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1.  Neonatal systemic inflammation in rats alters retinal vessel development and simulates pathologic features of retinopathy of prematurity 
Alteration of retinal angiogenesis during development leads to retinopathy of prematurity (ROP) in preterm infants, which is a leading cause of visual impairment in children. A number of clinical studies have reported higher rates of ROP in infants who had perinatal infections or inflammation, suggesting that exposure of the developing retina to inflammation may disturb retinal vessel development. Thus, we investigated the effects of systemic inflammation on retinal vessel development and retinal inflammation in neonatal rats.
To induce systemic inflammation, we intraperitoneally injected 100 μl lipopolysaccharide (LPS, 0.25 mg/ml) or the same volume of normal saline in rat pups on postnatal days 1, 3, and 5. The retinas were extracted on postnatal days 7 and 14, and subjected to assays for retinal vessels, inflammatory cells and molecules, and apoptosis.
We found that intraperitoneal injection of LPS impaired retinal vessel development by decreasing vessel extension, reducing capillary density, and inducing localized overgrowth of abnormal retinal vessels and dilated peripheral vascular ridge, all of which are characteristic findings of ROP. Also, a large number of CD11c+ inflammatory cells and astrocytes were localized in the lesion of abnormal vessels. Further analysis revealed that the number of major histocompatibility complex (MHC) class IIloCD68loCD11bloCD11chi cells in the retina was higher in LPS-treated rats compared to controls. Similarly, the levels of TNF-α, IL-1β, and IL-12a were increased in LPS-treated retina. Also, apoptosis was increased in the inner retinal layer where retinal vessels are located.
Our data demonstrate that systemic LPS-induced inflammation elicits retinal inflammation and impairs retinal angiogenesis in neonatal rats, implicating perinatal inflammation in the pathogenesis of ROP.
PMCID: PMC4030274  PMID: 24886524
angiogenesis; inflammation; lipopolysaccharide; retina; retinopathy of prematurity
3.  Effects of Different Types of Contraction in Abdominal Bracing on the Asymmetry of Left and Right Abdominal Muscles 
Journal of Physical Therapy Science  2014;26(12):1843-1845.
[Purpose] The purpose of this study was to investigate the effective strength levels of abdominal muscle contraction using the bracing contraction method. [Subjects] The experiment was conducted with 31 healthy male (M=15) and female (F=16) adults attending D University in Busan; all participants had less than obesity level BMI (BMI<30). [Methods] Bracing contraction was performed by the subjects in the hook-lying position at maximum and minimum pressure levels, five times each, using a Pressure Biofeedback Unit (PBU), and the mean measurement value was calculated. The maximum pressure level was set at 100% and the half maximum pressure level was set at 50%. Each subject’s left and right abdominal muscle thicknesses were then measured by ultrasound imaging in each state: at rest, 100% contraction, and 50% contraction. [Results] No significant differences were found between the left and right sides of the transversus abdominis (TrA) at rest, 50%, or 100% contraction. The external oblique abdominis (EO) and internal oblique abdominis (IO) showed no significant difference at rest or at the 50% contraction. However, a significant difference was noted at 100% contraction for the EO and IO. [Conclusion] Application of abdominal contraction using bracing can achieve symmetry in the left and right abdominal muscles at less than the maximum contractile strength. The occurrence of asymmetry in the left and right abdominal muscles at the maximum contractile strength suggests that the most suitable contractile strength in this exercise is less than the maximum contractile strength.
PMCID: PMC4273038  PMID: 25540478
Abdominal bracing; Symmetry; Ultrasound imaging
4.  Influence of reactive species on the modification of biomolecules generated from the soft plasma 
Scientific Reports  2015;5:8221.
Plasma medicine is an upcoming research area that has attracted the scientists to explore more deeply the utility of plasma. So, apart from the treating biomaterials and tissues with plasma, we have studied the effect of soft plasma with different feeding gases such as Air, N2 and Ar on modification of biomolecules. Hence, in this work we have used the soft plasma on biomolecules such as proteins ((Hemoglobin (Hb) and Myoglobin (Mb)), calf thymus DNA and amino acids. The structural changes or structural modification of proteins and DNA have been studied using circular dichroism (CD), fluorescence spectroscopy, protein oxidation test, gel electrophoresis, UV-vis spectroscopy, dynamic light scattering (DLS) and 1D NMR, while Liquid Chromatograph/Capillary Electrophoresis-Mass Spectrometer (LC/CE-MS) based on qualitative and quantitative bio-analysis have been used to study the modification of amino acids. Further, the thermal analysis of the protein has been studied with differential scanning calorimetry (DSC) and CD. Additionally, we have performed docking studies of H2O2 with Hb and Mb, which reveals that H2O2 molecules preferably attack the amino acids near heme group. We have also shown that N2 gas plasma has strong deformation action on biomolecules and compared to other gases plasma.
PMCID: PMC4316168  PMID: 25649786
5.  Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors. Corrigendum 
The article by Lee et al. [(2014) Acta Cryst. D70, 1357–1365] is corrected.
A correction is made to the article by Lee et al. [(2014) Acta Cryst. D70, 1357–1365].
PMCID: PMC4321492  PMID: 25664753
sialidase; NanI; geranylated flavonoid; diplacone; sialidase inhibitor; corrigendum
6.  The Correlation between Dynamic Balance Measures and Stance Sub-phase COP Displacement Time in Older Adults during Obstacle Crossing 
Journal of Physical Therapy Science  2013;25(9):1193-1196.
[Purpose] This study examined the relationship between the center of pressure (COP) displacement time during the stance subphases and dynamic balance ability when elderly cross obstacles 0, 10, and 40 cm in height. [Subjects] Fifteen older adults were enrolled in this study (≥65 years of age). [Methods] An F-Scan System was used to measure the COP displacement time when subjects crossed obstacles 0, 10, and 40 cm in height, and the Dynamic Gait Index, Berg Balance Scale, and Four Square Step Test were used to measure dynamic balance ability. [Results] The Dynamic Gait Index, Berg Balance Scale, and Four Square Step Test were correlated with each other. Dynamic balance tests were correlated with the COP displacement time during the stance phase. At obstacle heights of 10 and 40 cm during loading response and at all heights during pre-swing, there were correlations with dynamic balance ability. However, dynamic balance ability did not affect the COP displacement time during mid-stance and terminal stance. [Conclusion] People with a lower dynamic balance ability show a larger COP displacement time during loading response and pre-swing. Therefore, dynamic balance ability can be predicted by measuring the COP displacement time.
PMCID: PMC3818769  PMID: 24259944
Dynamic balance; Obstacle crossing; Center of pressure
7.  Complete Nucleotide Sequence Analysis of the Norovirus GII.4 Sydney Variant in South Korea 
BioMed Research International  2015;2015:374637.
Norovirus is the primary cause of acute gastroenteritis in individuals of all ages. In Australia, a new strain of norovirus (GII.4) was identified in March 2012, and this strain has spread rapidly around the world. In August 2012, this new GII.4 strain was identified in patients in South Korea. Therefore, to examine the characteristics of the epidemic norovirus GII.4 2012 variant in South Korea, we conducted KM272334 full-length genomic analysis. The genome of the gg-12-08-04 strain consisted of 7,558 bp and contained three open reading frame (ORF) composites throughout the whole genome: ORF1 (5,100 bp), ORF2 (1,623 bp), and ORF3 (807 bp). Phylogenetic analyses showed that gg-12-08-04 belonged to the GII.4 Sydney 2012 variant, sharing 98.92% nucleotide similarity with this variant strain. According to SimPlot analysis, the gg-12-08-04 strain was a recombinant strain with breakpoint at the ORF1/2 junction between Osaka 2007 and Apeldoorn 2008 strains. This study is the first report of the complete sequence of the GII.4 Sydney 2012 strain in South Korea. Therefore, this may represent the standard sequence of the norovirus GII.4 2012 variant in South Korea and could therefore be useful for the development of norovirus vaccines.
PMCID: PMC4320898
8.  Prevalence of Antibody to Toxic Shock Syndrome Toxin-1 in Burn Patients 
Annals of Laboratory Medicine  2014;35(1):89-93.
Burn wounds lack normal barriers that protect against pathogenic bacteria, and burn patients are easily colonized and infected by Staphylococcus aureus. Toxic shock syndrome (TSS) is a rare but fatal disease caused by S. aureus. A lack of detectable antibodies to TSS toxin-1 (TSST-1) in serum indicates susceptibility to TSS.
A total of 207 patients (169 men and 38 women; median age, 42.5 yr) admitted to a burn center in Korea were enrolled in this study. The serum antibody titer to TSST-1 was measured by sandwich ELISA. S. aureus isolates from the patients' nasal swab culture were tested for TSST-1 toxin production by PCR-based detection of the TSST-1 toxin gene.
One hundred seventy-four (84.1%) patients showed positive results for antibody against TSST-1. All patients aged ≥61 yr (n=28) and <26 months (n=7) were positive for the anti-TSST-1 antibody. S. aureus was isolated from 70 patients (33.8%), and 58.6% of the isolates were methicillin resistant. Seventeen patients were colonized with TSST-1-producing S. aureus. The antibody positivity in these 17 carriers was 88.2%, and the positivity in the non-carriers was 83.7%.
Most burn patients had antibody to TSST-1, and nasal colonization with TSST-1-producing S. aureus was associated with positive titers of anti-TSST-1 antibody. Additionally, patients with negative titers of anti-TSST-1 antibody might be susceptible to TSS.
PMCID: PMC4272971  PMID: 25553286
Burns; Toxic shock syndrome; Toxic shock syndrome toxin-1; Staphylococcus aureus; Antibodies; Prevalence
9.  Erratum: Correction of 1.3 Investigators in Supplementary Materials 
PMCID: PMC4278020  PMID: 25547240
10.  A study of structural foot deformity in stroke patients 
[Purpose] The aim of this study was to evaluate the structural deformity of the foot joint on the affected side in hemiplegic patients to examine factors that affect this kind of structural deformity. [Subjects and Methods] Thirty-one hemiplegic patients and 32 normal adults participated. The foot posture index (FPI) was used to examine the shape of the foot, the modified Ashworth scale test was used to examine the degree of ankle joint rigidity, the navicular drop test was used to investigate the degree of navicular change, and the resting calcaneal stance position test was used to identify location change of the heel bone. [Results] The FPIs of the paretic side of the hemiplegic patients, the non-paretic side of the hemiplegic patients, and normal participants were −0.25 ± 2.1, 1.74 ± 2.3, and 2.12 ± 3.4 respectively. [Conclusion] Our findings indicated that in stroke-related hemiplegic patients, the more severe the spasticity, the more supinated the foot. Further, the smaller the degree of change in the navicular height of hemiplegic patients is, the more supinated the paretic side foot is. Additionally, a greater change in the location of the calcaneus was associated with greater supination of the overall foot.
PMCID: PMC4305560  PMID: 25642071
Foot posture index; Hemiplegic foot; Foot deformity
11.  Impact of Coronary Artery Anatomy on Clinical Course and Prognosis in Apical Hypertrophic Cardiomyopathy: Analysis of Coronary Angiography and Computed Tomography 
Korean Circulation Journal  2015;45(1):38-43.
Background and Objectives
Apical hypertrophic cardiomyopathy (AHCM) is an uncommon variant of hypertrophic cardiomyopathy with a relatively benign course. However, the prognostic factors of AHCM-particularly those associated with coronary artery disease (CAD) and its anatomical subtypes-are not well known.
Subjects and Methods
We enrolled 98 consecutive patients with AHCM who underwent coronary angiography or coronary computed tomography scanning at two general hospitals in Korea from January 2002 to March 2012. Patient charts were reviewed for information regarding cardiovascular (CV) risk factors, symptoms, and occurrence of CV events and/or mortality. We also reviewed echocardiographic data and angiography records.
The mean age at the time of enrollment was 61.45±9.78 years, with female patients comprising 38.6%. The proportions of mixed and pure types of AHCM were 34.4% and 65.6%, respectively. CAD was found in 31 (31.6%) patients. The mean follow-up period was 53.1±60.7 months. CV events occurred in 22.4% of patients, and the mortality rate was 5.1%. The mixed-type was more frequent in CV event group although this difference was not statistically significant (50% vs. 30%, p=0.097). The presence of CAD emerged as an independent risk factor for CV events in univariate and multivariate Cox regression analysis after adjusting for other CV risk factors.
Coronary artery disease is an independent risk factor for CV events in AHCM patients. However, AHCM without CAD has a benign natural course, comparable with the general population.
PMCID: PMC4310978  PMID: 25653702
Cardiomyopathy, hypertrophic; Coronary artery disease; Coronary angiography; Multidetector Computed Tomography
12.  Fucoidan promotes osteoblast differentiation via JNK- and ERK-dependent BMP2–Smad 1/5/8 signaling in human mesenchymal stem cells 
Fucoidan has attracted attention as a potential drug because of its biological activities, which include osteogenesis. However, the molecular mechanisms involved in the osteogenic activity of fucoidan in human alveolar bone marrow-derived mesenchymal stem cells (hABM-MSCs) remain largely unknown. We investigated the action of fucoidan on osteoblast differentiation in hABM-MSCs and its impact on signaling pathways. Its effect on proliferation was determined using the crystal violet staining assay. Osteoblast differentiation was evaluated based on alkaline phosphatase (ALP) activity and the mRNA expression of multiple osteoblast markers. Calcium accumulation was determined by Alizarin red S staining. We found that fucoidan induced hABM-MSC proliferation. It also significantly increased ALP activity, calcium accumulation and the expression of osteoblast-specific genes, such as ALP, runt-related transcription factor 2, type I collagen-α 1 and osteocalcin. Moreover, fucoidan induced the expression of bone morphogenetic protein 2 (BMP2) and stimulated the activation of extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase by increasing phosphorylation. However, the effect of fucoidan on osteogenic differentiation was inhibited by specific inhibitors of ERK (PD98059) and JNK (SP600125) but not p38 (SB203580). Fucoidan enhanced BMP2 expression and Smad 1/5/8, ERK and JNK phosphorylation. Moreover, the effect of fucoidan on osteoblast differentiation was diminished by BMP2 knockdown. These results indicate that fucoidan induces osteoblast differentiation through BMP2–Smad 1/5/8 signaling by activating ERK and JNK, elucidating the molecular basis of the osteogenic effects of fucoidan in hABM-MSCs.
PMCID: PMC4314586  PMID: 25572360
13.  Corrosive Esophagitis Caused by Ingestion of Picosulfate 
Clinical Endoscopy  2015;48(1):66-69.
Corrosive esophagitis is characterized by caustic injury due to the ingestion of chemical agents, mainly alkaline substances such as detergents. Esophageal bleeding, perforation, or stricture can be worsened by high-degree corrosive esophagitis. Picosulfate is a commonly used laxative frequently administered for bowel preparation before colonoscopy or colon surgery. Picosulfate powder should be completely dissolved in water before ingestion because the powder itself may cause chemical burning of the esophagus and stomach. Here, we report a case of corrosive esophagitis due to the ingestion of picosulfate powder that was not completely dissolved in water.
PMCID: PMC4323436
Caustics; Esophagitis; Picosulfate
14.  Is elective inguinal radiotherapy necessary for locally advanced rectal adenocarcinoma invading anal canal? 
We investigated whether routine elective irradiation of a clinically negative inguinal node (IGN) is necessary for patients with locally advanced distal rectal cancer and anal canal invasion (ACI).
We reviewed retrospectively 1,246 patients with locally advanced rectal adenocarcinoma managed using preoperative or postoperative chemoradiotherapy and radical surgery between 2001 and 2011. The patients’ IGN was clinically negative at presentation and IGN irradiation was not performed. ACI was defined as the lower edge of the tumor being within 3 cm of the anal verge. Patients were divided into two groups, those with ACI (n = 189, 15.2%) and without ACI (n = 1,057, 84.8%).
The follow-up period was a median of 66 months (range, 3–142 months). Among the 1,246 patients, 10 developed IGN recurrence; 7 with ACI and 3 without ACI. The actuarial IGN recurrence rate at 5 years was 0.7%; 3.5% and 0.2% in patients with and without ACI, respectively (p < 0.001). Isolated IGN recurrence occurred in three patients, all of whom had ACI tumors. These three patients received curative intent local treatments, and one was alive with no evidence of disease 10 years after IGN recurrence. Salvage treatments in the other two patients controlled successfully the IGN recurrence for >5 years, but they developed second malignancy or pelvic and distant recurrences. Seven patients with non-isolated IGN recurrence died of disease at 5–22 months after IGN recurrence.
The low IGN recurrence rate even with ACI and the feasibility of salvage of isolated IGN recurrence indicated that routine elective IGN irradiation is not necessary for rectal cancer with ACI.
PMCID: PMC4299686  PMID: 25533887
Rectal cancer; Radiotherapy; Inguinal lymph node; Anal canal invasion
15.  Signet-ring cell carcinoma arising from a fundic gland polyp in the stomach 
World Journal of Gastroenterology : WJG  2014;20(47):18044-18047.
Fundic gland polyps (FGPs) are currently the most common type of gastric polyps and are usually benign. However, although rare, gastric adenocarcinoma of FGP has been recently proposed as a new variant of gastric adenocarcinoma. Here we report the first case of a 49-year-old woman with focal signet ring cell carcinoma that arose from an FGP of the stomach. The tumor was completely excised by endoscopic snare polypectomy. FGPs should therefore be evaluated for malignant changes although they occur rarely, if the FGP has an erosive or irregular surface.
PMCID: PMC4273157  PMID: 25548505
Fundic gland polyp; Signet ring cell
16.  Increased risk of everolimus-associated acute kidney injury in cancer patients with impaired kidney function 
BMC Cancer  2014;14(1):906.
Everolimus was recently introduced as a second-line treatment for renal cell carcinoma (RCC) and many other cancers. Several prospective studies have shown that serum creatinine levels are increased in a significant proportion of patients receiving everolimus. However, data on the occurrence of acute kidney injury (AKI) during everolimus treatment in clinical practice are sparse. Here, we report the incidence, risk factors, and clinical significance of AKI associated with everolimus treatment in patients with cancer.
We analyzed patients who received everolimus for more than 4 weeks as an anticancer therapy. AKI was defined as increase in creatinine levels from baseline levels greater than 1.5-fold.
The majority of the 110 patients enrolled in this analysis had RCC (N=93, 84.5%). AKI developed in 21 (23%) RCC patients; none of the patients (N=17) with other cancers had AKI. Fourteen of 21 cases were considered to be everolimus-associated AKI, in which there were no other nephrotoxic insults other than everolimus at the onset of AKI. The incidence of AKI increased progressively as baseline estimated glomerular filtration rate (eGFR) decreased (10% in subjects with eGFR >90 mL/min/1.73 m2, 17% in subjects with eGFR 60–90 mL/min/1.73 m2, 28% in subjects with eGFR 30–60 mL/min/1.73 m2, and 100% in subjects with eGFR 15–30 mL/min/1.73 m2; P=0.029 for trend). Baseline eGFR was an independent risk factor for the development of everolimus-associated AKI (hazard ratio per 10 mL/min/1.73 m2 increase, 0.70; 95% confidential interval, 049–1.00; P=0.047). Nine of 14 patients with everolimus-associated AKI continued receiving the drug at a reduced dose or after a short-term off period. Administration of the drug was discontinued in four of 14 patients because of progression of an underlying malignancy. Only one patient stopped taking the drug because of AKI.
This paper suggests that AKI is a common adverse effect of everolimus treatment, especially in subjects with impaired renal function. However, the occurrence of AKI did not require the discontinuation of the drug, and the treatment decision should be made via a multidisciplinary approach, including the assessment of the oncological benefits of everolimus and other therapeutic options.
PMCID: PMC4265483  PMID: 25466872
Everolimus; mTOR inhibitor; Adverse effect; Renal cell carcinoma; Acute kidney injury
17.  Early and late outcomes of total repair of tetralogy of Fallot: risk factors for late right ventricular dilatation 
This study was undertaken to assess the early and long-term results of total repair of tetralogy of Fallot (TOF) and to identify the risk factors associated with late right ventricular (RV) dilatation.
The medical records of 326 patients (male:female = 192:134) who underwent total repair of TOF at Pusan National and Dong-A University Hospitals between July 1991 and May 2011 were retrospectively reviewed. Median age and weight at the time of operation were 13.0 months and 8.7 kg, respectively. Right ventricular end-diastolic dimensions and left ventricular end-diastolic dimensions were obtained during follow-up echocardiography to identify the risk factors associated with late RV dilatation.
There were one operative death (0.3%) and 8 late deaths (2.5%). Of late deaths, two were related to operation-related cardiac problems. Overall survival rates at 5, 10, and 15 years were 97.0%, 95.4%, and 95.4%, and the corresponding freedom from cardiac death were 98.8%, 98.8%, and 98.8%, respectively. Freedom from re-operation and re-intervention were 84.4%, 74.2% and 74.2%. Six patients underwent pulmonary valve replacement during the follow-up period. Transannular patch (P = 0.036) and postoperative ventilator support period (P < 0.001) were found to be significant risk factors of late RV dilatation in multivariate analysis.
Total correction of TOF can be performed with a very low mortality rate. However, the postoperative re-operation or re-intervention rates remain relatively high. Late RV dilatation after total repair of TOF was found to be associated with transannular patch enlargement and a longer postoperative ventilator support period.
PMCID: PMC3829492  PMID: 23956267
Congenital heart disease; Tetralogy of Fallot; Right ventricular dysfunction; Pulmonary regurgitation; Pulmonary valve replacement
18.  Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes 
Autophagy  2013;9(12):2103-2114.
ULK1 (unc-51 like kinase 1) is a serine/threonine protein kinase that plays a key role in regulating the induction of autophagy. Recent studies using autophagy-defective mouse models, such as atg5- or atg7-deficient mice, revealed an important function of autophagy in adipocyte differentiation. Suppression of adipogenesis in autophagy-defective conditions has made it difficult to study the roles of autophagy in metabolism of differentiated adipocytes. In this study, we established autophagy defective-differentiated 3T3-L1 adipocytes, and investigated the roles of Ulk1 and its close homolog Ulk2 in lipid and glucose metabolism using the established adipocytes. Through knockdown approaches, we determined that Ulk1 and Ulk2 are important for basal and MTORC1 inhibition-induced autophagy, basal lipolysis, and mitochondrial respiration. However, unlike other autophagy genes (Atg5, Atg13, Rb1cc1/Fip200, and Becn1) Ulk1 was dispensable for adipogenesis without affecting the expression of CCAAT/enhancer binding protein α (CEBPA) and peroxisome proliferation-activated receptor gamma (PPARG). Ulk1 knockdown reduced fatty acid oxidation and enhanced fatty acid uptake, the metabolic changes that could contribute to adipogenesis, whereas Ulk2 knockdown had opposing effects. We also found that the expression levels of insulin receptor (INSR), insulin receptor substrate 1 (IRS1), and glucose transporter 4 (SLC2A4/GLUT4) were increased in Ulk1-silenced adipocytes, which was accompanied by upregulation of insulin-stimulated glucose uptake. These results suggest that ULK1, albeit its important autophagic role, regulates lipid metabolism and glucose uptake in adipocytes distinctly from other autophagy proteins.
PMCID: PMC4028344  PMID: 24135897
ULK1; ULK2; mTORC1; adipogenesis; adipocytes; lipid metabolism
19.  Murine Gammaherpesvirus 68 Encoding Open Reading Frame 11 Targets TANK Binding Kinase 1 To Negatively Regulate the Host Type I Interferon Response 
Journal of Virology  2014;88(12):6832-6846.
Upon viral infection, type I interferons, such as alpha and beta interferon (IFN-α and IFN-β, respectively), are rapidly induced and activate multiple antiviral genes, thereby serving as the first line of host defense. Many DNA and RNA viruses counteract the host interferon system by modulating the production of IFNs. In this study, we report that murine gammaherpesvirus 68 (MHV-68), a double-stranded DNA virus, encodes open reading frame 11 (ORF11), a novel immune modulator, to block IFN-β production. ORF11-deficient recombinant viruses induced more IFN-β production in fibroblast and macrophage cells than the MHV-68 wild type or a marker rescue virus. MHV-68 ORF11 decreased IFN-β promoter activation by various factors, the signaling of which converges on TBK1-IRF3 activation. MHV-68 ORF11 directly interacted with both overexpressed and endogenous TBK1 but not with IRF3. Physical interactions between ORF11 and endogenous TBK1 were further confirmed during virus replication in fibroblasts using a recombinant virus expressing FLAG-ORF11. ORF11 efficiently reduced interaction between TBK1 and IRF3 and subsequently inhibited activation of IRF3, thereby negatively regulating IFN-β production. Our domain-mapping study showed that the central domain of ORF11 was responsible for both TBK1 binding and inhibition of IFN-β induction, while the kinase domain of TBK1 was sufficient for ORF11 binding. Taken together, these results suggest a mechanism underlying inhibition of IFN-β production by a gammaherpesvirus and highlight the importance of TBK1 in DNA virus replication.
IMPORTANCE Gammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors. Upon virus infection, the type I interferon pathway is activated by a series of signaling molecules and stimulates antiviral gene expression. To subvert such interferon antiviral responses, viruses are equipped with multiple factors that can inhibit its critical steps. In this study, we took an unbiased genomic approach using a mutant library of murine gammaherpesvirus 68 to screen a novel viral immune modulator that negatively regulates the type I interferon pathway and identified ORF11 as a strong candidate. ORF11-deficient virus infection produced more interferon than the wild type in both fibroblasts and macrophages. During virus replication, ORF11 directly bound to TBK1, a key regulatory protein in the interferon pathway, and inhibited TBK1-mediated interferon production. Our results highlight a crucial role of TBK1 in controlling DNA virus infection and a viral strategy to curtail host surveillance.
PMCID: PMC4054366  PMID: 24696485
20.  Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk 
Nature genetics  2014;46(6):533-542.
Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted the largest genome-wide association study in East Asians with 14,963 CRC cases and 31,945 controls and identified six new loci associated with CRC risk (P = 3.42 × 10−8 to 9.22 × 10−21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcription regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9) and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC loci. Our study provides insights into the genetic basis of CRC and suggests new biological pathways.
PMCID: PMC4068797  PMID: 24836286
21.  Ductal Carcinoma Arising from Ectopic Breast Tissue Following Microcalcification Observed on Screening Mammography: A Case Report and Review of the Literature 
Journal of Breast Cancer  2014;17(4):393-396.
Ectopic breast tissue can occur anywhere along the incompletely regressed mammary ridge. Among the various types of breast choristoma, ectopic breast tissue, which has only glandular tissue without a nipple or areola, is most commonly detected in axillary areas. However, ectopic breast cancer is often not detected until significant clinical symptoms have been revealed, or diagnosis is delayed. Furthermore, an examination of ectopic breast tissue tends to be omitted from a screening mammography. Especially, the microcalcifications of ectopic breast tissue are difficult to delineate on mammography. Herein, the authors report a case of ectopic breast carcinoma that showed clustered microcalcifications on screening mammography, and discuss the interpretation and implications of microcalcification in ectopic breast tissue.
PMCID: PMC4278060  PMID: 25548589
Breast; Calcification; Choristoma
22.  Ventricular arrhythmia in patients with prolonged QT interval during liver transplantation: two cases report 
Korean Journal of Anesthesiology  2014;67(6):416-420.
QT interval prolongation is associated with an increased risk of ventricular arrhythmia in various conditions. Cardiac electrophysiologic abnormalities including QT interval prolongation are well documented in patients with advanced liver cirrhosis. We report two cases of patients with QT interval prolongation on preoperative electrocardiography who exhibited repetitive ventricular arrhythmias with significant hemodynamic deterioration during liver transplantation. For the treatment and prevention of ventricular arrhythmias during the intraoperative period, we performed intravenous administration of lidocaine and isoproterenol, corrected imbalances of electrolytes including potassium and magnesium, and prepared a defibrillator. These cases emphasize that preoperative recognition of QT interval prolongation and adequate management to prevent fatal arrhythmias are important in patients undergoing liver transplantation.
PMCID: PMC4280480  PMID: 25558343
Arrhythmia; Intraoperative complications; Liver transplantation
23.  In vivo verification of regional hyperthermia in the liver 
Radiation Oncology Journal  2014;32(4):256-261.
We performed invasive thermometry to verify the elevation of local temperature in the liver during hyperthermia.
Materials and Methods
Three 40-kg pigs were used for the experiments. Under general anesthesia with ultrasonography guidance, two glass fiber-optic sensors were placed in the liver, and one was placed in the peritoneal cavity in front of the liver. Another sensor was placed on the skin surface to assess superficial cooling. Six sessions of hyperthermia were delivered using the Celsius TCS electro-hyperthermia system. The energy delivered was increased from 240 kJ to 507 kJ during the 60-minute sessions. The inter-session cooling periods were at least 30 minutes. The temperature was recorded every 5 minutes by the four sensors during hyperthermia, and the increased temperatures recorded during the consecutive sessions were analyzed.
As the animals were anesthetized, the baseline temperature at the start of each session decreased by 1.3℃ to 2.8℃ (median, 2.1℃). The mean increases in temperature measured by the intrahepatic sensors were 2.42℃ (95% confidence interval [CI], 1.70-3.13) and 2.67℃ (95% CI, 2.05-3.28) during the fifth and sixth sessions, respectively. The corresponding values for the intraperitoneal sensor were 2.10℃ (95% CI, 0.71-3.49) and 2.87℃ (1.13-4.43), respectively. Conversely, the skin temperature was not increased but rather decreased according to application of the cooling system.
We observed mean 2.67℃ and 2.87℃ increases in temperature at the liver and peritoneal cavity, respectively, during hyperthermia. In vivo real-time thermometry is useful for directly measuring internal temperature during hyperthermia.
PMCID: PMC4283000  PMID: 25568854
Hyperthermia; Thermometry; Radiation therapy; Liver
24.  Using Growth Hormone Levels to Detect Macroadenoma in Patients with Acromegaly 
Endocrinology and Metabolism  2014;29(4):450-456.
The aim of this study was to assess the clinical differences between acromegalic patients with microadenoma and patients with macroadenoma, and to evaluate the predictive value of growth hormone (GH) levels for early detection of macroadenoma.
We performed a retrospective analysis of 215 patients diagnosed with a GH-secreting pituitary adenoma. The patients were divided into two groups: the microadenoma group and the macroadenoma group, and the clinical parameters were compared between these two groups. The most sensitive and specific GH values for predicting macroadenoma were selected using receiver operating characteristic (ROC) curves.
Compared with the microadenoma group, the macroadenoma group had a significantly younger age, higher body mass index, higher prevalence of hyperprolactinemia and hypogonadism, and a lower proportion of positive suppression to octreotide. However, there were no significant differences in the gender or in the prevalence of diabetes between the two groups. The tumor diameter was positively correlated with all GH values during the oral glucose tolerance test (OGTT). All GH values were significantly higher in the macroadenoma group than the microadenoma group. Cut-off values for GH levels at 0, 30, 60, 90, and 120 minutes for optimal discrimination between macroadenoma and microadenoma were 5.6, 5.7, 6.3, 6.0, and 5.8 ng/mL, respectively. ROC curve analysis revealed that the GH value at 30 minutes had the highest area under the curve.
The GH level of 5.7 ng/mL or higher at 30 minutes during OGTT could provide sufficient information to detect macroadenoma at the time of diagnosis.
PMCID: PMC4285038  PMID: 25325263
Acromegaly; Microadenoma; Macroadenoma; Growth hormone; Glucose tolerance test
25.  Uncut Roux-en-Y Reconstruction after Laparoscopic Distal Gastrectomy Can Be a Favorable Method in Terms of Gastritis, Bile Reflux, and Gastric Residue 
Journal of Gastric Cancer  2014;14(4):229-237.
Laparoscopic distal gastrectomy (LDG) is a well-established procedure for the treatment of early gastric cancer. Several reconstruction methods can be adopted after LDG according to tumor characteristics and surgeon preference. This study aimed to compare the remnant gastric functions after different reconstructions.
Materials and Methods
In total, 221 patients who underwent LDG between March 2005 and October 2013 were reviewed retrospectively. The patients were classified into four groups based on the reconstructive procedure: Billroth I (BI) anastomosis, Billroth II (BII) with Braun anastomosis, Roux-en-Y (RY) reconstruction, or uncut RY reconstruction. Patient demographics, surgical outcomes, and postoperative endoscopic findings were reviewed and compared among groups.
Endoscopic evaluations at 11.8±3.8 months postoperatively showed less frequent gastritis and bile reflux in the remnant stomach in the RY group compared to the BI and BII groups. There was no significant difference in the gastric residue among the BI, BII, and RY groups. The incidence of gastritis and bile reflux in the uncut RY group was similar to that in the RY group, while residual gastric content in the uncut RY group was significantly smaller and less frequently observed than that in the RY group (5.8% versus 35.3%, P=0.010).
RY and uncut RY reconstructions are equally superior to BI and BII with Braun anastomoses in terms of gastritis and bile reflux in the remnant stomach. Furthermore, uncut RY reconstruction showed improved stasis compared to conventional RY gastrojejunostomy. Uncut RY reconstruction can be a favorable reconstructive procedure after LDG.
PMCID: PMC4286901  PMID: 25580354
Stomach neoplasms; Gastrectomy; Reconstructive surgical procedures; Anastomosis, Roux-en-Y; Bile reflux

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