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1.  Clinical Factors Associated with Response or Survival after Chemotherapy in Patients with Waldenström Macroglobulinemia in Korea 
BioMed Research International  2014;2014:253243.
Waldenström's macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Clinical features and cytogenetics of WM in Asia including Republic of Korea remain unclear. Moreover, no study has reported treatment outcomes in patients with WM treated with novel agent combined with conventional chemotherapy. This study investigated clinical features and assessed treatment outcomes with novel agent and conventional chemotherapy in Republic of Korea. Data from all (n = 71) patients with newly diagnosed WM at 17 hospitals who received chemotherapy between January 2005 and December 2012 were collected retrospectively. The median age of patients was 66 years (range: 37–92 years) and male to female ratio was 5 : 1. Patients treated with novel agent combined chemotherapy displayed higher overall response rate (ORR) compared to conventional chemotherapy alone (92.9% versus 52.6%, P = 0.006). The 5-year overall survival rate was 62.6% (95% confidence interval: 34.73–111.07). Use of novel agents produced higher ORR but survival benefit was not apparent due to the small number of patients and short follow-up duration. Further studies are needed to confirm the efficacy of novel agents in patients with WM.
PMCID: PMC4065725  PMID: 24995279
2.  Clinical characteristics, pathological distribution, and prognostic factors in non-Hodgkin lymphoma of Waldeyer's ring: nationwide Korean study 
In Asia, the incidence of non-Hodgkin lymphoma (NHL) has increased in recent decades. Waldeyer's ring (WR) is the most common site of NHL involving the head and neck. In this study, the pathological distribution of WR-NHL and its clinical features were analyzed retrospectively.
From January 2000 through December 2010, we analyzed the medical records of 328 patients from nine Korean institutions who were diagnosed with WR-NHL.
The study group comprised 197 male and 131 female patients with a median age of 58 years (range, 14 to 89). The rate of localized disease (stage I/II) was 64.9%, and that of low-risk disease (low/low-intermediate, as defined by the International Prognostic Index) was 76.8%. Diffuse large B-cell lymphoma (DLBCL; 240 patients, 73.2%) was the most common pathologic subtype, followed by peripheral T-cell lymphoma (14 patients, 4.3%) and nasal NK/T-cell lymphoma (14 patients, 4.3%). WR-NHL occurred most frequently in the tonsils (199 patients, 60.6%). Extranodal involvement was greater with the T-cell subtype (20 patients, 42.5%) compared with the B-cell subtype (69 patients, 24.5%). Multivariate analyses showed that age ≥ 62 years, T-cell subtype, and failure to achieve complete remission were significant risk factors for overall survival.
DLBCL was found to have a higher incidence in Korea than those incidences reported by other WR-NHL studies. T-cell lymphoma occurred more frequently than did follicular lymphoma. T-cell subtype, age ≥ 62 years, and complete remission failure after first-line treatment were significant poor prognostic factors for overall survival according to the multivariate analysis.
PMCID: PMC4028525  PMID: 24851070
Head and neck; Non-Hodgkin lymphoma; Diffuse large B-cell lymphoma; T-cell lymphoma
3.  Mechanism of μ-Conotoxin PIIIA Binding to the Voltage-Gated Na+ Channel NaV1.4 
PLoS ONE  2014;9(3):e93267.
Several subtypes of voltage-gated Na+ (NaV) channels are important targets for pain management. μ-Conotoxins isolated from venoms of cone snails are potent and specific blockers of different NaV channel isoforms. The inhibitory effect of μ-conotoxins on NaV channels has been examined extensively, but the mechanism of toxin specificity has not been understood in detail. Here the known structure of μ-conotoxin PIIIA and a model of the skeletal muscle channel NaV1.4 are used to elucidate elements that contribute to the structural basis of μ-conotoxin binding and specificity. The model of NaV1.4 is constructed based on the crystal structure of the bacterial NaV channel, NaVAb. Six different binding modes, in which the side chain of each of the basic residues carried by the toxin protrudes into the selectivity filter of NaV1.4, are examined in atomic detail using molecular dynamics simulations with explicit solvent. The dissociation constants (Kd) computed for two selected binding modes in which Lys9 or Arg14 from the toxin protrudes into the filter of the channel are within 2 fold; both values in close proximity to those determined from dose response data for the block of NaV currents. To explore the mechanism of PIIIA specificity, a double mutant of NaV1.4 mimicking NaV channels resistant to μ-conotoxins and tetrodotoxin is constructed and the binding of PIIIA to this mutant channel examined. The double mutation causes the affinity of PIIIA to reduce by two orders of magnitude.
PMCID: PMC3968119  PMID: 24676211
5.  Vaccination with Lentiviral Vector Expressing the nfa1 Gene Confers a Protective Immune Response to Mice Infected with Naegleria fowleri 
Naegleria fowleri, a pathogenic free-living amoeba, causes fatal primary amoebic meningoencephalitis (PAM) in humans and animals. The nfa1 gene (360 bp), cloned from a cDNA library of N. fowleri, produces a 13.1-kDa recombinant protein which is located on pseudopodia, particularly the food cup structure. The nfa1 gene plays an important role in the pathogenesis of N. fowleri infection. To examine the effect of nfa1 DNA vaccination against N. fowleri infection, we constructed a lentiviral vector (pCDH) expressing the nfa1 gene. For the in vivo mouse study, BALB/c mice were intranasally vaccinated with viral particles of a viral vector expressing the nfa1 gene. To evaluate the effect of vaccination and immune responses of mice, we analyzed the IgG levels (IgG, IgG1, and IgG2a), cytokine induction (interleukin-4 [IL-4] and gamma interferon [IFN-γ]), and survival rates of mice that developed PAM. The levels of both IgG and IgG subclasses (IgG1 and IgG2a) in vaccinated mice were significantly increased. The cytokine analysis showed that vaccinated mice exhibited greater IL-4 and IFN-γ production than the other control groups, suggesting a Th1/Th2 mixed-type immune response. In vaccinated mice, high levels of Nfa1-specific IgG antibodies continued until 12 weeks postvaccination. The mice vaccinated with viral vector expressing the nfa1 gene also exhibited significantly higher survival rates (90%) after challenge with N. fowleri trophozoites. Finally, the nfa1 vaccination effectively induced protective immunity by humoral and cellular immune responses in N. fowleri-infected mice. These results suggest that DNA vaccination using a viral vector may be a potential tool against N. fowleri infection.
PMCID: PMC3697439  PMID: 23677321
6.  Clinical Outcomes and Prognostic Factors of Empirical Antifungal Therapy with Itraconazole in the Patients with Hematological Malignancies: A Prospective Multicenter Observational Study in Korea 
Yonsei Medical Journal  2013;55(1):9-18.
To identify prognostic factors for the outcomes of empirical antifungal therapy, we performed a multicenter, prospective, observational study in immunocompromised patients with hematological malignancies.
Materials and Methods
Three hundred seventy-six patients (median age of 48) who had neutropenic fever and who received intravenous (IV) itraconazole as an empirical antifungal therapy for 3 or more days were analyzed. The patients with possible or probable categories of invasive fungal disease (IFD) were enrolled.
The overall success rate was 51.3% (196/376). Age >50 years, underlying lung disease (co-morbidity), poor performance status [Eastern Cooperative Oncology Group (ECOG) ≥2], radiologic evidence of IFD, longer duration of baseline neutropenic fever (≥4 days), no antifungal prophylaxis or prophylactic use of antifungal agents other than itraconazole, and high tumor burden were associated with decreased success rate in univariate analysis. In multivariate analysis, age >50 years (p=0.009) and poor ECOG performance status (p=0.005) were significantly associated with poor outcomes of empirical antifungal therapy. Twenty-two patients (5.9%) discontinued itraconazole therapy due to toxicity.
We concluded that empirical antifungal therapy with IV itraconazole in immunocompromised patients is effective and safe. Additionally, age over 50 years and poor performance status were poor prognostic factors for the outcomes of empirical antifungal therapy with IV itraconazole.
PMCID: PMC3874917  PMID: 24339281
Hematological malignancy; prognosis; itraconazole; empirical antifungal therapy
7.  Spinal Noradrenergic Modulation and the Role of the Alpha-2 Receptor in the Antinociceptive Effect of Intrathecal Nefopam in the Formalin Test 
The Korean Journal of Pain  2013;27(1):23-29.
Nefopam has shown an analgesic effect on acute pain including postoperative pain. The reuptake of monoamines including serotonin and noradrenaline has been proposed as the mechanism of the analgesic action of nefopam, but it remains unclear. Although alpha-adrenergic agents are being widely used in the perioperative period, the role of noradrenergic modulation in the analgesic effect of nefopam has not been fully addressed.
Changes in the antinociceptive effect of intrathecal (i.t.) nefopam against formalin-elicited flinching responses were explored in Sprague-Dawley rats pretreated with i.t. 6-hydroxydopamine (6-OHDA), which depletes spinal noradrenaline. In addition, antagonism to the effect of nefopam by prazosin and yohimbine was evaluated to further elucidate the antinociceptive mechanism of i.t. nefopam.
Pretreatment with i.t. 6-OHDA alone did not alter the flinching responses in either phase of the formalin test, while it attenuated the antinociceptive effect of i.t. nefopam significantly during phase 1, but not phase 2. The antagonist of the alpha-2 receptor, but not the alpha-1 receptor, reduced partially, but significantly, the antinociceptive effect of i.t. nefopam during phase 1, but not during phase 2.
This study demonstrates that spinal noradrenergic modulation plays an important role in the antinociceptive effect of i.t. nefopam against formalin-elicited acute initial pain, but not facilitated pain, and this action involves the spinal alpha-2 but not the alpha-1 receptor.
PMCID: PMC3903796  PMID: 24478897
alpha-2 receptor; formalin; nefopam; noradrenergic system; spinal cord
8.  Practice guideline for the performance of breast ultrasound elastography 
Ultrasonography  2013;33(1):3-10.
Ultrasound (US) elastography is a valuable imaging technique for tissue characterization. Two main types of elastography, strain and shear-wave, are commonly used to image breast tissue. The use of elastography is expected to increase, particularly with the increased use of US for breast screening. Recently, the US elastographic features of breast masses have been incorporated into the 2nd edition of the Breast Imaging Reporting and Data System (BI-RADS) US lexicon as associated findings. This review suggests practical guidelines for breast US elastography in consensus with the Korean Breast Elastography Study Group, which was formed in August 2013 to perform a multicenter prospective study on the use of elastography for US breast screening. This article is focused on the role of elastography in combination with B-mode US for the evaluation of breast masses. Practical tips for adequate data acquisition and the interpretation of elastography results are also presented.
PMCID: PMC4058975  PMID: 24936489
Breast, neoplasms; Ultrasonography; Elasticity imaging techniques
9.  An Elderly Man with Fatal Respiratory Failure after Eating a Poisonous Mushroom Podostroma cornu-damae 
A 73-year-old, previously healthy man presented with nausea, vomiting, diarrhea, dry mouth and febrile sensation 3 hours after eating boiled wild mushrooms. After admission, he showed progressive severe respiratory distress, pancytopenia, azotemia, hypotension, hypoxemia and consolidation of the entire left lung on chest radiography. With a preliminary diagnosis of necrotizing pneumonia, he underwent left pneumonectomy in order to remove all necrotic lung tissue. Lung histology showed extensive hemorrhagic necrosis, massive inflammatory cell infiltration, prominent proliferation of young fibroblasts and the formation of an early-stage hyaline membrane along the alveolar wall. Despite aggressive treatment, including mechanical ventilation, continuous renal replacement therapy and administration of granulocyte colony stimulating factor and broad spectrum antibiotics, he died on hospitalization day 13. Subsequently, the mushroom was identified as Podostroma cornu-damae. This is the first case of a histological evidence of lung involvement by Podostroma cornu-damae poisoning in Korea.
PMCID: PMC3884116  PMID: 24416059
Korea; Mushroom Poisoning
10.  Iatrogenic catheter sheath shearing during radial artery cannulation 
Korean Journal of Anesthesiology  2013;65(6 Suppl):S12-S13.
PMCID: PMC3903827  PMID: 24478839
11.  Determination of imidocarb in animal biosamples using simple high-performance liquid chromatography with diode-array detection 
Biomedical Reports  2013;2(1):89-92.
The aim of this study was to develop an analytical method for detection of imidocarb [1,3-bis[3-(4,5-dihydro-1h-imidazol-2-yl)phenyl]urea] in beef and milk using high-performance liquid chromatography (HPLC) with diode-array detection (DAD). Imidocarb was separated on a reversed-phase column (4.6×250 mm, 5 μm) with a mobile phase consisting of 85:15 (v/v) 0.1% trifluoroacetic acid/acetonitrile. The flow rate was 1 ml/min, and the column temperature was maintained at 20°C. Detection was carried out at 260 nm using a DAD detector. The analytical samples were extracted using a solid-phase extraction (SPE) method. The calibration curves showed good linearity (r≥0.998). Limits of quantifications (LOQs) were 0.15 mg/kg in beef and 0.025 mg/kg in milk. Intra- and inter-day precisions were 3.2–6.1 and 1.4–6.9%, respectively, and the accuracy (recovery) was 80.4–82.2% and 80.1–89.5% in beef and milk, respectively. Thus, an analytical protocol using SPE extraction followed by HPLC with DAD was successfully developed, which demonstrated acceptable precision and recovery.
PMCID: PMC3917563  PMID: 24649075
imidocarb; residue analysis; milk; beef; high-performance liquid chromatography
12.  Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D, L-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin 
Concurrent delivery of multiple poorly water-soluble anticancer drugs has been a great challenge due to the toxicities exerted by different surfactants or organic solvents used in solubilizing individual drugs. We previously found that poly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-b-PLA) micelles can serve as a safe delivery platform for simultaneous delivery of paclitaxel (PTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP) to mice. The high tolerance of this polymeric micelle formulation by mice allowed us to investigate the pharmacokinetics of the 3 co-delivered drugs. In this study, it was shown that 3-in-1 PEG-b-PLA micelle delivering high doses of PTX, 17-AAG, and RAP (60, 60, and 30 mg/kg, respectively) significantly increased the values of the area under the plasma concentration-time curves (AUC) of PTX and RAP in mice compared to the drugs delivered individually, while the pharmacokinetic parameters of 17-AAG were similar in both 3-in-1 and single drug-loaded PEG-b-PLA micelle formulations. Moreover, pharmacokinetic study using 2-in-1 micelles indicated that the augmented AUC value of RAP was due to the co-delivery of 17-AAG, while the increase in AUC of PTX was more likely caused by the co-delivery of RAP. In contrast, when 3-in-1 and single drug-loaded PEG-b-PLA micelles were administrated at modest dose (PTX, 17-AAG, and RAP at 10, 10, and 5 mg/kg, respectively), pharmacokinetic differences of individual drugs between 3-in-1 and single drug formulations were eliminated. These results suggest that 3-in-1 PEG-b-PLA micelles can concurrently deliver PTX, 17-AAG, and RAP without changing the pharmacokinetics of each drug at modest doses, but altered pharmacokinetic profiles emerge when drugs are delivered at higher doses.
PMCID: PMC3422612  PMID: 22549011
Paclitaxel; 17-Allylamino-17-demethoxygeldanamycin (17-AAG); Rapamycin; PEG-b-PLA micelles; Pharmacokinetics
13.  Anti-tumor Activity of Triolimus: A Novel Multi-Drug Loaded Micelle Containing Paclitaxel, Rapamycin and 17-AAG 
Molecular cancer therapeutics  2012;11(10):2233-2242.
Triolimus is a first-in-class, multi-drug loaded micelle containing paclitaxel, rapamycin and 17-AAG. In this study, we examine the anti-tumor mechanisms of action, efficacy and toxicity of Triolimus in vitro and in vivo. In vitro cytotoxicity testing of Triolimus was conducted using two aggressive adenocarcinomas including the lung cancer cell line, A549, and breast cancer cell line, MDA-MB-231. The three-drug combination of paclitaxel, rapamycin and 17-AAG displayed potent cytotoxic synergy in both A549 and MDA-MB-231 cell lines. Mechanistically, the drug combination inhibited both the Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. Triolimus was advanced into tumor xenograft models for assessment of efficacy, toxicity and mechanisms of action. In vivo, a three-infusion schedule of Triolimus inhibited A549 and MDA-MB-231 tumor growth far more potently than paclitaxel-containing micelles and effected tumor cures in MDA-MB-231 tumor-bearing animals. Tumor growth delays resulted from a doubling in tumor cell apoptosis and a 50% reduction in tumor cell proliferation compared to paclitaxel-containing micelles. Enhanced anti-tumor efficacy was achieved without clinically significant increases in acute toxicity. Thus, Triolimus displays potent synergistic activity in vitro and anti-tumor activity in vivo with comparable toxicity to paclitaxel. These observations provide strong support for further development of Triolimus and an important proof of concept for safe, effective nanoparticle-based delivery of three complementary anti-cancer agents.
PMCID: PMC3469732  PMID: 22896668
Multi-targeting; Hsp90; mTOR; paclitaxel; micelles
14.  Treadmill exercise ameliorates impairment of spatial learning ability through enhancing dopamine expression in hypoxic ischemia brain injury in neonatal rats 
Substantia nigra and striatum are vulnerable to hypoxic ischemia brain injury. Physical exercise promotes cell survival and functional recovery after brain injury. However, the effects of treadmill exercise on nigro-striatal dopaminergic neuronal loss induced by hypoxic ischemia brain injury in neonatal stage are largely unknown. We determined the effects of treadmill exercise on survival of dopamine neurons in the substantia nigra and dopaminergic fibers in the striatum after hypoxic ischemia brain injury. On postnatal 7 day, left common carotid artery of the neonatal rats ligated for two hours and the neonatal rats were exposed to hypoxia conditions for one hour. The rat pups in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 12 weeks, starting 22 days after induction of hypoxic ischemia brain injury. Spatial learning ability in rat pups was determined by Morris water maze test after last treadmill exercise. The viability of dopamine neurons in the substantia nigra and dopamine fibers in the striatum were analyzed using immunohistochemistry. In this study, hypoxic ischemia injury caused loss of dopamine neurons in the substantia nigra and dopaminergic fibers in the striatum. Induction of hypoxic ischemia deteriorated spatial learning ability. Treadmill exercise ameliorated nigro-striatal dopaminergic neuronal loss, resulting in the improvement of spatial learning ability. The present study suggests the possibility that treadmill exercise in early adolescent period may provide a useful strategy for the recovery after neonatal hypoxic ischemia brain injury.
PMCID: PMC3836536  PMID: 24278893
Hypoxic ischemia; Substantia nigra; Striatum; Dopamine; Treadmill exercise
16.  Exposure to Music and Noise During Pregnancy Influences Neurogenesis and Thickness in Motor and Somatosensory Cortex of Rat Pups 
Prenatal environmental conditions affect the development of the fetus. In the present study, we investigated the effects of exposure to music and noise during pregnancy on neurogenesis and thickness in the motor and somatosensory cortex of rat pups.
The pregnant rats in the music-applied group were exposed to 65 dB of comfortable music for 1 hour, once per day, from the 15th day of pregnancy until delivery. The pregnant rats in the noise-applied group were exposed to 95 dB of sound from a supersonic sound machine for 1 hour, once per day, from the 15th day of pregnancy until delivery. After birth, the offspring were left undisturbed together with their mother. The rat pups were sacrificed at 21 days after birth.
Exposure to music during pregnancy increased neurogenesis in the motor and somatosensory cortex of rat pups. In contrast, rat pups exposed to noise during pregnancy showed decreased neurogenesis and thickness in the motor and somatosensory cortex.
Our study suggests that music and noise during the developmental period are important factors influencing brain development and urogenital disorders.
PMCID: PMC3797889  PMID: 24143288
Music; Noise; Neurogenesis; Motor cortex; Somatosensory cortex
17.  Designing a C84 fullerene as a specific voltage-gated sodium channel blocker 
Nanoscale Research Letters  2013;8(1):323.
Fullerene derivatives demonstrate considerable potential for numerous biological applications, such as the effective inhibition of HIV protease. Recently, they were identified for their ability to indiscriminately block biological ion channels. A fullerene derivative which specifically blocks a particular ion channel could lead to a new set of drug leads for the treatment of various ion channel-related diseases. Here, we demonstrate their extraordinary potential by designing a fullerene which mimics some of the functions of μ-conotoxin, a peptide derived from cone snail venom which potently binds to the bacterial voltage-gated sodium channel (NavAb). We show, using molecular dynamics simulations, that the C84 fullerene with six lysine derivatives uniformly attached to its surface is selective to NavAb over a voltage-gated potassium channel (Kv1.3). The side chain of one of the lysine residues protrudes into the selectivity filter of the channel, while the methionine residues located just outside of the channel form hydrophobic contacts with the carbon atoms of the fullerene. The modified C84 fullerene strongly binds to the NavAb channel with an affinity of 46 nM but binds weakly to Kv1.3 with an affinity of 3 mM. This potent blocker of NavAb may serve as a structural template from which potent compounds can be designed for the targeting of mammalian Nav channels. There is a genuine need to target mammalian Nav channels as a form of treatment of various diseases which have been linked to their malfunction, such as epilepsy and chronic pain.
PMCID: PMC3726465  PMID: 23855749
C84 fullerene derivative; Bacterial voltage-gated sodium channel NavAb; Voltage-gated potassium channel Kv1.3; Binding; Molecular dynamics; 87.85.Qr; 87.85.Rs; 87.10.Tf
18.  The First Korean Case of Sphingobacterium spiritivorum Bacteremia in a Patient with Acute Myeloid Leukemia 
Annals of Laboratory Medicine  2013;33(4):283-287.
Sphingobacterium spiritivorum has been rarely isolated from clinical specimens of immunocompromised patients, and there have been no case reports of S. spiritivorum infection in Korea to our knowledge. We report a case of S. spiritivorum bacteremia in a 68-yr-old woman, who was diagnosed with acute myeloid leukemia and subsequently received chemotherapy. One day after chemotherapy ended, her body temperature increased to 38.3℃. A gram-negative bacillus was isolated in aerobic blood cultures and identified as S. spiritivorum by an automated biochemical system. A 16S rRNA sequencing analysis confirmed that the isolate was S. spiritivorum. The patient received antibiotic therapy for 11 days but died of septic shock. This is the first reported case of human S. spiritivorum infection in Korea. Although human infection is rare, S. spiritivorum can be a fatal opportunistic pathogen in immunocompromised patients.
PMCID: PMC3698308  PMID: 23826566
Sphingobacterium spiritivorum; Bacteremia; Immunocompromised patient; 16S rRNA sequencing
19.  A Case of Synchronous Presentation of Primary Non-Small Cell Lung Carcinoma and Pheochromocytoma 
We report a rare synchronous presentation of primary lung cancer and adrenal pheochromocytoma. A 59-year-old woman was diagnosed with right upper lobe non-small cell lung carcinoma measuring 2.8 cm and a right adrenal gland mass measuring 3.5 cm, which displayed increased metabolic activity on 18F-fluorodeoxyglucose positron emission tomography-computed tomography. The adrenal lesion was revealed to be asymptomatic. The patient underwent right adrenalectomy and histological examination revealed a pheochromocytoma. Ten days later, right upper lobectomy was performed for lung cancer. This case indicates that incidental adrenal lesions found in cases of resectable primary lung cancer should be investigated.
PMCID: PMC3651929  PMID: 23678360
Carcinoma; Lung; Pheochromocytoma
20.  Repeated Migration of a Fusion Cage after Posterior Lumbar Interbody Fusion 
Korean Journal of Spine  2013;10(1):25-27.
Although posterior lumbar interbody fusion (PLIF) is a widely accepted procedure, perioperative and postoperative complications are still encountered. In particular, cage migration can result in severe sequelae, and revision surgery is technically demanded. Here, we report a rare case of repeated migration of a fusion cage after PLIF. To the best of our knowledge, no report has been previously issued on repeated migration of a fusion cage after PLIF. The authors discuss the radiological and clinical findings of this unusual complication with a review of the literature.
PMCID: PMC3941729  PMID: 24757453
Cage; Migration; Complication
21.  Gintonin, Newly Identified Compounds from Ginseng, Is Novel Lysophosphatidic Acids-Protein Complexes and Activates G Protein-Coupled Lysophosphatidic Acid Receptors with High Affinity 
Molecules and Cells  2012;33(2):151-162.
Recently, we isolated a subset of glycolipoproteins from Panax ginseng, that we designated gintonin, and demonstrated that it induced [Ca2+]i transients in cells via G-protein-coupled receptor (GPCR) signaling pathway(s). However, active components responsible for Ca2+ mobilization and the corresponding receptor(s) were unknown. Active component(s) for [Ca2+]i transients of gintonin were analyzed by liquid chromatography-electrospray ionization-tandem mass spectrometry and ion-mobility mass spectrometry, respectively. The corresponding receptor(s) were investigated through gene expression assays. We found that gintonin contains LPA C18:2 and other LPAs. Proteomic analysis showed that ginseng major latex-like protein and ribonuclease-like storage proteins are protein components of gintonin. Gintonin induced [Ca2+]i transients in B103 rat neuroblastoma cells transfected with human LPA receptors with high affinity in order of LPA2 > LPA5 > LPA1 > LPA3 > LPA4. The LPA1/LPA3 receptor antagonist Ki16425 blocked gintonin action in cells expressing LPA1 or LPA3. Mutations of binding sites in the LPA3 receptor attenuated gintonin action. Gintonin acted via pertussis toxin (PTX)-sensitive and -insensitive G protein-phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP3)-Ca2+ pathways. However, gintonin had no effects on other receptors examined. In human umbilical vein endothelial cells (HUVECs) gintonin stimulated cell proliferation and migration. Gintonin stimulated ERK1/2 phosphorylation. PTX blocked gintonin-mediated migration and ERK1/2 phosphorylation. In PC12 cells gintonin induced morphological changes, which were blocked by Rho kinase inhibitor Y-27632. Gintonin contains GPCR ligand LPAs in complexes with ginseng proteins and could be useful in the development of drugs targeting LPA receptors.
PMCID: PMC3887723  PMID: 22286231
ginseng; gintonin; LPA-protein complexes; LPA receptors
22.  In vivo cancer imaging by poly(ethylene glycol)-b-poly(ε-caprolactone) micelles containing a near-infrared probe 
Nanomedicine  2011;8(2):228-236.
Non-invasive near infrared (NIR) fluorescence imaging is a promising technique for the intra-operative assessment of solid tumor removal. We incorporated a lipophilic NIR probe, 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide (DiR), in poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) micelles, resulting in DiR solubilization in water, occupying nanoscopic PEG-b-PCL micelles. DiR in a self-quenched or non-quenched state showed different kinetics of release from PEG-b-PCL micelles in vitro; however, both obtained high tumor delineation (tumor-to-muscle ratio of 30-43 from collected organs). These results suggest that PEG-b-PCL micelles with DiR are a promising nano-sized imaging agent that will provide a basis for enhanced surgical guidance via NIR visualization of tumors.
PMCID: PMC3193583  PMID: 21704593
Near infrared (NIR) fluorescence imaging; Poly(ethylene glycol)-b-poly(ε-caprolactone); Polymeric micelles; Self-quenching
23.  Short Segment Fixation for Thoracolumbar Burst Fracture Accompanying Osteopenia : A Comparative Study 
The purpose of this study was to compare the results of three types of short segment screw fixation for thoracolumbar burst fracture accompanying osteopenia.
The records of 70 patients who underwent short segment screw fixation for a thoracolumbar burst fracture accompanying osteopenia (-2.5< mean T score by bone mineral densitometry <-1.0) from January 2005 to January 2008 were reviewed. Patients were divided into three groups based on whether or not bone fusion and bone cement augmentation procedure 1) Group I (n=26) : short segment fixation with posterolateral bone fusion; 2) Group II (n=23) : bone cement augmented short segment fixation with posterolateral bone fusion; 3) Group III (n=21) : bone cement augmented, short segment percutaneous screw fixation without bone fusion. Clinical outcomes were assessed using a visual analogue scale and modified MacNab's criteria. Radiological findings, including kyphotic angle and vertebral height, and procedure-related complications, such as screw loosening or pull-out, were analyzed.
No significant difference in radiographic or clinical outcomes was noted between patients managed using the three different techniques at last follow up. However, Group I showed more correction loss of kyphotic deformities and vertebral height loss at final follow-up, and Group I had higher screw loosening and implant failure rates than Group II or III.
Bone cement augmented procedure can be an efficient and safe surgical techniques in terms of achieving better outcomes with minimal complications for thoracolumbar burst fracture accompanying osteopenia.
PMCID: PMC3579078  PMID: 23440679
Burst fracture; Osteopenia; Fusion
24.  Simultaneous determination of methylcarbamate and ethylcarbamate in fermented foods and beverages by derivatization and GC-MS analysis 
Methylcarbamate (MC) and ethylcarbamate (EC) are toxic compounds that commonly exist in fermented food and beverages. In order to estimate the risk for their exposure, a sensitive simultaneous analytical method is required
A simultaneous determination of MC and EC was described based on derivatization with 9-xanthydrol and consecutive detection using gas chromatography–mass spectrometry. The derivatization of MC and EC was performed directly in food or beverages and the reaction conditions were established through changing various parameters. The detection and the quantification limits were 0.01-0.03 μg/kg and 0.03-0.1 μg/kg, respectively, and the interday relative standard deviation was less than 12% at concentrations of 2.0 and 50 μg/kg. MC and EC were measured from 0.4 μg/kg to 85.8 μg/kg in sixteen Korean fermented foods and eleven beverages.
A simple, sensitive method to detect MC and EC in several solid foods and liquid foods was developed based on derivatization with 9-xanthydrol for 10 min at an ambient temperature. The method may useful for routine analysis of MC and EC in numerous food samples.
PMCID: PMC3537662  PMID: 23234430
Methylcarbamate; Ethylcarbamate; Fermented food; Beverages; GC-MS
25.  Binding of Hanatoxin to the Voltage Sensor of Kv2.1 
Toxins  2012;4(12):1552-1564.
Hanatoxin 1 (HaTx1) is a polypeptide toxin isolated from spider venoms. HaTx1 inhibits the voltage-gated potassium channel kv2.1 potently with nanomolar affinities. Its receptor site has been shown to contain the S3b-S4a paddle of the voltage sensor (VS). Here, the binding of HaTx1 to the VSs of human Kv2.1 in the open and resting states are examined using a molecular docking method and molecular dynamics. Molecular docking calculations predict two distinct binding modes for the VS in the resting state. In the two binding modes, the toxin binds the S3b-S4a from S2 and S3 helices, or from S1 and S4 helices. Both modes are found to be stable when embedded in a lipid bilayer. Only the mode in which the toxin binds the S3b-S4a paddle from S2 and S3 helices is consistent with mutagenesis experiments, and considered to be correct. The toxin is then docked to the VS in the open state, and the toxin-VS interactions are found to be less favorable. Computational mutagenesis calculations performed on F278R and E281K mutant VSs show that the mutations may reduce toxin binding affinity by weakening the non-bonded interactions between the toxin and the VS. Overall, our calculations reproduce a wide range of experimental data, and suggest that HaTx1 binds to the S3b-S4a paddle of Kv2.1 from S2 and S3 helices.
PMCID: PMC3528262  PMID: 23250329
hanatoxin; Kv2.1; voltage sensor; gating modifier toxin; molecular dynamics

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