Mi-Seon Kang

Current trends in the epidemiological and pathological characteristics of gastrointestinal stromal tumors in Korea, 2003-2004.

Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet. Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain. We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings. The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000. Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries. In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patients survival. However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patients survival in multivariate analysis. The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patients survival, but the mechanism still needs to be clarified through future studies.

Protective role of V‐set and immunoglobulin domain‐containing 4 expressed on kupffer cells during immune‐mediated liver injury by inducing tolerance of liver T‐ and natural killer T‐cells

V‐set and Ig domain‐containing 4 (VSIG4, CRIg, or Z39Ig), a newly identified B7‐related cosignaling molecule, is a complement receptor and a coinhibitory ligand that negatively regulates T‐cell immunity. Despite its exclusive expression on liver Kupffer cells (KCs) that play key roles in liver tolerance, the physiological role of VSIG4 in liver tolerance remains undefined. Mice lacking VSIG4 had poor survival rates and severe liver pathology in a concanavalin A (ConA)‐induced hepatitis (CIH) model, which could be prevented by adoptive transfer of VSIG4+ KCs. The absence of VSIG4 rendered endogenous liver T‐ and natural killer T (NKT)‐cells more responsive to antigen‐specific stimulation and impaired tolerance induction in those cells against their cognate antigens. T‐cell costimulation with VSIG4.Ig suppressed Th1‐, Th2‐, and Th17‐type cytokine production and arrested the cell cycle at the G0/G1 phase but did not induce apoptosis in vitro. VSIG4‐mediated tolerance induction and cell‐cycle arrest were further supported by down‐regulation of G1 phase‐specific Cdk2, Cdk4, and Cdk6, and up‐regulation of tolerance‐inducing p27KIP‐1 in VSIG4.Ig‐stimulated T‐cells. Administration of soluble VSIG4.Ig to wildtype mice prevented CIH development and prolonged the survival of mice with established CIH. Conclusion: Collectively, our results suggest that VSIG4+ KCs play a critical role in the induction and maintenance of liver T‐ and NKT‐cell tolerance, and that modulation of the VSIG4 pathway using a VSIG4.Ig fusion protein may provide useful immunological therapies against immune‐mediated liver injury including autoimmune hepatitis. (HEPATOLOGY 2012;56:1838–1848)

Expression of galectin-9 by IFN-γ stimulated human nasal polyp fibroblasts through MAPK, PI3K, and JAK/STAT signaling pathways.

Galectin-9 exhibited potent and selective eosinophil chemoattractant activity and attracted eosinophils in vitro and in vivo. Nasal polyposis is a chronic inflammatory disease of the upper airway characterized by the marked presence of inflammatory cells, particularly eosinophils. Thus, galectin-9 may be implicated in the pathogenesis of nasal polyposis. The study was designed to investigate whether interferon-gamma (IFN-γ) can induce the augmentation of galectin-9 expression and induce the expression of galectin-9 in nasal polyps. We examined the correlation between galectin-9 expression and eosinophil infiltration in nasal polyps. In addition, we identified the signaling pathways involved in the elevation of galectin-9 expression in response to IFN-γ. Our data demonstrate that the involvement of mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3 phosphate kinase (PI3K), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) may play important roles in the selective recruitment of eosinophils in nasal polyp tissues through the production of galectin-9. These findings suggest that galectin-9 expression is associated with eosinophil infiltration in polyps of patients with nasal polyposis.

Attenuation of IFN-γ-induced B7-H1 expression by 15-deoxy-delta12,14-prostaglandin J2 via downregulation of the Jak/STAT/IRF-1 signaling pathway

AIM B7-H1, which belongs to the B7 family of costimulatory molecules, is implicated in the ability of tumors to evade the host immune response. The development of evasion mechanisms within the tumor microenvironment may be responsible for poor therapeutic responses. In this manuscript, we report that the 15-deoxy-δ(12,14)-prostaglandin J2 (15d-PGJ2), peroxisome proliferator-activated receptor gamma (PPARγ) activator leads to the downregulation of the cancer-associated expression of B7-H1 in response to interferon-gamma (IFN-γ) and the associated signaling cascades. MAIN METHODS The expression of B7-H1 from IFN-γ-induced B16F10 melanoma cells was measured with flow cytometric analysis. The regulatory mechanisms of 15d-PGJ2 on cellular signaling pathways were examined using Western blot and electrophoretic mobility shift assays. KEY FINDINGS The flow cytometric analysis revealed that the B7-H1 costimulatory molecule is significantly upregulated in B16F10 melanoma cells by stimulation with IFN-γ. However, 15d-PGJ2 strongly downregulates B7-H1 expression in IFN-γ-stimulated B16F10 melanoma cells. Furthermore, the significant damping effect of 15d-PGJ2 on B7-H1 expression involves the inhibition of the tyrosine phosphorylation of Janus kinase (Jak) and signal transducer(s) and activator(s) of transcription (STAT) and, thereby, the interferon regulatory factor-1 (IRF-1) trans-activation of STAT. These effects of 15d-PGJ2 were not abrogated by the PPARγ antagonist GW9662, indicating that they occur through a PPARγ-independent mechanism. SIGNIFICANCE In this study, we demonstrate that 15d-PGJ2 suppresses the IFN-γ-elicited expression of B7-H1 by the inhibition of IRF-1 transcription via the Jak/STAT signaling pathway through a PPARγ-independent mechanism in mouse melanoma cells.

Reuse of a Previously Transplanted Kidney From a Deceased Donor Using Luminex Virtual Crossmatching: A Case Report

Kidney transplantation is the most desired modality of renal replacement therapy for patients with end-stage renal disease (ESRD). We have attempted to expand the organ donor pool through several methods, including the use of expanded donor criteria. Although previously transplanted kidneys are rarely reused, they can be suitable for transplantation into patients in need. We report a case of successful reuse of a previously transplanted kidney from a deceased donor by means of Luminex virtual crossmatching with the first donor and actual crossmatching with the second donor.

Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis.

Abstract Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti‐fibrotic agents is urgently needed. Although histone deacetylases (HDACs) have been reported to be involved in renal fibrosis, current HDAC inhibitors are unsatisfactory anti‐fibrosis drugs. Therefore, more potentially relevant anti‐renal fibrosis HDAC inhibitors are needed. We initially found that non‐cytotoxic concentrations of SB939 (pracinostat) had strong anti‐fibrotic activity, drastically decreasing TGF‐&bgr;1‐induced alpha smooth muscle actin (&agr;‐SMA) expression in the NRK renal fibroblast cell line. Similar anti‐fibrotic activity of SB939 on epithelial‐to‐mesenchymal transition (EMT) was confirmed using the HK‐2 human renal proximal tubular epithelial cell line. SB939 inhibited Smad‐independent TGF‐&bgr; signaling involving the MAPK and PI3K/AKT pathways. To evaluate in vivo anti‐fibrotic activity, we administered SB939 in a unilateral ureteric obstruction (UUO) model. SB939 treatment markedly inhibited the accumulation of &agr;‐SMA and tissue injury. Inflammatory and pro‐fibrotic cytokines in the obstructed kidney were also significantly decreased by SB939 treatment. Our results suggest that SB939 might be a promising therapeutic drug for preventing renal fibrosis. HighlightsPan‐HDAC inhibitor SB939 was investigated on renal fibrosis.SB939 inhibits TGF‐&bgr;1‐induced myofibroblast generation.SB939 inhibits Smad‐independent pathways in TGF‐&bgr; signaling.Administration of SB939 into UUO model reduces renal fibrosis and inflammation.