Eun Young Park

Evaluation of Cadmium-Induced Nephrotoxicity Using Urinary Metabolomic Profiles in Sprague-Dawley Male Rats

The aim of this study was to investigate urinary metabolomic profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl2 (1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl2 accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl2 exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl2 (25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-binding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citrate, serine, 3-hydroxyisovalerate, 4-hydroxyphenyllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phenylalanine and carbohydrate (glucose) were altered in urine after CdCl2 exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellular mechanism underlying Cd-induced renal injury in humans.

Histologic confirmation of huge pancreatic lipoma: a case report and review of literatures.

Pancreatic lipomas are commonly diagnosed based on radiologic images, although the prevalence of lipomas has not been established. Histologic confirmation of pancreatic lipomas is extremely rare because surgical treatment is unnecessary in most cases. Endoscopic ultrasound-guided fine-needle aspiration cytology has been suggested to avoid unnecessary surgery to distinguish between a lipoma and a well-differentiated liposarcoma; however, surgery would be needed when the tumor is associated with symptoms or difficult to distinguish from a liposarcoma. We present a case of a pancreatic lipoma in a 54-year-old male patient that was histologically-confirmed by subtotal pancreatectomy.

The Role of TWIST in Ovarian Epithelial Cancers

Background Epithelial-mesenchymal transition (EMT) is associated with tumor hypoxia. EMT is regulated, in part, by the action of TWIST, which inhibits of E-cadherin expression and may interfere with the p53 tumor-suppressor pathway. Methods We examined the expression of TWIST, E-cadherin, hypoxia-inducible factor 1α (HIF1α), and p53 by immunohistochemistry in 123 cases of ovarian epithelial cancers (OEC) to evaluate the role of TWIST in OEC. We assessed the association between protein expression and clinicopathologic parameters. Results The expression of TWIST, E-cadherin, HIF1α, and p53 proteins was found in 28.5%, 51.2%, 35.0%, and 29.3% of cases, respectively. TWIST expression was associated with higher histologic grade and unfavorable survival. TWIST expression was correlated with HIF1α expression and reduced E-cadherin expression. The altered HIF1α/TWIST/E-cadherin pathway was associated with lower overall survival (OS), while the co-expression of TWIST and p53 was correlated with lower progression-free survival. In the multivariate analyses, TWIST expression was an independent prognostic factor for OS. Conclusions Our data imply that TWIST expression could be a useful predictor of unfavorable prognosis for OEC. TWIST may affect the p53 tumor-suppressor pathway. Moreover, hypoxia-mediated EMT, which involves the HIF1α/TWIST/E-cadherin pathway may play an important role in the progression of OEC.

Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding.

The sirtuins (SIRTs), a family of NAD+-dependent class III histone deacetylase, are involved in various biological processes including cell survival, division, senescence, and metabolism via activation of the stress-response pathway. Recently, inhibition of SIRTs has been considered a promising anticancer strategy, but their precise mechanisms of action are not well understood. In particular, the relevance of p53 to SIRT-induced effects has not been fully elucidated. We investigated the anticancer effects of a novel SIRT inhibitor, MHY2256, and its efficacy was compared to that of salermide in MCF-7 (wild-type p53) and SKOV-3 (null-type p53) cells. Cell viability, SIRT1 enzyme activity, cell cycle regulation, apoptosis, and autophagic cell death were measured. We compared sensitivity to cytotoxicity in MCF-7 and SKOV-3 cells. MHY2256 significantly decreased the viability of MCF-7 (IC50, 4.8 μM) and SKOV-3 (IC50, 5.6 μM) cells after a 48 h treatment period. MHY2256 showed potent inhibition (IC50, 0.27 mM) against SIRT1 enzyme activity compared with nicotinamide (IC50, >1 mM). Moreover, expression of SIRT (1, 2, or 3) protein levels was significantly reduced by MHY2256 treatment in both MCF-7 and SKOV-3 cells. Flow cytometry analysis revealed that MHY2256 significantly induced cell cycle arrest in the G1 phase, leading to an effective increase in apoptotic cell death in MCF-7 and SKOV-3 cells. A significant increase in acetylated p53, a target protein of SIRT, was observed in MCF-7 cells after MHY2256 treatment. MHY2256 up-regulated LC3-II and induced autophagic cell death in MCF-7 cells. Furthermore, MHY2256 markedly inhibited tumor growth in a tumor xenograft model of MCF-7 cells. These results suggest that a new SIRT inhibitor, MHY2256, has anticancer activity through p53 acetylation in MCF-7 human breast cancer cells.

Primary leiomyosarcoma of gallbladder

Malignant mesenchymalneoplasms of the gallbladder are extremely rare with only 105 cases of primary gallbladder sarcoma having been described. It has a very aggressive behavior and is usually diagnosed at advanced stages. Therefore, curative surgical management may not be possible. We performed a radical cholecystectomy (S4b + S5 segmentectomy), omentectomy and small bowel resection in a 54-year-old patient with locally invasive leiomyosarcoma of the gallbladder. Further studies are needed to confirm the benefit of aggressive treatment for patients with leiomyosarcoma of the gallbladder.

Prognostic significance of WT1 expression in soft tissue sarcoma

BackgroundSoft tissue sarcomas (STS) are rare. We evaluated the WT1 protein expression level in various types of STS and elucidated the value of WT1 as a prognostic factor and a possible therapeutic target.MethodsImmunohistochemical staining for WT1 was performed in 87 cases of STS using formalin-fixed, paraffin-embedded blocks. The correlation between WT1 expression and clinicopathological factors was analyzed. Survival analysis was conducted in 67 patients. We assessed the validity of WT1 immunohistochemistry as an index of WT1 protein expression using Western blot analysis.ResultsWT1 expression was noted in 47 cases (54.0%). Most rhabdomyosarcomas and malignant peripheral nerve sheath tumors showed WT1 expression (91.7% and 71.4%, respectively; P = 0.005). WT1 expression was related to higher FNCLCC histologic grade and AJCC tumor stage. In the group with high grade STS, strong WT1 expression was correlated with better survival (P = 0.025). The immunohistochemical results were correlated quantitatively with the staining score and the concentration of the Western blot band.ConclusionsThis study demonstrates that various types of STS show positive immunostaining for WT1 and that WT1 expression has a prognostic significance. So STS should be considered candidates for WT1 peptide--based immunotherapy.

Novel SIRT1 inhibitor 15-deoxy-Δ12,14-prostaglandin J2 and its derivatives exhibit anticancer activity through apoptotic or autophagic cell death pathways in SKOV3 cells

Clinically relevant sirtuin (SIRT) inhibitors may possess antitumor activities. A previous study indicated that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exhibited potent anticancer activity by SIRT1 inhibition. Therefore, the aim of the present study was to investigate whether its derivatives (J11-C1 and J19) exhibited anticancer activity against ovarian cancer SKOV3 cells. Cell viability was determined using an MTT assay. Cell cycle arrest, apoptosis and autophagy were determined using flow cytometry or western blot analysis. J11-Cl and J19 were less cytotoxic to SKOV3 cells compared with 15d-PGJ2. Molecular docking studies supported the interactions of 15d-PGJ2, J11-Cl and J19 with various amino acids in SIRT1 proteins. Similar to 15d-PGJ2, J11-C1 and J19 inhibited SIRT1 enzymatic activity and decreased SIRT1 expression levels in a concentration-dependent manner. J11-C1 induced apoptotic cell death more effectively compared with J19, which was associated with markedly decreased expression of the anti-apoptotic molecule B-cell lymphoma 2 (Bcl-2). Furthermore, the levels of light chain 3-II (LC3-II) and beclin-1 were clearly induced in SKOV3 cells treated with J11-Cl. Thus, 15d-PGJ2 and its derivatives exhibited anticancer activity possibly by inducing apoptotic or autophagic cell death pathways. Collectively, the results of the present study suggest that 15d-PGJ2 and its derivatives exerted antitumor activity by selectively modulating the expression of genes associated with cell cycle arrest, apoptosis and autophagy. Notably, J11-C1 is a novel candidate SIRT1 inhibitor with anticancer activity.

Endosonographic Findings and the Natural Course of Chronic Gastric Anisakiasis: A Single-Center Experience

Background Chronic gastric anisakiasis is a rare, usually asymptomatic, and difficult to diagnose infection incidentally discovered during endoscopy, resembling a subepithelial tumor (SET). Because its endoscopic ultrasonography (EUS) findings are not established, it is occasionally misdiagnosed as gastrointestinal mesenchymal tumors and removed by endoscopic or surgical resection. We aimed to assess the characteristic EUS findings of chronic gastric anisakiasis and the clinical course during follow-up. Methods The database of all patients who underwent EUS at Pusan National University Hospital (Busan, Korea) between January 2011 and December 2016 was retrospectively analyzed. A total of 28 SET cases with EUS features suggesting chronic gastric anisakiasis were included in the study. The EUS, histopathologic, and follow-up endoscopic features were analyzed. Results On EUS, the lesions were mainly located in the submucosal and/or propria muscle layers. Twenty-seven lesions (27/28, 96%) showed hypoechoic echogenicity, and 22 lesions (22/28, 79%) were heterogeneous. Hyperechoic tubular structures suggesting denaturalized Anisakidae larvae were seen in 22 lesions (22/28, 79%). Endoscopic biopsies revealed significant eosinophil infiltration (≥30 per high-power field) in 12 lesions (12/21, 57%). During the median follow-up period of 9 months (range, 1–55 months), SETs decreased or subsided in 26 lesions (26/28, 93%) with no change in the size of the two lesions (2/28, 7%). Conclusions Chronic gastric anisakiasis, although rare, should be included in the differential diagnoses for gastric SETs, especially in regions where raw fish is widely consumed. EUS findings suggesting chronic gastric anisakiasis are heterogeneously hypoechoic lesions with hyperechoic tubular structures, mainly in the submucosal and/or muscularis propria layers. Because chronic gastric anisakiasis decreases or subsides in most cases, follow-up endoscopy 6–12 months later is recommended.