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1.  Establishment of an Orthotopic Mouse Non-Muscle Invasive Bladder Cancer Model Expressing the Mammalian Target of Rapamycin Signaling Pathway 
Journal of Korean Medical Science  2014;29(3):343-350.
We established an orthotopic non-muscle invasive bladder cancer (NMIBC) mouse model expressing the mammalian target of the rapamycin (mTOR) signaling pathway. After intravesical instillation of KU-7-lucs (day 0), animals were subsequently monitored by bioluminescence imaging (BLI) on days 4, 7, 14, and 21, and performed histopathological examination. We also validated the orthotopic mouse model expressing the mTOR signaling pathway immunohistochemically. In vitro BLI photon density was correlated with KU-7-luc cell number (r2 = 0.97, P < 0.01) and in vivo BLI photon densities increased steadily with time after intravesical instillation. The tumor take rate was 84.2%, formed initially on day 4 and remained NMIBC up to day 21. T1 photon densities were significantly higher than Ta (P < 0.01), and histological tumor volume was positively correlated with BLI photon density (r2 = 0.87, P < 0.01). The mTOR signaling pathway-related proteins were expressed in the bladder, and were correlated with the western blot results. Our results suggest successful establishment of an orthotopic mouse NMIBC model expressing the mTOR signaling pathway using KU-7-luc cells. This model is expected to be helpful to evaluate preclinical testing of intravesical therapy based on the mTOR signaling pathway against NMIBC.
PMCID: PMC3945128  PMID: 24616582
Urinary Bladder Neoplasms; Mouse Orthotopic Model; mTOR
2.  Isolated cricoid fracture associated with blunt neck trauma 
Emergency Medicine Journal : EMJ  2007;24(7):505-506.
A 32‐year‐old woman without a remarkable history presented at the emergency department with strangulation of the neck. CT scans of the neck revealed a displaced cricoid fracture. Six days after admission to hospital, hoarseness and dyspnoea disappeared. On the 10th day, the patient was discharged without complications. The traditional treatment guidelines for laryngeal trauma have recommended an early surgical intervention after immediate tracheotomy in cases of displaced fractures of the cricoid cartilage. The patient could be treated successfully through continuous monitoring of airway obstruction without surgical management.
PMCID: PMC2658407  PMID: 17582051
3.  Antitumor activity of the c-Myc inhibitor KSI-3716 in gemcitabine-resistant bladder cancer 
Oncotarget  2014;5(2):326-337.
Intravesical instillation of chemotherapeutic agents is a well-established treatment strategy to decrease recurrence following transurethral resection in non-muscle invasive bladder cancer. Gemcitabine is a recently developed treatment option. However, the curative effects of gemcitabine are far from satisfactory due to de novo or acquired drug resistance. In a previous study, we reported that intravesical administration of the c-Myc inhibitor KSI-3716 suppresses tumor growth in an orthotopic bladder cancer model. Here, we explored whether KSI-3716 inhibits gemcitabine-resistant bladder cancer cell proliferation. As expected from the in vitro cytotoxicity of gemcitabine in several bladder cancer cell lines, gemcitabine effectively suppressed the growth of KU19-19 xenografts in nude mice, although all mice relapsed later. Long-term in vitro exposure to gemcitabine induced gemcitabine-specific resistance. Gemcitabine-resistant cells, termed KU19-19/GEM, formed xenograft tumors even in the presence of 2 mg/kg gemcitabine. Interestingly, KU19-19/GEM cells up-regulated c-Myc expression in the presence of the gemcitabine and resisted to the gemcitabine, however was suppressed by the KSI-3716. The sequential addition of gemcitabine and KSI-3716 inhibited gemcitabine-resistant cell proliferation to a great extent than each drug alone. These results suggest that sequential treatment with gemcitabine and KSI-3716 may be beneficial to bladder cancer patients.
PMCID: PMC3964210  PMID: 24504118
Bladder cancer; c-Myc; inhibitor; gemcitabine; gemcitabine resistance
4.  Measurement of antioxidant capacity using the biological antioxidant potential test and its role as a predictive marker of metabolic syndrome 
Oxidative stress increases the risk of cardiovascular complications of metabolic syndrome (MetS). This study was conducted to examine the difference in antioxidant capacity according to the presence of MetS, and to characterize the association between antioxidant capacity and MetS-related factors.
We used the biological antioxidant potential (BAP) test to estimate antioxidant capacity. The BAP test has recently been used as an indicator of antioxidant capacity. We measured BAP levels in 45 patients with MetS (mean age, 44.6 ± 1.1 years) and 47 age- and sex-matched controls (mean age, 42.7 ± 1.1 years). To evaluate the association between antioxidant capacity and MetS, adiponectin, high-sensitivity C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor-α, and homeostatic model assessment for insulin resistance (HOMA-IR), linear regression and logistic analyses were performed.
The mean BAP of the MetS group (1,937.3 ± 36.5 µmol/L) was significantly lower than that of the non-MetS group (2,101.7 ± 29.5 µmol/L). Also, the mean BAP was low in persons having low high density lipoprotein and high triglyceride. Reduced antioxidant capacity was significantly associated with adiponectin, HOMA-IR and hs-CRP after adjusting for age and sex. The odds ratios for MetS with BAP, log adiponectin, log HOMA-IR, and log hs-CRP were 0.63 (95% confidence interval [CI], 0.49 to 0.82), 0.22 (0.10 to 0.51), 14.24 (4.35 to 46.58), and 1.93 (1.36 to 2.75), respectively.
Persons with MetS showed reduced antioxidant capacity. We identified relationships between antioxidant capacity measured by BAP test and MetS, as well as MetS-related factors, such as insulin resistance, hs-CRP, and adiponectin.
PMCID: PMC3932393  PMID: 24574831
Metabolic syndrome; Oxidative stress; Adiponectin; Insulin
5.  Understanding the Role of Growth Factors in Modulating Stem Cell Tenogenesis 
PLoS ONE  2013;8(12):e83734.
Current treatments for tendon injuries often fail to fully restore joint biomechanics leading to the recurrence of symptoms, and thus resulting in a significant health problem with a relevant social impact worldwide. Cell-based approaches involving the use of stem cells might enable tailoring a successful tendon regeneration outcome. As growth factors (GFs) powerfully regulate the cell biological response, their exogenous addition can further stimulate stem cells into the tenogenic lineage, which might eventually depend on stem cells source. In the present study we investigate the tenogenic differentiation potential of human- amniotic fluid stem cells (hAFSCs) and adipose-derived stem cells (hASCs) with several GFs associated to tendon development and healing; namely, EGF, bFGF, PDGF-BB and TGF-β1. Stem cells response to biochemical stimuli was studied by screening of tendon-related genes (collagen type I, III, decorin, tenascin C and scleraxis) and proteins found in tendon extracellular matrix (ECM) (Collagen I, III, and Tenascin C). Despite the fact that GFs did not seem to influence the synthesis of tendon ECM proteins, EGF and bFGF influenced the expression of tendon-related genes in hAFSCs, while EGF and PDGF-BB stimulated the genetic expression in hASCs. Overall results on cellular alignment morphology, immunolocalization and PCR analysis indicated that both stem cell source can be biochemically induced towards tenogenic commitment, validating the potential of hASCs and hAFSCs for tendon regeneration strategies.
PMCID: PMC3875481  PMID: 24386267
6.  Genetic Variations of α-Methylacyl-CoA Racemase Are Associated with Sporadic Prostate Cancer Risk in Ethnically Homogenous Koreans 
BioMed Research International  2013;2013:394285.
Background. To assess if the variants of (R)-alpha-methyl-CoA racemase (AMACR) gene would be associated with the risk of sporadic prostate cancer in ethnically homogenous Koreans. Materials and Methods. We enrolled 194 patients with prostate cancer and 169 healthy controls. A total of 17 single nucleotide polymorphisms of the AMACR gene were selected. The distribution of each genotype and haplotype was analyzed and their association with the incidence of prostate cancer was evaluated. Further, we detected AMACR expression in tumor with immunohistochemistry and analyzed its association with genotype regarding prostate cancer risk. Results. AG or GG genotype of rs2278008 (E277K) tended to lower prostate cancer risk. The minor G allele was found to be a significant allele that decreased the risk of prostate cancer (adjusted OR, 0.57; 95% CI, 0.35–0.93, P value = 0.025). In patients expression AMACR, AG or GG genotype was also significant genotype in terms of prostate cancer risk (adjusted OR, 0.47; 95% CI, 0.26–0.87, P value = 0.017). Further, [GGCGG] haplotype consisted of five coding SNPs of rs2278008, rs34677, rs2287939, rs10941112, and rs3195676 which decreased the risk of prostate cancer (P value = 0.047). Conclusions. Genetic variations of AMACR are associated with the risk of sporadic prostate cancer that underwent radical prostatectomy in Koreans.
PMCID: PMC3870614  PMID: 24383053
7.  Development of an immunotherapeutic adenovirus targeting hormone-independent prostate cancer 
OncoTargets and therapy  2013;6:1635-1642.
To develop a targeting therapy for hormone-independent prostate cancer, we constructed and characterized conditionally replicating oncolytic adenovirus (Ad) equipped with mRFP (monomeric red fluorescence protein)/ttk (modified herpes simplex virus thymidine kinase). This construct was then further modified to express both mRFP/ttk and a soluble form of cytokine FLT3L (fms-related tyrosine kinase 3 ligand) simultaneously.
To construct the recombinant oncolytic adenovirus, E1a and E4 genes, which are necessary for adenovirus replication, were controlled by the prostate-specific enhancer sequence (PSES) targeting prostate cancer cells expressing prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA). Simultaneously, it expressed the mRFP/ttk fusion protein in order to be able to elicit the cytotoxic effect.
The Ad5/35PSES.mRFP/ttk chimeric recombinant adenovirus was generated successfully. When replication of Ad5/35PSES.mRFP/ttk was evaluated in prostate cancer cell lines under fluorescence microscopy, red fluorescence intensity increased more in LNCaP cells, suggesting that the mRFP/ttk fusion protein was folded functionally. In addition, the replication assay including wild-type adenovirus as a positive control showed that PSES-positive cells (LNCaP and CWR22rv) permitted virus replication but not PSES-negative cells (DU145 and PC3). Next, we evaluated the killing activity of this recombinant adenovirus. The Ad5/35PSES. mRFP/ttk killed LNCaP and CWR22rv more effectively. Unlike PSES-positive cells, DU145 and PC3 were resistant to killing by this recombinant adenovirus. Finally, in order to potentiate therapeutic efficacy, we developed a recombinant adenovirus expressing multiexogenous genes, mRFP/ttk and sFLT3L.
In the present study, a replication-competent adenovirus was successfully designed to replicate conditionally in PSA-positive and PSMA-positive prostate cancer cells. This recombinant adenovirus is equipped with the fusion protein of suicidal and red-fluorescence fusion protein together with sFLT3L. This construct would be expected to have potent antitumor effects and deserves more extensive investigation.
PMCID: PMC3829676  PMID: 24250230
adenovirus; prostate cancer; hormone-independent; suicide gene
8.  In situ tissue regeneration through host stem cell recruitment 
The field of tissue engineering has made steady progress in translating various tissue applications. Although the classical tissue engineering strategy, which involves the use of culture-expanded cells and scaffolds to produce a tissue construct for implantation, has been validated, this approach involves extensive cell expansion steps, requiring a lot of time and laborious effort before implantation. To bypass this ex vivo process, a new approach has been introduced. In situ tissue regeneration utilizes the body's own regenerating capacity by mobilizing host endogenous stem cells or tissue-specific progenitor cells to the site of injury. This approach relies on development of a target-specific biomaterial scaffolding system that can effectively control the host microenvironment and mobilize host stem/progenitor cells to target tissues. An appropriate microenvironment provided by implanted scaffolds would facilitate recruitment of host cells that can be guided to regenerating structural and functional tissues.
PMCID: PMC3849571  PMID: 24232256
bioactive molecules; biomaterials; in situ tissue regeneration; protein delivery system; stem cells; tissue engineering
9.  Upregulation of adenylate cyclase 3 (ADCY3) increases the tumorigenic potential of cells by activating the CREB pathway 
Oncotarget  2013;4(10):1791-1803.
Adenylate cyclase 3 (ADCY3) is a widely expressed membrane-associated protein in human tissues, which catalyzes the formation of cyclic adenosine-3′,5′-monophosphate (cAMP). However, our transcriptome analysis of gastric cancer tissue samples (NCBI GEO GSE30727) revealed that ADCY3 expression was specifically altered in cancer samples. Here we investigated the tumor-promoting effects of ADCY3 overexpression and confirmed a significant correlation between the upregulation of ADCY3 and Lauren's intestinal-type gastric cancers. ADCY3 overexpression increased cell migration, invasion, proliferation, and clonogenicity in HEK293 cells; conversely, silencing ADCY3 expression in SNU-216 cells reduced these phenotypes. Interestingly, ADCY3 overexpression increased both the mRNA level and activity of matrix metalloproteinase 2 (MMP2) and MMP9 by increasing the levels of cAMP and phosphorylated cAMP-responsive element-binding protein (CREB). Consistent with these findings, treatment with a protein kinase A (PKA) inhibitor decreased MMP2 and MMP9 expression levels in ADCY3-overexpressing cells. Knockdown of ADCY3 expression by stable shRNA in human gastric cancer cells suppressed tumor growth in a tumor xenograft model. Thus, ADCY3 overexpression may exert its tumor-promoting effects via the cAMP/PKA/CREB pathway. Additionally, bisulfite sequencing of the ADCY3 promoter region revealed that gene expression was reduced by hypermethylation of CpG sites, and increased by 5-Aza-2′-deoxycytidine (5-Aza-dC)-induced demethylation. Our study is the first to report an association of ADCY3 with gastric cancer as well as its tumorigenic potentials. In addition, we demonstrate that the expression of ADCY3 is regulated through an epigenetic mechanism. Further study on the mechanism of ADCY3 in tumorigenesis will provide the basis as a new molecular target of gastric cancer.
PMCID: PMC3858564  PMID: 24113161
gastric cancer; adenylate cyclase; tumorigenesis; cAMP/PKA/CREB pathway; promoter methylation
10.  The effect of controlled release of PDGF-BB from heparin-conjugated electrospun PCL/gelatin scaffolds on cellular bioactivity and infiltration 
Biomaterials  2012;33(28):6709-6720.
Heparin-conjugated electrospun poly(ε-caprolactone) (PCL)/gelatin scaffolds were developed to provide controlled release of platelet-derived growth factor-BB (PDGF-BB) and allow prolonged bioactivity of this molecule. A mixture of PCL and gelatin was electrospun into three different morphologies. Next, heparin molecules were conjugated to the reactive surface of the scaffolds. This heparin-conjugated scaffold allowed the immobilization of PDGF-BB via electrostatic interaction. In vitro PDGF-BB release profiles indicated that passive physical adsorption of PDGF-BB to non-heparinized scaffolds resulted in an initial burst release of PDGF-BB within 5 days, which then leveled off. However, electrostatic interaction between PDGF-BB and the heparin-conjugated scaffolds gave rise to a sustained release of PDGF-BB over the course of 20 days without an initial burst. Moreover, PDGF-BB that was strongly bound to the heparin-conjugated scaffolds enhanced smooth muscle cell (SMC) proliferation. In addition, scaffolds composed of 3.0 µm diameter fibers that were immobilized with PDGF-BB accelerated SMC infiltration into the scaffold when compared to scaffolds composed of smaller diameter fibers or scaffolds that did not release PDGF-BB. We concluded that the combination of the large pore structure in the scaffolds and the heparin-mediated delivery of PDGF-BB provided the most effective cellular interactions through synergistic physical and chemical cues.
PMCID: PMC3760265  PMID: 22770570
Scaffold; Heparin; Bioactivity; Protein delivery; Cellular infiltration; Vascular tissue engineering
11.  Survey of Potentially Inappropriate Prescription Using STOPP/START Criteria in Inha University Hospital 
Korean Journal of Family Medicine  2013;34(5):319-326.
Prescribing potentially harmful drugs and omitting essential drugs to older patients is a common problem because they take so many medications. In this study, our goal was to identify potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) using Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) and Screening Tool to Alert doctors to the Right Treatment (START) criteria to improve proper prescription and reduce improper prescription.
Enrolled in this study were 117 patients older than 65 years old who were hospitalized at Inha University Hospital in Incheon due to pneumonia from January 2012 to March 2012. Patient data, including medical histories, current diagnoses, current medications, and biochemical data were recorded from electronic records. STOPP and START were applied to their clinical datasheets.
STOPP criteria identified 24 patients who had 29 PIMs. Most potential inappropriate prescribing was of cardiovascular medications, followed by drugs whose primary effect is on the urogenital system and gastrointestinal system. START criteria identified 31 patients who had 46 PPOs. The cardiovascular system drugs comprised most of the PPOs. No PPOs were identified under the central nervous system criteria.
Given the current Korean medical system conditions and considering the many clinically important situations when prescribing drugs, STOPP/START criteria are not absolute criteria to prevent improper prescription, but sagacious usage of these standards can help physicians to prescribe properly in clinical practice.
PMCID: PMC3791339  PMID: 24106584
Aged Patients; STOPP/START Criteria; Potentially Inappropriate Medications; Potential Prescribing Omissions
12.  A Case of Gastric Inverted Hyperplastic Polyp Found with Gastritis Cystica Profunda and Early Gastric Cancer 
Clinical Endoscopy  2013;46(5):568-571.
A gastric inverted hyperplastic polyp is a rare type of gastric polyp and is characterized by downward growth of a variety of mucosal components into the submucosa. The polyp consists of columnar cells resembling foveolar epithelium and pyloric gland epithelium and can coexist with gastritis cystica profunda. Frequently, adenocarcinoma can coexist, but the relation is not clear. A 77-year-old male underwent endoscopic submucosal dissection due to early gastric cancer. A gastric inverted hyperplastic polyp was found in the removed specimen and gastric cystica profunda was also found. We report a case of gastric inverted hyperplastic polyp coexisting with gastric cystica profunda and gastric adenocarcinoma.
PMCID: PMC3797945  PMID: 24143322
Stomach; Inverted hyperplastic polyp; Gastritis cystica profunda; Adenocarcinoma
13.  Advanced Gastric Cancer Associated with Disseminated Intravascular Coagulation Successfully Treated with 5-fluorouracil and Oxaliplatin 
Journal of Gastric Cancer  2013;13(2):121-125.
Gastric cancer patients with acute disseminated intravascular coagulation experiences a rare but severe complication resulting in a dismal prognosis. We report a case of advanced gastric cancer complicated with disseminated intravascular coagulation with intractable tumor bleeding which was successfully treated with chemotherapy consisting of 5-fluorouracil and oxaliplatin. The patient was a 63-year-old man who complained of abdominal pain, melena, and dyspnea on 24 November 2010. We diagnosed stage IV gastric cancer complicated by disseminated intravascular coagulation. Gastric tumor bleeding was not controlled after procedures were repeated three times using gastrofiberscopy. With the patient's consent, we selected the 5-fluorouracil and oxaliplatin combination chemotherapy for treatment. After one cycle of 5-fluorouracil and oxaliplatin therapy, symptoms of bleeding improved and the disseminated intravascular coagulation process was successfully controlled. The primary tumor and multiple metastatic bone lesions were remarkably shrunken and metabolically remitted after eight cycles of chemotherapy. In spite of progression, systemic chemotherapy is effective in disease control; further, the patient gained the longest survival time among cases of gastric cancer with disseminated intravascular coagulation.
PMCID: PMC3705133  PMID: 23844328
Stomach neoplasms; Disseminated intravascular coagulation; Fluorouracil; Oxaliplatin
14.  Ginsenoside Rg2 Inhibits Lipopolysaccharide-Induced Adhesion Molecule Expression in Human Umbilical Vein Endothelial Cell 
Vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), P- and E-selectin play a pivotal role for initiation of atherosclerosis. Ginsenoside, a class of steroid glycosides, is abundant in Panax ginseng root, which has been used for prevention of illness in Korea. In this study, we investigated the mechanism(s) by which ginsenoside Rg2 may inhibit VCAM-1 and ICAM-1 expressions stimulated with lipopolysaccharide (LPS) in human umbilical vein endothelial cell (HUVEC). LPS increased VCAM-1 and ICAM-1 expression. Ginsenoside Rg2 prevented LPS-mediated increase of VCAM-1 and ICAM-1 expression. On the other hand, JSH, a nuclear factor kappa B (NF-κB) inhibitor, reduced both VCAM-1 and ICAM-1 expression stimulated with LPS. SB202190, inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), and wortmannin, phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, reduced LPS-mediated VCAM-1 but not ICAM-1 expression. PD98059, inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) did not affect VCAM-1 and ICAM-1 expression stimulated with LPS. SP600125, inhibitor of c-Jun N-terminal kinase (JNK), reduced LPS-mediated ICAM-1 but not VCAM-1 expression. LPS reduced IkappaBα (IκBα) expression, in a time-dependent manner within 1 hr. Ginsenoside Rg2 prevented the decrease of IκBα expression stimulated with LPS. Moreover, ginsenoside Rg2 reduced LPS-mediated THP-1 monocyte adhesion to HUVEC, in a concentration-dependent manner. These data provide a novel mechanism where the ginsenoside Rg2 may provide direct vascular benefits with inhibition of leukocyte adhesion into vascular wall thereby providing protection against vascular inflammatory disease.
PMCID: PMC3634090  PMID: 23626475
Endothelial cell; Ginsenoside Rg2; ICAM-1; VCAM-1
15.  Highly charged cyanine fluorophores for trafficking scaffold degradation 
Biodegradable scaffolds have been extensively used in the field of tissue engineering and regenerative medicine. However, noninvasive monitoring of in vivo scaffold degradation is still lacking. In order to develop a real-time trafficking technique, a series of meso-brominated near-infrared (NIR) fluorophores were synthesized and conjugated to biodegradable gelatin scaffolds. Since the pentamethine cyanine core is highly lipophilic, the side chain of each fluorophore was modified with either quaternary ammonium salts or sulfonate groups. The physicochemical properties such as lipophilicity and net charge of fluorophores played a key role in the fate of NIR-conjugated scaffolds in vivo after biodegradation. The positively charged fluorophore-conjugated scaffold fragments were found in salivary glands, lymph nodes, and most of the hepatobiliary excretion route. However, halogenated fluorophores intensively accumulated into lymph nodes and the liver. Interestingly, balanced-charged gelatin scaffolds were degraded into urine in a short period of time. These results demonstrate that the noninvasive optical imaging using NIR fluorophores can be useful for the translation of biodegradable scaffolds into the clinic.
PMCID: PMC3600611  PMID: 23353870
16.  Near-Infrared Fluorescence Imaging for Noninvasive Trafficking of Scaffold Degradation 
Scientific Reports  2013;3:1198.
Biodegradable scaffolds could revolutionize tissue engineering and regenerative medicine; however, in vivo matrix degradation and tissue ingrowth processes are not fully understood. Currently a large number of samples and animals are required to track biodegradation of implanted scaffolds, and such nonconsecutive single-time-point information from various batches result in inaccurate conclusions. To overcome this limitation, we developed functional biodegradable scaffolds by employing invisible near-infrared fluorescence and followed their degradation behaviors in vitro and in vivo. Using optical fluorescence imaging, the degradation could be quantified in real-time, while tissue ingrowth was tracked by measuring vascularization using magnetic resonance imaging in the same animal over a month. Moreover, we optimized the in vitro process of enzyme-based biodegradation to predict implanted scaffold behaviors in vivo, which was closely related to the site of inoculation. This combined multimodal imaging will benefit tissue engineers by saving time, reducing animal numbers, and offering more accurate conclusions.
PMCID: PMC3564022  PMID: 23386968
17.  Safety Evaluation of Stamp Type Digital Microneedle Devices in Hairless Mice 
Annals of Dermatology  2013;25(1):46-53.
Microneedles provide a minimally invasive means to transport molecules into the skin. A number of specific strategies have been employed to use microneedles for transdermal delivery.
The purpose of this study was to investigate the safety of two new digital microneedle devices (Digital Hand® and Digital Pro®; Bomtech Electronics Co., Ltd., Seoul, Korea) for the perforation of skin in skin-hairless-1 mice. This device replaces conventional needles and is designed specifically for intradermal delivery.
We used two newly developed digital microneedle devices to perforate the skin of skin-hairless-1 mice. We conducted a comparative study of the two digital microneedle devices and DTS® (Disk type-microneedle Therapy System; DTS lab., Seoul, Korea). To evaluate skin stability, we performed visual and dermatoscopic inspections, measurements of transepidermal water loss, and biopsies.
The two novel digital microneedle devices did not induce significant abnormalities of the skin on visual or dermatoscopic inspection, regardless of needle size (0.25~2.0 mm). No significant histopathological changes, such as inflammatory cell infiltration, desquamation of the stratum corneum, or disruption of the basal layer, were observed. The digital microneedle devices and microneedle therapy system produced similar results on measures of skin stability.
These two novel digital microneedle devices are safe transdermal drug delivery systems.
PMCID: PMC3582927  PMID: 23467706
Digital; Mesotherapy; Safety; Water loss
18.  Effect of the Number of Involved Spinal Cord Segments on Gait Function in Patients with Cervical Spondylotic Myelopathy 
Asian Spine Journal  2012;6(4):233-240.
Study Design
To determine the effect of severity of cervical spondylotic myelopathy (CSM) on gait parameters according to the number of involved spinal cord segments.
Overview of Literature
Although there are a large number of studies on CSM, almost all studies have focused on hand function and only a few studies have examined the gait function in patients with CSM.
Twenty-three patients with CSM underwent magnetic resonance imaging and gait analysis. The subjects were divided into 2 groups; group I consisted of 9 patients with a single-level stenotic lesion and group II comprised 14 patients with multi-level stenotic lesions. Gait parameters were compared between the 2 groups and the normal control group.
There was no significant difference in the Japanese Orthopaedic Association score between the 2 groups. Cadence, walking speed, stride length, and step length were decreased in group II compared to group I and normal control group. Peak ankle plantar flexion moments during the stance phase and peak knee flexion angle during the swing phase were decreased in group II. Peak ankle, knee, and hi p power generation during the stance phase were decreased in group II; in addition, the peak ankle power generation was decreased in group II than in the normal control group.
Patients with multi-level stenotic lesions had decreased gait ability compared to that in patients with a single-level stenotic lesion. The number of involved spinal cord segments can be one cause of gait deterioration in patients with CSM. Performing a gait analysis is useful for accurate evaluation of the patient.
PMCID: PMC3530697  PMID: 23275806
Cervical spondylotic myelopathy; Gait analysis; Multi-level
19.  Parathyroid Hormone 1-34(Teriparatide) Treatment in Pelvic Insufficiency Fractures - A Report of Two Cases - 
Journal of Bone Metabolism  2012;19(2):147-151.
As a result of aging population, the incidence of pelvic insufficiency fracture has been increasing. Pain-related immobility caused by pelvic insufficiency fractures may result in a serious dependency and high mortality with preexisting comorbidities. We present two cases of pelvic insufficiency fracture in elderly patients which had good clinical outcome by parathyroid hormone 1-34(teriparatide) treatment as well as a literature review.
PMCID: PMC3780923  PMID: 24524046
Osteoporosis; Parathyroid hormone; Pelvis; Pelvis (Pelvic) insufficiency fracture
20.  High K+-Induced Relaxation by Nitric Oxide in Human Gastric Fundus 
This study was designed to elucidate high K+-induced relaxation in the human gastric fundus. Circular smooth muscle from the human gastric fundus greater curvature showed stretch-dependent high K+ (50 mM)-induced contractions. However, longitudinal smooth muscle produced stretch-dependent high K+-induced relaxation. We investigated several relaxation mechanisms to understand the reason for the discrepancy. Protein kinase inhibitors such as KT 5823 (1 µM) and KT 5720 (1 µM) which block protein kinases (PKG and PKA) had no effect on high K+-induced relaxation. K+ channel blockers except 4-aminopyridine (4-AP), a voltage-dependent K+ channel (KV) blocker, did not affect high K+-induced relaxation. However, N(G)-nitro-L-arginine and 1H-(1,2,4)oxadiazolo (4,3-A)quinoxalin-1-one, an inhibitors of soluble guanylate cyclase (sGC) and 4-AP inhibited relaxation and reversed relaxation to contraction. High K+-induced relaxation of the human gastric fundus was observed only in the longitudinal muscles from the greater curvature. These data suggest that the longitudinal muscle of the human gastric fundus greater curvature produced high K+-induced relaxation that was activated by the nitric oxide/sGC pathway through a KV channel-dependent mechanism.
PMCID: PMC3484514  PMID: 23118553
Fundus; High K+; Human stomach; Longitudinal smooth muscle; Nitric oxide; Relaxation
21.  Inhibitory Effects of Ethanol Extracts from Nuruk on Oxidative Stress, Melanogenesis, and Photo-Aging 
Mycobiology  2012;40(2):117-123.
Nuruk contributes to the unique characteristics of Korean alcoholic beverages. In this study, the effects of nuruk extracts (NE) on anti-oxidant characters, melanogenesis, and anti-photoaging activity were investigated. NEs were obtained from the 70% ethanol extracts of six types of nuruk, which have been used in brewing of fermented alcohol beverages in Korea. First, various antioxidant characteristics were identified in terms of 2,2'-azino-bis(3-ethylbenzthiozoline-6-sulphonic acid) (ABTS) radical scavenging activity, superoxide dismutase (SOD) expression, and inhibition of xanthine oxidase activity. NE#4 exhibited potent ABTS radical scavenging activity (IC50 = 19.51 µg/mL). Compared with NE#4, relatively lower levels of activity were observed for NE#3 and NE#6, with IC50 values of 90.99 and 76.88 µg/mL, respectively. According to results of western blot analysis for determination of SOD expression in H2O2-treated HepG2 cells, NE#5 and NE#6 induced a dramatic increase in the expression ratio of SOD, compared to the group treated with H2O2 only. Activity of xanthine oxidase, which converts xanthine into uric acid, generating superoxide ions, was inhibited by NE#4 and NE#6 in a dose-dependent manner. NE#4 induced significant inhibition of mushroom tyrosinase activity. A reduction in cellular melanin contents of 80% was observed in B16F1 melanocytes treated with NE#5 and NE#6; these effects were similar to those of arbutin at 100 µM. In addition, gelatin zymography and reverse transcription-PCR analysis were performed for assessment of anti-photoaging activity of Nuruk. Treatment with NE#6 resulted in dramatically inhibited activities of matrix metalloproteinase (MMP)-2/-9, suppressed expression of MMP-1, and increased expression of type-1 procollagen. Results of gelatin zymography for NE#4 and NE#5 were similar, to a slightly lesser degree. These results suggest the potential of NE#4 and NE#6 as natural ingredients for use in functional foods and cosmetics.
PMCID: PMC3408301  PMID: 22870054
Anti-oxidant activity; Anti-photoaging; Melanogenesis; Nuruk
22.  Effects of L- and T-type Ca2+ channel blockers on spermatogenesis and steroidogenesis in the prepubertal mouse testis 
To assess the involvement of L-type and T-type Ca2+ channel blockers in inducing male infertility.
Prepubertal male mice were fed Ca2+ channel blockers nifedipine and ethosuximide for 20 days at dosages below maximum tolerated dose (MTD) and assayed for gross morphological changes in the testis such as body weight, testis size and weight. Sperm and Leydig cell counting were conducted concomitantly with serum testosterone level measurement by radioimmunoassay (RIA) and StAR protein mRNA measurement by reverse transcription and polymerase chain reaction (RT-PCR).
A chronic exposure to nifedipine or ethosuximide caused a significant reduction in body weight, testis size/weight and sperm production in a dose-dependent fashion associated with a spermatogenic arrest largely at the elongating spermatid stage. The number of Leydig cells, the serum testosterone level but not the luteinizing hormone level, and the content of StAR protein mRNA were also drastically reduced relative to the controls.
Both T- and L-type Ca2+ channel blockers play an adverse role in normal spermatogenesis and steroidogenesis partly by blocking postmeiotic germ cell maturation and/or by abrogating StAR protein expression, contributing to male sterility. Therefore, any therapeutic application of Ca2+ channel blockers must be used with caution due to its potential adverse side effects on male infertility.
PMCID: PMC3045488  PMID: 20859763
Ca2+ channel blockers; Spermatogenesis; Steroidogenesis; Mouse prepubertal testis
23.  Diffusion-Weighted Imaging of a Prostate Cancer Xenograft Model Seen on a 7 Tesla Animal MR Scanner: Comparison of ADC Values and Pathologic Findings 
Korean Journal of Radiology  2011;13(1):82-89.
To assess the relationship between apparent diffusion coefficient (ADC) values on diffusion-weighted magnetic resonance (MR) imaging and pathologic measures of a tumor using a prostate cancer xenograft model.
Materials and Methods
Eighteen athymic nude mice with 36 PC-3-induced tumors were sacrificed to obtain specimens immediately after MR imaging in order to compare the findings on MR images with those seen on pathological specimens. Using a high-field small-animal MR scanner, T1- and T2-weighted imaging and DW MR imaging was performed. Tumors were then processed for Hematoxylin and Eosin staining to evaluate tumor cellularity, intratumoral necrosis and immunostaining using antibodies directed against CD31 and vascular endothelial growth factor (VEGF) to determine the levels of microvessel density (MVD). Mean ADC values that were measured on the solid portion within each tumor were compared with tumor volume, cellularity, degree of necrosis, VEGF expression, and MVD in the corresponding section of the pathological specimen.
Mean ADC values of the solid portion within the PC-3-induced high-grade tumors were significantly correlated with the degree of intratumoral necrosis (r = 0.63, p < 0.0001) and MVD (r = -0.44, p = 0.008) on pathologic slides. The ADC values were not significantly correlated with tumor cellularity, VEGF expression, or tumor volume in high-grade prostate cancer tissues.
In the xenografted prostate cancer model, the ADC values of the solid portion of the tumors are significantly correlated with tumor necrosis and MVD of the pathologic specimens. The ADC values may be utilized as surrogate markers for the noninvasive assessment of tumor necrosis and MVD in high-grade prostate cancer.
PMCID: PMC3253407  PMID: 22247640
PC3; Prostate; Diffusion weighted imaging; MR; Necrosis; MVD
24.  Nitric Oxide-mediated Relaxation by High K+ in Human Gastric Longitudinal Smooth Muscle 
This study was designed to elucidate high-K+induced response of circular and longitudinal smooth muscle from human gastric corpus using isometric contraction. Contraction from circular and longitudinal muscle stripes of gastric corpus greater curvature and lesser curvature were compared. Circular smooth muscle from corpus greater curvature showed high K+ (50 mM)-induced tonic contraction. On the contrary, however, longitudinal smooth muscle strips showed high K+ (50 mM)-induced sustained relaxation. To find out the reason for the discrepancy we tested several relaxation mechanisms. Protein kinase blockers like KT5720, PKA inhibitor, and KT5823, PKG inhibitor, did not affect high K+-induced relaxation. K+ channel blockers like tetraethylammonium (TEA), apamin (APA), glibenclamide (Glib) and barium (Ba2+) also had no effect. However, N(G)-nitro-L-arginine (L-NNA) and 1H-(1,2,4) oxadiazolo (4,3-A) quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC) and 4-AP (4-aminopyridine), voltage-dependent K+ channel (KV) blocker, inhibited high K+-induced relaxation, hence reversing to tonic contraction. High K+-induced relaxation was observed in gastric corpus of human stomach, but only in the longitudinal muscles from greater curvature not lesser curvature. L-NNA, ODQ and KV channel blocker sensitive high K+-induced relaxation in longitudinal muscle of higher portion of corpus was also observed. These results suggest that longitudinal smooth muscle from greater curvature of gastric corpus produced high K+-induced relaxation which was activated by NO/sGC pathway and by KV channel dependent mechanism.
PMCID: PMC3282229  PMID: 22359479
Human stomach; Relaxation; Nitric oxide (NO); Longitudinal smooth muscle; High K+
25.  Short-term Clinical Outcomes Based on Risk Factors of Recurrence after Removing Common Bile Duct Stones with Endoscopic Papillary Large Balloon Dilatation 
Clinical Endoscopy  2011;44(2):123-128.
Recurrence is an important late complication of endotherapy of bile duct stones. Endoscopic papillary large balloon dilation (EPLBD) can be used as an alternative method of removing difficult bile duct stones. The aim of this study was to evaluate short term clinical outcomes after removing common bile duct (CBD) stones using EPLBD.
A retrospective review was performed based on the medical records of 141 patients who received EPLBD, with or without endoscopic sphincterotomy, between September 2008 and February 2010. Of these, 50 patients, were enrolled in the study. Clinical and endoscopic parameters were analyzed to identify risk factors for CBD stones recurrence.
Male:Female ratio was 22:28 (mean age, 67.4±14.4 years). Recurrence rate was 24.0% (12/50). Mean follow-up period was 10.8±4.5 months. Nineteen (38.0%) had a history of surgery and 20 (40.0%) were comorbid with periampullary diverticula. Mean diameters of the stones and CBD were 13.8±4.3 mm and 20.1±7.2 mm, respectively. In univariate analysis, large CBD stones (≥12 mm) and angulated CBD (angle ≤145°) were identified as the significant predictors of recurrence. In multivariate analysis, angulated CBD (angle ≤145°) was the significant independent risk factor for recurrence.
Close follow-up seems necessary in patients with angulated CBD (angle ≤145°).
PMCID: PMC3363062  PMID: 22741123
Endoscopic papillary large balloon dilatation; Common bile duct stones; Recurrence; Risk factors

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