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1.  Phenylethanolamine N-methyltransferase downregulation is associated with malignant pheochromocytoma/paraganglioma 
Oncotarget  2016;7(17):24141-24153.
Malignant pheochromocytoma/paraganglioma (PCC/PGL) is defined by the presence of metastases at non-chromaffin sites, which makes it difficult to prospectively diagnose malignancy. Here, we performed array CGH (aCGH) and paired gene expression profiling of fresh, frozen PCC/PGL samples (n = 12), including three malignant tumors, to identify genes that distinguish benign from malignant tumors. Most PCC/PGL cases showed few copy number aberrations, regardless of malignancy status, but mRNA analysis revealed that 390 genes were differentially expressed in benign and malignant tumors. Expression of the enzyme, phenylethanolamine N-methyltransferase (PNMT), which catalyzes the methylation of norepinephrine to epinephrine, was significantly lower in malignant PCC/PGL as compared to benign samples. In 62 additional samples, we confirmed that PNMT mRNA and protein levels were decreased in malignant PCC/PGL using quantitative real-time polymerase chain reaction and immunohistochemistry. The present study demonstrates that PNMT downregulation correlates with malignancy in PCC/PGL and identifies PNMT as one of the most differentially expressed genes between malignant and benign tumors.
PMCID: PMC5029690  PMID: 27007161
pheochromocytoma/paraganglioma; phenylethanolamine N-methyltransferase; biomarker; metastasis; endocrine tumors
2.  Filiform polyposis in the sigmoid colon: A case series 
Filiform polyposis is a rare condition of uncertain pathogenesis that is usually found in association with Crohn’s disease, ulcerative colitis, intestinal tuberculosis or histiocytosis X. We report seven interesting cases of polyposis with various pathologic components, mainly located in the left side of the colon with no associated inflammatory bowel disease, intestinal tuberculosis or histiocytosis X. Multiple finger-like polypoid lesions with the appearance of stalactites were noted on the left side of the colon, especially in the sigmoid area, at the time of colonoscopy. The polyps had a variety of sizes and shapes and were shown to have various histopathologic components among the different patients. Although filiform polyposis localized in the sigmoid colon appears not to have high oncogenic potential, periodic follow-up seems to be needed.
PMCID: PMC2874153  PMID: 20480534
Filiform polyposis; Sigmoid colon; Inflammatory bowel disease
3.  CD24 Overexpression Is Associated with Poor Prognosis in Luminal A and Triple-Negative Breast Cancer 
PLoS ONE  2015;10(10):e0139112.
CD24 is associated with unfavourable prognoses in various cancers, but the prevalence of CD24 expression and its influence on clinical outcome in subtypes of breast cancers remain unclear. CD24 expression was analyzed by immunohistochemistry in 747 breast cancer tissues, and DNA methylation and histone modification status in the promoter region of CD24 were assessed using bisulfite sequencing and chromatin immunoprecipitation assay. 213 (28.5%) samples exhibited high CD24 expression in the membrane and/or cytoplasm of breast cancer cells, and CD24 overexpression was significantly correlated with the presence of lymph node metastasis and more advanced pathological stage. Patients with CD24-high tumours had significantly shorter patient survival than those with CD24-low tumours. Importantly, multivariate analysis that included tumour size, lymph node metastasis and chemotherapy demonstrated that high CD24 expression is independently associated with poorer survival in luminal A and triple-negative breast cancer (TNBC) subtypes. Furthermore, CD24 gene expression was associated with histone acetylation independent of DNA methylation, suggesting its epigenetic regulation in breast cancer. Our results suggest that CD24 overexpression is an independent unfavourable prognostic factor in breast cancer, especially for luminal A and TNBC subtypes, and CD24 may be a promising therapeutic target for specific subtypes of breast cancer.
PMCID: PMC4596701  PMID: 26444008
4.  Human Papillomavirus E6/E7-Specific siRNA Potentiates the Effect of Radiotherapy for Cervical Cancer in Vitro and in Vivo 
The functional inactivation of TP53 and Rb tumor suppressor proteins by the HPV-derived E6 and E7 oncoproteins is likely an important step in cervical carcinogenesis. We have previously shown siRNA technology to selectively silence both E6/E7 oncogenes and demonstrated that the synthetic siRNAs could specifically block its expression in HPV-positive cervical cancer cells. Herein, we investigated the potentiality of E6/E7 siRNA candidates as radiosensitizers of radiotherapy for the human cervical carcinomas. HeLa and SiHa cells were transfected with HPV E6/E7 siRNA; the combined cytotoxic effect of E6/E7 siRNA and radiation was assessed by using the cell viability assay, flow cytometric analysis and the senescence-associated β-galactosidase (SA-β-Gal) assay. In addition, we also investigated the effect of combined therapy with irradiation and E6/E7 siRNA intravenous injection in an in vivo xenograft model. Combination therapy with siRNA and irradiation efficiently retarded tumor growth in established tumors of human cervical cancer cell xenografted mice. In addition, the chemically-modified HPV16 and 18 E6/E7 pooled siRNA in combination with irradiation strongly inhibited the growth of cervical cancer cells. Our results indicated that simultaneous inhibition of HPV E6/E7 oncogene expression with radiotherapy can promote potent antitumor activity and radiosensitizing activity in human cervical carcinomas.
PMCID: PMC4490442  PMID: 26035754
E6; E7; siRNA; Concurrent Chemoradiation therapy (CCRT); radiotherapy; radiosensitizer; cervical cancer
5.  Identification of Leukocyte-Specific Protein 1-Positive Cells: A Clue to the Cell of Origin and a Marker for the Diagnosis of Dermatofibroma 
Annals of Dermatology  2015;27(2):157-162.
Dermatofibroma (DF) comprises a heterogeneous group of mesenchymal tumors, with fibroblastic and histiocytic elements present in varying proportions. The cell of origin of DF has been investigated, but remains unclear.
The present study attempted to investigate the expression of leukocyte-specific protein 1 (LSP1), a marker of fibrocytes, in DF. Additionally, we evaluated the effectiveness of LSP1 in the differential diagnosis of DF from dermatofibrosarcoma protuberans (DFSP).
Immunohistochemical staining was performed on 20 cases of DF using antibodies against LSP1, CD68, and factor XIIIa (FXIIIa). In addition, the expression of LSP1 and FXIIIa was evaluated in 20 cases of DFSP.
Eighteen of 20 cases (90%) of DF stained positive for LSP1, with variation in the intensity of expression. CD68 was positive in 10 cases (50%), and FXIIIa was expressed in all cases of DF. There were differences between the regional expression patterns of the three markers in individual tumors. In contrast, only 2 of 20 cases of DFSP expressed LSP1, and none of DFSP cases stained positive for FXIIIa.
The LSP1-positive cells in DF could potentially be fibrocyte-like cells. FXIIIa and CD68 expression suggests that dermal dendritic cells and histiocytes are constituent cells of DF. It is known that fibrocytes, dermal dendritic cells and histiocytes are all derived from CD14+ monocytes. Therefore, we suggest that DF may originate from CD14+ monocytes. Additionally, the LSP1 immunohistochemical stain could be useful in distinguishing between DF and DFSP.
PMCID: PMC4377404  PMID: 25834354
Dermatofibroma; Dermatofibrosarcoma; Leukocyte-specific protein 1
6.  Vocal Fold Augmentation with Injectable Polycaprolactone Microspheres/Pluronic F127 Hydrogel: Long-Term In Vivo Study for the Treatment of Glottal Insufficiency 
PLoS ONE  2014;9(1):e85512.
There is increasing demand for reconstruction of glottal insufficiency. Several injection materials have been examined for this purpose, but all had limitations, such as poor long-term durability, migration from the injection site, inflammation, granuloma formation, and interference with vocal fold vibration due to viscoelastic mismatch. Here, we developed a novel injection material, consisting of polycaprolactone (PCL) microspheres, which exhibits better viscoelasticity than conventional materials, and Pluronic F127 carrier, which decreases the migration of the injection materials. The material was injected into rabbits with glottal insufficiency and compared with the FDA-approved injection material, calcium hydroxylapatite (CaHA). Endoscopic and histological examinations indicated that PCL/Pluronic F127 remained at the injection site with no inflammatory response or granuloma formation, whereas CaHA leaked out and migrated from the injection site. Therefore, vocal fold augmentation was almost completely retained during the 12-month follow-up period in this study. Moreover, induced phonation and high-speed recording of vocal fold vibration showed decreased vocal fold gap area in the PCL/Pluronic F127 group. Our newly developed injection material, PCL/Pluronic F127, permits efficient augmentation of paralyzed vocal fold without complications, a concept that can be applied clinically, as demonstrated by the successful long-term follow-up.
PMCID: PMC3899012  PMID: 24465582
7.  Prevalence and Risk Factors of Esophageal Candidiasis in Healthy Individuals: A Single Center Experience in Korea 
Yonsei Medical Journal  2012;54(1):160-165.
Esophageal candidiasis (EC) is the most frequent opportunistic fungal infection in immunocompromised host. However, we have found EC in healthy individuals through esophagogastroduodenoscopy (EGD). The aim of this study was to determine the prevalence and risk factors for EC in healthy individuals.
Materials and Methods
We retrospectively reviewed the medical records of 281 patients who had been incidentally diagnosed with EC. We also conducted age and sex matched case control study to identify the risk factor for EC.
The prevalence of EC was 0.32% (281/88125). The most common coexisting EGD finding was reflux esophagitis (49/281, 17.4%). An antifungal agent was prescribed in about half of EC, 139 cases (49.5%). Follow-up EGD was undertaken in 83 cases (29.5%) and 20 cases of candidiasis was persistently found. Case control study revealed EC were more often found in user of antibiotics (p=0.015), corticosteroids (p=0.002) and herb medication (p=0.006) as well as heavy drinking (p<0.001).
The prevalence of EC was 0.32% (281/88125) in Korea. Use of antibiotics, corticosteroids and herb as well as heavy drinking were significant risk factors for EC in healthy individuals.
PMCID: PMC3521253  PMID: 23225813
Candidiasis; healthy; prevalence; risk factors
9.  A Case of Monoclonal Gammopathy in Extranodal Marginal Zone B-cell Lymphoma of the Small Intestine 
Monoclonal gammopathy occurs in one-third of the patients with mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). However, monoclonal gammopathy has been rarely reported in Korea. Paraprotenemia accompanying MALT lymphoma is strongly correlated with involvement of the bone marrow, and this involvement leads to the progression of the disease. Here, we present a case of a 66-yr-old man diagnosed with IgM monoclonal gammopathy and stage IV extranodal marginal zone lymphoma of the small intestine, with the involvement of the bone marrow.
PMCID: PMC3111039  PMID: 21239866
Marginal zone B-cell lymphoma; Monoclonal gammopathy; Bone marrow
10.  Cyclooxygenase-2-expressing macrophages in human pterygium co-express vascular endothelial growth factor 
Molecular Vision  2011;17:3468-3480.
To evaluate cyclooxygenase-2 (COX-2) expression and to characterize COX-2-expressing stromal cells in human pterygium.
Primary pterygium tissue of Korean patients (eight males and nine females) was analyzed. The clinical characteristics were classified, and immunohistochemical staining using primary antibodies against cyclooxygenease-2, vascular endothelial growth factor-A, cluster of differentiation (CD)68, CD3, CD20, and leukocyte common antigen was performed.
COX-2 expression was detected in all pterygium tissues evaluated (17 primary pterygia). Diffuse expression of COX-2 in the epithelial layer was observed in nine samples. Infiltration of strongly positive COX-2 cells into the epithelial layer was a more common observation than diffuse epithelial COX-2 expression. Scattered COX-2-expressing cells in the stromal layer were found in all samples. Some COX-2-positive cells were found within microvessels. In addition to stromal COX-2-expressing cells, a few vascular endothelial cells strongly expressed COX-2; however most of the vessels were negative for COX-2 expression. Stromal COX-2-expressing cells were positive for the macrophage marker CD68 and co-expressed vascular endothelial growth factor. COX-2 expression in normal conjunctiva was not observed in seven control samples.
These COX-2- and vascular endothelial growth factor-expressing macrophages may have relevance to the pathogenesis of pterygium.
PMCID: PMC3249431  PMID: 22219642
11.  Triple-negative, basal-like, and quintuple-negative breast cancers: better prediction model for survival 
BMC Cancer  2010;10:507.
Triple-negative breast cancers (TNBCs) and basal-like breast cancers (BLBCs) are known as poor outcome subtypes with a lack of targeted therapy. Previous studies have shown conflicting results regarding the difference of prognostic significance between TNBCs and BLBCs. In this study, we aimed to characterize the prognostic features of TNBCs, in view of BLBCs and quintuple-negative breast cancers (QNBC/5NPs).
Using tissue microarray-based immunohistochemical analysis, we categorized 951 primary breast cancers into four or five subtypes according to the expression of ER, PR, HER2, and basal markers (CK5/6, EGFR).
The results of this study showed that both TNBCs and BLBCs were associated with high histological and/or nuclear grades. When the TNBCs are divided into two subtypes by the presence of basal markers, the clinicopathologic characteristics of TNBCs were mainly maintained in the BLBCs. The 5-subgrouping was the better prediction model for both disease free and overall survival in breast cancers than the 4-subgrouping. After multivariate analysis of TNBCs, the BLBCs did not have a worse prognosis than the QNBC/5NPs. Interestingly, the patients with BLBCs showed significant adjuvant chemotherapy benefit. In addition, QNBC/5NPs comprised about 6~8% of breast cancers in publicly available breast cancer datasets
The QNBC/5NP subtype is a worse prognostic subgroup of TNBCs, especially in higher stage and this result may be related to adjuvant chemotherapy benefit of BLBCs, calling for caution in the identification of subgroups of patients for therapeutic classification.
PMCID: PMC2957395  PMID: 20860845
12.  The role of macrophage migration inhibitory factor in ocular surface disease pathogenesis after chemical burn in the murine eye 
Molecular Vision  2010;16:2402-2411.
To evaluate the role of macrophage migration inhibitory factor (MIF) in the wound healing process following severe chemical burns to the ocular surface.
Chemical burning of the ocular surface was induced in mice (C57BL/6) via the application of 0.1 M NaOH. Macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) mRNA expression in the ocular surface and lacrimal gland was evaluated via real-time reverse transcription PCR on days 2, 7, and 30 after induction of the chemical burn. The expression of MIF protein in the ocular surface and lacrimal gland was evaluated via western blot analysis. Immunohistochemical staining was conducted to detect MIF and vasculoendothelial growth factor in the cornea during the wound healing process. The angiogenic role of MIF was further evaluated using an 8–0 polyglactin suture technique to induce corneal neovascularization.
MIF, TNF-α, and IL-1β mRNA expression were elevated significantly in the ocular surface up to day 30 after chemical burn induction. TNF-α alone was elevated in the lacrimal gland. MIF protein elevation was confirmed via western blot analysis, and the spatial similarity of MIF and VEGF expression in the cornea was noted during the wound healing process. 8–0 polyglactin sutures soaked in MIF induced significantly higher numbers of new vessels on the mouse cornea after 7 days (p=0.003, Mann–Whitney test).
These findings indicate that MIF performs a crucial role in wound healing on the ocular surface after the induction of chemical burns.
PMCID: PMC2994759  PMID: 21152395
13.  A Case of Argyria Following Colloidal Silver Ingestion 
Annals of Dermatology  2009;21(3):308-310.
Argyria is a rare cutaneous discoloration caused by the intake of silver or various compounds containing silver. We report a case of argyria in a 73-year-old male following ingestion of colloidal silver as an alternative medicine over 5 years. He had a diffuse, slate gray discoloration of his face and hands. A biopsy specimen from the face revealed brown-black extracellular granules in the upper dermis and between collagen bundles. We also found silver particles in the mucous of the colon. The ingestion of colloidal silver appears to be increasing among patients using alternative health practices. We report this case to bring people's attention to the problems associated with the ingestion of colloidal silver.
PMCID: PMC2861249  PMID: 20523812
Argyria; Colloidal silver
14.  In Vivo MR Imaging of Magnetically Labeled Mesenchymal Stem Cells in a Rat Model of Renal Ischemia 
Korean Journal of Radiology  2009;10(3):277-284.
This study was designed to evaluate in vivo MR imaging for the depiction of intraarterially injected superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs) in an experimental rat model of renal ischemia.
Materials and Methods
Left renal ischemia was induced in 12 male Sprague-Dawley rats by use of the catheter lodging method. In vivo MR signal intensity variations depicted on T2*-weighted sequences were evaluated in both the left and right kidneys prior to injection (n = 2), two hours (n = 4), 15 hours (n = 2), 30 hours (n = 2) and 72 hours (n = 2) after injection of SPIO-labeled MSCs in both kidneys. Signal intensity variations were correlated with the number of Prussian blue stain-positive cells as visualized in histological specimens.
In an in vivo study, it was determined that there was a significant difference in signal intensity variation for both the left and right cortex (40.8 ± 4.12 and 26.4 ± 7.92, respectively) and for both the left and right medulla (23.2 ± 3.32 and 15.2 ± 3.31, respectively) until two hours after injection (p < 0.05). In addition, signal intensity variation in the left renal cortex was well correlated with the number of Prussian blue stain-positive cells per high power field (r = 0.98, p < 0.05).
Intraarterial injected SPIO-labeled MSCs in an experimental rat model of renal ischemia can be detected with the use of in vivo MR imaging immediately after injection.
PMCID: PMC2672183  PMID: 19412516
Mesenchymal stem cell; Superparamagnetic iron oxide, MR; Kidney, ischemia
15.  Sonographic Findings of Uterine Endometrial Stromal Sarcoma 
Korean Journal of Radiology  2006;7(4):281-286.
The study was performed to present the sonographic findings of uterine endometrial stromal sarcoma (ESS).
Materials and Methods
We conducted a retrospective review of sonographic findings of 10 cases that were diagnosed as uterine ESS. The patients' ages ranged from 25 to 51 years (mean age: 36.1 years). The reviews focused on the location, margin, size, number and echotexture of the lesions. Hysterectomy (n = 9) and myomectomy (n = 1) were performed and a pathologic diagnosis was obtained in all cases.
The masses were located in the uterine wall (n = 6), or they presented as a polypoid mass protruding into the endometrial cavity from the myometrium (n = 3) or as a central cavity mass (n = 1). The lesion margins were smooth (n = 5), ill defined (n = 2), or smooth with partially nodular extensions (n = 3). The maximal mass length was 38 mm to 160 mm with a mean mass length of 83.5 mm. There were single lesions in eight cases and multiple lesions in two cases. The lesion echotextures were hypoechoic solid (n = 3), heterogeneously intermediate echoic (n = 5), diffuse myometrial thickening with heterogeneous echogenicity (n = 1) and septated cystic (n = 1).
Endometrial stromal sarcoma presents with four patterns of its sonographic appearance; a polypoid mass with nodular myometrial extension, an intramural mass with an ill defined margin and heterogeneous echogenicity, an ill defined large central cavity mass or, diffuse myometrial thickening.
PMCID: PMC2667615  PMID: 17143032
Ultrasound (US); Uterine sarcoma; Endometrial stromal sarcoma
16.  MET Expression in Sporadic Renal Cell Carcinomas 
Journal of Korean Medical Science  2006;21(4):672-677.
Although germline mutations of met proto-oncogene on human chromosome 7q31-34 have been known as useful molecular markers of hereditary papillary renal cell carcinoma (RCC), the expression of MET, a product of met proto-oncogene, has not been fully studied in sporadic RCC, along with its clinical significance. We investigated the expression of MET by immunohistochemistry in 182 cases of renal neoplasm encompassing 145 RCC, 25 urothelial carcinomas of renal pelvis, and 12 oncocytomas. MET was diffusely and strongly expressed in 90% of papillary RCC, all collecting duct carcinomas, and 92% of urothelial carcinomas of renal pelvis. On the contrary, clear cell RCC, chromophobe RCC, and oncocytomas were negative or focally positive for MET expression. In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion. In conclusion, diffuse and strong expression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubular or papillary growth. In case of MET expression observed in clear cell RCC, it might correlate with those clinicopathological parameters implying aggressive behavior.
PMCID: PMC2729889  PMID: 16891811
Proto-Oncogene Proteins c-met; Carcinoma, Renal Cell; Kidney Neoplasms; Kidney; Immunohistochemistry
17.  Prenatal Sonographic Diagnosis of Focal Musculoskeletal Anomalies 
Korean Journal of Radiology  2003;4(4):243-251.
Focal musculoskeletal anomalies vary, and can manifest as part of a syndrome or be accompanied by numerous other conditions such as genetic disorders, karyotype abnormalities, central nervous system anomalies and other skeletal anomalies. Isolated focal musculoskeletal anomaly does, however, also occur; its early prenatal diagnosis is important in deciding prenatal care, and also helps in counseling parents about the postnatal effects of numerous possible associated anomalies. We have encountered 50 cases involving focal musculoskeletal anomalies, including focal limb dysplasia [radial ray abnormality (n=3), mesomelic dysplasia (n=1)]; anomalies of the hand [polydactyly (n=8), syndactyly (n=3), ectrodactyly (n=1), clinodactyly (n=6), clenched hand (n=5)]; anomalies of the foot [clubfoot (n=10), rockerbottom foot (n=5), sandal gap deformity (n=1), curly toe (n=2)]; amniotic band syndrome (n=3); and anomalies of the focal spine [block vertebra (n=1), hemivertebra (n=1)]. Among these 50 cases, five [polydactyly (n=1), syndactyly (n=2) and curly toe (n=2)] were confirmed by postnatal physical evaluation, two (focal spine anomalies) were diagnosed after postnatal radiologic examination, and the remaining 43 were proven at autopsy.
For each condition, we describe the prenatal sonographic findings, and include a brief review.
PMCID: PMC2698103  PMID: 14726642
Fetus, abnormalities; Fetus, US; Fetus, skeletal system
18.  Correlation of mutation and immunohistochemistry of p53 in hepatocellular carcinomas in Korean people. 
Journal of Korean Medical Science  2002;17(6):801-805.
The degree of correlation between sequencing and immunohistochemisty (IHC) for detecting mutations of p53 has not been well established in human hepatocellular carcinoma (HCC). We analyzed 36 HCCs from Korean people for p53 mutation at exons 4-10 by PCR-SSCP and sequencing, and compared the results with the IHC positivity. p53 mutations were identified in 7 out of 36 HCCs (19.4%). These mutations were found widely throughout exons 4-8. No mutation was detected in codon 249. Among the 7 mutations, 6 missense mutations were detected in 15 HCCs with > or =5% immunoreactive tumor cells and one nonsense mutation was in 21 HCCs with <5% immunoreactive tumor cells. The sensitivity for p53 mutation was 85.7% (6/7), the specificity 69.0% (20/29), the predictive value of positive IHC 40.0% (6/15), and the predictive value of negative IHC 95.2% (20/21). Two missense mutations were detected in 25 cases with <10% immunoreactive tumor cells. Predictive values of both positive IHC and negative IHC were higher in > or =5% overexpression group than in > or =10% overexpression group or >0% overexpression group. This study suggests that 5% immunoreactivity is a reliable immunohistochemical threshold value to detect p53 mutations in HCCs and the spectrum of p53 mutations in HCCs in Korean people is different from that of high aflatoxin B1 exposure areas.
PMCID: PMC3054961  PMID: 12483005

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