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1.  Mitochondrial DNA Copy Number in Peripheral Blood Is Independently Associated with Visceral Fat Accumulation in Healthy Young Adults 
Aims. Visceral obesity is associated with an increased risk of cardiometabolic diseases and it is important to identify the underlying mechanisms. There is growing evidence that mitochondrial dysfunction is associated with metabolic disturbances related to visceral obesity. In addition, maintaining mitochondrial DNA (mtDNA) copy number is important for preserving mitochondrial function. Therefore, we investigated the relationship between mtDNA copy number and visceral fat in healthy young adults. Methods. A total of 94 healthy young subjects were studied. Biomarkers of metabolic risk factors were assessed along with body composition by computed tomography. mtDNA copy number was measured in peripheral leukocytes using real-time polymerase chain reaction (PCR) methods. Results. The mtDNA copy number correlated with BMI (r = −0.22, P = 0.04), waist circumference (r = −0.23, P = 0.03), visceral fat area (r = −0.28, P = -0.01), HDL-cholesterol levels (r = 0.25, P = 0.02), and hs-CRP (r = 0.32, P = 0.02) after adjusting for age and sex. Both stepwise and nonstepwise multiple regression analyses confirmed that visceral fat area was independently associated with mtDNA copy number (β = -0.33, P < 0.01, β = 0.32, and P = 0.03, resp.). Conclusions. An independent association between mtDNA content and visceral adiposity was identified. These data suggest that mtDNA copy number is a potential predictive marker for metabolic disturbances. Further studies are required to understand the causality and clinical significance of our findings.
PMCID: PMC3953665
2.  MR Findings of the Osteofibrous Dysplasia 
Korean Journal of Radiology  2014;15(1):114-122.
The aim of this study was to describe MR findings of osteofibrous dysplasia.
Materials and Methods
MR images of 24 pathologically proven osteofibrous dysplasia cases were retrospectively analyzed for a signal intensity of the lesion, presence of intralesional fat signal, internal hypointense band, multilocular appearance, cortical expansion, intramedullary extension, cystic area, cortical breakage and extraosseous extension, abnormal signal from the adjacent bone marrow and soft tissue and patterns of contrast enhancement.
All cases of osteofibrous dysplasia exhibited intermediate signal intensity on T1-weighted images. On T2-weighted images, 20 and 4 cases exhibited heterogeneously intermediate and high signal intensity, respectively. Intralesional fat was identified in 12% of the cases. Internal low-signal bands and multilocular appearance were observed in 91%. Cortical expansion was present in 58%. Intramedullary extension was present in all cases, and an entire intramedullary replacement was observed in 33%. Cortical breakage (n = 3) and extraosseous mass formation (n = 1) were observed in cases with pathologic fractures only. A cystic area was observed in one case. Among 21 cases without a pathologic fracture, abnormal signal intensity in the surrounding bone marrow and adjacent soft tissue was observed in 43% and 48%, respectively. All cases exhibited diffuse contrast enhancement.
Osteofibrous dysplasia exhibited diverse imaging features ranging from lesions confined to the cortex to more aggressive lesions with complete intramedullary involvement or perilesional marrow edema.
PMCID: PMC3909842  PMID: 24497800
Osteofibrous dysplasia; Bone neoplasms; Magnetic resonance imaging
3.  Up-Regulation of Cyclooxygenase 2 and Matrix Metalloproteinases-2 and -9 in Cutaneous Squamous Cell Carcinoma: Active Role of Inflammation and Tissue Remodeling in Carcinogenesis 
Annals of Dermatology  2013;25(2):145-151.
Tissue inflammation and remodeling have been extensively studied in various tumors in relation with their invasiveness and metastasis.
The purpose of this study was to investigate the change in tissue inflammation and remodeling markers in cutaneous squamous cell carcinoma (SCC).
Expression levels of cyclooxygenase-2 (COX-2) as an inflammatory marker and matrix metalloproteinases-2 and -9 (MMPs 2/9) as remodeling markers were studied in mouse and human SCCs. Western blot analysis and RT-PCR for COX-2 and MMPs 2/9 were performed with skin samples from SCC patients and chronic ultraviolet B (UVB)-induced SCC from hairless mice.
mRNA and protein levels of COX-2 and MMPs 2/9 were up-regulated with the higher sensitivity for MMP-9 in mouse SCCs, which were induced by chronic UVB irradiation. Consistently, COX-2 and MMPs 2/9 were up-regulated with the higher sensitivity for MMP-9 in human SCCs.
COX-2 and MMPs 2/9 are up-regulated in well-differentiated cutanous SCC. Our findings indicate that inflammatory and tissue remodeling processes are actively induced during carcinogenesis of cutaneous SCC.
PMCID: PMC3662905  PMID: 23717003
Cyclooxygenase 2; MMP-2; MMP-9; SCC
5.  Empty follicle syndrome 
Empty follicle syndrome (EFS) is a condition in which no oocytes are retrieved after an apparently adequate ovarian response to stimulation and meticulous follicular aspiration. EFS can be classified into 'genuine' and 'false' types according to hCG levels. It is a rare condition of obscure etiology. The existence of genuine EFS has been questioned and is still controversial. The limitation around EFS is that the definition of EFS is obscure. Management of patients with EFS is a challenge to physicians. No single treatment is known to be universally effective. However, patients should be adequately informed regarding the importance of correct hCG administration because improper hCG administration is a common and preventable cause of EFS. EFS is a syndrome that deserves additional study because such investigation could lead to a further understanding of ovarian biology and infertility.
PMCID: PMC3548070  PMID: 23346522
Infertility; Ovarian stimulation; Retrieval; Oocyte; Chorionic gonadotropin
6.  Complete Genome Sequence of Bacteriophage phiAS7, a T7-Like Virus That Infects Aeromonas salmonicida subsp. salmonicida 
Journal of Virology  2012;86(5):2894-2895.
To date, a number of Myoviridae bacteriophages that infect Aeromonadaceae have been identified and characterized. However, the genome sequences of Aeromonas phages that not belong to the Myoviridae have not been investigated yet. Herein, we report the complete genome sequence of Aeromonas phage phiAS7, which belongs to the Podoviridae and infects Aeromonas salmonicida subsp. salmonicida.
PMCID: PMC3302256  PMID: 22328699
7.  In vitro growth of mouse preantral follicles: effect of animal age and stem cell factor/insulin-like growth factor supplementation 
To determine whether animal age impacts in vitro preantral follicle growth. Effects of hCG, stem cell factor (SCF), and/or insulin-like growth factor (IGF) supplementation in growth medium were also investigated.
Intact preantral follicles were mechanically isolated from fresh ovaries of BDF1 mice and cultured in growth medium for 9 to 11 days. Surviving follicles with antrum formation were transferred to maturation medium for 14 to 18 hours. Follicle survival, antrum formation, and retrieval of metaphase II (MII) oocytes were compared among three age categories (4-5, 7-8, and 10-11 week-old). By using 7- to 8-week-old mice, preantral follicles were cultured in growth medium supplemented with hCG (0, 5, or 10 mIU/mL), SCF (50 ng/mL), IGF-1 (50 ng/mL), and SCF+IGF-1.
Seven- to eight-week-old mice showed a higher follicle survival and antrum formation and produced more MII oocytes compared to other groups. In the 7- to 8-week-old mice, supplementation of 5 mIU/mL hCG significantly enhanced the antrum formation but the percentage of MII oocytes was similar to that of the control. Supplementation of SCF+IGF-1 did not enhance follicle survival or antrum formation but the percentage of MII oocytes increased modestly (39.1%) than in the control (28.6%, statistically not significant).
Seven- to eight-week-old mice showed better outcomes in growth of preantral follicles in vitro than 4- to 5- or 10- to 11-week-old mice. Supplementation of hCG enhanced antrum formation and supplementation of SCF+IGF-1 yielded more mature oocytes; hence, these should be considered in the growth of preantral follicles in vitro.
PMCID: PMC3479233  PMID: 23106041
Ovarian follicle; Oocyte; Age groups; Stem cell factor; Insulin-like growth factor
8.  Serum Ferritin Is Differentially Associated with Anti-oxidative Status and Insulin Resistance in Healthy Obese and Non-obese Women 
Korean Journal of Family Medicine  2012;33(4):205-210.
Ferritin is known to be associated with insulin resistance (IR) and oxidative stress; however, recent studies have shown that there is an association between ferritin and anti-oxidative status. To date, the biphasic response of ferritin to oxidative stress has not been fully evaluated. Thus, we investigated the association between ferritin and IR and anti-oxidative status in obese and non-obese women.
We evaluated the homeostasis model assessment of insulin resistance (HOMA-IR) and total anti-oxidant status (TAS) in a total of 111 healthy women between the ages of 32 and 68 years.
In all of the study subjects, ferritin levels were positively correlated with age (r = 0.38, P < 0.001), body mass index (r = 0.24, P = 0.01), TAS (r = 0.38, P < 0.001) and HOMA-IR (r = 0.20, P = 0.04). In the subgroup analysis, ferritin levels were correlated with age (r = 0.39, P < 0.001) and TAS (r = 0.43, P < 0.001) in the non-obese group and with insulin (r = 0.50, P = 0.02) and HOMA-IR (r = 0.52, P = 0.01) levels in the obese group. On stepwise multiple linear regression analysis, ferritin was found to be independently associated with TAS (B = 177.16, P < 0.0001) in the non-obese group and independently associated with HOMA-IR (B = 30.36, P = 0.01) in the obese group.
Our findings suggest ferritin is associated with IR in obese women and with anti-oxidative status in non-obese women. Further studies are warranted to elucidate the precise role of ferritin in obesity.
PMCID: PMC3418339  PMID: 22916322
Ferritins; Obesity; Oxidative Stress
9.  Serum biomarkers for predicting pregnancy outcome in women undergoing IVF: human chorionic gonadotropin, progesterone, and inhibin A level at 11 days post-ET 
This study was performed to assess the prognostic value of serum hCG, progesterone, and inhibin A levels measured at 11 days post-ET for predicting pregnancy outcome in women participating in IVF.
Between May 2005 and April 2008, sera were obtained from 70 infertile women who underwent IVF-ET at 11 days post-ET and stored. HCG, progesterone, and inhibin A levels were measured by commercial enzyme-linked immunosorbent assay kits. The predictive accuracy of hCG, progesterone, and inhibin A levels for establishment of intrauterine pregnancy and ongoing pregnancy was calculated by receiver-operating characteristic curve analysis.
For the prediction of intrauterine and ongoing pregnancy, serum hCG was better than progesterone and inhibin A. The predictive performance of progesterone and inhibin A was similar. The serum progesterone and inhibin A levels were significantly correlated each other (r=0.915, p=0.010).
A single measurement of the serum hCG level is sufficient to predict pregnancy outcome in IVF-ET patients.
PMCID: PMC3341449  PMID: 22563548
Chorionic gonadotropin; Progesterone; Inhibins; In vitro fertilization; Embryo transfer; Outcomes, pregnancy
10.  A Clinical Study of Cutaneous Adverse Reactions to Nonionic Contrast Media in Korea 
Annals of Dermatology  2012;24(1):22-25.
The use of intravenous contrast media (CM) has increased for the diagnosis of several diseases. The newly developed low osmolar nonionic contrast agents cause significantly decreased adverse reactions than the higher osmolar ones. However, adverse reactions may still occur, ranging in severity from minor side effects to severe complications. However, there have been few reports about cutaneous adverse reactions (CARs) to nonionic monomer CM.
The purpose of this study was to evaluate clinical features of CAR to intravenous nonionic monomer CM.
A total 47,338 examinees underwent intravenous iodinated contrast-enhanced computed tomography scan using nonionic monomer CM. Among the adverse reactions to the CM, we divided them into cutaneous or noncutaneous and immediate (<1 hr) or late (≥1 hr) adverse reactions.
Adverse reactions were noted in 62 cases out of the total 47,338 cases; 50 cases (80.7%) were categorized CARs. Among them, there were 24 male and 26 female patients. There was no significant difference between the sexes, and CARs occurred in all age groups. The highest occurrence was in the age range of 50~59 years. CARs included urticaria (78%), angioedema (10%), maculopapular rash (8%), erythema (2%), and pruritus without rash (2%). Immediate reactions were 92% (46 cases), while late reactions were 8% (4 cases).
CARs to nonionic monomer CM accounted for most of the adverse reactions (80.7%) and urticaria was the most common.
PMCID: PMC3283846  PMID: 22363151
Contrast media; CT; Cutaneous adverse reaction
11.  Molecular characterization of tetracycline- and quinolone-resistant Aeromonas salmonicida isolated in Korea 
Journal of Veterinary Science  2011;12(1):41-48.
The antibiotic resistance of 16 Aeromonas (A.) salmonicida strains isolated from diseased fish and environmental samples in Korea from 2006 to 2009 were investigated in this study. Tetracycline or quinolone resistance was observed in eight and 16 of the isolates, respectively, based on the measured minimal inhibitory concentrations. Among the tetracycline-resistant strains, seven of the isolates harbored tetA gene and one isolate harbored tetE gene. Additionally, quinolone-resistance determining regions (QRDRs) consisting of the gyrA and parC genes were amplified and sequenced. Among the quinolone-resistant A. salmonicida strains, 15 harbored point mutations in the gyrA codon 83 which were responsible for the corresponding amino acid substitutions of Ser83→Arg83 or Ser83→Asn83. We detected no point mutations in other QRDRs, such as gyrA codons 87 and 92, and parC codons 80 and 84. Genetic similarity was assessed via pulsed-field gel electrophoresis, and the results indicated high clonality among the Korean antibiotic-resistant strains of A. salmonicida.
PMCID: PMC3053466  PMID: 21368562
Aeromonas salmonicida; minimal inhibitory concentration; pulsed-field gel electrophoresis; quinolone-resistance determining region; tetracycline-resistance
12.  Lateral Decubitus Positioning Stereotactic Vacuum-Assisted Breast Biopsy with True Lateral Mammography 
Journal of Breast Cancer  2011;14(1):64-68.
Stereotactic vacuum-assisted breast biopsy (VAB) has been used to evaluate microcalcifications or non-palpable breast lesions on mammography. Although stereotactic VAB is usually performed in a prone or upright position, an expensive prone table is necessary and vasovagal reactions often occur during the procedure. For these reasons, the lateral decubitus position can be applied for stereotactic VAB, and true lateral mammography can be used to detect the lesion. We report on 15 cases of lateral decubitus positioning for stereotactic VAB with true lateral mammography for non-palpable breast lesions or microcalcifications. The mean procedure time was approximately 30.1 minutes, and no complications occurred during the procedures. Fourteen cases had benign breast lesions and one case had a ductal carcinoma in situ. The lateral decubitus stereotactic VAB with true lateral mammography can be applied for microcalcifications or non-palpable breast lesions and helps to minimize anxiety and vasovagal reactions in patients.
PMCID: PMC3148512  PMID: 21847397
Stereotactic techniques; Breast biopsy; Lateral positioning; Mammography
13.  Sequence and structure of Brassica rapa chromosome A3 
Genome Biology  2010;11(9):R94.
The species Brassica rapa includes important vegetable and oil crops. It also serves as an excellent model system to study polyploidy-related genome evolution because of its paleohexaploid ancestry and its close evolutionary relationships with Arabidopsis thaliana and other Brassica species with larger genomes. Therefore, its genome sequence will be used to accelerate both basic research on genome evolution and applied research across the cultivated Brassica species.
We have determined and analyzed the sequence of B. rapa chromosome A3. We obtained 31.9 Mb of sequences, organized into nine contigs, which incorporated 348 overlapping BAC clones. Annotation revealed 7,058 protein-coding genes, with an average gene density of 4.6 kb per gene. Analysis of chromosome collinearity with the A. thaliana genome identified conserved synteny blocks encompassing the whole of the B. rapa chromosome A3 and sections of four A. thaliana chromosomes. The frequency of tandem duplication of genes differed between the conserved genome segments in B. rapa and A. thaliana, indicating differential rates of occurrence/retention of such duplicate copies of genes. Analysis of 'ancestral karyotype' genome building blocks enabled the development of a hypothetical model for the derivation of the B. rapa chromosome A3.
We report the near-complete chromosome sequence from a dicotyledonous crop species. This provides an example of the complexity of genome evolution following polyploidy. The high degree of contiguity afforded by the clone-by-clone approach provides a benchmark for the performance of whole genome shotgun approaches presently being applied in B. rapa and other species with complex genomes.
PMCID: PMC2965386  PMID: 20875114
14.  A Case of Complication after Matridex® Injection 
Annals of Dermatology  2010;22(1):81-84.
Matridex® is an injectable skin filler that's composed of a mixture of cross linked hyaluronic acid and dextranomer particles, and it was recently developed for soft tissue augmentation. To the best of our knowledge, there have been few previous reports on complications associated with Matridex. We report here on a delayed inflammatory reaction to an injection of Matridex in the glabellar fold, and this developed five weeks after the injection and it lasted more than a year. The patient was treated with oral doxycycline and intralesional injection of triamcinolone acetonide; this resulted in almost complete resolution of the lesion. The patient should be informed of the potential complications with the use of injectable fillers before treatment, for it could lead to undesirable aesthetic consequences.
PMCID: PMC2883406  PMID: 20548890
Complication; Delayed inflammatory reaction; Filler; Matridex
15.  Necrotizing Fasciitis versus Pyomyositis: Discrimination with Using MR Imaging 
Korean Journal of Radiology  2009;10(2):121-128.
We wanted to evaluate the MR findings for differentiating between necrotizing fasciitis (NF) and pyomyositis (PM).
Materials and Methods
The MR images of 19 patients with surgically confirmed NF (n = 11) and pathologically confirmed PM (n = 8) were retrospectively reviewed with regard to the presence or absence of any MRI finding criteria that could differentiate between them.
The patients with NF had a significantly greater prevalence of the following MR findings (p < 0.05): a peripheral band-like hyperintense signal in muscles on fat-suppressed T2-weighted images (73% of the patients with NF vs. 0% of the patients with PM), peripheral band-like contrast enhancement (CE) of muscles (82% vs. 0%, respectively) and thin smooth enhancement of the deep fascia (82% vs. 13%, respectively). The patients with PM had a significantly greater prevalence of the following MRI findings (p < 0.05): a diffuse hyperintense signal in muscles on fat-suppressed T2-weighted images (27% of the patients with NF vs. 100% in the patients with PM), diffuse CE of muscles (18% vs. 100%, respectively), thick irregular enhancement of the deep fascia (0% vs. 75%, respectively) and intramuscular abscess (0% vs. 88%, respectively). For all patients with NF and PM, the superficial fascia and muscle showed hyperintense signals on T2-weighted images and CE was seen on fat-suppressed CE T1-weighted images. The subcutaneous tissue and deep fascia showed hyperintense signals on T2-weighted images and CE was seen in all the patients with NF and in seven (88%) of the eight patients with PM, respectively.
MR imaging is helpful for differentiating between NF and PM.
PMCID: PMC2651441  PMID: 19270857
Soft tissue; Infection; Necrotizing fasciitis; Pyomyositis, MR
16.  Multiple Sclerosis and Peripheral Multifocal Demyelinating Neuropathies Occurring in a Same Patient 
The co-occurrence of multiple sclerosis and peripheral demyelinating neuropathy is rare. It has been disputed whether these are pathologically related or coincidental findings. We report a 36-year-old woman who presented with diplopia, right facial palsy and left-sided weakness. Brain magnetic resonance imaging showed a lesion indicative of central demyelinating disease. Nerve conduction studies revealed peripheral multifocal demyelinating neuropathies. We suggest that the central and the peripheral lesions may be continua of a demyelinating process.
PMCID: PMC2686880  PMID: 19513326
Multiple sclerosis; Demyelinating neuropathy; Conduction block
17.  Identification of Enteroviruses by Using Monoclonal Antibodies against a Putative Common Epitope 
Journal of Clinical Microbiology  2003;41(7):3028-3034.
A common epitope region of enteroviruses was identified by sequence-independent single-primer amplification (SISPA), followed by immunoscreening of 11 cDNA libraries from two Korean enterovirus isolates (echoviruses 7 and 30) and a coxsackievirus B3 (ATCC-VR 30). The putative common epitope region was localized in the N terminus of VP1 when the displayed recombinant proteins from the phages were chased by the convalescent-phase sera. The genomic region encoding the common epitope region was amplified and then expressed by using the vector pGEX-5X-1. The antigenicity of the expressed recombinant protein was identified by Western blotting with guinea pig antisera for six different serotypes of enteroviruses. After successive immunization of mice with the recombinant common epitope protein, splenocytes were extracted and hybridized with P3X63-Ag8-653 cells. A total of 24 hybridomas that produced monoclonal antibodies (MAbs) against the putative common epitope of enteroviruses were selected. Four of these were immunoglobulin G1 isotypes with a kappa light chain. These MAbs recognized 15 Korean endemic serotypes and prototypes of enteroviruses in an indirect immunofluorescence assay. These results suggest that the expressed protein might be a useful antigen for producing group common antibodies and that the use of the MAbs against the putative common epitope of enteroviruses might be a valuable diagnostic tool for rapidly identifying a broad range of enteroviruses.
PMCID: PMC165318  PMID: 12843038
18.  What physicians should know about the management of chronic hepatitis B in children: East side story 
Understanding the natural course of chronic hepatitis B virus (HBV) infection is very important for the management and treatment of chronic hepatitis B in children. Based on treatment guidelines, the management of HBV carriers and treatment of active hepatitis have been advancing and resulted in increased survival, as well as decreased risks of complications such as liver cirrhosis and hepatocellular carcinoma. Development of a continuing medical education (CME) program for primary physicians becomes an important responsibility of pediatric hepatologists. CME could prevent misdiagnosis and unnecessary treatment that could lead to liver complications or antiviral resistance. In addition, education of patients and their parents is necessary to achieve better therapeutic outcomes.
PMCID: PMC3974525
Hepatitis B virus; Natural course; Diagnosis; Treatment; Lamivudine; Resistance
19.  Effect of Bcl-2 rs956572 SNP on regional gray matter volumes and cognitive function in elderly males without dementia 
Age  2011;35(2):343-352.
The Bcl-2 gene is a major regulator of neural plasticity and cellular resilience. A single-nucleotide polymorphism (SNP) in the Bcl-2 gene, Bcl-2 rs956572, significantly modulates the expression of Bcl-2 protein and cellular vulnerability to apoptosis. This study investigated the association between the Bcl-2 rs956572 SNP and brain structural abnormalities in non-demented elders, and to test the relationship between neuropsychological performance and regional gray matter (GM) volumes. Our sample comprised 97 non-demented elderly men with a mean age of 80.6 ± 5.6 years (range, 65 to 92 years). Cognitive test results, magnetic resonance imaging, and genotyping of Bcl-2 rs956572 were examined for each subject. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. Subjects with G homozygotes exhibited significantly worse performance in the language domain of the Cognitive Abilities Screening Instrument (CASI; p = 0.009). They also showed significantly smaller GM volumes in the right middle temporal gyrus (MTG) (BA 21), but larger GM volumes in the left precuneus (BA 31), right lingual gyrus (BA 18), and left superior occipital gyrus (BA 19) relative to A-allele carriers (p < 0.001). A trend toward a positive correlation between right MTG GM volumes and the language domain of CASI was also evident (r = 0.181; p = 0.081). The findings suggest that Bcl-2 rs956572 SNP may modulate cognitive function and regional GM volume in non-demented elderly men, and that this polymorphism may affect language performance through its effect on the right MTG.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9367-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3592959  PMID: 22198673
Bcl-2; MRI; Volumetry; Cognition; Aged; Polymorphism
20.  X- linked markers in DMD associated with oral clefts 
As part of an international consortium, case-parent trios were collected for a genome wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP) and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes, environmental factors, and differs markedly by gender. Family based association tests (FBAT) were used on 14,486 SNPs spanning the X chromosome, stratified by type of cleft and racial group. Significant results even after multiple comparisons correction were obtained for the Duchene’s muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P trios (both CL and CLP combined). When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asians. Although conventional sliding window haplotype analysis showed no increase in significance, analysis selected combinations of the 25 most significant SNPs in DMD identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within DMD.
PMCID: PMC3600648  PMID: 23489894
oral clefts; case-parent trios; X-linked; family-based association; DMD
21.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis 
Peters, Ulrike | Jiao, Shuo | Schumacher, Fredrick R. | Hutter, Carolyn M. | Aragaki, Aaron K. | Baron, John A. | Berndt, Sonja I. | Bézieau, Stéphane | Brenner, Hermann | Butterbach, Katja | Caan, Bette J. | Campbell, Peter T. | Carlson, Christopher S. | Casey, Graham | Chan, Andrew T. | Chang-Claude, Jenny | Chanock, Stephen J. | Chen, Lin S. | Coetzee, Gerhard A. | Coetzee, Simon G. | Conti, David V. | Curtis, Keith R. | Duggan, David | Edwards, Todd | Fuchs, Charles S. | Gallinger, Steven | Giovannucci, Edward L. | Gogarten, Stephanie M. | Gruber, Stephen B. | Haile, Robert W. | Harrison, Tabitha A. | Hayes, Richard B. | Henderson, Brian E. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Hunter, David J. | Jackson, Rebecca D. | Jee, Sun Ha | Jenkins, Mark A. | Jia, Wei-Hua | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | Lacroix, Andrea Z. | Laurie, Cathy C. | Laurie, Cecelia A. | Le Marchand, Loic | Lemire, Mathieu | Levine, David | Lindor, Noralane M. | Liu, Yan | Ma, Jing | Makar, Karen W. | Matsuo, Keitaro | Newcomb, Polly A. | Potter, John D. | Prentice, Ross L. | Qu, Conghui | Rohan, Thomas | Rosse, Stephanie A. | Schoen, Robert E. | Seminara, Daniela | Shrubsole, Martha | Shu, Xiao-Ou | Slattery, Martha L. | Taverna, Darin | Thibodeau, Stephen N. | Ulrich, Cornelia M. | White, Emily | Xiang, Yongbing | Zanke, Brent W. | Zeng, Yi-Xin | Zhang, Ben | Zheng, Wei | Hsu, Li
Gastroenterology  2012;144(4):799-807.e24.
Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7).
In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID: PMC3636812  PMID: 23266556
Colon Cancer; Genetics; Risk Factors; SNP
22.  Long-term stabilization of leptomeningeal disease with whole-brain radiation therapy in a patient with metastatic melanoma treated with vemurafenib: a case report 
Melanoma research  2013;23(2):10.1097/CMR.0b013e32835e589c.
We present a patient with metastatic BRAF-mutated melanoma who achieved long-term stabilization of leptomeningeal disease with sequential whole-brain radiation therapy and vemurafenib. A 53-year-old woman with melanoma that harboured the BRAF V600E mutation and had that metastasized to multiple lymph nodes, both lungs, one breast, and subcutaneous tissue had developed symptomatic leptomeningeal disease 16 months after starting vemurafenib treatment despite achieving a substantial response at the existing metastatic sites. Vemurafenib was discontinued for 7 days, she received whole-brain radiation therapy (30 Gy in 10 fractions), and 7 days after completing the radiation therapy, she resumed vemurafenib therapy. The neurologic symptoms improved significantly, and a cerebrospinal fluid examination revealed disappearance of melanoma cells. She remained alive with radiologically stable leptomeningeal disease for at least 18 months after the whole-brain radiation therapy.
PMCID: PMC3880202  PMID: 23358426
metastatic melanoma; leptomeningeal disease; radiation therapy; vemurafenib
23.  Routes of Allergic Sensitization and Myeloid Cell IKKβ Differentially Regulate Antibody Responses and Allergic Airway Inflammation in Male and Female Mice 
PLoS ONE  2014;9(3):e92307.
Gender influences the incidence and/or the severity of several diseases and evidence suggests a higher rate of allergy and asthma among women. Most experimental models of allergy use mice sensitized via the parenteral route despite the fact that the mucosal tissues of the gastrointestinal and respiratory tracts are major sites of allergic sensitization and/or allergic responses. We analyzed allergen-specific Ab responses in mice sensitized either by gavage or intraperitoneal injection of ovalbumin together with cholera toxin as adjuvant, as well as allergic inflammation and lung functions following subsequent nasal challenge with the allergen. Female mice sensitized intraperitoneally exhibited higher levels of serum IgE than their male counterparts. After nasal allergen challenge, these female mice expressed higher Th2 responses and associated inflammation in the lung than males. On the other hand, male and female mice sensitized orally developed the same levels of allergen-specific Ab responses and similar levels of lung inflammation after allergen challenge. Interestingly, the difference in allergen-specific Ab responses between male and female mice sensitized by the intraperitoneal route was abolished in IKKβΔMye mice, which lack IKKβ in myeloid cells. In summary, the oral or systemic route of allergic sensitization and IKKβ signaling in myeloid cells regulate how the gender influences allergen-specific responses and lung allergic inflammation.
PMCID: PMC3965427  PMID: 24667561
24.  Successful Conservative Management of Ruptured Ovarian Cysts with Hemoperitoneum in Healthy Women 
PLoS ONE  2014;9(3):e91171.
Study Objective
To determine the success rate of the “intended conservative management strategy” of ruptured ovarian cysts with hemoperitoneum and the risk factors for surgical interventions in healthy women of reproductive age.
Patients who visited the emergency department with abdominal pain and were diagnosed with a ruptured ovarian cyst with hemoperitoneum between August 2008 and June 2013 were included in this retrospective study. The diagnosis of the ruptured ovarian cysts and hemoperitoneum was based on the clinical symptoms, physical examination and ultrasound and CT imaging. The rate of surgical interventions and the risk factors for surgical intervention were determined.
A total of 78 women were diagnosed with a ruptured ovarian cyst with hemoperitoneum. Most patients (80.8%, 63/78) were managed conservatively, and 19.2% of the patients (15/78) required a surgical intervention. In the multiple logistic regression analysis, the diastolic blood pressure (dBP) (odds ratio [OR] of 0.921 with 95% confidence interval [CI] of 0.855–0.993) and the depth of the total pelvic fluid collection in CT (DTFC_CT) (OR 1.599 with 95% CI 1.092–2.343) were the significant determining factors of surgical intervention after adjustment. The rate of surgical intervention was 6.5% vs. 15.8% vs. 77.8% in the patients with neither dBP≤70 mmHg nor DTFC_CT≥5.6 cm, those with only one of those features, and those with both, respectively.
Most cases of ruptured ovarian cysts with hemoperitoneum can be managed conservatively. A low diastolic blood pressure and a large amount of hemoperitoneum suggest the need for surgical intervention.
PMCID: PMC3946718  PMID: 24608424
25.  Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells or Their Conditioned Medium Prevents Bone Loss in Ovariectomized Nude Mice 
Tissue Engineering. Part A  2013;19(5-6):685-696.
Umbilical cord blood (UCB) has recently been recognized as a new source of mesenchymal stem cells (MSCs) for use in stem cell therapy. We studied the effects of systemic injection of human UCB-MSCs and their conditioned medium (CM) on ovariectomy (OVX)-induced bone loss in nude mice. Ten-week-old female nude mice were divided into six groups: Sham-operated mice treated with vehicle (Sham-Vehicle), OVX mice subjected to UCB-MSCs (OVX-MSC), or human dermal fibroblast (OVX-DFB) transplantation, OVX mice treated with UCB-MSC CM (OVX-CM), zoledronate (OVX-Zol), or vehicle (OVX-Vehicle). Although the OVX-Vehicle group exhibited significantly less bone mineral density (BMD) gain compared with the Sham-Vehicle group, transplantation of hUCB-MSCs (OVX-MSC group) has effectively prevented OVX-induced bone mass attenuation. Notably, the OVX-CM group also showed BMD preservation comparable to the OVX-MSC group. In addition, microcomputed tomography analysis demonstrated improved trabecular parameters in both the OVX-MSC and OVX-CM groups compared to the OVX-Vehicle or OVX-DFB group. Histomorphometric analysis showed increased bone formation parameters, accompanied by increased serum procollagen type-I N-telopeptide levels in OVX-MSC and OVX-CM mice. However, cell-trafficking analysis failed to demonstrate engraftment of MSCs in bone tissue 48 h after cell infusion. In vitro, hUCB-MSC CM increased alkaline phosphatase (ALP) activity in human bone marrow-derived MSCs and mRNA expression of collagen type 1, Runx2, osterix, and ALP in C3H10T1/2 cells. Furthermore, hUCB-MSC CM significantly increased survival of osteocyte-like MLO-Y4 cells, while it inhibited osteoclastic differentiation. To summarize, transplantation of hUCB-MSCs could effectively prevent OVX-mediated bone loss in nude mice, which appears to be mediated by a paracrine mechanism rather than direct engraftment of the MSCs.
PMCID: PMC3568969  PMID: 23215868

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