, pro- and anti-inflammatory cytokines, growth factors, caspase-3, NO, K+ATP channels, and α2-receptors were investigated. Violacein exhibited significant gastroprotective effect against indomethacin-induced lesions, while pretreatment with L-NAME and glibenclamide (but not with NEM or yohimbine) was able to reverse this action. Pretreatment with violacein also restored cNOS level to normal and led to attenuation of enhanced apoptosis and gastric microvascular permeability. Our results suggest that violacein provides a significant gastroprotective effect in an indomethacin-induced ulcer model through the maintenance of some vital protein molecules, and this effect appears to be mediated, at least in part, by endogenous prostaglandins, NOS, K+ATP channel opening, and inhibition of apoptosis and gastric microvascular permeability.
PMCID: PMC4138890  PMID: 25162059
3.  IKKβ-Targeted Anti-Inflammatory Activities of a Butanol Fraction of Artificially Cultivated Cordyceps pruinosa Fruit Bodies 
The inhibitory activities of the Cordyceps pruinosa butanol fraction (Cp-BF) were investigated by determining inflammatory responses of lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells and by evaluating HCl/ethanol (EtOH)-triggered gastric ulcers in mice. The molecular mechanisms of the inhibitory effects of Cp-BF were investigated by identifying target enzymes using biochemical and molecular biological approaches. Cp-BF strongly inhibited the production of NO and TNF-α, release of reactive oxygen species (ROS), phagocytic uptake of FITC-dextran, and mRNA expression levels of interleukin (IL)-6, inducible NO synthase (iNOS), and tumour necrosis factor-alpha (TNF)-α in activated RAW264.7 cells. Cp-BF also strongly downregulated the NF-κB pathway by suppressing IKKβ according to luciferase reporter assays and immunoblot analysis. Furthermore, Cp-BF blocked both increased levels of NF-κB-mediated luciferase activities and phosphorylation of p65/p50 observed by IKKβ overexpression. Finally, orally administered Cp-BF was found to attenuate gastric ulcer and block the phosphorylation of IκBα induced by HCl/EtOH. Therefore, these results suggest that the anti-inflammatory activity of Cp-BF may be mediated by suppression of IKKα and its downstream NF-κB activation. Since our group has established the mass cultivation conditions by developing culture conditions for Cordyceps pruinosa, the information presented in this study may be useful for developing new anti-inflammatory agents.
PMCID: PMC4123572  PMID: 25132860
4.  Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses 
Mediators of Inflammation  2014;2014:270302.
Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.
PMCID: PMC4090447  PMID: 25045209
5.  Engraftment Potential of Spheroid-Forming Hepatic Endoderm Derived from Human Embryonic Stem Cells 
Stem Cells and Development  2013;22(12):1818-1829.
Transplantation and drug discovery programs for liver diseases are hampered by the shortage of donor tissue. While recent studies have shown that hepatic cells can be derived from human embryonic stem cells (hESCs), few cases have shown selective enrichment of hESC-derived hepatocytes and their integration into host liver tissues. Here we demonstrate that the dissociation and reaggregation procedure after an endodermal differentiation of hESC produces spheroids mainly consisted of cells showing hepatic phenotypes in vitro and in vivo. A combined treatment with Wnt3a and bone morphogenic protein 4 efficiently differentiated hESCs into definitive endoderm in an adherent culture. Dissociation followed by reaggregation of these cells in a nonadherent condition lead to the isolation of spheroid-forming cells that preferentially expressed early hepatic markers from the adherent cell population. Further differentiation of these spheroid cells in the presence of the hepatocyte growth factor, oncostatin M, and dexamethasone produced a highly enriched population of cells exhibiting characteristics of early hepatocytes, including glycogen storage, indocyanine green uptake, and synthesis of urea and albumin. Furthermore, we show that grafted spheroid cells express hepatic features and attenuate the serum aspartate aminotransferase level in a model of acute liver injury. These data suggest that hepatic progenitor cells can be enriched by the spheroid formation of differentiating hESCs and that these cells have engraftment potential to replace damaged liver tissues.
PMCID: PMC3668500  PMID: 23373441
6.  Korean Red Ginseng Induced Cardioprotection against Myocardial Ischemia in Guinea Pig 
This study was designed to evaluate the protective effect of Korean red ginseng (KRG) against ischemia/reperfusion (I/R) injury in isolated guinea pig heart. KRG has been shown to possess various ginsenosides, which are the major components of Panax ginseng. These components are known naturally occurring compounds with beneficial effects and free radical scavenging activity. The heart was induced to ischemia for 60 min, followed by 120 min reperfusion. The hearts were randomly allocated into five groups (n=8 for each group): normal control (N/C), KRG control, I/R control, 250 mg/kg KRG group and 500 mg/kg KRG group. KRG significantly increased hemodynamics parameters such as aortic flow, coronary flow and cardiac output. Moreover, KRG significantly increased left ventricular systolic pressure (LVSP), the maximal rate of contraction (+dP/dtmax) and maximal rate of relaxation (-dP/dtmax). Also, treatment of KRG ameliorated electrocardiographic index such as the QRS, QT and RR intervals. Moreover, KRG significantly suppressed the lactate dehydrogenase, creatine kinase-MB fraction and cardiac troponin I and ameliorated the oxidative stress markers such as malondialdehyde and glutathione. KRG was standardized through ultra performance liquid chromatograph analysis for its major ginsenosides. Taken together, KRG has been shown to prevent cardiac injury by normalizing the biochemical and oxidative stress.
PMCID: PMC3741484  PMID: 23946687
Antioxidant; Cardioprotection; Hemodynamics; Ischemia and reperfusion injury; Korean red ginseng
7.  Altered heart rate dynamics associated with antipsychotic-induced subjective restlessness in patients with schizophrenia 
Antipsychotic-induced subjective inner restlessness is one of the common and distressing adverse effects associated with antipsychotics; however, its underlying neurobiological basis is not well understood. We examined the relationship between antipsychotic-induced subjective inner restlessness and autonomic neurocardiac function.
Twenty-two schizophrenia patients with antipsychotic-induced subjective restlessness, 28 schizophrenia patients without antipsychotic-induced subjective restlessness, and 28 matched healthy control subjects were evaluated. Assessments of the linear and nonlinear complexity measures of heart rate dynamics were performed. Multivariate analysis of variance and correlation analysis were conducted.
The mean interbeat (RR) interval value was significantly higher in control subjects than in patients with and without antipsychotic-induced subjective restlessness (P < 0.05). The low frequency/high frequency ratio was significantly higher in patients with antipsychotic-induced subjective restlessness than in control subjects and in patients without antipsychotic-induced subjective restlessness (P < 0.05), while the approximate entropy value was significantly lower in patients with antipsychotic-induced subjective restlessness than in control subjects and in patients without antipsychotic-induced subjective restlessness (P < 0.05). Correlation analyses controlling for psychotic symptom severity showed that the degree of antipsychotic-induced restlessness had a significant negative correlation with the value of approximate entropy (P < 0.05).
The results indicate that antipsychotic-induced subjective restlessness is associated with altered heart rate dynamics parameters, particularly the nonlinear complexity measure, suggesting that it might adversely affect autonomic neurocardiac integrity. Further prospective research is necessary to elucidate the precise interrelationships and causality.
PMCID: PMC3753732  PMID: 23986638
antipsychotics; subjective restlessness; heart rate dynamics
8.  Generation of CD2+CD8+ NK Cells from c-kit+ Bone Marrow Cells in Porcine 
Natural killer (NK) cells provide one of the initial barriers of cellular host defense against pathogens, in particular intracellular pathogens. Because bone marrow-derived hematopoietic stem cells (HSCs), lymphoid protenitors, can give rise to NK cells, NK ontogeny has been considered to be exclusively lymphoid. Here, we show that porcine c-kit+ bone marrow cells (c-kit+ BM cells) develop into NK cells in vitro in the presence of various cytokines [interleukin (IL)-2, IL-7, IL-15, IL-21, stem cell factor (SCF), and fms-like tyrosine kinase-3 ligand (FLT3L)]. Adding hydrocortisone (HDC) and stromal cells greatly increases the frequency of c-kit+ BM cells that give rise to CD2+CD8+ NK cells. Also, intracellular levels of perforin, granzyme B, and NKG2D were determined by RT-PCR and western blotting analysis. It was found that of perforin, granzyme B, and NKG2D levels significantly were increased in cytokine-stimulated c-kit+ BM cells than those of controls. And, we compared the ability of the cytotoxicity of CD2+CD8+ NK cells differentiated by cytokines from c-kit+ BM cells against K562 target cells for 28 days. Cytokines-induced NK cells as effector cells were incubated with K562 cells as target in a ratio of 100:1 for 4 h once a week. In results, CD2+CD8+ NK cells induced by cytokines and stromal cells showed a significantly increased cytotoxicity 21 days later. Whereas, our results indicated that c-kit+ BM cells not pretreated with cytokines have lower levels of cytotoxicity. Taken together, this study suggests that cytokines-induced NK cells from porcine c-kit+ BM cells may be used as adoptive transfer therapy if the known obstacles to xenografting (e.g. immune and non-immune problems) were overcome in the future.
PMCID: PMC3394918  PMID: 22802697
Hematopoietic stem cells; Natural killer cells; Differentiation; Cytokines; Cytotoxicity
9.  HIV Transmission by Stage of Infection and Pattern of Sexual Partnerships 
Epidemiology (Cambridge, Mass.)  2010;21(5):676-684.
Most model analyses examining the role of primary HIV infection in the HIV epidemic ignore the fact that HIV is often transmitted through long-term, concurrent sexual partnerships. We sought to understand how duration and concurrency of sexual partnerships affect the role of transmissions during primary HIV infection.
We constructed a stochastic individual-based model of HIV transmission in a homogeneous population where partnerships form and dissolve. Using observed contagiousness by stage of HIV infection, the fraction of transmissions during primary HIV infection at equilibrium was examined across varying partnership durations and concurrencies.
The fraction of transmissions during primary HIV infection has a U-shaped relationship with partnership duration. The fraction drops with increasing partnership duration for partnerships with shorter average duration but rises for partnerships with longer average duration. Partnership concurrency modifies this relationship. The fraction of transmissions during primary HIV infection increases with increasing partnership concurrency for partnerships with shorter average duration, but decreases for partnerships with longer average duration.
Partnership patterns strongly influence the transmission of HIV and do so differentially by stage of infection. Dynamic partnerships need to be taken into account to make a robust inference on the role of different stages of HIV infection.
PMCID: PMC3018805  PMID: 20571409
10.  A comparison of Bonfils intubation fiberscopy and fiberoptic bronchoscopy in difficult airways assisted with direct laryngoscopy 
Korean Journal of Anesthesiology  2010;58(3):249-255.
To evaluate the usefulness of Bonfils intubation fiberscope assisted by direct laryngoscopy (BIF-DL) and flexible fiberoptic bronchoscope assisted by direct laryngoscopy (FOB-DL) using video recording in cases of unanticipated difficult intubation with respect to the time required to visualize the vocal cords and place the endotracheal tube. We compared two fiberscopes in patients with authentic difficult airways.
In this randomized, controlled clinical trial, 40 patients (grade 3 according to grades of difficulty in laryngoscopy), scheduled for surgery under general anesthesia were randomly allocated to BIF-DL group or FOB-DL group. Number of attempts, time required for visualization of the vocal cord (T1) and placement of the endotracheal tube (T2) from insertion of instrument during the last successful attempt, and duration of scope manipulation during all attempts (Ttotal) were recorded. If intubation failed with one method, the other method was tried; these cases were then excluded. The incidence of sore throat and hoarseness was assessed.
T1, T2, and Ttotal were significantly shorter in BIF-DL group (T1: 21.9 ± 8.2 sec vs. 80.4 ± 29.9 sec, P < 0.001, Ttotal: 77.9 ± 41.2 sec vs. 145.5 ± 83.9 sec, P = 0.003). In two cases, it was impossible to intubate with BIF-DL, but the procedure was subsequently successful using fibreoptic bronchoscope.
Intubation of difficult airways can be performed more rapidly with BIF-DL, but sometimes it may not be possible to intubate with the scope.
PMCID: PMC2872830  PMID: 20498773
Bronchoscopes; Fiberoptics; Intubation; Laryngoscopy; Video recording
11.  Effects of ethanol on insulin-like growth factor-I system in primary cultured rat hepatocytes: Implications of JNK1/2 and alcoholdehydrogenase 
AIM: To evaluate the effects of ethanol on the insulin-like growth factor-I (IGF-I) system involved in c-Jun N-terminal kinase (JNK1/2) and alcoholdehydrogenase (ADH) activity in primary cultured rat hepatocytes.
METHODS: Hepatocytes isolated from male Sprague-Dawley rats were incubated with various concentrations of ethanol for different durations of time. The cells were pretreated with SP600125 (10 μmol/L) and 4-MP (200 μmol/L), and then treated with ethanol (200 mmol/L). We then measured IGF-Isecretion, IGF-I mRNA expression, cell viability and JNK1/2 activity by radioimmunoassay, RT-PCR, MTT assay and Western blot, respectively (n = 6).
RESULTS: Ethanol induced the activity of phospho (p)-JNK1/2, reaching a maximum at 60 min and then decreasing at 180 min. The effects of ethanol on the IGF-I system were increased at 60 min (secretion: 7.11 ± 0.59 ng/mg protein vs 4.91 ± 0.51 ng/mg, mRNA expression: 150.2% ± 10.2% vs 101.5% ± 11.3%, P = 0.045) and then decreased at 180 min (secretion: 3.89 ± 0.25 ng/mg vs 5.4 ± 0.54 ng/mg protein; mRNA expression: 41.5% ± 10.4% vs 84.7% ± 12.1%, P = 0.04), however cell viability was decreased in a dose- and time-dependent manner. SP600125 blocked the ethanol-induced changes (at 60 min). Additionally, 4-methylpyrazole prevented the ethanol-induced decreases in the IGF-I system, cell viability and p-JNK1/2 activity (at 180 min).
CONCLUSION: This study suggests that ethanol-induced p-JNK1/2 activation is associated with the IGF-I system and cell viability in hepatocytes. Furthermore, alcohol dehydrogenase is involved in the relationship between ethanol-induced inactivation of p-JNK1/2 and the changes of the IGF-I system and cell viability.
PMCID: PMC2731183  PMID: 18666320
Insulin-like growth factor-I; Insulin-like growth factor-I receptor; C-Jun N-terminal kinase; Hepatocyte; Ethanol
12.  Optimal Timing for the Administration of Capecitabine with Preoperative Chemoradiation for Locally Advanced Rectal Cancer 
Capecitabine is an oral fluoropyrimidine carbamate and it is known as an effective radiosensitizer. Capecitabine and its metabolite reach their peak concentration in the plasma at 1~2 hours after a single oral administration of capecitabine and the levels fall rapidly thereafter. To verify the radiosensitizing effect of capecitabine that is based on such pharmacokinetic characteristics, we performed a retrospective analysis on the optimal timing of capecitabine administration with performing preoperative chemoradiation for locally advanced rectal cancer.
Materials and Methods
Among 171 patients who were treated with preoperative radiotherapy and concurrent capecitabine administration for rectal cancer, 56 patients were administered capecitabine at 1~2 hours before radiotherapy (group A), and at other time in the other 115 patients (group B). Total mesorectal excision was done at 4 to 6 weeks after the completion of chemoradiation. The radiosensitizing effect of capecitabine was evaluated on the basis of the pathological response.
Complete pathological regression of the primary tumor was observed in 12 patients (21.4%) for group A and in 11 patients (9.6%) for group B (p=0.031). Residual disease less than 0.5 cm (a good response) was observed in 19 patients (33.9%) for group A and in 23 patients (20.0%) for group B (p=0.038). On multivariate analysis, the capecitabine ingestion time showed marginal significance.
When performing preoperative chemoradiation for locally advanced rectal cancer, the radiosensitizing effect of capecitabine was enhanced when it was administered 1 hour before radiotherapy.
PMCID: PMC2741651  PMID: 19771256
Rectal neoplasms; Combined modality therapy; Capecitabine
13.  Prospective Phase II Study of Preoperative Chemoradiation with Capecitabine in Locally Advanced Rectal Cancer 
Capecitabine is an attractive oral chemotherapeutic agent that has a radiosensitizing effect and tumor-selectivity. This study was performed to evaluate the efficacy and toxicity of preoperative chemoradiation therapy, when used with oral capecitabine, for locally advanced rectal cancer.
Materials and Methods
A prospective phase II trial of preoperative chemoradiation for locally advanced adenocarcinomas of the lower two-thirds of the rectum was conducted. A radiation dose of 50 Gy over five weeks and a daily dose of 1650 mg/m2 capecitabine in two potions was administered during the entire course of radiation therapy. Surgery was performed with standardized total mesorectal excision four to six weeks after completion of the chemoradiation.
Between January 2002 and September 2003, 61 patients were enrolled onto this prospective phase II trial. The pretreatment clinical stages were T3 in 64% (n=39), T4 in 36% (n=22) and N1-2 in 82% (n=50) of these patients. Fifty-six (92%) patients completed the chemoradiation as initially planned and a complete resection performed in 58 (95%). Down-staging was observed in 45 patients (74%) and a pathologic complete response in 6 (10%). Among the 37 patients with tumors located within 5 cm from the anal verge on colonoscopy, 27 (73%) underwent a sphincter-preserving procedure. No grade 3 and 4 proctitis or hematological toxicities were observed.
Preoperative chemoradiation therapy with capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation, with a low toxicity profile. This combined modality can be regarded as a safe and effective treatment for locally advanced rectal cancer.
PMCID: PMC2843876  PMID: 20368828
Rectal cancer; Preoperative; Chemoradiotherapy; Capecitabine
14.  Radioresponse of Hepatocellular Carcinoma-Treatment of Lymph Node Metastasis 
To analyze the radioresponse of hepatocellular carcinomas (HCC), using accurate measurements of the tumor size in extrahepatic lymph node metastasis, and to obtain information for the future treatment of primary intrahepatic lesions.
Materials and Methods
Fifty-one extrahepatic lymph node metastases from primary HCCs, which could be treated by external radiotherapy alone, were included in this study. The radiation dose ranged from 30 to 51 Gy with fraction sizes of 2.0~3.0 Gy. Responses were determined by measuring the areas on CT scans 0, 1 and 3 months after the completion of radiotherapy. The median follow-up period of the surviving patients was 10 months.
The overall response rate was 76%, and the important factors were; total dose of radiation, time dose fractionation (TDF) value and the biologically effective dose (BED). A dose of 45 Gy or higher showed an objective response rate of 93%, and if the TDF value was higher than 90, a similar result was observed. In about half (47%) of the patients the maximum response was observed at 3 months or later. The response duration was observable in 14 patients surviving 12 months or longer. Regrowth of irradiated lesions were observed in 4 (66.7%) patients among those who received less than 45 Gy, and in 4 (50%) among those who were treated with 45 Gy or more. There was a statistically significant difference in the survivals between the responders and non-responders (p=0.008). Gastrointestinal bleeding or ulceration was observed in 8 patients, including 3 with NCI common toxicity criteria grade III or higher.
Radiotherapy was an effective palliative modality for extrahepatic metastasis in HCCs. A radiation dose of 45 Gy or higher (or a TDF value ≥90), was required for a major response.
PMCID: PMC2855105  PMID: 20396570
Hepatocellular carcinoma; Radiotherapy
15.  Contact Angle Changes Induced by Immunocomplex Formation† 
The Analyst  2014;139(6):1340-1344.
Immunoassays analyzing interactions between antigens and antibodies can be affected by capillary action together with binding affinity. This paper studies contact-angle changes of bacterial suspensions on antibody immobilized surfaces. The capillary action and the dried pattern of the cell suspensions are analyzed and correlated with specific- and nonspecific bindings between bacteria and antibodies.
PMCID: PMC3977604  PMID: 24482797
16.  Microfluidic one-step synthesis of alginate microspheres immobilized with antibodies 
Micrometre- and submicrometre-size functionalized beads are frequently used to capture targets of interest from a biological sample for biological characterizations and disease diagnosis. The main challenge of the microbead-based assay is in the immobilization of probe molecules onto the microbead surfaces. In this paper, we report a versatile droplet microfluidics method to fabricate alginate microspheres while simultaneously immobilizing anti-Mycobacterium tuberculosis complex IgY and anti-Escherichia coli IgG antibodies primarily on the porous alginate carriers for specific binding and binding affinity tests. The binding affinity of antibodies is directly measured by fluorescence intensity of stained target bacteria on the microspheres. We demonstrate that the functionalized alginate microspheres yield specificity comparable with an enzyme-linked immunosorbent assay. The high surface area-to-volume ratio of the functionalized porous alginate microspheres improves the detection limit. By using the droplet microfluidics, we can easily modify the size and shape of alginate microspheres, and increase the concentration of functionalized alginate microspheres to further enhance binding kinetics and enable multiplexing.
PMCID: PMC3785821  PMID: 23966617
antibodies; alginate; microfluidics
17.  Multicenter Validation Study of a Prognostic Index for Portal Vein Tumor Thrombosis in Hepatocellular Carcinoma 
We previously reported on a staging system and prognostic index (PITH) for portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) patients treated with radiotherapy (RT) at a single institution. The aim of this study is to validate the PITH staging system using data from patients at other institutions and to compare it with other published staging systems.
Materials and Methods
A total of 994 HCC patients with PVTT who were treated with RT between 1998 and 2011 by the Korean Radiation Oncology Group were analyzed retrospectively. All patients were staged using the Cancer of the Liver Italian Program (CLIP), Japanese Integrated Staging (JIS), Okuda, and PITH staging systems, and survival data were analyzed. The likelihood ratio, Akaike information criteria (AIC), time-dependent receiver operating characteristics, and prediction error curve analysis were used to determine discriminatory ability for comparison of staging systems.
The median survival was 9.2 months. Compared with the other staging systems, the PITH score gave the highest values for likelihood ratio and lowest AIC values, demonstrating that PITH may be a better prognostic model. Although the values were not significant and differences were not exceptional, the PITH score showed slightly better performance with respect to time-dependent area under curve and integrated Brier score of prediction error curve.
The PITH staging system was validated in this multicenter retrospective study and showed better stratification ability in HCC patients with PVTT than other systems.
PMCID: PMC4206074  PMID: 25036573
Hepatocellular carcinoma; Portal vein; Radiotherapy; Multicenter study; Validation
18.  Single Walled Carbon Nanotube-Based Junction Biosensor for Detection of Escherichia coli 
PLoS ONE  2014;9(9):e105767.
Foodborne pathogen detection using biomolecules and nanomaterials may lead to platforms for rapid and simple electronic biosensing. Integration of single walled carbon nanotubes (SWCNTs) and immobilized antibodies into a disposable bio-nano combinatorial junction sensor was fabricated for detection of Escherichia coli K-12. Gold tungsten wires (50 µm diameter) coated with polyethylenimine (PEI) and SWCNTs were aligned to form a crossbar junction, which was functionalized with streptavidin and biotinylated antibodies to allow for enhanced specificity towards targeted microbes. In this study, changes in electrical current (ΔI) after bioaffinity reactions between bacterial cells (E. coli K-12) and antibodies on the SWCNT surface were monitored to evaluate the sensor's performance. The averaged ΔI increased from 33.13 nA to 290.9 nA with the presence of SWCNTs in a 108 CFU/mL concentration of E. coli, thus showing an improvement in sensing magnitude. Electrical current measurements demonstrated a linear relationship (R2 = 0.973) between the changes in current and concentrations of bacterial suspension in range of 102–105 CFU/mL. Current decreased as cell concentrations increased, due to increased bacterial resistance on the bio-nano modified surface. The detection limit of the developed sensor was 102 CFU/mL with a detection time of less than 5 min with nanotubes. Therefore, the fabricated disposable junction biosensor with a functionalized SWCNT platform shows potential for high-performance biosensing and application as a detection device for foodborne pathogens.
PMCID: PMC4169404  PMID: 25233366
19.  Effects of total body irradiation-based conditioning on allogeneic stem cell transplantation for pediatric acute leukemia: a single-institution study 
Radiation Oncology Journal  2014;32(3):198-207.
To evaluate the effects of total body irradiation (TBI), as a conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), in pediatric acute leukemia patients.
Materials and Methods
From January 2001 to December 2011, 28 patients, aged less than 18 years, were treated with TBI-based conditioning for allo-SCT in our institution. Of the 28 patients, 21 patients were diagnosed with acute lymphoblastic leukemia (ALL, 75%) and 7 were diagnosed with acute myeloid leukemia (AML, 25%). TBI was completed 4 days or 1 day before stem cell infusion. Patients underwent radiation therapy with bilateral parallel opposing fields and 6-MV X-rays. The Kaplan-Meier method was used to calculate survival outcomes.
The 2-year event-free survival and overall survival rates were 66% and 56%, respectively (71.4% and 60.0% in AML patients vs. 64.3% and 52.4% in ALL patients, respectively). Treatment related mortality rate were 25%. Acute and chronic graft-versus-host disease was a major complication; other complications included endocrine dysfunction and pulmonary complications. Common complications from TBI were nausea (89%) and cataracts (7.1%).
The efficacy and toxicity data in this study of TBI-based conditioning to pediatric acute leukemia patients were comparable with previous studies. However, clinicians need to focus on the acute and chronic complications related to allo-SCT.
PMCID: PMC4194303  PMID: 25324992
Total body irradiation; Acute lymphoid leukemia; Acute myeloid leukemia; Child; Stem cell transplantation
20.  A dosimetric comparison of volumetric modulated arc therapy (VMAT) and non-coplanar intensity modulated radiotherapy (IMRT) for nasal cavity and paranasal sinus cancer 
To compare dosimetric parameters of volumetric modulated arc therapy (VMAT) and non-coplanar intensity modulated radiotherapy (IMRT) for nasal cavity and paranasal sinus cancer with regard to the coverage of planning target volume (PTV) and the sparing of organs at risk (OAR).
Ten patients with nasal cavity or paranasal sinus cancer were re-planned by VMAT (two-arc) plan and non-coplanar IMRT (7-, 11-, and 15-beam) plans. Planning objectives were to deliver 60 Gy in 30 fractions to 95% of PTV, with maximum doses (Dmax) of <50 Gy to the optic nerves, optic chiasm, and brainstem, <40 Gy to the eyes and <10 Gy to the lenses. The target mean dose (Dmean) to the parotid glands was <25 Gy, and no constraints were applied to the lacrimal glands. Planning was optimized to minimized doses to OAR without compromising coverage of the PTV. VMAT and three non-coplanar IMRT (7-, 11-, and 15-beam) plans were compared using the heterogeneity and conformity indices (HI and CI) of the PTV, Dmax and Dmean of the OAR, treatment delivery time, and monitor units (MUs).
The HI and CI of VMAT plan were superior to those of the 7-, 11-, and 15-beam non-coplanar IMRT. VMAT and non-coplanar IMRT (7-, 11-, and 15-beam) showed equivalent sparing effects for the optic nerves, optic chiasm, brainstem, and parotid glands. For the eyes and lenses, VMAT achieved equivalent or better sparing effects when compared with the non-coplanar IMRT plans. VMAT showed lower MUs and reduced treatment delivery time when compared with non-coplanar IMRT.
In 10 patients with nasal cavity or paranasal sinus cancer, a VMAT plan provided better homogeneity and conformity for PTV than non-coplanar IMRT plans, with a shorter treatment delivery time, while achieving equal or better OAR-sparing effects and using fewer MUs.
PMCID: PMC4261880  PMID: 25175383
Paranasal sinus cancer; Nasal cavity cancer; Volumetric modulated arc therapy; Non-coplanar intensity modulated radiotherapy; Planning target volume; Organs at risk
21.  Cytochalasin B Modulates Macrophage-Mediated Inflammatory Responses 
Biomolecules & Therapeutics  2014;22(4):295-300.
The actin cytoskeleton plays an important role in macrophage-mediated inflammatory responses by modulating the activation of Src and subsequently inducing nuclear factor (NF)-κB translocation. In spite of its critical functions, few papers have examined how the actin cytoskeleton can be regulated by the activation of toll-like receptor (TLR). Therefore, in this study, we further characterized the biological value of the actin cytoskeleton in the functional activation of macrophages using an actin cytoskeleton disruptor, cytochalasin B (Cyto B), and explored the actin cytoskeleton’s involvement in morphological changes, cellular attachment, and signaling events. Cyto B strongly suppressed the TLR4-mediated mRNA expression of inflammatory genes such as cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and inducible nitric oxide (iNOS), without altering cell viability. This compound also strongly suppressed the morphological changes induced by lipopolysaccharide (LPS), a TLR4 ligand. Cyto B also remarkably suppressed NO production under non-adherent conditions but not in an adherent environment. Cyto B did not block the co-localization between surface glycoprotein myeloid differentiation protein-2 (MD2), a LPS signaling glycoprotein, and the actin cytoskeleton under LPS conditions. Interestingly, Cyto B and PP2, a Src inhibitor, enhanced the phagocytic uptake of fluorescein isothiocyanate (FITC)-dextran. Finally, it was found that Cyto B blocked the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at 1 min and the phosphorylation of heat shock protein 27 (HSP27) at 5 min. Therefore, our data suggest that the actin cytoskeleton may be one of the key components involved in the control of TLR4-mediated inflammatory responses in macrophages.
PMCID: PMC4131529  PMID: 25143807
Actin cytoskeleton; Inflammation; Cytochalasin B; Macrophages; TLR4
22.  Molecular mechanism of protopanaxadiol saponin fraction-mediated anti-inflammatory actions 
Journal of Ginseng Research  2014;39(1):61-68.
Korean Red Ginseng (KRG) is a representative traditional herbal medicine with many different pharmacological properties including anticancer, anti-atherosclerosis, anti-diabetes, and anti-inflammatory activities. Only a few studies have explored the molecular mechanism of KRG-mediated anti-inflammatory activity.
We investigated the anti-inflammatory mechanisms of the protopanaxadiol saponin fraction (PPD-SF) of KRG using in vitro and in vivo inflammatory models.
PPD-SF dose-dependently diminished the release of inflammatory mediators [nitric oxide (NO), tumor necrosis factor-α, and prostaglandin E2], and downregulated the mRNA expression of their corresponding genes (inducible NO synthase, tumor necrosis factor-α, and cyclooxygenase-2), without altering cell viability. The PPD-SF-mediated suppression of these events appeared to be regulated by a blockade of p38, c-Jun N-terminal kinase (JNK), and TANK (TRAF family member-associated NF-kappa-B activator)-binding kinase 1 (TBK1), which are linked to the activation of activating transcription factor 2 (ATF2) and interferon regulatory transcription factor 3 (IRF3). Moreover, this fraction also ameliorated HCl/ethanol/-induced gastritis via suppression of phospho-JNK2 levels.
These results strongly suggest that the anti-inflammatory action of PPD-SF could be mediated by a reduction in the activation of p38-, JNK2-, and TANK-binding-kinase-1-linked pathways and their corresponding transcription factors (ATF2 and IRF3).
PMCID: PMC4268567  PMID: 25535478
activating transcription factor 2; anti-inflammatory activity; interferon regulatory transcription factor 3; Korean red ginseng; protopanaxadiol saponin fraction
23.  A systematic review of the epidemiology of hepatitis E virus in Africa 
BMC Infectious Diseases  2014;14:308.
Hepatitis E Virus (HEV) infection is a newly recognized serious threat to global public health and Africa is suspected to be among the most severely affected regions in the world. Understanding HEV epidemiology in Africa will expedite the implementation of evidence-based control policies aimed at preventing the spread of HEV including policies for the use of available resources such as HEV vaccines.
Here we present a comprehensive review of HEV epidemiology in Africa based on published data. We searched for articles on HEV epidemiology in Africa from online databases such as PubMed, Scopus, and ISI Web of Science and critically reviewed appropriate publications to extract consistent findings, identify knowledge gaps, and suggest future studies.
Taking a particularly high toll in pregnant women and their fetuses, HEV has infected human populations in 28 of 56 African countries. Since 1979, 17 HEV outbreaks have been reported about once every other year from Africa causing a reported 35,300 cases with 650 deaths.
In Africa, HEV infection is not new, is widespread, and the number of reported outbreaks are likely a significant underestimate. The authors suggest that this is a continent-wide public health problem that deserves the attention of local, regional and international agencies to implement control policies that can save numerous lives, especially those of pregnant women and their fetuses.
PMCID: PMC4055251  PMID: 24902967
Hepatitis E; Africa; Review; Outbreak; Pregnancy
24.  Postoperative radiation therapy following the incomplete resection of a non-small cell lung cancer 
Radiation Oncology Journal  2014;32(2):70-76.
To review the results of postoperative radiation therapy (PORT) for residual non-small cell lung cancer (NSCLC) following surgical resection and evaluate multiple clinicopathologic prognostic factors.
Materials and Methods
A total of 58 patients, who completed scheduled PORT for positive resection margin, among 658 patients treated with PORT from January 2001 to November 2011 were retrospectively analyzed. Radiation therapy was started at 4 to 6 weeks after surgery. Chemotherapy was also administered to 35 patients, either sequentially or concurrently with PORT.
The median age of patients was 63 years (range, 40 to 82 years). The postoperative pathological stage I NSCLC was diagnosed in 10 (17.2%), stage II in 18 (31.0%), and stage III in 30 patients (51.7%). Squamous cell carcinoma was identified in 43, adenocarcinoma in 10, large cell in 1, others in 4 patients. Microscopic residual disease (R1) was diagnosed in 55 patients (94.8%), and the remaining three patients were diagnosed with gross residual disease (R2). The median dose of PORT was 59.4 Gy (range, 50.0 to 64.8 Gy). Chemotherapy was administered to 35 patients (60%), and the median follow-up time was 22.0 months (range, 6.0 to 84.0 months). The 3-year locoregional relapse-free survival and distant metastasis-free survival rates were 82.1% and 52.9%, respectively. The median overall survival was 23.8 months (range, 6.0 to 84.1 months), and the 3-year overall survival rate was 58.2%. Chemotherapy did not influence the failure pattern or survival outcome.
PORT is an effective modality for improving local tumor control in incompletely resected NSCLC patients. Major failure pattern was distant metastasis despite chemotherapy.
PMCID: PMC4104222  PMID: 25061575
Non-small-cell lung carcinoma; R1 resection; Microscopic residual disease; Postoperative radiotherapy
25.  A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases 
Journal of Ginseng Research  2014;38(3):161-166.
Ginseng is widely used for its promising healing and restorative properties as well as for its possible tonic effect in traditional medicine. Nowadays, many studies focus on purified individual ginsenoside, an important constituent in ginseng, and study its specific mechanism of action instead of whole-plant extracts on cardiovascular diseases (CVDs). Of the various ginsenosides, purified ginsenosides such as Rb1, Rg1, Rg3, Rh1, Re, and Rd are the most frequently studied. Although there are many reports on the molecular mechanisms and medical applications of ginsenosides in the treatment of CVDs, many concerns exist in their application. This review discusses current works on the countless pharmacological functions and the potential benefits of ginseng in the area of CVDs. Results: Both in vitro and in vivo results indicate that ginseng has potentially positive effects on heart disease through its various properties including antioxidation, reduced platelet adhesion, vasomotor regulation, improving lipid profiles, and influencing various ion channels. To date, approximately 40 ginsenosides have been identified, and each has a different mechanism of action owing to the differences in chemical structure. This review aims to present comprehensive information on the traditional uses, phytochemistry, and pharmacology of ginseng, especially in the control of hypertension and cardiovascular function. In addition, the review also provides an insight into the opportunities for future research and development on the biological activities of ginseng.
PMCID: PMC4213864  PMID: 25378989
antioxidant effect; cardiovascular diseases; lipid profile; myocardial protection; vasomotor tone

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