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1.  Prolonged survival of islet allografts in mice treated with rosmarinic acid and anti-CD154 antibody 
Pancreatic islet transplantation can correct the abnormal glucose metabolism of Type 1 diabetes. Although immunosuppressants greatly reduce the acute rejection rate in transplant patients, the long-term side effects can be debilitating. Therefore, researchers are seeking to develop new immunosuppressive regimens that induce maximal levels of immunosuppression with minor side effects. Rosmarinic acid (Ros A) is a secondary metabolite of certain herbs and has multiple biological activities, including anti-inflammatory effects. Here, we have investigated whether treatment of mice with a combination of Ros A and anti-CD154 monoclonal antibody (MR1) improves islet allograft survival in a murine model. After transplantation, the mice were treated with either Ros A, MR1, or both (the "double" treatment). Allograft survival was prolonged in the double-treated animals compared to animals that received only Ros A or MR1. As is the case with the single-treated animals at 15 days after transplantation, the double-treated recipients did not display a significant decrease in the expression of cytokines or the population of activated T cells. Infiltrating CD3+ T cells were reduced in the MR1- or double therapy relative to control or RosA group. However, at the same time point, double-treated graft showed fewer apoptotic cells and increased expression of insulin and glucagons, compared to the single-treatment groups. Furthermore, long-term (> 150 days) allografts that were received with double therapy exhibited larger islet clusters and contained more insulin- and glucagon-positive cells, relative to the MR1-treated grafts. In conclusion, treatment with both Ros A and MR1 has a synergistic effect in murine islet allotransplantation.
doi:10.3858/emm.2008.40.1.1
PMCID: PMC2679315  PMID: 18305392
apoptosis; CD40 ligand; graft survival; immunosuppressive agents; islets of Langerhans transplantation; rosmarinic acid
2.  Comparing Self-Selected Speed Walking of the Elderly With Self-Selected Slow, Moderate, and Fast Speed Walking of Young Adults 
Annals of Rehabilitation Medicine  2014;38(1):101-108.
Objective
To find the characteristics of elderly gait, we compared the elderly walking at a moderate speed with the young adult walking at a slow, moderate, and fast speed.
Methods
3D gait analysis was performed on 15 elderly and 15 young adults. Temporo-spatial, kinematic, and kinetic parameters were obtained. Self-selected moderate speed of the elderly walking was compared with self-selected varying speed of the young adults walking.
Results
The elderly walked at slower speeds and had shorter step length, but showed similar cadences compared to the young adults. These results remained identical even after the normalization with height. The kinematic and the kinetic graph patterns did not show specific differences between the elderly and the young subjects. Ankle plantarflexion (APF) motion was prominently decreased in the elderly subjects. Hip flexion (HF) motion remained within similar range for the young adults'. HF moment and power were similar with the young adults', but APF power and hip extension power were decreased in the elderly subjects'.
Conclusion
A decreased APF motion and power were thought to be specific findings in the elderly walking. The preservation of HF motion and power could be considered a compensation mechanism or a modified neuromuscular pattern in the elderly. The characteristics of the elderly walking should be taken into account when planning rehabilitation strategies of elderly gait training and for future studies on the elderly population.
doi:10.5535/arm.2014.38.1.101
PMCID: PMC3953351  PMID: 24639933
Aging; Gait
3.  Role of Repeated Endoscopic Ultrasound-Guided Fine Needle Aspiration for Inconclusive Initial Cytology Result 
Clinical Endoscopy  2013;46(5):540-542.
For tissue diagnosis of suspected pancreatic cancer, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the procedure of choice with high safety and accuracy profiles. However, about 10% of cytologic findings of EUS-FNA are inconclusive. In that situation, careful observation, surgical exploration, or alternative diagnostic tools such as bile duct brushing with endoscopic retrograde cholangiopancreatography or computed tomography-guided biopsy can be considered. However, some concerns and/or risks of these options render repeat EUS-FNA a reasonable choice. Repeated EUS-FNA may impose substantial clinical impact with low risk.
doi:10.5946/ce.2013.46.5.540
PMCID: PMC3797941  PMID: 24143318
Endosonography; Endoscopic ultrasound-guided fine needle aspiration; Pancreatic neoplasms
4.  Diagnosis of Subepithelial Lesion: Still "Tissue Is the Issue" 
Clinical Endoscopy  2013;46(4):313-314.
doi:10.5946/ce.2013.46.4.313
PMCID: PMC3746133  PMID: 23964325
5.  Endoscopic Ultrasound, Where Are We Now in 2012? 
Clinical Endoscopy  2012;45(3):321-323.
Topics related with endoscopic ultrasound (EUS) made up considerable portion among many invited lectures presented in International Digestive Endoscopy Network 2012 meeting. While the scientific programs were divided into the fields of upper gastrointestinal (UGI), lower gastrointestinal, and pancreato-biliary (PB) categories, UGI and PB parts mainly dealt with EUS related issues. EUS diagnosis in subepithelial lesions, estimation of the invasion depth of early gastrointestinal cancers with EUS, and usefulness of EUS in esophageal varices were discussed in UGI sessions. In the PB part, pancreatic cystic lesions, EUS-guided biliopancreatic drainage, EUS-guided tissue acquisition, and improvement of diagnostic yield in indeterminate biliary lesions by using intraductal ultrasound were discussed. Advanced techniques such as contrast-enhanced EUS, EUS elastography and forward-viewing echoendoscopy were also discussed. In this paper, I focused mainly on topics of UGI and briefly mentioned about advanced EUS techniques since more EUS related papers by other invited speakers were presented afterwards.
doi:10.5946/ce.2012.45.3.321
PMCID: PMC3429761  PMID: 22977827
Endosonography; Early gastrointestinal cancer; Subepithelial lesion; Technique
6.  Introduction; Value of Endoscopic Ultrasound-Guided Fine Needle Aspiration 
Clinical Endoscopy  2012;45(2):115-116.
Introduction of endoscopic ultrasound (EUS) to medical practice has brought a huge change in diagnostic algorithm of many gastrointestinal diseases. Addition of EUS-guided fine needle aspiration (FNA) upgraded diagnostic power of EUS. In this focused review series, value of EUS-FNA in the diagnosis of various diseases and tips for getting the best results with EUS-FNA are described by four invited authors including myself. First, Dr. Jeong Seop Moon discussed about EUS-FNA in submucosal lesion. He also touched on basic techniques and needles of EUS-FNA in his article. Next, I focused on additional value of EUS-FNA in the staging of hollow viscus cancer to optimize the treatment strategy. World's well-known endosonographer, Dr. Robert H. Hawes kindly presented his profound thoughts on EUS-FNA in pancreatic cystic lesions. Dr. Jayapal Ramesh and Dr. Shyam Varadarajulu shared their valuable tips for getting the best results when using EUS-FNA. Nobody doubts now EUS-FNA is an indispensable procedure in gastrointestinal endoscopy. Therefore, this focused review series will provide the readers with the concentrated knowledge of "What should we know about EUS-FNA."
doi:10.5946/ce.2012.45.2.115
PMCID: PMC3401612  PMID: 22866249
Endosonography; Fine-needle biopsy; Aspiration; Technique
7.  Endoscopic Ultrasound-Guided Fine Needle Aspiration in Hollow Viscus Cancer 
Clinical Endoscopy  2012;45(2):124-127.
Accurate cancer staging is essential in patients with hollow viscus malignancy to decide therapeutic modalities. Endoscopic ultrasound (EUS) is considered as the best modality for local staging of hollow viscus cancer. EUS-guided fine needle aspiration (FNA) is a minimally invasive and effective sampling method. EUS-FNA should be applied when positive diagnosis of malignancy can possibly change the choice of therapeutic options. EUS in conjunction with EUS-FNA can optimize stage-directed therapy which is helpful in selecting minimally invasive treatment option including endoscopic treatment and avoiding unnecessary surgery in advanced cases.
doi:10.5946/ce.2012.45.2.124
PMCID: PMC3401614  PMID: 22866251
Endosonography; Fine needle biopsy; Staging; Neoplasms
8.  Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish 
Neuro-Oncology  2013;15(3):290-304.
Background
Ongoing characterization of glioma has revealed that Akt signaling plays a crucial role in gliomagenesis. In mouse models, however, Akt alone was not sufficient to induce glioma.
Methods
We established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1G12V (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.
Results
Transgene expressions were spatiotemporally restricted without any developmental abnormality of embryos and persisted at cerebellum and medulla in adult zebrafish. DAAkt1 alone induced glioma (with visible bumps at the head), with incidences of 36.6% and 49% at 6 and 9 months, respectively. Histologically, gliomas showed various histologic grades, increased proliferation, and frequent invasion into the fourth ventricle. Preferential location of small tumors at periventricular area and coexpression of Her4 suggested that tumors originated from Ptf1a- and Her4-positive progenitor cells at ventricular zone. Gliomagenesis was principally mediated by activation of survival pathway through upregulation of survivin genes. Although DARac1 alone was incapable of gliomagenesis, when coexpressed with DAAkt1, gliomagenesis was accelerated, showing higher tumor incidences (62.0% and 73.3% at 6 and 9 months, respectively), advanced histologic grade, invasiveness, and shortened survival. DARac1 upregulated survivin2, cyclin D1, β-catenin, and snail1a but downregulated E-cadherin, indicating that DARac1 promotes gliomagenesis by enhancing proliferation, survival, and epithelial-to-mesenchymal transition. On pharmacologic tests, only Akt1/2 inhibitor effectively suppressed gliomagenesis, inhibited cellular proliferation, and induced apoptosis in established gliomas.
Conclusions
The zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.
doi:10.1093/neuonc/nos387
PMCID: PMC3578497  PMID: 23325864
Akt1; epithelial-mesenchymal transition; glioma; Rac1; transgenic zebrafish
9.  Assessment of Perfusion Pattern and Extent of Perfusion Defect on Dual-Energy CT Angiography: Correlations between the Causes of Pulmonary Hypertension and Vascular Parameters 
Korean Journal of Radiology  2014;15(2):286-294.
Objective
To assess perfusion patterns on a dual-energy pulmonary CT angiography (DECTA) of pulmonary hypertension (PHT) with variable causes and to assess whether the extent of perfusion defect can be used in the severity assessment of PHT.
Materials and Methods
Between March 2007 and February 2011, DECTA scans of 62 consecutive patients (24 men, 38 women; mean age, 58.5 ± 17.3 [standard deviation] years; range, 19-87 years) with PHT were retrospectively included with following inclusion criteria; 1) absence of acute pulmonary thromboembolism, 2) maximal velocity of tricuspid regurgitation jet (TR Vmax) above 3 m/s on echocardiography performed within one week of the DECTA study. Perfusion patterns of iodine map were divided into normal (NL), diffuse heterogeneously decreased (DH), multifocal geographic and multiple peripheral wedging patterns. The extent of perfusion defects (PD), the diameter of main pulmonary artery (MPA) and the ratio of ascending aorta diameter/MPA (aortopulmonary ratio, APR) were measured. Pearson correlation analysis was performed between TR Vmax on echocardiography and CT imaging parameters.
Results
Common perfusion patterns of primary PHT were DH (n = 15) and NL (n = 12). The perfusion patterns of secondary PHT were variable. On the correlation analysis, in primary PHT, TR Vmax significantly correlated with PD, MPA and APR (r = 0.52, r = 0.40, r = -0.50, respectively, all p < 0.05). In secondary PHT, TR Vmax significantly correlated with PD and MPA (r = 0.38, r = 0.53, respectively, all p < 0.05).
Conclusion
Different perfusion patterns are observed on DECTA of PHT according to the causes. PD and MPA are significantly correlated with the TR Vmax.
doi:10.3348/kjr.2014.15.2.286
PMCID: PMC3955797  PMID: 24642727
Pulmonary hypertension; Dual-energy CT; Pulmonary perfusion
10.  Endoscopic Experience Improves Interobserver Agreement in the Grading of Esophagitis by Los Angeles Classification: Conventional Endoscopy and Optimal Band Image System 
Gut and Liver  2013;8(2):154-159.
Background/Aims
Interobserver variation by experience was documented for the diagnosis of esophagitis using the Los Angeles classification. The aim of this study was to evaluate whether interobserver agreement can be improved by higher levels of endoscopic experience in the diagnosis of erosive esophagitis.
Methods
Endoscopic images of 51 patients with gastroesophageal reflux disease (GERD) symptoms were obtained with conventional endoscopy and optimal band imaging (OBI). Endoscopists were divided into an expert group (16 gastroenterologic endoscopic specialists guaranteed by the Korean Society of Gastrointestinal Endoscopy) and a trainee group (individuals with fellowships, first year of specialty training in gastroenterology). All endoscopists had no or minimal experience with OBI. GERD was diagnosed using the Los Angeles classification with or without OBI.
Results
The mean weighted paired κ statistics for interobserver agreement in grading erosive esophagitis by conventional endoscopy in the expert group was better than that in the trainee group (0.51 vs 0.42, p<0.05). The mean weighted paired k statistics in the expert group and in the trainee group based on conventional endoscopy with OBI did not differ (0.42, 0.42).
Conclusions
Interobserver agreement in the expert group using conventional endoscopy was better than that in the trainee group. Endoscopic experience can improve the interobserver agreement in the grading of esophagitis using the Los Angeles classification.
doi:10.5009/gnl.2014.8.2.154
PMCID: PMC3964265  PMID: 24672656
Gastroesophageal reflux; Agreement; Experience
11.  Inhibition of mTORC1 induces loss of E-cadherin through AKT/GSK-3β signaling-mediated upregulation of E-cadherin repressor complexes in non-small cell lung cancer cells 
Respiratory Research  2014;15(1):26.
Background
mTOR, which can form mTOR Complex 1 (mTORC1) or mTOR Complex 2 (mTORC2) depending on its binding partners, is frequently deregulated in the pulmonary neoplastic conditions and interstitial lung diseases of the patients treated with rapalogs. In this study, we investigated the relationship between mTOR signaling and epithelial mesenchymal transition (EMT) by dissecting mTOR pathways.
Methods
Components of mTOR signaling pathway were silenced by shRNA in a panel of non-small cell lung cancer cell lines and protein expression of epithelial and mesenchymal markers were evaluated by immunoblotting and immunocytochemistry. mRNA level of the E-cadherin repressor complexes were evaluated by qRT-PCR.
Results
IGF-1 treatment decreased expression of the E-cadherin and rapamycin increased its expression, suggesting hyperactivation of mTOR signaling relates to the loss of E-cadherin. Genetic ablation of rapamycin-insensitive companion of mTOR (Rictor), a component of mTORC2, did not influence E-cadherin expression, whereas genetic ablation of regulatory-associated protein of mTOR (Raptor), a component of mTORC1, led to a decrease in E-cadherin expression at the mRNA level. Increased phosphorylation of AKT at Ser473 and GSK-3β at Ser9 were observed in the Raptor-silenced NSCLC cells. Of the E-cadherin repressor complexes tested, Snail, Zeb2, and Twist1 mRNAs were elevated in raptor-silenced A549 cells, and Zeb2 and Twist1 mRNAs were elevated in Raptor-silenced H2009 cells. These findings were recapitulated by treatment with the GSK-3β inhibitor, LiCl. Raptor knockdown A549 cells showed increased expression of N-cadherin and vimentin with mesenchymal phenotypic changes.
Conclusions
In conclusion, selective inhibition of mTORC1 leads to hyperactivation of the AKT/GSK-3β pathway, inducing E-cadherin repressor complexes and EMT. These findings imply the existence of a feedback inhibition loop of mTORC1 onto mTORC2 that plays a role in the homeostasis of E-cadherin expression and EMT, requiring caution in the clinical use of rapalog and selective mTORC1 inhibitors.
doi:10.1186/1465-9921-15-26
PMCID: PMC3941688  PMID: 24571487
mTOR; mTORC1; mTORC2; E-Cadherin repressor complexes; Raptor; Rictor; EMT
12.  Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells 
Paclitaxel (Taxol) resistance remains a major obstacle for the successful treatment of ovarian cancer. MicroRNAs (miRNAs) have oncogenic and tumor suppressor activity and are associated with poor prognosis phenotypes. miRNA screenings for this drug resistance are needed to estimate the prognosis of the disease and find better drug targets. miRNAs that were differentially expressed in Taxol-resistant ovarian cancer cells, compared with Taxol-sensitive cells, were screened by Illumina Human MicroRNA Expression BeadChips. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to identify target genes of selected miRNAs. Kaplan–Meier survival analysis was applied to identify dysregulated miRNAs in ovarian cancer patients using data from The Cancer Genome Atlas. A total of 82 miRNAs were identified in ovarian carcinoma cells compared to normal ovarian cells. miR-141, miR-106a, miR-200c, miR-96, and miR-378 were overexpressed, and miR-411, miR-432, miR-494, miR-409-3p, and miR-655 were underexpressed in ovarian cancer cells. Seventeen miRNAs were overexpressed in Taxol-resistant cells, including miR-663, miR-622, and HS_188. Underexpressed miRNAs in Taxol-sensitive cells included miR-497, miR-187, miR-195, and miR-107. We further showed miR-663 and miR-622 as significant prognosis markers of the chemo-resistant patient group. In particular, the downregulation of the two miRNAs was associated with better survival, perhaps increasing the sensitivity of cancer cells to Taxol. In the chemo-sensitive patient group, only miR-647 could be a prognosis marker. These miRNAs inhibit several interacting genes of p53 networks, especially in TUOS-3 and TUOS-4, and showed cell line-specific inhibition effects. Taken together, the data indicate that the three miRNAs are closely associated with Taxol resistance and potentially better prognosis factors. Our results suggest that these miRNAs were successfully and reliably identified and would be used in the development of miRNA therapies in treating ovarian cancer.
doi:10.2147/DDDT.S51969
PMCID: PMC3938445  PMID: 24591819
microRNA; ovarian cancer; Taxol resistance; Kaplan–Meier survival analysis
13.  A Case of Gossypiboma Masquerading as a Gastrointestinal Stromal Tumor 
Clinical Endoscopy  2011;44(1):51-54.
Gossypiboma refers to a mass resulting from a retained gauze pad accidentally left within the body after surgery. Although the clinical features are diverse, it is often found incidentally as a mass having an internal cystic change and adhesion to adjacent organs. Abdominal computed tomography (CT) is helpful, yet the initial diagnosis can be misleading in cases with atypical findings. We report a case of gossypiboma in a 78-year-old woman that we suspected was a gastrointestinal stromal tumor according to abdominal CT and endoscopic ultrasound, yet was diagnosed as a gossypiboma postoperatively.
doi:10.5946/ce.2011.44.1.51
PMCID: PMC3363045  PMID: 22741113
Gossypiboma; Endoscopic ultrasonography; Gastrointestinal stromal tumor
14.  A Case of Occupational Hypersensitivity Pneumonitis Associated with Trichloroethylene 
Trichloroethylene (TCE) is a toxic chemical commonly used as a degreasing agent, and it is usually found in a colorless or blue liquid form. TCE has a sweet, chloroform-like odor, and this volatile chlorinated organic chemical can cause toxic hepatitis, neurophysiological disorders, skin disorders, and hypersensitivity syndromes. However, the hypersensitivity pneumonitis (HP) attributed to TCE has rarely been reported. We hereby describe a case of HP associated with TCE in a 29-year-old man who was employed as a lead welder at a computer repair center. He was installing the capacitors on computer chip boards and had been wiped down with TCE. He was admitted to our hospital with complaints of dry coughs, night sweats, and weight losses for the past two months. HP due to TCE exposure was being suspected due to his occupational history, and the results of a video-associated thoracoscopic biopsy confirmed the suspicions. Symptoms have resolved after the steroid pulse therapy and his occupational change. TCE should be taken into consideration as a potential trigger of HP. Early recognition and avoidance of the TCE exposure in the future is important for the treatment of TCE induced HP.
doi:10.4046/trd.2014.76.2.75
PMCID: PMC3948855  PMID: 24624216
Alveolitis, Extrinsic Allergic; Trichloroethylene; Occupational Exposure; Lung Diseases
15.  Sub-Toxic Dose of Apigenin Sensitizes HepG2 Cells to TRAIL through ERK-Dependent Up-Regulation of TRAIL Receptor DR5 
Molecules and Cells  2012;35(1):32-40.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a promising candidate for anticancer therapy due to its selective toxicity to cancer cells. Nevertheless, because of TRAIL resistance in some cancer cells, combined treatment with sensitizing agents is required to enhance the anticancer potential of TRAIL. In this study, we investigated the underlying mechanism of apigenin-induced sensitization of HepG2 cells to TRAIL-induced cell death. Synergistic induction of apoptosis by combination was confirmed by examining the typical morphology changes of apoptosis, PARP-cleavage, and activation of effector caspases. Z-VAD-fmk, a pan-caspase inhibitor, inhibited the enhanced cell death by combined treatment of apigenin and TRAIL, demonstrating that a caspase-dependent pathway is involved in apigenin/TRAIL-mediated apoptosis. In addition, we found that apigenin/TRAIL co-treatment up-regulates DR5 cell surface expression. The synergistic induction of cell death by the apigenin/TRAIL combination was significantly attenuated by DR5 blocking chimera antibody. Next, using pharmacological inhibitors, we found that ERK activation is involved in the induction of DR5 expression. Inhibition of ERK1/2 by U0126 significantly decreased the apigenin/TRAIL-induced DR5 expression and apoptosis. Taken together, our results indicate that apigenin can enhance the apoptotic effect of TRAIL via ERK-induced up-regulation of DR5.
doi:10.1007/s10059-013-2175-2
PMCID: PMC3887848  PMID: 23224239
apigenin; apoptosis; DR5; ERK; HepG2; TRAIL
16.  Chicken soup for teaching and learning ESD 
Endoscopic submucosal dissection (ESD) is becoming a popular procedure for the diagnosis and treatment of superficial mucosal lesions, and has the advantage of en bloc resection which yields a higher complete resection and remission rate compared to endoscopic mucosal resection (EMR). However, the learning process of this advanced endoscopic procedure requires a lengthy training period and considerable experience to be proficient. A well framed training protocol which is safe, effective, easily reproducible and cost-effective is desirable to teach ESD. In addition, the training course may need to be tailored around settings such as ethnicity, culture, workload, and disease incidence. In Asian countries with a large volume of early gastric lesions which need endoscopic treatment, endoscopists would be able to learn ESD expanding their skills from EMR to ESD under the supervision of experts. Whereas, in Western countries due to the low incidence of superficial gastric tumors, trials have utilized simulator models to improve learning. In Korea, the Korean Society of Gastrointestinal Endoscopy (KSGE) is playing an important role in training many gastroenterologists who have shown an interest in performing ESD by providing an annual live demonstration and a nationwide tutoring program. The purpose of this article is to introduce our ESD tutoring experience, review the published papers related to this topic, and propose several suggestions for future directions in teaching and learning ESD.
doi:10.3748/wjg.v17.i21.2618
PMCID: PMC3110923  PMID: 21677829
Endoscopic submucosal dissection; Learning; Teaching
17.  Preservation of Tetherin and CD4 Counter-Activities in Circulating Vpu Alleles despite Extensive Sequence Variation within HIV-1 Infected Individuals 
PLoS Pathogens  2014;10(1):e1003895.
The HIV-1 Vpu protein is expressed from a bi-cistronic message late in the viral life cycle. It functions during viral assembly to maximise infectious virus release by targeting CD4 for proteosomal degradation and counteracting the antiviral protein tetherin (BST2/CD317). Single genome analysis of vpu repertoires throughout infection in 14 individuals infected with HIV-1 clade B revealed extensive amino acid diversity of the Vpu protein. For the most part, this variation in Vpu increases over the course of infection and is associated with predicted epitopes of the individual's MHC class I haplotype, suggesting CD8+ T cell pressure is the major driver of Vpu sequence diversity within the host. Despite this variability, the Vpu functions of targeting CD4 and counteracting both physical virus restriction and NF-κB activation by tetherin are rigorously maintained throughout HIV-1 infection. Only a minority of circulating alleles bear lesions in either of these activities at any given time, suggesting functional Vpu mutants are heavily selected against even at later stages of infection. Comparison of Vpu proteins defective for one or several functions reveals novel determinants of CD4 downregulation, counteraction of tetherin restriction, and inhibition of NF-κB signalling. These data affirm the importance of Vpu functions for in vivo persistence of HIV-1 within infected individuals, not simply for transmission, and highlight its potential as a target for antiviral therapy.
Author Summary
The accessory protein Vpu, encoded by HIV-1, performs at least two major roles in the virus life cycle, namely the degradation of newly synthesized CD4 molecules and the counteraction of a host antiviral protein, tetherin. These activities promote the release of infectious viruses from host cells, and recent evidence suggests that Vpu function has been crucial for the cross-species transmission of HIV-1 from chimpanzees, and its subsequent pandemic spread in humans. Here we studied the functional variation in Vpu in infected individuals. We found that the Vpu amino acid sequence can be highly variable within an individual, and that this variation is likely to result from host immune responses targeting antigens derived from Vpu. However, despite this variation, Vpu's major functions are preserved, with only a minority of circulating alleles showing defects throughout the course of infection. These data suggest that defective Vpu proteins are selected against within the infected individual, implying that Vpu functions are critical for HIV-1 replication throughout natural infection, not simply at transmission. Therefore Vpu may represent a novel target for antiviral therapy to augment current treatment strategies for HIV/AIDS.
doi:10.1371/journal.ppat.1003895
PMCID: PMC3900648  PMID: 24465210
18.  Recurrent Insulin Autoimmune Syndrome Caused by α-Lipoic Acid in Type 2 Diabetes 
Endocrinology and Metabolism  2013;28(4):326-330.
Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia caused by insulin autoantibodies in the absence of exogenous insulin administration. Some drugs containing sulfhydryl compounds are known to initiate the onset of IAS. A 67-year-old female who had diabetes for 5 years visited the outpatient clinic at our institution due to diabetic peripheral polyneuropathy. She was prescribed α-lipoic acid (ALA), which contains two sulfur atoms. Two weeks later, she complained of recurrent hypoglycemic symptoms. We detected a high level of insulin and high titers of insulin autoantibodies. Her human leukocyte antigen (HLA) genotype included the DRB1*0406 allele, which indicates a high level of susceptibility to IAS. She was treated with prednisolone. After this episode, she experienced two more hypoglycemic events after taking ALA for diabetic neuropathy in other hospitals. As ALA can be used to treat diabetic peripheral polyneuropathy, physician discretion is advised based on the possibility of IAS due to ALA in diabetic patients.
doi:10.3803/EnM.2013.28.4.326
PMCID: PMC3871037  PMID: 24396698
Alpha-lipoic acid; HLA-DRB1*0406 antigen; Insulin antibodies; Insulin autoimmune syndrome
19.  Post-Death Cloning of Endangered Jeju Black Cattle (Korean Native Cattle): Fertility and Serum Chemistry in a Cloned Bull and Cow and Their Offspring 
Abstract
To preserve Jeju black cattle (JBC; endangered native Korean cattle), a pair of cattle, namely a post-death cloned JBC bull and cow, were produced by somatic cell nuclear transfer (SCNT) in a previous study. In the present study, we examined the in vitro fertilization and reproductive potentials of these post-death cloned animals. Sperm motility, in vitro fertilization and developmental capacity were examined in a post-death cloned bull (Heuk Oll Dolee) and an extinct nuclear donor bull (BK94-13). We assessed reproductive ability in another post-death cloned cow (Heuk Woo Sunee) using cloned sperm for artificial insemination (AI). There were no differences in sperm motility or developmental potential of in vitro fertilized embryos between the post-death cloned bull and its extinct nuclear donor bull; however, the embryo development ratio was slightly higher in the cloned sperm group than in the nuclear donor sperm group. After one attempt at AI, the post-death cloned JBC cow became pregnant, and gestation proceeded normally until day 287. From this post-death cloned sire and dam, a JBC male calf (Heuk Woo Dolee) was delivered naturally (weight, 25 kg). The genetic paternity/maternity of the cloned JBC bull and cow with regard to their offspring was confirmed using International Society for Animal Genetics standard microsatellite markers. Presently, Heuk Woo Dolee is 5 months of age and growing normally. In addition, there were no significant differences in blood chemistry among the post-death cloned JBC bull, the cow, their offspring and cattle bred by AI. This is the first report showing that a pair of cattle, namely, a post-death cloned JBC bull and cow, had normal fertility. Therefore, SCNT can be used effectively to increase the population of endangered JBC.
doi:10.1262/jrd.2013-047
PMCID: PMC3934153  PMID: 23955237
Fertility; Jeju black cattle; Offspring; Post-death cloning; SCNT
20.  Late Complications and Stone Recurrence Rates after Bile Duct Stone Removal by Endoscopic Sphincterotomy and Large Balloon Dilation are Similar to Those after Endoscopic Sphincterotomy Alone 
Clinical Endoscopy  2013;46(6):637-642.
Background/Aims
Between endoscopic sphincterotomy (ES) alone and combined endoscopic sphincterotomy and large balloon dilation (ES-LBD) groups, efficacy and long-term complications, difference in biliary stone recurrence rate, and risk factors of stone recurrence were compared.
Methods
Medical records of 222 patients who underwent ERCP for biliary stone removal were retrospectively reviewed. Patients with dilated CBD ≥11 mm and follow-up longer than 6 months were included.
Results
There were 101 patients in ES-LBD group and 121 patients in ES group. Mean follow-up duration was 25.0 (6-48) months and 13.0 (6-43) months, respectively (p=0.001). There was no difference in number of ERCP sessions, brown pigment stones, angle between mid and distal common bile duct (CBD angle) <135°, and lithotripsy rate. Complete retrieval success rate was excellent in both groups (100% vs. 99%). Early complication rate of ES-LBD and ES alone group was 4 and 4.1%, respectively (p=1.000). One patient in ES-LBD group died from delayed bleeding. Late complication rate was 5.9 and 3.3%, respectively (p=1.000). Stone recurrence rate was 6.9% and 5.8%, respectively (p=0.984). The only Independent risk factor of stone recurrence was presence of periampullary diverticulum.
Conclusions
Late complication and stone recurrence rates were similar between ES-LBD and ES alone groups.
doi:10.5946/ce.2013.46.6.637
PMCID: PMC3856265  PMID: 24340257
Common bile duct stone; Sphincterotomy, endoscopic; Endoscopic large balloon dilation; Stone recurrence; Late complication
21.  Neuronal cell differentiation of mesenchymal stem cells originating from canine amniotic fluid 
Human Cell  2013;27:51-58.
The amniotic fluid contains mesenchymal stem cells (MSCs) and can be readily available for tissue engineering. Regenerative treatments such as tissue engineering, cell therapy, and transplantation show potential in clinical trials of degenerative diseases. Disease presentation and clinical responses in the Canis familiaris not only are physiologically similar to human compared with other traditional mammalian models but is also a suitable model for human diseases. The aim of this study was to investigate whether canine amniotic-fluid-derived mesenchymal stem cells (cAF-MSCs) can differentiate into neural precursor cells in vitro when exposed to neural induction reagent. During neural differentiation, cAF-MSCs progressively acquire neuron-like morphology. Messenger RNA (mRNA) expression levels of neural-specific genes, such as NEFL, NSE, and TUBB3 (βIII-tubulin) dramatically increased in the differentiated cAF-MSCs after induction. In addition, protein expression levels of nestin, βIII-tubulin, and tyrosine hydroxylase remarkably increased in differentiated cAF-MSCs. This study demonstrates that cAF-MSCs have great potential for neural precursor differentiation in vitro. Therefore, amniotic fluid may be a suitable alternative source of stem cells and can be applied to cell therapy in neurodegenerative diseases.
doi:10.1007/s13577-013-0080-9
PMCID: PMC3964299  PMID: 24166061
Amniotic fluids; Mesenchymal stem cells; Degenerative diseases; Canine; Neural precursor; Neurodegenerative diseases
23.  Correlation of leptin, neuropeptide Y and amylin in childhood obesity 
doi:10.1186/1687-9856-2013-S1-P97
PMCID: PMC3890973
Leptin; Neuropeptide Y; Amylin; Childhood obesity
24.  Plasminogen Activator Inhibitor Type 1 (PAI-1) A15T Gene Polymorphism Is Associated with Prognosis in Patients with EGFR Mutation Positive Pulmonary Adenocarcinoma 
Background
Plasminogen activator inhibitor type 1 (PAI-1), an important regulator of plasminogen activator system which controls degradation of extracellular membrane and progression of tumor cells, and PAI-1 gene polymorphic variants have been known as the prognostic biomarkers of non-small cell lung cancer patients. Recently, experimental in vitro study revealed that transforming growth factor-β1 initiated PAI-1 transcription through epithelial growth factor receptor (EGFR) signaling pathway. However, there is little clinical evidence on the association between PAI-1 A15T gene polymorphism and prognosis of Korean population with pulmonary adenocarcinoma and the influence of activating mutation of EGFR kinase domain.
Methods
We retrospectively reviewed the medical records of 171 patients who were diagnosed with pulmonary adenocarcinoma and undergone EGFR mutation analysis from 1995 through 2009.
Results
In all patients with pulmonary adenocarcinoma, there was no significant association between PAI-1 A15T polymorphic variants and prognosis for overall survival. However, further subgroup analysis showed that the group with AG/AA genotype had a shorter 3-year survival time than the group with GG genotype in patients with EGFR mutant-type pulmonary adenocarcinoma (mean survival time, 24.9 months vs. 32.5 months, respectively; p=0.015). In multivariate analysis of 3-year survival for patients with pulmonary adenocarcinoma harboring mutant-type EGFR, the AG/AA genotype carriers had poorer prognosis than the GG genotype carriers (hazard ratio, 7.729; 95% confidence interval, 1.414-42.250; p=0.018).
Conclusion
According to our study of Korean population with pulmonary adenocarcinoma, AG/AA genotype of PAI-1 A15T would be a significant predictor of poor short-term survival in patients with pulmonary adenocarcinoma harboring mutant-type EGFR.
doi:10.4046/trd.2013.75.4.140
PMCID: PMC3833934  PMID: 24265642
Plasminogen Activator Inhibitor 1; Polymorphism, Single Nucleotide; Carcinoma, Non-Small-Cell Lung; Prognosis; Receptor, Epidermal Growth Factor
25.  Prevalence of and Risk Factors for Gastrointestinal Diseases in Korean Americans and Native Koreans Undergoing Screening Endoscopy 
Gut and Liver  2013;7(5):539-545.
Background/Aims
In South Korea, health check-ups are readily accessible to the public. We aimed to compare the prevalence of upper gastrointestinal (GI) and lower GI diseases in Korean Americans and native Koreans to determine differences and risk factors.
Methods
In total, 1,942 subjects who visited Gangnam Severance Hospital from July 2008 to November 2010 for a health check-up were enrolled. Basic characteristics and laboratory data for the subjects were collected. Esophagogastroduodenoscopy and colonoscopy were performed. In total, 940 Korean Americans (group 1) and 1,002 native Koreans (group 2) were enrolled.
Results
The overall prevalence of GI diseases for each group (group 1 vs group 2) were as follows: reflux esophagitis (RE) (9.65% vs 7.9%), gastric ulcer (2.8% vs 3.4%), duodenal ulcer (2.3% vs 3.6%), gastric cancer (0.4% vs 0.3%), colorectal polyp (35.9% vs 35.6%), colorectal cancer (0.5% vs 0.5%), and hemorrhoids (29.4% vs 21.3%). The prevalence of hemorrhoids was significantly higher in group 1 than in group 2 (p=0.001). In the multivariable analysis of group 1, male sex, age over 50 years, hypercholesterolemia and hypertriglyceridemia predicted colorectal polyps. Male sex and high fasting glucose levels were associated with RE.
Conclusions
Our study showed that the prevalence of GI diseases (except hemorrhoids) in Korean Americans was similar to that observed in native Koreans. Therefore, the Korean guidelines for upper and lower screening endoscopy may be applicable to Korean Americans.
doi:10.5009/gnl.2013.7.5.539
PMCID: PMC3782668  PMID: 24073311
Korean Americans; Screening endoscopy

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