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Sialodochitis fibrinosa is a disease characterized by salivary duct obstruction. A 21-year-old male presented with a painful submandibular gland (SMG) swelling. Serum eosinophilia and Whartons’ duct dilatation with strong enhancement were observed on contrast CT. Core needle biopsy (CNB) for SMG parenchyma revealed lymphocytic infiltration between dilated intralobular ducts. In another case, a 39-year-old male complained of recurrent major salivary glands swelling for ten years with an itching sensation on the overlying skin of the salivary gland. Enhancement of both SMG parenchyma, dilatation of both Wharton’s ducts and elevated serum eosinophilia were observed on contrast CT study. CNB for SMG parenchyma revealed lymphocytic infiltration with many eosinophils around a markedly dilated interlobular duct. The recurrent SMG swelling in both cases were relieved by antihistamine medication, warranting suspicion that these cases might organ-specific eosinophilic disease. We dicuss these two cases with a literature review.

Asthma is an incurable pulmonary disease with several symptoms, including abnormal breathing, coughing, and sleep apnea, which can lead to death, and the population of asthma patients has been increasing worldwide. There are many adverse effects in current drugs, and thus, we have tried to develop anti-asthmatic agents from natural products such as Codonopsis laceolata. To define the anti-asthmatic effect and the mechanism of Codonopsis laceolata, an animal study was conducted considering different cell counts of BALF, serum IgE levels, morphological changes in the pulmonary system, the Th2 cell transcription factor (GATA-3), and the apoptotic pathway (NF-κB/COX-2). Codonopsis laceolata significantly suppressed the representative asthmatic changes, such as airway remodeling, mucous hypersecretion, epithelial hyperplasia, and inflammatory cell infiltration, in the respiratory system. It suppressed the levels of GATA-3, IL-4, and IL-13. The down-regulation of Th2-related factors, such as GATA-3, IL-4, and IL-13, results from the stimulated apoptosis of Th2 cells and epithelial cells via a decrease in the levels of NF-κB and COX-2. We concluded that Codonopsis laceolata might be a promising anti-asthmatic drug.

Overdose of acetaminophen (APAP) has become one of the most frequent causes of acute liver failure. Macrophage-inducible C-type lectin (Mincle) acts as a key moderator in immune responses by recognizing spliceosome-associated protein 130 (SAP130), which is an endogenous ligand released by necrotic cells. This study aims to explore the function of Mincle in APAP-induced hepatotoxicity. Wild-type (WT) and Mincle knockout (KO) mice were used to induce acute liver injury by injection of APAP. The hepatic expressions of Mincle, SAP130, and Mincle signaling intermediate (Syk) were markedly upregulated after the APAP challenge. Mincle KO mice showed attenuated injury in the liver, as shown by reduced pathologic lesions, decreased alanine aminotransferase and aspartate aminotransferase levels, downregulated levels of inflammatory cytokines, and decreased neutrophil infiltration. Consistently, inhibition of Syk signaling by GS9973 alleviated APAP hepatotoxicity. Most importantly, Kupffer cells (KCs) were found as the major cellular source of Mincle. The depletion of KCs abolished the detrimental role of Mincle, and the adoptive transfer of WT KC to Mincle KO mice partially reversed the hyporesponsiveness to hepatotoxicity induced by APAP. Furthermore, the expression levels of interleukin (IL)-1β and neutrophil-attractant CXC chemokines were substantially lower in KCs isolated from APAP-treated Mincle KO mice compared with those from WT mice. Similar results were found in primary Mincle KO KCs treated with a ligand of Mincle (trehalose-6,6-dibehenate) or in conditioned media obtained from APAP-treated hepatocytes. Collectively, Mincle can regulate the inflammatory response of KCs, which is necessary for the complete progression of hepatotoxicity induced by APAP. SIGNIFICANCE STATEMENT: Acetaminophen (APAP) overdose is becoming a main cause of drug-induced acute liver damage in the developed world. This study showed that macrophage-inducible C-type lectin (Mincle) deletion or inhibition of Mincle downstream signaling attenuates APAP hepatotoxicity. Furthermore, Mincle as a modulator of Kupffer cell activation contributes to the full process of hepatotoxicity induced by APAP. This mechanism will offer valuable insights to overcome the limitation of APAP hepatotoxicity treatment.

Background IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. Methods Among 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. Results Of 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the “Jang & Kim's modified anatomical classification,” 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010–4.433]). Conclusions This is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.

p19arf, primarily known as a tumor suppressor, has also been reported to play an essential role in normal development of mouse eyes. Consistently, lack of p19arf has been associated with ocular defects, but the mixed background of the knockout (KO) mouse strain used raised a concern on the accuracy of the phenotypes observed in association with the targeted gene due to genetic heterogeneity. We carried out a study to investigate into the effect of genetic background on the manifestation of p19arf KO associated phenotypes. We characterized the phenotypes of novel p19arf KO mouse lines generated in FVB/N and C57BL/6J using a transcription activator-like effector nuclease (TALEN) system in comparison to the reported phenotypes of three other p19arf-deficient mouse lines generated using homologous recombination. Ninety-five percent of FVB/N-p19arf KO mice showed ocular opacity from week 4 after birth which worsened rapidly until week 6, while such abnormality was absent in C57BL/6J-p19arf KO mice up to the age of 26 weeks. Histopathological analysis revealed retrolental masses and dysplasia in the retinal layer in FVB/N-p19arf KO mice from week 4. Besides these, both strains developed normally from birth to week 26 without increased tumorigenesis except for a subcutaneous tumor found in a C57BL/6J-p19arf KO mouse. Our findings demonstrated surprisingly variable manifestation of p19arf-linked phenotypes between FVB/N and C57BL/6J mice, and furthermore between our mouse lines and the established lines, indicating a critical impact of genetic background on functional study of genes using gene targeting strategies in mice.

Fatty acid (FA) composition is one of the most important parameters for the assessment of meat quality in pigs. The FA composition in pork can also affect human health. Our aim was to identify quantitative trait loci (QTLs) and positional candidate genes affecting the FA profile of the longissimus dorsi muscle in a large F2 intercross between Landrace and Korean native pigs comprising 1105 F2 progeny by genome-wide association studies (GWAS) and post-GWAS high-resolution mapping analyses. We performed GWAS using the PorcineSNP60K BeadChip and a linear mixed model. Four genome-wide significant QTL regions in SSC8, SSC12, SSC14, and SSC16 were detected (p < 2.53 × 10−7). Several co-localizations of QTLs in SSC12 for oleic acid, linoleic acid, arachidonic acid, monounsaturated FAs, polyunsaturated FAs, and the polyunsaturated/saturated FA ratio were observed. To refine the QTL region in SSC12, a linkage and linkage disequilibrium analysis was applied and could narrow down the critical region to a 0.749 Mb region. Of the genes in this region, GAS7, MYH2, and MYH3 were identified as strong novel candidate genes based on further conditional association analyses. These findings provide a novel insight into the genetic basis of FA composition in pork and could contribute to the improvement of pork quality.

Fatty acid (FA) composition is one of the most important parameters for the assessment of meat quality in pigs. The FA composition in pork can also affect human health. Our aim was to identify quantitative trait loci (QTLs) and positional candidate genes affecting the FA profile of the longissimus dorsi muscle in a large F2 intercross between Landrace and Korean native pigs comprising 1105 F2 progeny by genome-wide association studies (GWAS) and post-GWAS high-resolution mapping analyses. We performed GWAS using the PorcineSNP60K BeadChip and a linear mixed model. Four genome-wide significant QTL regions in SSC8, SSC12, SSC14, and SSC16 were detected (p &lt, 2.53 × 10−7). Several co-localizations of QTLs in SSC12 for oleic acid, linoleic acid, arachidonic acid, monounsaturated FAs, polyunsaturated FAs, and the polyunsaturated/saturated FA ratio were observed. To refine the QTL region in SSC12, a linkage and linkage disequilibrium analysis was applied and could narrow down the critical region to a 0.749 Mb region. Of the genes in this region, GAS7, MYH2, and MYH3 were identified as strong novel candidate genes based on further conditional association analyses. These findings provide a novel insight into the genetic basis of FA composition in pork and could contribute to the improvement of pork quality.

Orostachys japonicus A. Berger and Momordica charantia Linn have been widely used as an alternative medicine. Recently, patients with type 2 diabetes (T2D) have paid increasing attention to medical nutrition therapy due to its safety and cost-effectiveness. Therefore, we have developed a new health functional food that consists of a mixed extract of O. japonicus and M. charantia. The aim of this study is designed to assess the antidiabetic efficacy of O. japonicus and M. charantia extracts (OME, in an 8:2 ratio), especially focusing on the effects of O. japonicus via in vivo and in vitro experiments. Seven-week-old C57BL/Ksj-db/db (db/db; a genetic animal model of T2D) mice were used for inducing diabetes. Mice were administered with various concentrations of OME (OME 0, 100, 200, or 400 mg/kg/day) for 6 weeks. Metabolic parameters, fasting blood glucose and glycosylated hemoglobin levels were measured. Histopathologic analysis and the levels of serum or hepatic biochemicals were assessed to evaluate diabetic liver injury and steatosis. The expression levels of lipogenic and gluconeogenic genes were determined by quantitative real-time polymerase chain reaction. Activation of Akt was assessed by western blot analysis. Administration of OME significantly improved metabolic parameters in db/db mice, and also reduced diabetic liver injury and steatosis were observed by OME administration in db/db mice as confirmed by histopathologic and serum or hepatic biochemical analysis. Consistently, treatment of OME significantly increased Akt activation resulting in decreased expression levels of lipid-accumulation or gluconeogenesis-related genes. Similar results were observed in in vitro experiments using single extract of O. japonicus and using OME. OME has antidiabetic effects with increased insulin sensitivity, and may be a safe alternative therapy for the management of T2D.

Background: Nonalcoholic steatohepatitis (NASH) is one of the chronic inflammatory liver diseases and a leading cause of advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The main purpose of this study was to clarify the effects of GBCK25 fermented by Saccharomyces servazzii GB-07 and pectinase, on NASH severity in mice. Methods: Six-wk-old male mice were fed either a normal diet (ND) or a Western diet (WD) for 12 wks to induce NASH. Each group was orally administered with vehicle or GBCK25 once daily at a dose of 10 mg/kg, 20 mg/kg, 100 mg/kg, 200 mg/kg, or 400 mg/kg during that time. The effects of GBCK25 on cellular damage and inflammation were determined by in vitro experiments. Results: Histopathologic analysis and hepatic/serum biochemical levels revealed that WD-fed mice showed severe steatosis and liver injury compared to ND-fed mice. Such lesions were significantly decreased in the livers of WD-fed mice with GBCK25 administration. Consistently, mRNA expression levels of NASH-related inflammatory-, fibrogenic-, and lipid metabolism-related genes were decreased in the livers of WD-fed mice administered with GBCK25 compared to WD-fed mice. Western blot analysis revealed decreased protein levels of cytochrome P450 2E1 (CYP2E1) with concomitantly reduced activation of c-Jun N-terminal kinase (JNK) in the livers of WD-fed mice administered with GBCK25. Also, decreased cellular damage and inflammation were observed in alpha mouse liver 12 (AML12) cells and RAW264.7 cells, respectively. Conclusion: Administration of GBCK25 ameliorates NASH severity through the modulation of CYP2E1 and its associated JNK-mediated cellular damage. GBCK25 could be a potentially effective prophylactic strategy to prevent metabolic diseases including NASH. Keywords: compound K, cytochrome P450 2E1, ginseng, mice, nonalcoholic steatohepatitis

Asthma is an incurable pulmonary disease with several symptoms, including abnormal breathing, coughing, and sleep apnea, which can lead to death, and the population of asthma patients has been increasing worldwide. There are many adverse effects in current drugs, and thus, we have tried to develop anti-asthmatic agents from natural products such as Codonopsis laceolata. To define the anti-asthmatic effect and the mechanism of Codonopsis laceolata, an animal study was conducted considering different cell counts of BALF, serum IgE levels, morphological changes in the pulmonary system, the Th2 cell transcription factor (GATA-3), and the apoptotic pathway (NF-κB/COX-2). Codonopsis laceolata significantly suppressed the representative asthmatic changes, such as airway remodeling, mucous hypersecretion, epithelial hyperplasia, and inflammatory cell infiltration, in the respiratory system. It suppressed the levels of GATA-3, IL-4, and IL-13. The down-regulation of Th2-related factors, such as GATA-3, IL-4, and IL-13, results from the stimulated apoptosis of Th2 cells and epithelial cells via a decrease in the levels of NF-κB and COX-2. We concluded that Codonopsis laceolata might be a promising anti-asthmatic drug.

Background Ginseng (Panax ginseng C.A. Mey.) has been used as a valuable ingredient in traditional medicine for thousands of years mostly in Asian countries due to its therapeutic effects in various diseases. Among the processed ginseng products, black ginseng is produced by a repeated steaming and drying process of ginseng roots and has been known for its superior efficacy based on high accumulation of minor ginsenosides as recently discovered. Despite its popularity and increasing use, the toxicity information on black ginseng still remained largely lacking, raising safety concerns. This study was therefore carried out to determine the repeated oral toxicity of black ginseng extract (BGE; CJ EnerG) with evaluation of cytotoxic activity as validation of its pharmacological activity for toxicity testing. Methods Prior to the toxicity test, we examined the cytotoxicity of BGE in six cancer cell lines derived from distinct human tissues in comparison with red ginseng extract (RGE), ginsenosides Rg5 and 20(S)-Rg3, and then assessed 28-day repeated oral toxicity in Sprague-Dawley (SD) rats using daily administration of up to 2000 mg/kg BGE. Results BGE showed higher cytotoxicity than RGE in all the cell lines used in this study. Interestingly, the efficacy of BGE closely resembled the cytotoxic pattern of Rg5, suggesting Rg5 as the main effector in the cytotoxic activity of BGE. During the toxicity study, BGE-treated groups showed no noticeable abnormality in clinical signs, body weight gain, food and water consumption and urinalysis. Furthermore, hematological, serum biochemical and histopathological analyses did not find any BGE-related toxicity. Conclusion Our findings demonstrated that BGE has broad-spectrum in vitro cytotoxic activity, and that NOAEL of BGE in SD rats is > 2000 mg/kg, providing the essential safety information for human consumption.

Diesel exhaust particulates (DEP) have adverse effects on the respiratory system. Endoplasmic reticulum (ER) abnormalities contribute to lung inflammation. However, the relationship between DEP exposure and ER stress in the respiratory immune system and especially the alveolar macrophages (AM) is poorly understood. Here, we examined ER stress and inflammatory responses using both in vivo and in vitro study. For in vivo study, mice were intratracheally instilled with 25, 50, and 100 &mu, g DEP and in vitro AM were stimulated with DEP at 1, 2, and 3 mg/mL. DEP increased lung weight and the number of inflammatory cells, especially neutrophils, and inflammatory cytokines in bronchoalveolar lavage fluid of mice. DEP also increased the number of DEP-pigmented AM and ER stress markers including bound immunoglobulin protein (BiP) and CCAAT/enhancer binding protein-homologous protein (CHOP) were upregulated in the lungs of DEP-treated mice. In an in vitro study, DEP caused cell damage, increased intracellular reactive oxygen species, and upregulated inflammatory genes and ER stress-related BiP, CHOP, splicing X-box binding protein 1, and activating transcription factor 4 expressions in AM. Furthermore, DEP released the C-X-C Motif Chemokine Ligand 1 (CXCL1/KC) in AM. In conclusion, DEP may contribute to neutrophilic lung inflammation pathogenesis by modulating ER stress-mediated CXCL1/KC expression in AM.

Hepatitis C virus (HCV) exploits cellular proteins to facilitate viral propagation. To identify the cellular factors involved in the HCV life cycle, we previously performed protein microarray assays using either HCV nonstructural 5A (NS5A) protein or core protein as a probe. Interestingly, cellular cortactin strongly interacted with both NS5A and core. Cortactin is an actin-binding protein critically involved in tumor progression by regulating the migration and invasion of cancerous cells. Protein interaction between cortactin and NS5A or core was confirmed by coimmunoprecipitation and immunofluorescence assays. We showed that cortactin interacted with NS5A and core via the N-terminal acidic domain of cortactin. Cortactin expression levels were not altered by HCV infection. Small interfering RNA (siRNA)-mediated knockdown of cortactin dramatically decreased HCV protein expression and infectivity levels, whereas overexpression of cortactin increased viral propagation. Ectopic expression of the siRNA-resistant cortactin recovered the viral infectivity, suggesting that cortactin was specifically required for HCV propagation. We further showed that cortactin was involved in the assembly step without affecting viral entry, HCV internal ribosome entry site (IRES)-mediated translation, and the replication steps of the HCV life cycle. Of note, silencing of cortactin markedly reduced both NS5A and core protein levels on the lipid droplets (LDs), and this effect was reversed by the overexpression of cortactin. Importantly, NS5A and core promoted cell migration by activating the phosphorylation of cortactin at tyrosine residues 421 and 466. Taken together, these data suggest that cortactin is not only involved in HCV assembly but also plays an important role in the cell migration. IMPORTANCE Cortactin is a cytoskeletal protein that regulates cell migration in response to a number of extracellular stimuli. The functional involvement of cortactin in the virus life cycle is not yet fully understood. The most significant finding is that cortactin strongly interacted with both hepatitis C virus (HCV) core and NS5A. Cortactin is involved in HCV assembly by tethering core and NS5A on the lipid droplets (LDs) with no effect on LD biogenesis. It was noteworthy that HCV NS5A and core activated cortactin by phosphorylation at tyrosines 421 and 466 to regulate cell migration. Collectively, our study shows that cortactin is a novel host factor involved in viral production and HCV-associated pathogenesis.

p19We carried out a study to investigate into the effect of genetic background on the manifestation of p19We characterized the phenotypes of novel p19Ninety-five percent of FVB/N-p19Our findings demonstrated surprisingly variable manifestation of p19

The 8th American Joint Committee on Cancer (AJCC) staging system for distal cholangiocarcinoma (DCC) included a positive lymph node count (PLNC), but a comparison of the prognostic predictive power of PLNC and lymph node ratio (LNR) is still under debate. This study aimed to compare various staging models made by combining the abovementioned factors, identify the model with the best predictive power, and propose a modified staging system. We retrospectively reviewed 251 patients who underwent surgery for DCC at four centers. To determine the superiority of various staging models for predicting overall OSR, Akaike information criterion (AIC), Bayesian information criterion (BIC), AIC correction (AICc), and Harrell&rsquo, s C-statistic were calculated. In multivariate analysis, age (p = 0.003), total lymph node count (p = 0.033), and revised T(LNR)M staging (p &lt, 0.001) were identified as independent factors for overall survival rate. The predictive performance of revised T (LNR) M staging (AIC: 1288.925, BIC: 1303.377, AICc: 1291.52, and Harrell&rsquo, s C statics: 0.667) was superior to other staging system. A modified staging system consisting of revised T category and LNR predicted better overall survival of DCC than AJCC 7th and AJCC 8th editions. In the future, external validation of the proposed new system using a larger cohort will be required.

Background Citrus sunki Hort. ex Tanaka peel has been traditionally used as an ingredient in folk medicine due to its therapeutic effects on promotion of splenic health and diuresis as well as relief of gastrointestinal symptoms. Although a growing interest in health-promoting natural products and the development of highly concentrated products have facilitated consumption of C. sunki peel, its safety assessment has not been explored, posing a potential health risk. In this study, we carried out a series of systemic and genetic toxicity tests on fermented C. sunki peel extract (FCPE) to provide the essential information required for safe use in human. Methods We conducted acute and 90-day repeated oral toxicity studies in Sprague-Dawley rats to evaluate systemic toxicity, and three genotoxicity assays to measure bacterial mutation reversion, cellular chromosome aberration and in vivo micronucleus formation. Results Single oral administration of FCPE did not cause any clinical signs and lethality in all animals, establishing LD50 to be over 2000 mg/kg BW. Repeated administration of up to 2000 mg/kg BW FCPE for 90 days revealed no test substance-related toxicity as demonstrated in analysis of body weight gain, food/water intake, blood, serum biochemistry, organ weight and histopathology, collectively determining that the no-observable-adverse-effect-level of FCPE is over 2000 mg/kg BW. In addition, we detected no mutagenicity and clastogenicity in FCPE at 5000 μg/plate for the in vitro assays and 2000 mg/kg BW for the in vivo micronucleus test. Conclusion FCPE did not cause systemic and genetic toxicity in our model systems at the tested dose levels. These results suggest a guideline for safe consumption of C. sunki peel in human.

We present a patient who showed a sterile abscess after facial bone fixation with bioabsorbable plates and screws. He had zygomaticomaxillary complex and periorbital fracture due to falling down. The displaced bones were treated by open reduction and internal fixation successfully using bioabsorbable plate system. However, at postoperative 11 months, abrupt painless swelling was noted on the previous operation sites, left lateral eyebrow and lower eyelid. By surgical exploration, pus-like discharge and degraded materials were observed and debrided. The pathologic analysis revealed foreign body reaction with sterile abscess. This complication followed by bioabsorbable device implantation on maxillofacial bone surgery has been rarely reported in which we call attention to the maxillofacial plastic surgeons.

A freely mobile calcified or noncalcified nodule in the pleural cavity, known as thoracolithiasis, is quite rare. There are several reports of CT findings of thoracolithiasis, but there is no report of thoracolithiasis mistakenly considered as a pleural plaque in a patient with a history of asbestos exposure. We report a case of a 61-year-old man with a mobile pleural stone thoracoscopically confirmed as thoracolithiasis and which was regarded as a pleural plaque on CT scan in a patient with a history of asbestos exposure.

Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by Fusarium species. The toxicity of ZEA has been evaluated for reproductive and developmental effects; however, there is little evidence about its acute toxicity or general immunotoxicity. In the present study, immune regulatory functions were investigated in mice that had been exposed to ZEA (5 or 20 mg/kg BW) daily for 14 days. Results showed that sub-populations of CD4+, CD8+ and CD11c+ cells in the spleen and CD4+, CD8+ and F4/80+ cells in the mesenteric lymph nodes (MLN) of ZEA (20 mg/kg)-exposed hosts were decreased compared to those in the control mice. However, CD19+ and CD11c+ cells were increased in the MLN of the ZEA mice and CD4+CD25+Foxp3+ cells were decreased in the spleen and MLN. There were differential changes in the immune cell populations of the small intestine of the ZEA mice as well, depending on small intestine location. In ex vivo experiments, ZEA treatments resulted in increased proliferative capacities of mitogen-induced splenocytes and MLN cells; such changes were paralleled by significant increases in interferon (IFN)-γ production. With regard to serum isotypes, IgM levels were decreased and IgE levels were increased in the 20 mg/kg ZEA-treated mice. Mucosal IgA levels were decreased in the duodenum and vagina of these hosts. Serum analyzes also revealed that tumor necrosis factor (TNF)-α levels were decreased and interleukin (IL)-6 levels increased as a result of ZEA exposures. ZEA treatment also led to increased apoptosis in the spleen and Peyer’s patches; these changes were associated with changes in the ratios of Bax:Bcl-2. Following priming with different TLR ligands, ZEA exposure led to differentially modulated TLR signaling and variable production of pro- and anti-inflammatory cytokines in RAW 264.7 macrophage cells. Taken together, these results indicated that ZEA could alter the normal expression/function of different immune system components and this would likely lead to immunomodulation in situ.

Hepatitis C virus (HCV) is the major causative agent of chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. The recent development of highly effective direct-acting antivirals (DAAs) has revolutionized the treatment of HCV patients. However, these DAAs are exorbitantly expensive for the majority of HCV patients worldwide. Moreover, these drugs still show genotypic difference in cure rate and have some resistant-associated variants. Tylophorine, a natural compound derived from Tylophora indica plants, is known to have anti-inflammatory and anti-cancerous growth activities. In the present study, we showed that two tylophorine intermediates, 5-Oxo-1-[(2,3,6,7-tetramethoxy-9-phenanthrenyl) methyl]-L-proline (O859585) and 2,3,6,7-tetramethoxy-9-phenanthrenecarboxylic acid (T298875), displayed anti-HCV activity with an EC50 of 38.25 µM for T298875 and 29.11~35.3 µM for O859585 in various HCV genotypes. We demonstrated that O859585 efficiently blocked HCV attachment by neutralizing free viral particles without affecting other stages of the HCV life cycle and interferon stimulation. O859585 interrupted binding between HCV E2 and CD81. Of note, co-treatment of O859585 with either interferon alpha (IFNα) or sofosbuvir exerted either an additive or synergistic antiviral activity in HCV-infected cells with no measurable effect on cell viability. Most importantly, O859585 in combination with IFNα and sofosbuvir exhibited synergistic effects on anti-HCV activity in primary human hepatocytes. Collectively, these data suggest that O859585 may be a novel antiviral agent for HCV therapy.

Background and Objective Lasers have been successfully used for decades to remove dark hair. However, laser removal of nonpigmented hair is challenging due to the lack of chromophores. The aim of this study was to use photodynamic therapy (PDT) to remove nonpigmented hair. Study Design/Material and Methods We compared the efficacy of permanent hair reduction in white BALB/c and black C57BL/6 mice treated with PDT or an 800-nm diode laser. We collected skin biopsy specimens and investigated post-PDT histologic changes and molecular changes. Results We observed keratin 15 staining in the bulge area and alkaline phosphatase staining in the dermal papilla following PDT. We observed a temporary, catagen-like transformation in nonpigmented hair follicles after PDT. We observed apoptotic cells in the hair matrix after PDT. Irradiation with an 800-nm diode laser did not achieve nonpigmented hair removal. Multiple PDT sessions achieved permanent reduction of nonpigmented hair. Interestingly, removal of black hair using PDT was less efficient. Conclusion Our results suggest that PDT can damage the nonpigmented hair matrix, but not stem cells or dermal papillae. Repeated PDT may impair the hair-regeneration capacity via a bystander effect on bulge stem cells or dermal papillae. In this study, we found it was possible to remove nonpigmented hair using PDT. Lasers Surg. Med. 48:748–762, 2016. © 2016 Wiley Periodicals, Inc.

Primary and metastatic non-epithelial tumors of the lung and pleura (NETs-LP) are presumed to represent a small proportion of pulmonary neoplasm, and their epidemiologic characterization is lacking. Moreover, classification of pulmonary mesenchymal tumor according to ‘WHO Classification of Tumors of Lung and Pleura’ (2004) is simple and necessary to give a supplementation like new ‘WHO Classification of Tumors of Soft Tissue and Bone’ (2013). Non-epithelial tumors of the lung and pleura diagnosed from January 1995 to April 2013 were retrospectively reviewed and classified in accordance with ‘WHO Classification of Tumors of Soft Tissue and Bone’ (2013). Of 681 cases represented in the study, smooth muscle tumor (13.1%) was most common, and tumor of uncertain differentiation (10.5%) and fibroblastic/myofibroblastic tumor (5.7%) were followed. Smooth muscle tumor (12.6%) was the common primary tumor, whereas chondrogenic or osteogenic tumor (21.6%) was common in metastatic ones. Pulmonary vascular sarcoma ( n = 15) was the most frequent primary pulmonary sarcoma with following synovial sarcoma ( n = 9) and malignant type of solitary fibrous tumor ( n = 9). This study is the first trial of epidemiologic investigation in Korea about NETs-LP, indirectly representing their incidence in Korea and northeast Asia, and we hope that this presentation offers guidance in further study of NETs-LP.

Rhabdomyosarcoma (RMS) of the breast is rare and there is scant information about the clinical behavior and treatment strategies. We report an adolescent female patient with metastatic RMS of the breast from the anus. An 18-year-old female patient was referred to our clinic due to palpable mass in the left breast. At age seven, she was diagnosed with acute lymphoblastic leukemia and treated with chemoradiation therapy. After 10 years of complete remission state, she presented with anal mass which was diagnosed as RMS and she received chemoradiation therapy. After 1 year of complete remission state, she noticed a palpable mass in her left breast. The breast mass was diagnosed as metastatic RMS based on core needle biopsy specimen. The RMS in breast was excised for the decreasing tumor burden despite of another metastatic lesion. Although rarely reported, metastasis of RMS should be considered as a cause of breast mass. Tissue biopsy is recommended when clinically suspected lesion is detected.

Studies have been focused on natural products with antibacterial and anti-inflammatory activities, such as fucoidan. Many in vivo studies have evaluated the effect of fucoidan on tumor growth, diabetes, obesity, ischemia reperfusion, and oxidative stress. However, the effects of fucoidan on bacteria-induced gingival inflammation and periodontitis have not been reported. We previously characterized the anti-inflammatory effect of fucoidan in vitro. Here, we confirmed the anti-inflammatory activity of fucoidan in a macrophage cell line in terms of its inhibition of the expression of inflammatory mediators and pro-inflammatory cytokines. Additionally, we confirmed the ability of fucoidan to inhibit gingival inflammation, expression of pro-inflammatory cytokines, and neutrophil recruitment in the gingival tissue of mice injected with LPS prepared from P. gingivalis. Interestingly, however, fucoidan did not inhibit the expression of pro-inflammatory cytokines in a P. gingivalis-infected mouse model of periodontitis. Additionally, fucoidan treatment did not lead to clearance of P. gingivalis or improvement of P. gingivalis infection-mediated bone loss in the periodontitis model. We conclude that fucoidan exerts anti-inflammatory effects in vitro and in vivo, together with a limited antibacterial effect in vivo.

Lasers have been successfully used for decades to remove dark hair. However, laser removal of nonpigmented hair is challenging due to the lack of chromophores. The aim of this study was to use photodynamic therapy (PDT) to remove nonpigmented hair.We compared the efficacy of permanent hair reduction in white BALB/c and black C57BL/6 mice treated with PDT or an 800-nm diode laser. We collected skin biopsy specimens and investigated post-PDT histologic changes and molecular changes.We observed keratin 15 staining in the bulge area and alkaline phosphatase staining in the dermal papilla following PDT. We observed a temporary, catagen-like transformation in nonpigmented hair follicles after PDT. We observed apoptotic cells in the hair matrix after PDT. Irradiation with an 800-nm diode laser did not achieve nonpigmented hair removal. Multiple PDT sessions achieved permanent reduction of nonpigmented hair. Interestingly, removal of black hair using PDT was less efficient.Our results suggest that PDT can damage the nonpigmented hair matrix, but not stem cells or dermal papillae. Repeated PDT may impair the hair-regeneration capacity via a bystander effect on bulge stem cells or dermal papillae. In this study, we found it was possible to remove nonpigmented hair using PDT. Lasers Surg. Med. 48:748-762, 2016. © 2016 Wiley Periodicals, Inc.

CD47 (integrin-associated protein), a multi-spanning transmembrane protein expressed in all cells including red blood cells (RBCs) and leukocytes, interacts with signal regulatory protein α (SIRPα) on macrophages and thereby inhibits phagocytosis of RBCs. Recently, we generated a novel C57BL/6J CD47 knockout (CD47-/- hereafter) mouse line by employing a CRISPR/Cas9 system at Center for Mouse Models of Human Disease, and here report their hematological phenotypes. On monitoring their birth and development, CD47-/- mice were born viable with a natural male-to-female sex ratio and normally developed from birth through puberty to adulthood without noticeable changes in growth, food/water intake compared to their age and sex-matched wild-type littermates up to 26 weeks. Hematological analysis revealed a mild but significant reduction of RBC counts and hemoglobin in 16 week-old male CD47-/- mice which were aggravated at the age of 26 weeks with increased reticulocyte counts and mean corpuscular volume (MCV), suggesting hemolytic anemia. Interestingly, anemia in female CD47-/- mice became evident at 26 weeks, but splenomegaly was identified in both genders of CD47-/- mice from the age of 16 weeks, consistent with development of hemolytic anemia. Additionally, helper and cytotoxic T cell populations were considerably reduced in the spleen, but not in thymus, of CD47-/- mice, suggesting a crucial role of CD47 in proliferation of T cells. Collectively, these findings indicate that our CD47-/- mice have progressive hemolytic anemia and splenic depletion of mature T cell populations and therefore may be useful as an in vivo model to study the function of CD47.

Background Previous studies have suggested an association between usual interstitial pneumonia (UIP) and lung cancer (Ca). However, clinical and histological information is not enough to determine such an association, due to the low incidence and short survival time of patients with both conditions. Methods We retrospectively reviewed the clinical and histological records of Ca patients with UIP between January 1999 and August 2013 at the Samsung Medical Center, Seoul, Korea. We found 43 patients who had Ca with UIP (UIP-Ca). Previously reported data of eighty-four patients with UIP-only were included as a comparison group. Results Smoking is related to poor prognosis in patients with UIP-Ca, and the number of patients with a high smoking index of more than 30 pack-years significantly increased in UIP-Ca patients compared with UIP-only patients. There is no significant prognostic differentiation between UIP-Ca patients and UIP-only patients. Microscopically, UIP-Ca patients showed characteristically heterogeneous histological patterns and degrees of differentiation. There were many foci of squamous metaplasia or dysplasia at the peripheral area of squamous cell carcinomas. Conclusions We report 43 cases of UIP-Ca. Our results suggest that smoking is related to cancer occurrence in UIP patients and poor prognosis in UIP-Ca patients.

Objectives Epithelial myoepithelial carcinoma (EMC) of the lung is a very rare tumor that is characterized by biphasic differentiation of epithelial and myoepithelial cells. Current discussion about this entity focuses on the malignant potential of the tumor and the role of myoepithelial cells in diagnosis and patient prognosis. This study reports five EMC cases in the lung and discusses issues related to EMC prognosis. Materials and methods The five EMC cases were diagnosed and collected at the Samsung Medical Center (Seoul, Korea) from 1998 to 2012. Four patients with EMC were received a lobectomy and one patient was given a bronchoscopy to excise the tumor. All cases were evaluated with hematoxylin and eosin and immunohistochemical staining, which included S-100 protein, smooth muscle actin, TTF-1, cytokeratin, vimentin, and p27 analysis. Results and conclusion All cases revealed biphasic differentiation of epithelial and myoepithelial tumor cells with various stromal patterns. One of the cases contained predominantly myoepithelial and focal epithelial differentiation, and the tumor showed recurrence and metastasized to the chest wall. This was the first case of metastatic pulmonary EMC. Therefore, we suggest that EMC of the lung has a malignant potential, and that myoepithelial tumor cells may be associated with a pulmonary EMC prognosis.

Primary breast lymphoma (PBL) is a rare disease, particularly in males. Diffuse large B cell lymphoma is the most common PBL, while follicular lymphoma is less common. Furthermore, primary follicular lymphoma of a male breast is rarely reported. We report a male patient with primary follicular lymphoma of the breast and hepatocellular carcinoma (HCC). A 46-year-old man was diagnosed with liver cirrhosis secondary to chronic hepatitis B infection. Ten years later, he underwent segmentectomy of the liver due to HCC. Another 5 months later, he presented with a painless mass in the right chest wall. The mass was diagnosed as follicular lymphoma of the breast. The stage was IEA and he did not receive adjuvant therapy. Although only a few cases have been reported, lymphoma should be considered as a possible cause of breast mass, even in male patients.

The purpose of this study was to investigate the correlative association between tumoral 2-deoxy-2-[(18)F]-fluoro-D-glucose (FDG) uptake, and the expressions of glucose transporter 1 (GLUT-1), glucose transporter 3 (GLUT-3), hexokinase II (HK-2), and Ki-67 expression in malignant melanoma.Nineteen patients with histologically proven malignant melanoma and pretreatment FDG PET/CT performance were involved in this preliminary study. For semi-quantitative analysis of FDG PET/CT, maximal standardized uptake values (SUVmax) were estimated. Immunohistochemical staining of tumor sections was performed for GLUT-1, GLUT-3, and HK-2, and for the cell proliferation maker Ki-67. Especially, by combining proportions and intensity of immunochemical staining, we evaluated modified immunohistologic scores of GLUT-1 and GLUT-3.The SUVmax of malignant melanoma lesions ranged from 2 to 18.7 (average; 9.1±5.4). Comparison between nodal and extranodal lesions revealed no significant difference of SUVmax (p=0.97). GLUT-1 staining showed the most positive expression level (89.5%, 17/19) among the diverse immunohistochemical markers. There were significant relationships between FDG uptake of malignant melanoma and GLUT-1 proportion (p0.0001), GLUT-1 intensity (p0.0001), GLUT-3 proportion (p=0.031), GLUT-3 intensity (p=0.009), GLUT-1 immunohistologic scores (p0.0001), and GLUT-3 immunohistologic scores (p=0.028). HK-2 was not expressed in all melanoma samples. Although Ki-67 expression showed a high grade in all staining, there was no significant link between FDG uptake and Ki-67 grades (p=0.38).The data in this preliminary study indicate that FDG uptake in malignant melanoma is determined by GLUT-1 and GLUT-3, whereas HK-2 and Ki-67 play no role in FDG uptake of malignant melanoma.

Background Lymphangioleiomyomatosis (LAM) is a slowly progressive neoplastic disease that predominantly affects females. Usually, LAM affects the lung; it can also affect extrapulmonary sites, such as the mediastinum, the retroperitoneum, or the lymph nodes, although these locations are rare. A localized form of LAM can manifest as extrapulmonary lesions; this form is referred to as extrapulmonary lymphangioleiomyoma (E-LAM). Due to the rare occurrence of E-LAM and its variable, atypical location, E-LAM is often difficult to diagnose. Herein, we report the clinicopathological information from four E-LAM cases, and also review previous articles investigating this disease. Methods Four patients with E-LAM were identified at the Samsung Medical Center (Seoul, Korea) from 1995 to 2012. All E-LAM lesions underwent surgical excision. Results All patients were females within the age range of 43 to 47 years. Two patients had para-aortic retroperitoneal masses, while the other two patients had pelvic lesions; two out of the four patients also had accompanying pulmonary LAM. In addition, no patient displayed any evidence of tuberous sclerosis. Histologically, two patients exhibited nuclear atypism with cytologic degeneration. Conclusions E-LAM should be considered in the differential diagnosis of patients presenting with pelvic or para-aortic masses. We also conclude that further clinical and pathological evaluation is needed in patients with E-LAM and nuclear atypism.

Purpose: Primary breast lymphoma is a very rare disease, accounting for 0.4–0.5% of all breast malignancies. Due to the rarity, there are only limited reports of this disease in Korean women. In this reason, we report the experience of a single institution in Korea with primary breast lymphoma (PBL). Methods: We retrospectively reviewed the medical records of 9 patients with PBL and evaluated the clinicopathologic characteristics and treatment outcomes. Results: All nine patients were female and had diffuse large B-cell lymphoma (DLBL). The median age at diagnosis was 47.9 years and the median tumor size was 3.8 cm in diameter. The most common symptom was a painless palpable mass. Five patients were classified as stage IEA and four patients were IIEA according to the Ann Arbor staging system. Four patients underwent excisional biopsy and one patient underwent a lumpectomy with sentinel lymph node biopsy due to uncertain histology of the preoperative core needle biopsy. Nine patients received anthracycline containing combined chemotherapy; among them, five patients were treated with a rituximab containing regimen. Four patients received radiotherapy combined with chemotherapy. A complete response was achieved in eight patients. During the 44 months of the median follow-up period, three cases of relapse occurred, and among them, two patients died due to disease progression. Conclusion: Most PBLs are B-cell origin, with DLBL being the most common histologic type. A combined treatment modality has been known to have positive effects on prognosis, and surgery should be limited to a diagnostic purpose.

Background: Although Kikuchi’s lymphadenitis (KL) has been known to have characteristic cytological features, pathologists encounter difficulties in making a diagnosis with fine needle aspira tion cytology (FNAC). The objective of this study was to assess the diagnostic pitfalls of KL with FNAC, particularly with emphasis on differential diagnosis with tuberculosis. Methods: FNAC of 10 patients with a histological diagnosis of KL and tuberculosis was reviewed. Results: Acidophilic cells were observed in all the 10 KL cases, even if the smears were insufficient. Crescentic histiocytes were seen in 8, granular background in 7, and karyorrhectic debris in 3 cases. Epithelioid histiocytes or neutrophils were not seen in any of the KL cases. Of the 10 cases of tuberculosis, acidophilic cells were observed in 6 cases, crescentic histiocytes in none of them, cheeselike background in 9, karyorrhectic debris in 8, epithelioid histiocytes in 4, and neutrophils in 8 cases. Conclusions: The acidophilic cell could be the most sensitive but not the specific mar ker of KL with FNAC. The crescentic histiocytes might be the sensitive and considerably specific mark er of KL. The cytological features distinguishing tuberculosis from KL may be cheese-like necrosis admixed with neutrophils and epithelioid histiocytes.

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor of low to intermediate malignant potential, and PEH can mimic other more common tumor entities pathologically as well as clinically. Compared to its well-recognized histological features, its cytological findings have been reported rarely to be plasmacytoid or epithelioid cells with abundant dense or finely granular cytoplasm, cytoplasmic vacuoles, round nuclei and prominent nucleoli. We report here on the fine needle aspiration cytologic findings of a 38-year-old woman with EH of the lung, that showed in addition to its classical cytomorphology, a somewhat peculiar cytologic finding such as big twig-like rosettoid structures with prominent hyalinized stroma. This tumor was histologically and immunohistochemically proven to be PEH by primary antibodies for CD31, CD34 and vimentin. We emphasize that the accuracy of making a cytologic diagnosis of this rare tumor can be increased by recognizing the peculiar cytologic finding that we report on here.

Intestinal duplication cysts are characterized by the attachment to some part of the gastrointestinal tract with which a blood supply is shared, and have an epithelial lining resembling some part of the alimentary tract. A 15-month-old female was admitted to our hospital with cyclic irritability, vomiting, and blood-tinged stool. The results of an ultrasound showed an ileocolic intussusception and a 1.3 cm cystic mass had double-wall sign and a Y-configuration with an adjacent ileal loop. She had a past history of two ileocolic intussusceptions. The cystic mass was considered to be a pathologic lead point, so resection and end-to-end anastomosis was performed. The gross and histologic evaluation of the specimen demonstrated a 2.4×2.4 cm cystic mass containing yellow mucoid fluid and the cyst wall was lined with intestinal and gastric mucosa and enclosed by a layer of muscle, which was shared with the adjacent ileum. (Korean J Pediatr Gastroenterol Nutr 2010; 13: 75∼80)

Anaplastic thyroid carcinoma (ATC) is an uncommon aggressive malignant tumor, and the osteoclastic variant of ATC is extremely rare. We report here on the fine needle aspiration cytology of the osteoclastic variant of ATC in an 83-year-old woman. The smear was composed of many oval to slightly elongated undifferentiated mononuclear cells admixed with multinucleated osteoclast-like giant cells. The mononuclear tumor cells revealed inconspicuous nuclear pleomorphism and the nuclei were characterized by vesicular chromatin and an indented or lobulated nuclear membrane with conspicuous nuclear grooves. A few epithelial clusters suggestive of a papillary carcinoma component were also observed. Making the proper cytological diagnosis of the osteoclastic variant of ATC is helpful to determine the proper treatment modality for these patients.