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1.  Regulation of retinal axon growth by secreted Vax1 homeodomain protein 
eLife  2014;3:e02671.
Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.
eLife digest
We see the world around us when light bounces off of objects and hits the retina at the back of our eyes. This triggers electrical signals in neurons called retinal ganglion cells (RGCs), which have long structures called axons that extend out from the retina and into the parts of the brain where the signals are interpreted. As the axons grow, various ‘guidance’ molecules direct the axons to the correct part of the brain.
One molecule that is important for the growth of retinal ganglion cells' axons is a protein called Vax1. This protein is a transcription factor and binds to DNA to control how and when the molecular templates used to make proteins are made—a process called transcription. Vax1 is not produced in retinal ganglion cells, but it does control the extension of these cells' axons into part of the brain called the ventral hypothalamus. In this study, the axons cross to the other side of the brain by forming a structure called optic chiasm. Humans and mice lacking Vax1 are unable to develop the optic chiasm, and the axons of their retinal ganglion cells do not reach their targets in the brain. These defects were thought to occur because the guidance molecules whose transcription is normally controlled by Vax1 were not produced in the correct amounts when Vax1 is absent.
Kim et al. now challenge this view by creating a mutant version of Vax1 that cannot bind to DNA or regulate the transcription of other proteins. Retinal ganglion cell axons could still grow correctly when they were put close to cells expressing this version of the Vax1 protein. This contradicts a hypothesis that Vax1 supports axonal growth by transcribing guidance molecules. Kim et al. followed up these results by examining developing mice and reached the unexpected conclusion that Vax1 is secreted from cells in the ventral hypothalamus and binds to a type of sugar molecule found on the surface of the axons. Once bound, Vax1 can enter the axons where it appears to stimulate the production of proteins inside axons, which helps the axons to grow.
These findings reveal unconventional functions for Vax1 that occur in addition to its role as a transcription factor. Vax1 is known to regulate the development of several structures in the brain, so the work of Kim et al. also raises new questions about how Vax1 controls these processes.
PMCID: PMC4178304  PMID: 25201875
ventral anterior homeobox 1 (Vax1); retinal axon growth; optic chiasm; intercellular protein transfer; mouse
2.  Stealth nanotubes: strategies of shielding carbon nanotubes to evade opsonization and improve biodistribution 
International Journal of Nanomedicine  2014;9(Suppl 1):85-105.
Carbon nanotubes (CNTs) have recently been in the limelight for their potential role in disease diagnostics and therapeutics, as well as in tissue engineering. Before these medical applications can be realized, there is a need to address issues like opsonization, phagocytosis by macrophages, and sequestration to the liver and spleen for eventual elimination from the body; along with equally important issues such as aqueous solubility, dispersion, biocompatibility, and biofunctionalization. CNTs have not been shown to be able to evade such biological obstacles, which include their nonspecific attachments to cells and other biological components in the bloodstream, before reaching target tissues and cells in vivo. This will eventually determine their longevity in circulation and clearance rate from the body. This review article discusses the current status, challenges, practical strategies, and implementations of coating CNTs with biocompatible and opsonin-resistant moieties, rendering CNTs transparent to opsonins and deceiving the innate immune response to make believe that the CNTs are not foreign. A holistic approach to the development of such “stealth” CNTs is presented, which encompasses not only several biophysicochemical factors that are not limited to surface treatment of CNTs, but also extraneous biological factors such as the protein corona formation that inevitably controls the in vivo fate of the particles. This review also discusses the present and potential applications, along with the future directions, of CNTs and their hybrid-based nanotheranostic agents for multiplex, multimodal molecular imaging and therapy, as well as in other applications, such as drug delivery and tissue engineering.
PMCID: PMC4024978  PMID: 24872705
opsonins; macrophage; in vivo biocompatibility; near-infrared contrast nanoagents; nanotheranostics; nanomedicine
3.  A comparison of dimensional standard of several nickel-titanium rotary files 
The aim of this study was to compare the dimensional standard of several nickel-titanium (Ni-Ti) rotary files and verify the size conformity.
Materials and Methods
ProFile (Dentsply Maillefer), RaCe (FKG Dentaire), and TF file (SybronEndo) #25 with a 0.04 and 0.06 taper were investigated, with 10 in each group for a total of 60 files. Digital images of Ni-Ti files were captured under light microscope (SZX16, Olympus) at 32×. Taper and diameter at D1 to D16 of each files were calculated digitally with AnalySIS TS Materials (OLYMPUS Soft Imaging Solutions). Differences in taper, the diameter of each level (D1 to D16) at 1 mm interval from (ANSI/ADA) specification No. 101 were statistically analyzed using one-way ANOVA and Scheffe's post-hoc test at 95% confidence level.
TF was the only group not conform to the nominal taper in both tapers (p < 0.05). All groups except 0.06 taper ProFile showed significant difference from the nominal diameter (p < 0.05).
Actual size of Ni-Ti file, especially TF, was different from the manufacturer's statements.
PMCID: PMC3916510  PMID: 24516823
Diameter; Ni-Ti rotary files; Size verification; Taper; TF
4.  Pleural Fluid Pentraxin-3 for the Differential Diagnosis of Pleural Effusions 
Conventional biomarkers cannot always establish the cause of pleural effusions; thus, alternative tests permitting rapid and accurate diagnosis are required. The primary aim of this study is to assess the ability of pentraxin-3 (PTX3) in order to diagnose the cause of pleural effusion and compare its efficacy to that of other previously identified biomarkers.
We studied 118 patients with pleural effusion, classified as transudates and exudates including malignant, tuberculous, and parapneumonic effusions (MPE, TPE, and PPE). The levels of PTX3, C-reactive protein (CRP), procalcitonin (PCT) and lactate in the pleural fluid were assessed.
The levels of pleural fluid PTX3 were significantly higher in patients with PPE than in those with MPE or TPE. PTX3 yielded the most favorable discriminating ability to predict PPE from MPE or TPE by providing the following: area under the curve, 0.74 (95% confidence interval, 0.63-0.84), sensitivity, 62.07%; and specificity, 81.08% with a cut-off point of 25.00 ng/mL.
Our data suggests that PTX3 may allow improved differentiation of PPE from MPE or TPE compared to the previously identified biomarkers CRP and PCT.
PMCID: PMC3884112  PMID: 24416055
PTX3 Protein; Pleural Effusion
5.  Assessing the Detection Capacity of Microarrays as Bio/Nanosensing Platforms 
BioMed Research International  2013;2013:310461.
Microarray is one of the most powerful detection systems with multiplexing and high throughput capability. It has significant potential as a versatile biosensing platform for environmental monitoring, pathogen detection, medical therapeutics, and drug screening to name a few. To date, however, microarray applications are still limited to preliminary screening of genome-scale transcription profiling or gene ontology analysis. Expanding the utility of microarrays as a detection tool for various biological and biomedical applications requires information about performance such as the limits of detection and quantification, which are considered as an essential information to decide the detection sensitivity of sensing devices. Here we present a calibration design that integrates detection limit theory and linear dynamic range to obtain a performance index of microarray detection platform using oligonucleotide arrays as a model system. Two different types of limits of detection and quantification are proposed by the prediction or tolerance interval for two common cyanine fluorescence dyes, Cy3 and Cy5. Besides oligonucleotide, the proposed method can be generalized to other microarray formats with various biomolecules such as complementary DNA, protein, peptide, carbohydrate, tissue, or other small biomolecules. Also, it can be easily applied to other fluorescence dyes for further dye chemistry improvement.
PMCID: PMC3845509  PMID: 24324959
6.  Accuracy of Root ZX in teeth with simulated root perforation in the presence of gel or liquid type endodontic irrigant 
To evaluate the accuracy of the Root ZX in teeth with simulated root perforation in the presence of gel or liquid type endodontic irrigants, such as saline, 5.25% sodium hypochlorite (NaOCl), 2% chlorhexidine liquid, 2% chlorhexidine gel, and RC-Prep, and also to determine the electrical conductivities of these endodontic irrigants.
Materials and Methods
A root perforation was simulated on twenty freshly extracted teeth by means of a small perforation made on the proximal surface of the root at 4 mm from the anatomic apex. Root ZX was used to locate root perforation and measure the electronic working lengths. The results obtained were compared with the actual working length (AWL) and the actual location of perforations (AP), allowing tolerances of 0.5 or 1.0 mm. Measurements within these limits were considered as acceptable. Chi-square test or the Fisher's exact test was used to evaluate significance. Electrical conductivities of each irrigant were also measured with an electrical conductivity tester.
The accuracies of the Root ZX in perforated teeth were significantly different between liquid types (saline, NaOCl) and gel types (chlorhexidine gel, RC-Prep). The accuracies of electronic working lengths in perforated teeth were higher in gel types than in liquid types. The accuracy in locating root perforation was higher in liquid types than gel types. 5.25% NaOCl had the highest electrical conductivity, whereas 2% chlorhexidine gel and RC-Prep gel had the lowest electrical conductivities among the five irrigants.
Different canal irrigants with different electrical conductivities may affect the accuracy of the Root ZX in perforated teeth.
PMCID: PMC3569399  PMID: 23431125
Electrical conductivity; Root canal irrigants; Root perforation; Root ZX
7.  Precipitate from a combination of sodium hypochlorite and chlorhexidine 
PMCID: PMC3569406  PMID: 23431504
8.  Clinical Utility of Alpha Fetoprotein and HCCR-1, Alone or in Combination, in Patients with Chronic Hepatitis, Liver Cirrhosis and Hepatocellular Carcinoma 
Disease markers  2011;30(6):307-315.
Serum alpha fetoprotein (AFP) is the most widely used tumor marker in detecting patients with hepatocellular carcinoma (HCC). However, it has been indicated that HCCR-1 (human cervical cancer oncogene 1) might be supplementary to AFP in the detection. We conducted a prospective study in 120 normal and 524 liver disease patients to evaluate the significance of simultaneous measurement of 2 tumor markers (AFP and HCCR-1) in the diagnosis of HCC through the cohort study in Korea and China. We also performed immunohistochemical studies using 25 normal subjects (N), 32 liver cirrhosis (LC) and 116 HCC tissues. The sensitivities of AFP (20 ng/mL) and HCCR-1 (10 ng/mL) in HCC were 55.8% (164/294) and 44.2% (130/294), respectively. When AFP was combined with HCCR-1, sensitivities increased to 4.2% (N), 12.7% (chronic hepatitis; CH), 50.0% (LC), and 77.2% (HCC), respectively. Although there was no significant difference in the diagnostic rate for HCC between AFP and HCCR-1, many cases for AFP-negative HCC were positive for HCCR-1 and vice versa. Moreover, the combined use of AFP and HCCR-1 improved the diagnostic rate to 70.8% in small HCC (< 2 cm) and 81.6% in large HCC (≥ 2 cm), respectively. AFP and HCCR-1 are independent markers. Our result suggests that the HCCR-1 could be an useful biomarker for HCC while the diagnostic rate could be significantly improved in the combined use of HCCR-1 and AFP.
PMCID: PMC3825078  PMID: 21725159
HCC; biomarker; AFP; HCCR-1
9.  Aqueous-phase synthesis of monodisperse plasmonic gold nanocrystals using shortened single-walled carbon nanotubes 
Monodisperse gold nanocrystals with unique near-infrared optical properties were synthesized by simple mixing of highly shortened and well disperse single-walled carbon nanotubes and chloroauric acid in water at ambient conditions with a step-wise increase of gold ion concentration.
PMCID: PMC4321945  PMID: 20737105
10.  Advanced contrast nanoagents for photoacoustic molecular imaging, cytometry, blood test and photothermal theranostics† 
Various nanoparticles have raised significant interest over the past decades for their unique physical and optical properties and biological utilities. Here we summarize the vast applications of advanced nanoparticles with a focus on carbon nanotube (CNT)-based or CNT-catalyzed contrast agents for photoacoustic (PA) imaging, cytometry and theranostics applications based on the photothermal (PT) effect. We briefly review the safety and potential toxicity of the PA/PT contrast nanoagents, while showing how the physical properties as well as multiple biological coatings change their toxicity profiles and contrasts. We provide general guidelines needed for the validation of a new molecular imaging agent in living subjects, and exemplify these guidelines with single-walled CNTs targeted to αvβ3, an integrin associated with tumor angiogenesis, and golden carbon nanotubes targeted to LYVE-1, endothelial lymphatic receptors. An extensive review of the potential applications of advanced contrast agents is provided, including imaging of static targets such as tumor angiogenesis receptors, in vivo cytometry of dynamic targets such as circulating tumor cells and nanoparticles in blood, lymph, bones and plants, methods to enhance the PA and PT effects with transient and stationary bubble conjugates, PT/PA Raman imaging and multispectral histology. Finally, theranostic applications are reviewed, including the nanophotothermolysis of individual tumor cells and bacteria with clustered nanoparticles, nanothrombolysis of blood clots, detection and purging metastasis in sentinel lymph nodes, spectral hole burning and multiplex therapy with ultrasharp rainbow nanoparticles.
PMCID: PMC4282188  PMID: 22025336
photoacoustic molecular imaging; photothermal theranostics; nanotechnology; carbon nanotubes; flow cytometry; blood test; cancer; metastasis
12.  Conditional Deletion of Pten Leads to Defects in Nerve Innervation and Neuronal Survival in Inner Ear Development 
PLoS ONE  2013;8(2):e55609.
All cellular phenomena and developmental events, including inner ear development, are modulated through harmonized signaling networks. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a major signaling component involved in cross talk with key regulators of development; i.e., Wnt, Notch, and bone morphogenetic proteins. Although Pten function has been studied in various systems, its role in inner ear development is poorly understood. Here, we used inner ear-specific Pten conditional knockout mice and examined the characteristics of the inner ear. In a detailed analysis of the phenotype, reduced cochlear turning and widened epithelia were observed. Phalloidin staining of sensory epithelium revealed that hair cell patterns were disturbed; i.e., additional rows of hair cells were discovered. The neural abnormality revealed a reduction in and disorganization of nerve fibers, including apoptosis at the neural precursor stage. Pten deficiency induced increased phosphorylation of Akt at Ser473. The elevation of inhibitory glycogen synthase kinase 3β Ser9 phosphorylation (pGSK3β) was sustained until the neuronal differentiation stage at embryonic day 14.5, instead of pGSK3β downregulation. This is the first report on the influence of Pten/Akt/GSK3β signaling on the development of spiral ganglia. These results suggest that Pten is required for the maintenance of neuroblast number, neural precursors, and differentiation in the inner ear.
PMCID: PMC3564925  PMID: 23393595
13.  Effects of adjunctive daily phototherapy on chronic periodontitis: a randomized single-blind controlled trial 
The purpose of this randomized single-blind controlled trial was to elucidate the clinical and antimicrobial effects of daily phototherapy (PT) as an adjunct to scaling and root planing (SRP) in patients with chronic periodontitis.
The study was conducted from December 2013 to May 2014 at Ewha Womans University Mokdong Hospital, Seoul, Korea. Forty-one patients with mild to moderate chronic periodontitis were randomly divided into two therapeutic groups in a 1:1 ratio: SRP+PT and SRP (control) groups. All participants underwent full-mouth SRP. PT was performed thrice a day for a month by using electric toothbrushes with embedded light-emitting diodes. Plaque index, gingival index, probing pocket depth (PPD), clinical attachment level (CAL), and bleeding on probing were assessed before (baseline) and four weeks after (follow-up) the treatment. Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia, Fusobacterium nucleatum, Parvimonas micra, Campylobacter rectus, Eikenella corrodens, Streptococcus mutans, and Streptococcus sobrinus levels were detected by a real-time polymerase chain reaction at the same points in time.
The clinical parameters improved in both the groups. At the follow-up assessment, PPD was significantly decreased in the SRP+PT group (P=0.00). Further, PPD and CAL showed significantly greater changes in the SRP+PT group than in the SRP group (PPD, P=0.03; CAL, P=0.04). P. gingivalis and T. forsythia levels decreased in this group, but no significant intergroup differences were noted.
Adjunctive PT seems to have clinical benefits, but evidence of its antimicrobial effects is not sufficient. Long-term studies are necessary to develop the most effective PT protocol and compare the effectiveness of PT with and without exogenous photosensitizers.
Graphical Abstract
PMCID: PMC4284376  PMID: 25568808
Dental scaling; Periodontal index; Periodontitis; Photochemotherapy; Photosensitizing agents
15.  A DNA-based pattern classifier with in vitro learning and associative recall for genomic characterization and biosensing without explicit sequence knowledge 
Genetic material extracted from in situ microbial communities has high promise as an indicator of biological system status. However, the challenge is to access genomic information from all organisms at the population or community scale to monitor the biosystem’s state. Hence, there is a need for a better diagnostic tool that provides a holistic view of a biosystem’s genomic status. Here, we introduce an in vitro methodology for genomic pattern classification of biological samples that taps large amounts of genetic information from all genes present and uses that information to detect changes in genomic patterns and classify them.
We developed a biosensing protocol, termed Biological Memory, that has in vitro computational capabilities to “learn” and “store” genomic sequence information directly from genomic samples without knowledge of their explicit sequences, and that discovers differences in vitro between previously unknown inputs and learned memory molecules. The Memory protocol was designed and optimized based upon (1) common in vitro recombinant DNA operations using 20-base random probes, including polymerization, nuclease digestion, and magnetic bead separation, to capture a snapshot of the genomic state of a biological sample as a DNA memory and (2) the thermal stability of DNA duplexes between new input and the memory to detect similarities and differences. For efficient read out, a microarray was used as an output method. When the microarray-based Memory protocol was implemented to test its capability and sensitivity using genomic DNA from two model bacterial strains, i.e., Escherichia coli K12 and Bacillus subtilis, results indicate that the Memory protocol can “learn” input DNA, “recall” similar DNA, differentiate between dissimilar DNA, and detect relatively small concentration differences in samples.
This study demonstrated not only the in vitro information processing capabilities of DNA, but also its promise as a genomic pattern classifier that could access information from all organisms in a biological system without explicit genomic information. The Memory protocol has high potential for many applications, including in situ biomonitoring of ecosystems, screening for diseases, biosensing of pathological features in water and food supplies, and non-biological information processing of memory devices, among many.
Electronic supplementary material
The online version of this article (doi:10.1186/1754-1611-8-25) contains supplementary material, which is available to authorized users.
PMCID: PMC4237745  PMID: 25414728
Biological memory protocol; In vitro learning and recall; Microarray; Genomic status; Ecological and environmental monitoring; Biological and biomedical sensing
16.  Injection-Site Reaction Following 5-Azacitidine Injection 
Annals of Dermatology  2014;26(5):669-670.
PMCID: PMC4198610  PMID: 25324675
17.  Development and Application of Quantitative Detection Method for Viral Hemorrhagic Septicemia Virus (VHSV) Genogroup IVa 
Viruses  2014;6(5):2204-2213.
Viral hemorrhagic septicemia virus (VHSV) is a problematic pathogen in olive flounder (Paralichthys olivaceus) aquaculture farms in Korea. Thus, it is necessary to develop a rapid and accurate diagnostic method to detect this virus. We developed a quantitative RT-PCR (qRT-PCR) method based on the nucleocapsid (N) gene sequence of Korean VHSV isolate (Genogroup IVa). The slope and R2 values of the primer set developed in this study were −0.2928 (96% efficiency) and 0.9979, respectively. Its comparison with viral infectivity calculated by traditional quantifying method (TCID50) showed a similar pattern of kinetic changes in vitro and in vivo. The qRT-PCR method reduced detection time compared to that of TCID50, making it a very useful tool for VHSV diagnosis.
PMCID: PMC4036551  PMID: 24859343
viral hemorrhagic septicemia virus (VHSV); quantitative detection; real-time PCR; diagnostic; olive flounder
18.  Nanotheranostics of Circulating Tumor Cells, Infections and Other Pathological Features In Vivo 
Molecular pharmaceutics  2013;10(3):813-830.
Many life-threatening diseases are disseminated through biological fluids, such as blood, lymph and cerebrospinal fluid. The migration of tumor cells through the vascular circulation is a mandatory step in metastasis, which is responsible for ∼90% of cancer-associated mortality. Circulating pathogenic bacteria, viruses, or blood clots lead to other serious conditions including bacteremia, sepsis, viremia and infarction. Therefore, technologies capable of detecting circulating tumor cells (CTCs), circulating bacterial cells (CBCs), circulating endothelial cells (CECs), cancer biomarkers such as microparticles and exosomes, which contain important microRNA signatures, and other abnormal features in biological fluids may facilitate early diagnosis and treatment of metastatic cancers, infections and adverse cardiovascular events. Unfortunately, even in a disease setting, circulating abnormal cells are rare events that are easily obscured by the overwhelming background material in whole blood. Existing detection methods mostly rely on ex vivo analyses of limited volumes (a few mL) of whole blood. These small volumes limit the probability of detecting CTCs, CECs, CBCs and other rare phenomena. In vivo detection platforms capable of continuously monitoring the entire circulation may substantially increase the probability of detecting circulating abnormal cells and, in particular, increase the opportunity to identify exceedingly rare and potentially dangerous subsets of these cells, such as circulating cancer stem cells (CCSCs). In addition, in vivo detection technologies capable of destroying and/or capturing circulating abnormal cells may inhibit disease progression. This article reviews novel therapeutic and diagnostic (theranostic) platforms integrating in vivo realtime early diagnosis of CTCs, CECs, CBCs and other abnormal objects in circulation. This critical review particularly focuses on nanotechnology-based theranostic (nanotheranostic) approaches, especially in vivo photoacoustic (PA) and photothermal (PT) nanotheranostic platforms. We emphasize an urgent need for in vivo platforms comprised of multifunctional contrast nanoagents, which utilize diverse modalities to realize a breakthrough for early detection and treatment of harmful diseases disseminated through the circulation.
PMCID: PMC3752784  PMID: 23379366
Metastasis; circulating tumor cells (CTCs); circulating endothelial cells (CECs); circulating cancer stem cells (CCSCs); circulating microparticles and exosomes; circulating pathogens and viruses; blood clots; blood and lymph flow; contrast nanoagents; positive and negative photoacoustic contrasts; microbubbles; multimodal; multicolor; nanotechnology; multifunctional real-time nanotheranostics; nanomedicine
19.  Chronic maxillary sinusitis caused by root canal overfilling of Calcipex II 
This is a case report of chronic maxillary sinusitis caused by root canal overfilling of Calcipex II (Techno-Dent). A 60 year-old male complained of dull pain in the right maxillary molar area after complicated endodontic treatment using Calcipex II paste and was finally diagnosed with a chronic maxillary sinusitis through a clinical and radiological observation. In the biopsy examination, the periapical granuloma contained a lot of dark and translucent Calcipex II granules which were not stained with hematoxylin and eosin. They were usually engulfed by macrophages but rarely resorbed, resulting in scattering and migrating into antral mucosa. Most of the Calcipex II granules were also accumulated in the cytoplasms of secretory columnar epithelial cells, and small amount of Calcipex II granules were gradually secreted into sinus lumen by exocytosis. However, chronic granulomatous inflammation occurred without the additional recruitment of polymorphonuclear leukocytes (PMNs) and lymphocytes, and many macrophages which engulfed the Calcipex II granules were finally destroyed in the processes of cellular apoptosis. It is presumed that Calcipex II granules are likely to have a causative role to induce the granulomatous foreign body inflammation in the periapical region, and subsequently to exacerbate the chronic maxillary sinusitis in this study.
PMCID: PMC3916508  PMID: 24516832
Calcipex II; Foreign body granuloma; Maxillary sinusitis
20.  A Cathepsin B Inhibitor, E-64, Improves the Preimplantation Development of Bovine Somatic Cell Nuclear Transfer Embryos 
Bovine somatic cell nuclear transfer (SCNT) is an important and powerful tool for basic research and biomedical and agricultural applications, however, the efficiency of SCNT has remained extremely low. In this study, we investigated the effects of cathepsin B inhibitor (E-64) supplementation of culture medium on in vitro development of bovine SCNT embryos. We initially used three concentrations of E-64 (0.1, 0.5, 1.0 μm), among which 0.5 μm resulted in the highest rate of blastocysts production after in vitro fertilization (IVF), and was therefore used for further experiments. Blastocyst development of SCNT embryos in the E-64 treatment group also increased relative to the control. Moreover, the cryosurvival rates of IVF and SCNT blastocysts were increased in E-64 treatment groups when compared with the control. On the other hand, we found that IVF and SCNT blastocysts derived from E-64-treated groups had increased total cell numbers and decreased apoptotic nuclei. Furthermore, assessment of the expression of apoptosis-related genes (Bax and Bcl-xL) in bovine IVF and SCNT blastocysts treated with E-64 by real-time RT-PCR analysis revealed suppressed expression of the pro-apoptotic gene Bax and stimulated expression of the anti-apoptotic gene Bcl-xL. Taken together, these finding indicate that addition of E-64 to embryo culture medium may have important implications for improving developmental competence and preimplantation quality in bovine IVF and SCNT embryos.
PMCID: PMC3963301  PMID: 24240170
Apoptosis; Blastocysts; Bovine; Cathepsin B inhibitor (E-64); Somatic cell nuclear transfer (SCNT)
21.  Mutations in Isocitrate Dehydrogenase 1 and 2 Occur Frequently in Intrahepatic Cholangiocarcinomas and Share Hypermethylation Targets with Glioblastomas 
Oncogene  2012;32(25):3091-3100.
Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas, and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine (5hmC) and higher 5-methylcytosine (5mC) levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were associated with longer overall survival (p = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (p = 0.021). IDH1 and IDH2 mutations are significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2,309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.
PMCID: PMC3500578  PMID: 22824796
DNA methylation; Epigenetics; Tumor metabolism
22.  Effect of Korean red ginseng on cold hypersensitivity in the hands and feet: study protocol for a randomized controlled trial 
Trials  2013;14:438.
Cold hypersensitivity in the hands and feet (CHHF) is one of the most common complaints among Asians, especially in women. Korean red ginseng (KRG), which is a steamed form of Panax ginseng, has vasodilating action in the peripheral vessels and increases blood flow under cold stress. However, few studies have evaluated the effect of KRG on cold hypersensitivity.
This trial is a randomized, double-blind, placebo-controlled trial in 80 CHHF patients. The trial will be implemented at Kyung Hee University Hospital at Gangdong in Seoul, Korea. The participants will take KRG or a placebo for eight weeks, after which they will be followed-up for four weeks. During the administration period, six capsules of 500 mg KRG or placebo will be provided twice a day. The primary outcome is change of skin temperature in the hands between baseline and after treatment. The secondary outcomes include the visual analogue scale scores of cold hypersensitivity in the hands, change of skin temperature and the VAS scores of cold hypersensitivity in the feet, the recovery rate of the skin temperature by the cold stress test of the hands, the distal-dorsal difference of the hands, power variables of heart rate variability, and the 36-item short form health survey.
This study is the first trial to evaluate the efficacy of KRG on CHHF by using infrared thermography. Our study will provide basic evidence regarding CHHF.
Trial registration NCT01664156
PMCID: PMC3878242  PMID: 24354675
Cold hypersensitivity in the hands and feet; Korean red ginseng; Infrared thermography; Cold stress test; Distal-dorsal difference
23.  Placental Transmogrification of the Lung 
Korean Journal of Radiology  2013;14(6):977-980.
Placental transmogrification is a very rare lung disease, where the alveoli resemble the chorionic villi of placenta, and this change is a characteristic finding. A 31-year-old female patient presented with cough and dyspnea that had begun 2 weeks prior to admission. Along with giant bulla found in the left upper lung field, subsegmental consolidation was also identified in the lingular segment on plain chest radiograph and CT scan. Wedge resection was performed to remove the bulla. Pathologic examination of the resected bulla revealed destruction of the normal structures and characteristic villous and papillary changes. These changes led to a diagnosis of placental transmogrification. We made an encounter of an unusual placental transmogrification which had different image findings from other reported transmogrification cases. Thus, we report an atypical placental transmogrification case where both consolidation and giant bulla coexist.
PMCID: PMC3835648  PMID: 24265576
Lung; Placenta; Chorionic villi; Emphysema
24.  Effects of Vibratory Stimulations on Maximal Voluntary Isometric Contraction from Delayed Onset Muscle Soreness 
Journal of Physical Therapy Science  2013;25(9):1093-1095.
[Purpose] The aim of this study was to investigate the effect of vibratory stimulation on maximal voluntary isometric contraction (MVIC) from delayed onset muscle soreness (DOMS). [Subjects] Sixty healthy adults participated in this study. The exclusion criteria were orthopedic or neurologic disease. [Methods] The researchers induced DOMS in the musculus extensor carpi radialis longus of each participant. Subjects in the control group received no treatment. The ultrasound group received ultrasound treatment (intensity, 1.0 W/cm2; frequency 1 MHz; time, 10 minutes). The vibration group received vibration stimulation (frequency, 20 MHz; time, 10 minutes). Maximal voluntary isometric contraction (MVIC) was recorded at baseline, immediately after exercise, and 24, 48, and 72 hours after exercise. [Results] MVIC measurements showed statistically significant differences in the vibration group compared with the control group. [Conclusion] Vibratory stimulation had a positive effect on recovery of muscle function from DOMS.
PMCID: PMC3818754  PMID: 24259922
Vibratory stimulation; Ultrasound; Isometric contraction
25.  A Study of Effect of the Compound Physical Activity Therapy on Muscular Strength in Obese Women 
Journal of Physical Therapy Science  2013;25(8):1039-1041.
[Purpose] The aim of this study was to determine how compound physical activity affects muscular strength of middle-aged obese women. [Subjects] The research subjects were 40–50 year-old middle-aged women with excess body fat (30%). [Methods] The subjects were randomly assigned to two group, the experimental group and the control group. The experimental group performed two types of exercise programs for 16 weeks. Aerobic physical activity was performed 5 times per week, and anaerobic physical activity was performed every two days, and the exercise program each day was composed of a warm-up, the main exercise, and cooldown. The type of exercise focused on walking at a quick pace, and the intensity of the exercise focused on long periods of exercise at low intensity with the level of HRmax being 40–60%. The weight training, which was useful for beginners, as a type of kinetic load exercise, was applied with a composition recommended by the ACSM for muscle fitness (intensity of 40–60% of 1 RM and 10–15 repetitions). SPSS version 16.0 was used to analyze the data by ANCOVA and the t-test. [Results] The chest, leg, and abdominal strengths were significantly increased in the experimental group, and this indicates that compound physical activity is effective for improvement of muscular strength. [Conclusion] In conclusion, there were significant differences between groups in terms of muscular strength.
PMCID: PMC3820232  PMID: 24259911
Therapy; Muscular; Strength

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