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1.  A patient fatality following the ingestion of a small amount of chlorfenapyr 
Chlorfenapyr has been used worldwide for agricultural pest control since 1995. Despite its widespread use, acute human poisoning data are insufficient; only a small number of fatalities from chlorfenapyr poisoning have been reported. The signs and symptoms of chlorfenapyr toxicity include nausea, vomiting, fever, rhabdomyolysis, among others. In addition, central nervous system effects in association with delayed toxicity have also been observed. Here, we detail a fatality resulting from delayed chlorfenapyr toxicity following the ingestion of a small amount of pesticide.
PMCID: PMC4126128  PMID: 25114438
Chlorfenapyr; insecticide; poisoning
2.  Epidermal growth factor upregulates Skp2/Cks1 and p27kip1 in human extrahepatic cholangiocarcinoma cells 
AIM: To evaluate the expression status of S-phase kinase-associated protein 2 (Skp2)/cyclin-dependent kinases regulatory subunit 1 (Cks1) and p27kip1, and assess the prognostic significance of Skp2/Cks1 expression with p27kip1 in patients with extrahepatic cholangiocarcinoma.
METHODS: Seventy-six patients who underwent curative resection for histologically confirmed extrahepatic cholangiocarcinoma at our institution from December 1994 to March 2008 were enrolled. Immunohistochemical staining for Skp2, Cks1, p27kip1, and Ki67, along with other relevant molecular biologic experiments, were performed.
RESULTS: By Cox regression analyses, advanced age (> 65 years), advanced AJCC tumor stage, poorly differentiated histology, and higher immunostaining intensity of Skp2 were identified as independent prognostic factors in patients with extrahepatic cholangiocarcinoma. Exogenous epidermal growth factor (EGF, especially 0.1-10 ng/mL) significantly increased the proliferation indices by MTT assay and the mRNA levels of Skp2/Cks1 and p27kip1 in SNU-1196, SNU-1079, and SNU-245 cells. The protein levels of Skp2/Cks1 (from nuclear lysates) and p27kip1 (from cytosolic lysate) were also significantly increased in these cells. There were significant reductions in the protein levels of Skp2/Cks1 and p27kip1 (from nuclear lysate) after the treatment of LY294002. By chromatin immunoprecipitation assay, we found that E2F1 transcription factor directly binds to the promoter site of Skp2.
CONCLUSION: Higher immunostaining intensity of Skp2/Cks1 was an independent prognostic factor for patients with extrahepatic cholangiocarcinoma. EGF upregulates the mRNA and protein levels of Skp2/Cks1 and p27kip1 via the PI3K/Akt pathway and direct binding of E2F1 transcription factor with the Skp2 promoter.
PMCID: PMC3921485  PMID: 24574749
S-phase kinase-associated protein 2; Cyclin-dependent kinases regulatory subunit 1; P27kip1; Cholangiocarcinoma; E2F1; PI3K/Akt
3.  Heterotopic Intestinal Cyst of the Submandibular Gland: A Case Study 
Korean Journal of Pathology  2013;47(3):279-283.
Heterotopic gastrointestinal cysts are rarely found in the oral cavity. Most of these cysts are lined with gastric mucosa and involve the tongue. There have been no reported heterotopic intestinal cysts of the submandibular gland that are completely lined with colonic mucosa. An 8-year-old girl presented with an enlarging swelling in the left submandibular area, and a 4-cm unilocular cyst was fully excised. The cyst was completely lined with colonic mucosa that was surrounded by smooth muscle layer, and the lining cells were positive for CDX-2, an intestinal marker, indicating a high degree of differentiation. The pathogenesis remains unclear, but it may be related to the misplacement of embryonic rests within the oral cavity during early fetal development. Although heterotopic intestinal cysts rarely occur in the submandibular gland, they should be considered in the differential diagnosis of facial swellings in the pediatric population.
PMCID: PMC3701825  PMID: 23837022
Submandibular gland; Cysts; Heterotopia; Intestines
4.  Extranodal Follicular Dendritic Cell Sarcoma with Rapid Growth in Parapharynx: A Case Report 
Korean Journal of Pathology  2012;46(3):306-310.
Follicular dendritic cell sarcoma (FDCS) is a rare malignancy arising from the antigen-presenting cells in the lymph node and extranodal tissue. We describe a 31-year-old male patient who presented with a swelling of the left parapharynx. The radiologic findings showed a 4.7×4.5×1.9 cm-sized, ill-defined mass in the left parapharyngeal space. A fine-needle aspiration cytology was performed and it showed scattered, irregular, cohesive clusters of tumor cells with a spindle-to-ovoid shape with irregular contours in a background of lymphocytes. Based on these findings, a diagnosis of spindle cell neoplasm was made. The surgically resected tumor was composed of elongated, ovoid or polygonal cells showing positive immunohistochemistry for CD21, CD23, and CD35. Postoperatively, the residual tumor was observed to undergo a rapidly growth. There is an overlap in the cytologic and histologic findings between FDCS of the parapharynx and other tumors. Pathologists should therefore be aware of its characteristics not only to provide an accurate diagnosis but also to recommend the appropriate clinical management.
PMCID: PMC3479760  PMID: 23110021
Dendritic cell sarcoma, follicular; Extranodal; Parapharynx
5.  Overexpressions of Cyclin B1, cdc2, p16 and p53 in Human Breast Cancer: The Clinicopathologic Correlations and Prognostic Implications 
Yonsei Medical Journal  2011;52(3):445-453.
The molecular mechanisms that are responsible for the initiation and progression of breast cancers are largely unknown. This study was to analyze the cyclin B1, cdc2, p53 and p16 tumor suppressor genes in human breast cancer.
Materials and Methods
To investigate the role of cyclin B1, cdc2, p53 and p16 in the pathogenesis and progression of breast carcinomas, 98 cases of breast cancers were examined by immunohistochemical method. The correlations of cyclin B1, cdc2, p53 and p16 expression with various clinico-pathologic findings were analysed.
In the normal breast tissues, cyclin B1, cdc2 and p16 were weakly expressed, while p53 was not expressed. On the other hand, cyclin B1, cdc2, p53 and p16 were overexpressed in breast cancer, showing correlation between the expression of cyclin B1 and cdc2 and breast cancers (p=0.00). The overexpressions of cdc2 and p16 were correlated with an infiltrative tumor border pattern and this was statistically significant (p<0.05). In addition, the overexpression of cdc2 was correlated with histologic high grade carcinomas (p=0.00).
Cyclin B1 and cdc2 appeared to be involved in the genesis or progression of breast cancers. In addition, the overexpressions of p16 and p53 may play important roles in more aggressive tumor and the overexpression of cdc2 is associated with progression of tumor to a higher grade of breast carcinomas. The deranged overexpressions of cyclin B1, cdc2, p16 and p53 may play an important role in human breast carcinogenesis.
PMCID: PMC3101063  PMID: 21488187
Breast carcinoma; cyclin B1; cdc2; p16; p53; overexpression; prognosis
6.  Stress-induced Alterations in Mast Cell Numbers and Proteinase-activated Receptor-2 Expression of the Colon: Role of Corticotrophin-releasing Factor 
Journal of Korean Medical Science  2010;25(9):1330-1335.
This study was performed in order to assess whether acute stress can increase mast cell and enterochromaffin (EC) cell numbers, and proteinase-activated receptor-2 (PAR2) expression in the rat colon. In addition, we aimed to investigate the involvement of corticotrophin-releasing factor in these stress-related alterations. Eighteen adult rats were divided into 3 experimental groups: 1) a saline-pretreated non-stressed group, 2) a saline-pretreated stressed group, and 3) an astressin-pretreated stressed group. The numbers of mast cells, EC cells, and PAR2-positive cells were counted in 6 high power fields. In proximal colonic segments, mast cell numbers of stressed rats tended to be higher than those of non-stressed rats, and their PAR2-positive cell numbers were significantly higher than those of non-stressed rats. In distal colonic segments, mast cell numbers and PAR2-positive cell numbers of stressed rats were significantly higher than those of non-stressed rats. Mast cell and PAR2-positive cell numbers of astressin-pretreated stressed rats were significantly lower than those of saline-pretreated stressed rats. EC cell numbers did not differ among the three experimental groups. Acute stress in rats increases mast cell numbers and mucosal PAR2 expression in the colon. These stress-related alterations seem to be mediated by release of corticotrophin-releasing factor.
PMCID: PMC2923781  PMID: 20808677
Corticotropin-releasing Factor; Enterochromaffin Cells; Irritable Bowel Syndrome; Mast cells; Receptor, PAR-2; Stress
7.  Evaporated Liquid Nitrogen-Induced Asphyxia: A Case Report 
Journal of Korean Medical Science  2008;23(1):163-165.
A 27-yr-old postgraduate student was found lying at the floor of an unsealed underground dry area, where a valve-opened empty cylinder of liquid nitrogen (150 L) was connected to a cap-removed empty Dewar-flask (10 L) via a copper infusion tube. No injury was found externally or internally. There were petechiae in the bilateral conjunctivae and periorbital skin. The dry area, measuring 300×130×260 cm, had a communication to the basement of the research building by a window measuring 90×60 cm in size at 130 cm above the floor. The scene reconstruction and atmosphere gas analysis revealed that the O2 concentration at 60 cm above the base dropped to 12.0% in 3 min and 10 sec, 10.0% in 8 min and 53 sec, 6.0% in 18 min and 40 sec, and 4.2% in 20 min and 28 sec. The primary cause of death was asphyxia by evaporated liquid nitrogen.
PMCID: PMC2526498  PMID: 18303222
Asphyxia; Liquid Nitrogen; Gas Analysis; Dry Area
8.  Prognostic Implications of Cyclin B1, p34cdc2, p27Kip1 and p53 Expression in Gastric Cancer 
Yonsei Medical Journal  2007;48(4):694-700.
Cell cycle progression is regulated by interactions of specific cyclins and cyclin dependent kinases (CDKs) at the G1-S and G2-M checkpoints and cell cycle deregulation plays a major role in carcinogenesis of human cancers.
Patients and Methods
To investigate the role of cell cycle regulators in the pathogenesis and progression of human gastric cancers, 23 cases of gastric carcinomas were examined for the expression of cyclin B1, p34cdc2, p27Kip1 and p53 by immunohistochemical methods, and gene expression was correlated with various clinicopathologic findings.
Out of 23 cases studied, cyclin B1 was diffusely expressed in 20 cases (87.0%), p34cdc2 in 14 cases (60.9%) and p53 in 12 cases (52.2%), whereas in normal gastric tissues, cyclin B1 and p34cdc2 were weakly expressed and p53 was not expressed. In contrast, p27Kip1 was expressed in only 8.7% of gastric carcinomas compared with 78.3% of normal gastric tissues. There was correlation between the expression of cyclin B1 and expression of p34cdc2 (p = 0.002), between the expression of cyclin B1 and loss of p27Kip1 (p = 0.025), and between the expression of p34cdc2 and loss of p27Kip1 (p = 0.065). In addition, expression of cyclin B1 was correlated with regional lymph node metastasis (p = 0.032).
Our results indicate that cyclin B1 and p34cdc2 are involved in the genesis or progression of gastric cancers. Furthermore, overexpression of cyclin B1 may play an important role in lymph node metastatic potential of gastric cancer. Thus, abnormal expression of cyclin B1 and CDKs, overexpression of p53 and loss of p27Kip1 expression may play important roles in human gastric carcinogenesis.
PMCID: PMC2628048  PMID: 17722244
Gastric cancer; cyclin B1; p34cdc2; p27Kip1; p53
9.  Expression of Histone Deacetylases HDAC1, HDAC2, HDAC3, and HDAC6 in Invasive Ductal Carcinomas of the Breast 
Journal of Breast Cancer  2014;17(4):323-331.
DNA deacetylation by histone deacetylase (HDAC) is an important mechanism involved in the oncogenic tumorigenesis of breast cancer. Previous studies have reported an association of the estrogen receptor (ER) with HDACs and demonstrated the efficacy of HDAC inhibitors for the treatment of breast cancers via in vitro experiments. In this study, we examined the association of HDAC expression with clinicopathological parameters and disease-specific survival.
Immunohistochemical (IHC) analysis of HDAC1, HDAC2, HDAC3, and HDAC6 was performed using tissue microarrays in 300 invasive ductal carcinomas. IHC scoring was determined by multiplication of the intensity (0 to 3) and the proportion (0 to 4) of staining, and we classified tumors into low- and high-HDAC expression groups.
High expression of HDAC1 was correlated with the molecular subtype (p=0.001) and human epidermal growth factor 2 (HER2) amplification (p=0.012). High expression of HDAC6 was correlated with a younger age (p<0.001), ER expression (p=0.025), progesterone receptor expression (p=0.034), molecular subtype (p=0.023), and HER2 amplification (p=0.011). High HDAC1 expression was correlated with luminal A tumors (p=0.001), while high HDAC6 expression was more common in luminal B tumors (p=0.023). Although the expression of HDACs did not exhibit prognostic significance in the entire cohort, high expression of HDAC1 and HDAC6 was associated with improved overall survival (OS) in patients with ER-positive tumors (p=0.017 and p=0.029, respectively), and high expression of HDAC2 was correlated with improved OS in ER-negative tumors (p=0.048) on univariate analysis. Furthermore, high HDAC6 expression was associated with improved disease-free survival (p=0.048) on multivariate analysis.
HDAC1 expression is significantly correlated with the molecular subtypes of tumors, with the highest expression being observed in luminal A tumors. HDAC6 is a significantly correlated with ER expression and the molecular subtype, thereby supporting the estrogen regulatory property of HDAC6. HDAC1 and HDAC6 expression are good prognostic factors for ER-positive tumors.
PMCID: PMC4278050  PMID: 25548579
Breast neoplasms; Histone deacetylases; Immunohistochemistry
10.  Identification and In Vitro Derivation of Spermatogonia in Beagle Testis 
PLoS ONE  2014;9(10):e109963.
In vitro culture of spermatogonial stem cells (SSCs) is important for exploration of SSCs self-renewal, differentiation, and manipulation. There are several reports on rodent SSC cultures; however, data on SSC cultures in domestic animals are limited. To provide basic scientific information on canine SSC cultures, we report canine testes development, and the development of spermatogonia-derived colonies (SDCs) for in vitro cultures.
Methodology/Principal Findings
Testes from 2-, 3-, and 12-month-old beagles were used for histology, immunohistochemistry, in vitro culture, immunocytochemistry, and PCR. Protein gene product 9.5 (PGP9.5)-positive spermatogonia, both single and paired, were found to be abundant in the testes of 2-month-old beagles. stempro-34 and Dulbecco's modified Eagle medium with 5% fetal bovine serum provided as useful substrates for culture of SDCs, and fibroblast growth factor (FGF) played a key role in colony formation. Colonies were positive for alkaline phosphatase and anti-PGP9.5 staining. The early spermatogonia and stem cell markers such as octamer binding protein 4 (Oct4), Nanog homeobox (Nanog), promyelocytic leukemia zinc finger (PLZF), PGP9.5, and GDNF family receptor alpha-1 (GFRα-1) were expressed in the colonies at higher levels than in the testis tissue.
Testes of the 2-month-old beagles had abundant single and paired spermatogonia, which can be used for derivation of SDCs, and FGF was important for colony formation.
PMCID: PMC4198177  PMID: 25333749
11.  Enhanced photo-fermentative H2 production using Rhodobacter sphaeroides by ethanol addition and analysis of soluble microbial products 
Biological fermentation routes can provide an environmentally friendly way of producing H2 since they use renewable biomass as feedstock and proceed under ambient temperature and pressure. In particular, photo-fermentation has superior properties in terms of achieving high H2 yield through complete degradation of substrates. However, long-term H2 production data with stable performance is limited, and this data is essential for practical applications. In the present work, continuous photo-fermentative H2 production from lactate was attempted using the purple non-sulfur bacterium, Rhodobacter sphaeroides KD131. As a gradual drop in H2 production was observed, we attempted to add ethanol (0.2% v/v) to the medium.
As continuous operation went on, H2 production was not sustained and showed a negligible H2 yield (< 0.5 mol H2/mol lactateadded) within two weeks. Electron balance analysis showed that the reason for the gradual drop in H2 production was ascribed to the increase in production of soluble microbial products (SMPs). To see the possible effect of ethanol addition, a batch test was first conducted. The presence of ethanol significantly increased the H2 yield from 1.15 to 2.20 mol H2/mol lactateadded, by suppressing the production of SMPs. The analysis of SMPs by size exclusion chromatography showed that, in the later period of fermentation, more than half of the low molecular weight SMPs (< 1 kDa) were consumed and used for H2 production when ethanol had been added, while the concentration of SMPs continuously increased in the absence of ethanol. It was found that the addition of ethanol facilitated the utilization of reducing power, resulting in an increase in the cellular levels of NAD+ and NADP+. In continuous operation, ethanol addition was effective, such that stable H2 production was attained with an H2 yield of 2.5 mol H2/mol lactateadded. Less than 15% of substrate electrons were used for SMP production, whereas 35% were used in the control.
We have found that SMPs are the key factor in photo-fermentative H2 production, and their production can be suppressed by ethanol addition. However, since external addition of ethanol to the medium represents an extra economic burden, ethanol should be prepared in a cost-effective way.
PMCID: PMC4038723  PMID: 24883103
Photo-fermentative hydrogen production; Electron balance; Soluble microbial products; Ethanol; Lactate; Size exclusion chromatography
13.  Favorable Vocal Fold Wound Healing Induced by Platelet-Rich Plasma Injection 
To introduce a new injection material for vocal fold diseases, which could be readily translated to clinical practice, we investigated the effectiveness of platelet-rich plasma (PRP) injection on the injured vocal fold in terms of histological recovery.
Blood samples were drawn from New Zealand White rabbits and PRP was isolated through centrifugation and separation of the samples. Using a CO2 laser, we made a linear wound in the 24 vocal fold sides of 12 rabbits and injected each wound with PRP on one vocal fold side and normal saline (NS) on the other. Morphologic analyses were conducted at 2, 4, and 12 weeks after injection, and inflammatory response, collagen deposit, and changes in growth factors were assessed using H&E and masson trichrome (MT) staining and western blot assay.
PRP was prepared in approximately 40 minutes. The mean platelet concentration was 1,315,000 platelets/mm3. In morphological analyses, decreased granulation was observed in the PRP-injected vocal folds (P<0.05). However, the irregular surface and atrophic change were not difference. Histological findings revealed significant inflammation and collagen deposition in NS-injected vocal folds, whereas the PRP-injected vocal folds exhibited less (P<0.05). However, the inflammatory reaction and fibrosis were not difference. In western blot assay, increased amounts of growth factors were observed in PRP-injected vocal folds.
Injection of injured rabbit vocal folds with PRP led to improved wound healing and fewer signs of scarring as demonstrated by decreased inflammation and collagen deposition. The increased vocal fold regeneration may be due to the growth factors associated with PRP.
PMCID: PMC3932349  PMID: 24587881
Vocal fold; Scar; Wound healing; Growth factor; Platelet-rich plasma
14.  Polyphenols Isolated from Allium cepa L. Induces Apoptosis by Induction of p53 and Suppression of Bcl-2 through Inhibiting PI3K/Akt Signaling Pathway in AGS Human Cancer Cells 
Journal of Cancer Prevention  2014;19(1):14-22.
The extract of Allium cepa Linn is commonly used as adjuvant food for cancer therapy. We assumed that it includes a potential source of anti-cancer properties.
We investigated anti-cancer effects of polyphenols extracted from lyophilized A. cepa Linn (PEAL) in AGS human cancer cells.
PEAL inhibited cell growth in a dose-dependent manner. It was related to caspase-dependent apoptosis. We confirmed this finding with annexin V staining. PEAL up-regulated p53 expression, and subsequent Bax induction, down regulated Bcl-2 protein, anti-apoptotic protein. In addition, PEAL suppressed Akt activity and PEAL-induced apoptosis were significantly accentuated with Akt inhibitor (LY294002).
Our data suggested that PEAL induce caspase-dependent apoptosis through mitochondrial pathway by up-regulating p53 protein, and subsequent Bax protein as well as by modulating Bcl-2 protein, and that PEAL induces caspase-dependent apoptosis at least in part through the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. This study provides evidence that PEAL might be useful for the treatment of cancer.
PMCID: PMC4189478  PMID: 25337568
Allium cepa; polyphenols; Apoptosis; Bcl-2; Akt
15.  Increased adipose tissue hypoxia and capacity for angiogenesis and inflammation in young diet-sensitive C57 mice compared to diet-resistant FVB mice 
High-fat diets result in increased body weight. However, this is not uniform and determining the factors that make some animals or individual more susceptible to this diet-induced weight gain is a critical research question. The expansion of white adipose tissue (WAT) associated with weight gain requires high rates of angiogenesis to support the expanding tissue mass. We hypothesized that diet-induced obese (DIO) mice have a greater capacity for WAT angiogenesis and remodeling than diet-resistant (DR) mice at a young age, prior to age or diet-induced obesity.
We measured body weight and body composition by NMR. We compared the expression of genes related to lipid metabolism, angiogenesis and inflammation by RT-qPCR and PCR arrays. WAT morphology and distribution of adipocyte size were analyzed. The level of hypoxia and vascular density was assessed by immunohistochemistry in WAT of young mice.
C57Bl/6 mice were DIO and FVB/N mice DR after 8 weeks on a low fat diet or high fat diet (HFD). However, C57Bl/6 mice had lower body weight, lower adiposity, smaller adipocytes and decreased leptin and lipogenic genes expression in AT than FVB/N mice at 9 weeks of age on a chow diet. Despite having smaller adipocytes, the level of hypoxia and the expression of pro-angiogenesis genes were higher in WAT of young C57Bl/6 mice than young FVB/N mice. In addition, expression of genes related to macrophages and their recruitment, and to proinflammatory cytokines, was significantly higher in WAT of young C57Bl/6 mice than young FVB/N mice.
These data suggest that the potential for WAT remodeling in early period of growth is higher in C57Bl/6 mice as compared to FVB/N mice and we hypothesize that it may contribute to the increased susceptibility to DIO of C57Bl/6 mice.
PMCID: PMC3525796  PMID: 22964790
adipose tissue; angiogenesis; inflammation; hypoxia; diet-induced obesity; diet-resistant; body weight; high-fat diet
16.  Absolute Lymphocyte Count as a Predictor of Mortality in Emergency Department Patients with Paraquat Poisoning 
PLoS ONE  2013;8(10):e78160.
Paraquat (PQ) is a potent, highly toxic and widely used herbicide. The major medical problems associated with PQ are accidental or suicidal ingestion. There are several prognostic markers of PQ poisoning, with the serum PQ concentration considered to be the best indicator of outcome. However, the measurement of such markers is limited in many hospitals.
The present study was conducted to investigate the association of absolute lymphocyte count (ALC) and the 30-day mortality rate in patients with PQ poisoning.
We performed a retrospective analysis of patients admitted to the emergency department after paraquat poisoning between January 2010 and April 2013. Independent risk factors including ALC for 30-day mortality were determined. The ALC was categorized in quartiles as ≤1700, 1700 to 3200, 3200 to 5000, and >5000. Univariate and multivariate Cox proportional hazard analysis were performed to determine the independent risk factors for mortality.
A total of 136 patients were included in the study, and the 30-day mortality was 73.5%. ALC was significantly higher in nonsurvivors than in survivors. The highest ALC quartile (ALC>5000; hazard ratio, 2.58; 95% CI, 1.08–6.21) was associated with increased mortality in multivariate analysis. In addition, old age, lower arterial PaCO2, increased peripheral neutrophil count, and high serum levels of creatinine were associated with mortality.
The absolute lymphocyte count is associated with the 30-day mortality rate in patients with paraquat poisoning.
PMCID: PMC3813447  PMID: 24205140
17.  Sex Differences in Hippocampal Neuronal Sensitization by Nicotine in M. gerbils 
We studied the sex different nicotine effect on evoked population spike amplitudes (ePSA) and connexin (Cx) expression in the hippocampus CA1 area of gerbils. Acute doses of nicotine bitartrate (0.5 mg/kg: NT-0.5) slightly reduced ePSA in males but markedly augmented that in females. Acute NT (5.0 mg/kg) markedly increased the ePSA in all gerbils. Unlike acute NT-0.5, repeated NT-0.5 injection (twice a day for 7 days) significantly increased the ePSA in males and slightly affected the NT-0.5 effect in females. The Cx36 and Cx43 expression levels as well as Cx expressing neuronal populations were significantly increased by repeated NT-0.5 in in both male and female gerbils, and particularly, Cx43 expression was somewhat prominent in females. These results demonstrated a sex difference with respect to the nicotine effect on hippocampal bisynaptic excitability, irrelevant to connexin expression.
PMCID: PMC3823952  PMID: 24227940
Connexin; Evoked population spike; Hippocampus; Nicotine; Sex difference
18.  Rapid and Weight-Independent Improvement of Glucose Tolerance Induced by a Peptide Designed to Elicit Apoptosis in Adipose Tissue Endothelium 
Diabetes  2012;61(9):2299-2310.
A peptide designed to induce apoptosis of endothelium in white adipose tissue (WAT) decreases adiposity. The goal of this work is to determine whether targeting of WAT endothelium results in impaired glucose regulation as a result of impaired WAT function. Glucose tolerance tests were performed on days 2 and 3 of treatment with vehicle (HF-V) or proapoptotic peptide (HF-PP) and mice pair-fed to HF-PP (HF-PF) in obese mice on a high-fat diet (HFD). Serum metabolic variables, including lipid profile, adipokines, individual fatty acids, and acylcarnitines, were measured. Microarray analysis was performed in epididymal fat of lean or obese mice treated with vehicle or proapoptotic peptide (PP). PP rapidly and potently improved glucose tolerance of obese mice in a weight- and food intake–independent manner. Serum insulin and triglycerides were decreased in HF-PP relative to HF-V. Levels of fatty acids and acylcarnitines were distinctive in HF-PP compared with HF-V or HF-PF. Microarray analysis in AT revealed that pathways involved in mitochondrial dysfunction, oxidative phosphorylation, and branched-chain amino acid degradation were changed by exposure to HFD and were reversed by PP administration. These studies suggest a novel role of the AT vasculature in glucose homeostasis and lipid metabolism.
PMCID: PMC3425411  PMID: 22733798
19.  Low Rate of Detection of Mucosal High-Risk-Type Human Papillomavirus in Korean Patients with Extragenital Bowen's Disease and Squamous Cell Carcinoma, Especially in Digital Cases 
BioMed Research International  2013;2013:421205.
Human papillomavirus (HPV) infection has been demonstrated in some of the nonmelanoma skin cancers as well as in precancerous lesions. Multiple infections of mucosal high-risk HPV may contribute to the onset of digital Bowen's disease through, if any, digital-genital transmission. We screened for the presence of the mucosal HPV DNA in patients with extragenital Bowen's disease (n = 30), squamous cell carcinoma (n = 11), bowenoid papulosis (n = 9), verrucous carcinoma (n = 1), actinic keratosis (n = 5), and basal cell carcinoma (n = 5). We used a PANArray HPV Genotyping Chip for high-risk and low-risk mucosal types. Genotyping data was confirmed using a conventional direct DNA sequencing method. Two cases of extragenital Bowen's disease were positive for types 16 and 33 of mucosal HPV, respectively. None of the squamous cell carcinoma cases were positive. Neither patients with digital Bowen's disease (n = 5) nor those with squamous cell carcinoma (n = 3) showed any mucosal high-risk HPV. Mucosal high-risk HPV DNA was confirmed in 5 (55.6%) of the 9 patients with bowenoid papulosis. HPV 16 was most prevalent (n = 3), while the DNA of HPVs 35 and 67 was detected in one sample for each of the two types. Our study demonstrated that two (6.7%) of the patients with 30 extragenital Bowen's disease were positive for types 16 and 33 of mucosal HPV, respectively. HPVs belonging to the mucosal high-risk group may participate in the development of extragenital Bowen's disease. However, we could not find any relationship between the mucosal high-risk HPV and Bowen's disease or squamous cell carcinoma in the fingers.
PMCID: PMC3760177  PMID: 24024191
20.  Malakoplakia in a healthy young female patient 
Malakoplakia is a rare granulomatous disease that occurs commonly in the urinary tract and secondarily in the gastrointestinal tract. Most reported cases of malakoplakia are associated with immunosuppressive diseases or chronic prolonged illness. Here, we report a rare case of malakoplakia in a young healthy adolescent without any underlying disease. A 19-year-old female was referred to our hospital following the discovery of multiple rectal polyps with sigmoidoscopy. She had no specific past medical history but complained of recurrent abdominal pain and diarrhea for 3 months. A colonoscopy revealed diverse mucosal lesions including plaques, polyps, nodules, and mass-like lesions. Histological examination revealed a sheet of histiocytes with pathognomonic Michaelis-Gutmann bodies. We treated the patient with ciprofloxacin, the cholinergic agonist bethanechol, and a multivitamin for 6 months. A follow-up colonoscopy revealed that her condition was resolved with this course of treatment.
PMCID: PMC3712156  PMID: 23864806
Malakoplakia; Michaelis-Gutmann bodies; Diverse mucosal lesions
21.  Associations between the Expression of Mucins (MUC1, MUC2, MUC5AC, and MUC6) and Clinicopathologic Parameters of Human Breast Ductal Carcinomas 
Journal of Breast Cancer  2013;16(2):152-158.
Mucins are members of the glycoprotein family expressed in benign and malignant epithelial cells. The aim of this study is to evaluate the relationships between the expression of mucins in breast ductal carcinoma and clinicopathologic parameters.
We constructed tumor microarrays based on 240 cases of invasive ductal carcinoma and 40 cases of ductal carcinoma in situ (DCIS) using formalin fixed, paraffin embedded tissues. We examined the expressions of MUC1, MUC2, MUC5AC, and MUC6 by immunohistochemistry.
MUC1 demonstrated cytoplasmic, membranous, apical, and combinative expressions. Other mucins demonstrated cytoplasmic expression. In invasive ductal carcinoma, MUC1, MUC2, MUC5AC, and MUC6 were expressed in 93.6%, 6.2%, 4.8%, and 12.4% of cases, respectively; these rates were slightly, but not significantly, higher than observed in cases of DCIS. MUC1 expression was associated with estrogen receptor (ER) expression and negative MUC1 expression was associated with triple negativity. MUC6 expression was correlated with higher histologic grade, lymphatic invasion, lymph node metastasis, and HER2 positivity. No associations with any other clinicopathologic parameters were observed.
Most invasive ductal carcinomas of the breast express MUC1, and this expression is associated with ER expression. MUC6 expression is correlated with some clinicopathologic parameters that are indicators of poor prognosis. To evaluate the role of MUC6 as a potential biomarker, further studies are warranted.
PMCID: PMC3706859  PMID: 23843846
Breast neoplasms; Human MUC1 protein; Human MUC6 protein; Mucins
22.  A case of hemophagocytic syndrome in a patient with fulminant ulcerative colitis superinfected by cytomegalovirus 
Hemophagocytic syndrome (HPS) is an uncommon hematological disorder that manifests as fever, splenomegaly, and jaundice, with hemophagocytosis in the bone marrow and other tissues pathologically. Secondary HPS is associated with malignancy and infection, especially viral infection. The prevalence of cytomegalovirus (CMV) infection in ulcerative colitis (UC) patients is approximately 16%. Nevertheless, HPS in UC superinfected by CMV is very rare. A 52-year-old female visited the hospital complaining of abdominal pain and hematochezia for 6 days. She was diagnosed with UC 3 years earlier and had been treated with sulfasalazine, but had stopped her medication 4 months earlier. On admission, her spleen was enlarged. The peripheral blood count revealed pancytopenia and bone marrow aspiration smears showed hemophagocytosis. Viral studies revealed CMV infection. She was treated successfully with ganciclovir. We report this case with a review of the related literature.
PMCID: PMC3654134  PMID: 23682230
Colitis, ulcerative; Inflammatory bowel diseases; Cytomegalovirus infections; Lymphohistiocytosis, hemophagocytic
23.  A Proposal for Creating a Guideline for Cancer Registration of the Fibromatosis, PEComa Group, Malignant Lymphoma In Situ and Dendritic Cell Tumors (III) 
Korean Journal of Pathology  2012;46(5):436-442.
Understanding the biologic behavior of a tumor is a prerequisite for tumor registration code assignment. The aim of this report was to propose appropriate behavior codes of the International Classification of Disease Oncology 3 (ICD-O3) to rare, yet pathologically interesting hematopoietic and soft tissue tumors.
The Study Group for Hematopathology, the Bone and Soft Tissue Pathology Study Group, and the Cancer Registration Committee prepared the questionnaire containing provisional behavior codes of selected diseases.
In situ lesions of mantle cell and follicular lymphomas, dendritic cell tumors, and neoplasms with perivascular epithelioid cell differentiation (PEComa), not otherwise specified were classified as malignant (-/3). The fibromatosis group, with the exception of lipofibromatosis, was proposed as benign (-/0). Lipofibromatosis and several diseases that belong to the PEComa group were proposed as uncertain malignant potential (-/1). For the hematologic and soft tissue tumors, 274 and 288 members of the Korean Society of Pathologists, respectively, provided opinions through questionnaire, and most responders showed agreement with the provisional behavior code proposed.
The determination of behavior codes for the rare diseases described in this study, especially those of the PEComa group or malignant lymphoma, could be viewed as impractical and premature, but this study provides the basis for future research on this topic.
PMCID: PMC3490119  PMID: 23136570
ICD-O3; Behavior code; Hematologic malignancy; Soft tissue neoplasms
24.  Relationships between Lymph Node Metastasis and Expression of CD31, D2-40, and Vascular Endothelial Growth Factors A and C in Papillary Thyroid Cancer 
To investigate the relationships between lymph node metastasis (LNM) and expression of CD31, D2-40 and vascular endothelial growth factors (VEGF)-A and -C in patients with papillary thyroid cancer (PTC).
Paraffin-embedded thyroid tissues of 72 patients were evaluated, which included 25 patients with thyroid nodular hyperplasia (TNH), 24 PTC patients without LNM, and 23 PTC patients with LNM. Three pathologists, who were blinded to the patient's clinical information, assessed the immunohistochemical staining results. The amount of expression was scored as high (>25% of cells stained) or low (0-25%).
A higher level of VEGF-A expression was observed in the PTC groups regardless of LNM when compared to the group with TNH (91.3%, 79.2%, 4.0%, respectively). VEGF-C expression in the PTC with LNM group was significantly higher than the other two groups (P<0.05). No difference in microvessel density (MVD) scores was observed using CD31 among the three groups. The lymphatic vessel density (LVD) score using D2-40 was significantly higher in patients having PTC with LNM than the other groups (P<0.05).
VEGF-C and D2-40 were more highly expressed in patients having PTC with LNM than in patients having PTC without LNM or in those having TNH. Analysis of VEGF-C level and LVD using D2-40 may be helpful in the diagnosis of PTC and the evaluation of LNM potential in patients with PTC.
PMCID: PMC3437416  PMID: 22977712
Thyroid; Papillary carcinoma; Lymph node; Metastasis; VEGF-A; VEGF-C
25.  Plastic Bronchitis in an Adult with Asthma 
Plastic bronchitis is a rare disease characterized by marked airway obstruction, via the formation of large gelatinous or rigid airway cast. In Korea, there were a few case reports with plastic bronchitis not in adults, but in children. So we report a case of an adult who was diagnosed as plastic bronchitis with eosinophilic casts, with no history of atopic and cardiac disease.
PMCID: PMC3492376  PMID: 23166545
Bronchitis; Etiology; Asthma; Adult

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