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1.  Immune Suppressive Effects of Tonsil-Derived Mesenchymal Stem Cells on Mouse Bone-Marrow-Derived Dendritic Cells 
Stem Cells International  2015;2015:106540.
Mesenchymal stem cells (MSCs) are considered valuable sources for cell therapy because of their immune regulatory function. Here, we investigated the effects of tonsil-derived MSCs (T-MSCs) on the differentiation, maturation, and function of dendritic cells (DCs). We examined the effect of T-MSCs on differentiation and maturation of bone-marrow- (BM-) derived monocytes into DCs and we found suppressive effect of T-MSCs on DCs via direct contact as well as soluble mediators. Moreover, T cell proliferation, normally increased in the presence of DCs, was inhibited by T-MSCs. Differentiation of CD4+ T cell subsets by the DC-T cell interaction also was inhibited by T-MSCs. The soluble mediators suppressed by T-MSCs were granulocyte-macrophage colony-stimulating factor (GM-CSF), RANTES, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Taken together, T-MSCs exert immune modulatory function via suppression of the differentiation, maturation, and function of BM-derived DCs. Our data suggests that T-MSCs could be used as a novel source of stem cell therapy as immune modulators.
PMCID: PMC4345276  PMID: 25784940
3.  Tonsil-derived Mesenchymal Stem Cells Ameliorate CCl4–induced Liver Fibrosis in Mice via Autophagy Activation 
Scientific Reports  2015;5:8616.
Liver transplantation is the treatment of choice for chronic liver failure, although it is complicated by donor shortage, surgery-related complications, and immunological rejection. Cell transplantation is an alternative, minimally invasive treatment option with potentially fewer complications. We used human palatine tonsil as a novel source of mesenchymal stem cells (T-MSCs) and examined their ability to differentiate into hepatocyte-like cells in vivo and in vitro. Carbon tetrachloride (CCl4) mouse model was used to investigate the ability of T-MSCs to home to the site of liver injury. T-MSCs were only detected in the damaged liver, suggesting that they are disease-responsive. Differentiation of T-MSCs into hepatocyte-like cells was confirmed in vitro as determined by expression of hepatocyte markers. Next, we showed resolution of liver fibrosis by T-MSCs via reduction of TGF-β expression and collagen deposition in the liver. We hypothesized that autophagy activation was a possible mechanism for T-MSC-mediated liver recovery. In this report, we demonstrate for the first time that T-MSCs can differentiate into hepatocyte-like cells and ameliorate liver fibrosis via autophagy activation and down-regulation of TGF-β. These findings suggest that T-MSCs could be used as a novel source for stem cell therapy targeting liver diseases.
PMCID: PMC4342568  PMID: 25722117
4.  Clinical experience with 18F-fluorodeoxyglucose positron emission tomography and 123I-metaiodobenzylguanine scintigraphy in pediatric neuroblastoma: complementary roles in follow-up of patients 
Korean Journal of Pediatrics  2014;57(6):278-286.
To evaluate the potential utility of 123I-metaiodobenzylguanine (123I-MIBG) scintigraphy and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for the detection of primary and metastatic lesions in pediatric neuroblastoma (NBL) patients, and to determine whether 18F-FDG PET is as beneficial as 123I-MIBG imaging.
We selected 8 NBL patients with significant residual mass after operation and who had paired 123I-MIBG and 18F-FDG PET images that were obtained during the follow-up. We retrospectively reviewed the clinical charts and the findings of 45 paired scans.
Both scans correlated relatively well with the disease status as determined by standard imaging modalities during follow-up; the overall concordance rates were 32/45 (71.1%) for primary tumor sites and 33/45 (73.3%) for bone-bone marrow (BM) metastatic sites. In detecting primary tumor sites, 123I-MIBG might be superior to 18F-FDG PET. The sensitivity of 123I-MIBG and 18F-FDG PET were 96.7% and 70.9%, respectively, and their specificity were 85.7% and 92.8%, respectively. 18F-FDG PET failed to detect 9 true NBL lesions in 45 follow-up scans (false negative rate, 29%) with positive 123I-MIBG. For bone-BM metastatic sites, the sensitivity of 123I-MIBG and 18F-FDG PET were 72.7% and 81.8%, respectively, and the specificity were 79.1% and 100%, respectively. 123I-MIBG scan showed higher false positivity (20.8%) than 18F-FDG PET (0%).
123I-MIBG is superior for delineating primary tumor sites, and 18F-FDG PET could aid in discriminating inconclusive findings on bony metastatic NBL. Both scans can be complementarily used to clearly determine discrepancies or inconclusive findings on primary or bone-BM metastatic NBL during follow-up.
PMCID: PMC4115069  PMID: 25076973
Neuroblastoma; Positron emission tomography; MIBG; Child; Follow-up studies
5.  Clinical characteristics of hemophagocytic lymphohistiocytosis following Kawasaki disease: differentiation from recurrent Kawasaki disease 
Blood research  2013;48(4):254-257.
Our aim was to investigate the clinical pattern of hemophagocytic lymphohistiocytosis following Kawasaki disease (HLH-KD), to enable differentiation of HLH from recurrent or refractory KD and facilitate early diagnosis.
We performed a nationwide retrospective survey and reviewed the clinical characteristics of patients with HLH-KD, including the interval between KD and HLH, clinical and laboratory findings, treatment responses, and outcomes, and compared them with historical data for both diseases.
Twelve patients with HLH-KD, including 5 previously reported cases, were recruited. The median age was 6.5 years (range, 9 months-14.7 years). Eight patients were male and 4 were female. The median interval between the first episode of KD and the second visit with recurrent fever was 12 days (3-22 days). Of the 12 children, 2 were initially treated with intravenous IgG (IVIG) for recurrent KD when they presented at the hospital with recurrent fever. Eventually, 10 children received chemotherapy under an HLH protocol and 2 received supportive treatment. Two patients died of combined infections during chemotherapy, 1 was lost to follow up, and 9 remain alive. The overall survival rate at 4 years was 81.1% with a median follow up of 45.1 months.
A diagnosis of HLH-KD should be considered when symptoms similar to recurrent KD develop within 1 month of the first episode of KD. Our findings will help physicians differentiate between HLH and the recurrent form of KD.
PMCID: PMC3894383  PMID: 24466549
Hemophagocytic lymphohistiocytosis; Kawasaki disease; Recurrent
6.  Posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors 
Blood research  2013;48(4):258-265.
Hemophagocytic lymphohistiocytosis (HLH) is a rare multiorgan disease of toxic immune activation caused by the interaction of cytotoxic T cells and innate immune cells and frequently involves the central nervous system (CNS). Posterior reversible encephalopathy syndrome (PRES) might develop during treatment with the HLH-2004 protocol from the Histiocyte Society. The aims of this study were to evaluate clinical outcomes and putative risk factors for prediction of PRES related to HLH.
We reviewed the medical records of 28 patients with HLH who were treated between April 2005 and April 2012. We compared various clinical and laboratory parameters in patients without or with PRES to evaluate putative risk factors related to development of PRES.
Six (21.4%) of the patients experienced PRES during treatment with the HLH-2004 protocol. Clinical and laboratory manifestations were not different compared with other conditions causing PRES. The main mechanism of PRES may be related to the HLH-2004 protocol and a high pro-inflammatory state. Most patients recovered quickly from neurologic manifestations without significant long-term sequelae. Preceding hypertension, an increase in ferritin level >50% compared with 1 week before development of PRES and hyponatremia were statistically significant factors.
PRES is clinically reversible and has a favorable outcome in patients with HLH. Awareness of PRES and a differential diagnosis of other causes of neurologic complications, including CNS involvement of HLH, can help avoid unnecessary treatment or delayed management. Patients with preceding hypertension, hyponatremia, and rising ferritin levels during HLH treatment should be closely monitored for PRES.
PMCID: PMC3894384  PMID: 24466550
Hemophagocytic lymphohistiocytosis; Posterior reversible encephalopathy syndrome; HLH-2004; Risk factors; Reversible; Child
7.  Clinical and hematologic manifestations in patients with Diamond Blackfan anemia in Korea 
The Korean Journal of Hematology  2012;47(2):131-135.
Diamond Blackfan anemia (DBA), characterized by impaired red cell production, is a rare condition that is usually symptomatic in early infancy. The purpose of this study was to assess nationwide experiences of DBA encountered over a period of 20 years.
The medical records of 56 patients diagnosed with DBA were retrospectively reviewed from November 1984 to July 2010. Fifteen institutions, including 13 university hospitals, participated in this study.
The male-to-female ratio of patients with DBA was 1.67:1. The median age of diagnosis was 4 months, and 74.1% were diagnosed before 1 year of age. From 2000 to 2009, annual incidence was 6.6 cases per million. Excluding growth retardation, 38.2% showed congenital defects: thumb deformities, ptosis, coarctation of aorta, ventricular septal defect, strabismus, etc. The mean hemoglobin concentration was 5.1±1.9 g/dL, mean corpuscular volume was 93.4±11.6 fL, and mean number of reticulocytes was 19,700/mm3. The mean cellularity of bone marrow was 75%, with myeloid:erythroid ratio of 20.4:1. After remission, 48.9% of patients did not need further steroids. Five patients with DBA who received hematopoietic transplantation have survived. Cancer developed in 2 cases (3.6%).
The incidence of DBA is similar to data already published, but our study had a male predilection. Although all patients responded to initial treatment with steroids, about half needed further steroids after remission. It is necessary to collect further data, including information regarding management pathways, from nationwide DBA registries, along with data on molecular analyses.
PMCID: PMC3389062  PMID: 22783360
Diamond Blackfan anemia; Anemia; Congenital defects
8.  Antitumor effects of imatinib mesylate and synergistic cytotoxicity with an arsenic compound in neuroblastoma cell lines 
Neuroblastoma is a common tumor in childhood and exhibits heterogeneity and malignant progression. MYCN expression and amplification profiles are frequently correlated with the efficacy of therapy. Arsenic trioxide and imatinib mesylate (STI-571) have been suggested as promising therapeutic agents for neuroblastoma, which has been shown to be resistant to conventional therapy. In order to ascertain whether the combination of arsenic trioxide and STI-571 exerts a synergistic cytotoxic effect on neuroblastoma cells in relation to MYCN status, we evaluated cellular proliferation after 72 h of exposure to arsenic trioxide and STI-571 with or without siRNA against MYCN in SH-SY5Y, SK-N-SH and SK-N-BE(2) neuroblastoma cells. Arsenic trioxide and STI-571 demonstrated a synergistic inhibitory effect on cellular proliferation, while MYCN knockdown had an antagonistic effect on this combined treatment. These results indicate that STI-571 treatment may prove effective for MYCN-expressing or MYCN-amplified neuroblastoma. Furthermore, siRNA therapy targeted to MYCN should be avoided in combination with STI-571 treatment in cases of neuroblastoma.
PMCID: PMC3440685  PMID: 22977540
imatinib mesylate (STI-571); arsenic trioxide; neuroblastoma cells; MYCN
9.  Effect on Cell Cycle Progression by N-Myc Knockdown in SK-N-BE(2) Neuroblastoma Cell Line and Cytotoxicity with STI-571 Compound 
Neuroblastoma is a common tumor in childhood, and generally exhibits heterogeneity and a malignant progression. MYCN expression and amplification profiles frequently correlate with therapeutic prognosis. Although it has been reported that MYCN silencing causes differentiation and apoptosis in human neuroblastoma cells, MYCN expression influences the cytotoxic potential of chemotherapeutic drugs via the deregulation of the cell cycle. STI-571 may constitute a promising therapeutic agent against neuroblastoma, particularly in cases in which c-Kit is expressed preferentially in MYCN-amplified neuroblastoma.
Materials and Methods
To determine whether STI-571 exerts a synergistic effect on cytotoxicity with MYCN expression, we assessed apoptotic cell death and cell cycle distribution after 72 h of exposure to STI-571 with or with out treatment of SK-N-BE(2) neuroblastoma cells with MYCN siRNA.
MYCN siRNA-treated SK-N-BE(2) cells did not affect apoptosis and cells were arrested in G0/G1 phase after STI-571 treatment.
siRNA therapy targeted to MYCN may not be effective when administered in combination with STI-571 treatment in cases of neuroblastoma. Therefore, chemotherapeutic drugs that target S or G2-M phase may prove ineffective when applied to cells arrested in the G0/1 phase as the result of MYCN knockdown and STI-571 treatment.
PMCID: PMC2699088  PMID: 19688062
Imatinib mesylate (STI-571); Cell cycle; Neuroblastoma; MYCN; SK-N-BE(2)
10.  Myeloablative treatment supported by autologous stem cell infusion with neuroblastoma. 
Journal of Korean Medical Science  2003;18(2):184-190.
Bcr-abl antisense oligodeoxynucleotides (AS-ODNs) have provided evidence of an antileukemia effect when tested in vitro against Philadelphia-positive cells. In order to investigate the efficacy of AS-ODNs as purging agents in chronic myeloid leukemia (CML) patients, K562 cells, a human CML cell line, were treated in vitro with various types of AS-ODNs and interferon-alpha. Cells were treated in vitro for 0 and 36 hr with 40 microgram/mL of AS-ODNs, respectively, and incubated at 37 degrees C for 36 hr. Cytotoxic effects were measured by counting the number of viable cells as well as by MTT test. Clonogenic activities were evaluated by methylcellulose culture for 2 weeks. The effects of purging agents on the rearrangement of bcrabl gene were evaluated by RT-PCR. AS-ODNs inhibited the proliferation of K562 cells with time in cell count assay and MTT test. AS-ODNs were superior to INF-alpha in inhibiting clonogenic activity (recovery rate; 26.3% vs 64.0%). After incubation with bcr-abl AS-ODNs primers and mRNA isolated from K562 cells, positive bands were abolished, especially of b3a2 type and phosphorothioate type. Our results suggest that AS-ODNs mediated purging may be one of the efficient methods and that autograft may be an alternative treatment for allograft in high-risk group patients of CML if they do not have a stem cell donor.
PMCID: PMC3055011  PMID: 12692414
11.  Autologous stem cell transplantation for the treatment of neuroblastoma in Korea. 
Journal of Korean Medical Science  2003;18(2):242-247.
Autologous stem cell transplantation (ASCT) for the treatment of high-risk neuroblastoma (NBL) is an accepted method for restoring bone marrow depression after high dose chemotherapy. We retrospectively analyzed eighty eight cases of NBL that underwent ASCT following marrow ablative therapy at 12 transplant centers of the Korean Society of Pediatric Hematology-Oncology between January 1996 and September 2000. Seventy nine children were of stage IV NBL and 9 were of stage III with N-myc amplification. Various cytoreductive regimens were used. However, the main regimen was 'CEM' consisting of carboplatin, etoposide and melphalan, and this was used in 66 patients. Total body irradiation was also added in 36 patients for myeloablation. To reduce tumor cell contamination, stem cell infusions after CD34+ cell selection were performed in 16 patients. Post-transplantation therapies included the second transplantation in 18 patients, interleukin2 therapy in 45, 13-cis retinoic acid in 40, 131-meta-iodobenzylguanidine in 4, conventional chemotherapy in 11, and local radiotherapy in 8. Twenty two patients died, sixty six patients are surviving 1 to 46 months after ASCT (median followup duration, 14.5 months). Although the follow-up period was short and the number of patients small, we believe that ASCT might improve the survival rate in high-risk NBL.
PMCID: PMC3055035  PMID: 12692423

Results 1-11 (11)