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1.  GMP-Compliant, Large-Scale Expanded Allogeneic Natural Killer Cells Have Potent Cytolytic Activity against Cancer Cells In Vitro and In Vivo 
PLoS ONE  2013;8(1):e53611.
Ex vivo-expanded, allogeneic natural killer (NK) cells can be used for the treatment of various types of cancer. In allogeneic NK cell therapy, NK cells from healthy donors must be expanded in order to obtain a sufficient number of highly purified, activated NK cells. In the present study, we established a simplified and efficient method for the large-scale expansion and activation of NK cells from healthy donors under good manufacturing practice (GMP) conditions. After a single step of magnetic depletion of CD3+ T cells, the depleted peripheral blood mononuclear cells (PBMCs) were stimulated and expanded with irradiated autologous PBMCs in the presence of OKT3 and IL-2 for 14 days, resulting in a highly pure population of CD3−CD16+CD56+ NK cells which is desired for allogeneic purpose. Compared with freshly isolated NK cells, these expanded NK cells showed robust cytokine production and potent cytolytic activity against various cancer cell lines. Of note, expanded NK cells selectively killed cancer cells without demonstrating cytotoxicity against allogeneic non-tumor cells in coculture assays. The anti-tumor activity of expanded human NK cells was examined in SCID mice injected with human lymphoma cells. In this model, expanded NK cells efficiently controlled lymphoma progression. In conclusion, allogeneic NK cells were efficiently expanded in a GMP-compliant facility and demonstrated potent anti-tumor activity both in vitro and in vivo.
doi:10.1371/journal.pone.0053611
PMCID: PMC3543306  PMID: 23326467
2.  Neuronal Apoptosis Inhibitory Protein is Overexpressed in Patients with Unfavorable Prognostic Factors in Breast Cancer 
Journal of Korean Medical Science  2007;22(Suppl):S17-S23.
Neuronal apoptosis inhibitory protein (NAIP) is a recently identified inhibitor of apoptosis protein. However, the clinical relevance of NAIP expression is not completely understood. In an attempt to determine the clinical relevance of NAIP expression in breast cancer, the levels of NAIP and survivin expression were measured in 117 breast cancer samples and 10 normal breast tissues using quantitative reverse-transcriptase-polymerase chain reaction. While there was no evidence of NAIP expression in the normal breast tissue, NAIP was expressed in all breast cancer samples. The level of NAIP expression in breast cancer was significantly higher (257 times) than in the universal tumor control. There was a strong correlation between the level of NAIP expression and the level of survivin expression (p=0.001). The level of NAIP expression in patients with a large tumor (≥T2) and patients with an unfavorable histology (nuclear grade III) was significantly higher than in those patients with a small tumor (T1) and patients with a favorable histology (nuclear grade I, II) (p=0.026 and p=0.050, respectively). Although the level of NAIP expression was higher in patients with other unfavorable prognostic factors, it was not significant. The three-year relapse-free survival rate was not significantly the patients showing high NAIP expression and patients showing low NAIP expression (86.47±4.79% vs. 78.74±6.57%). Further studies should include the expressions of NAIP in a larger number of patients and for a longer period of follow-up to evaluate correlation with metastasis and treatment outcome. In conclusion, NAIP is overexpressed in breast cancer patients with unfavorable clinical features such as stage and tumor size, suggesting that NAIP would play a role in the disease manifestation.
doi:10.3346/jkms.2007.22.S.S17
PMCID: PMC2694398  PMID: 17923748
Breast Cancer; Neuronal Apoptosis Inhibitory rotein (NAIP); Apoptosis; Prognostic Factor; Clinical Relevance
3.  Human Apolipoprotein(a) Kringle V Inhibits Ischemia-Induced Retinal Neovascularization via Suppression of Fibronectin-Mediated Angiogenesis 
Diabetes  2012;61(6):1599-1608.
Retinal neovascularization is observed in progression of diabetic retinopathy. New vessels grow into the vitreous cavity in proliferative diabetic retinopathy, resulting in traction retinal detachment and vitreous hemorrhage. To overcome the catastrophic visual loss due to these complications, efforts have been focused on the treatment of retinal neovascularization. In this study, we demonstrated the inhibitory effect of recombinant human apolipoprotein(a) kringle V (rhLK8) in an animal model of ischemia-induced retinal neovascularization. rhLK8 induced no definite toxicity on endothelial cells and retinal tissues at the therapeutic dosage. Interestingly, rhLK8 showed antiangiogenic effect, particularly on fibronectin-mediated migration of endothelial cells. Further experiments demonstrated high binding affinity of rhLK8 to α3β1 integrin, and suppression of it might be the mechanism of antiangiogenic effect of rhLK8. Furthermore, rhLK8 inhibited phosphorylation of focal adhesion kinase, resulting in suppression of activation of consequent p130CAS-Jun NH2-terminal kinase. Taken together, our data suggested the possible application of rhLK8 in the treatment of retinal neovascularization by suppression of fibronectin-mediated angiogenesis.
doi:10.2337/db11-1541
PMCID: PMC3357289  PMID: 22427380
4.  Overexpression of X-linked Inhibitor of Apoptosis Protein (XIAP) is an Independent Unfavorable Prognostic Factor in Childhood de Novo Acute Myeloid Leukemia 
Journal of Korean Medical Science  2009;24(4):605-613.
The overexpression of X-linked inhibitor of apoptosis protein (XIAP), a member of IAP family protein, is intuitively expected to be associated with unfavorable clinical features in malignancies; however, there have been only a very limited number of studies reporting the clinical relevance of XIAP expression. This study was performed to investigate the prognostic relevance of XIAP expression in childhood acute myeloid leukemia (AML). In 53 children with de novo AML, the level of XIAP expression was determined by using quantitative reverse transcriptase-polymerase chain reaction and was analyzed with respect to the clinical characteristics at diagnosis and treatment outcomes. As a result, the XIAP expression was found to be higher in patients with extramedullary disease than in those without (P=0.014). In addition, XIAP overexpression (≥median expression) was associated with an unfavorable day 7 response to induction chemotherapy and also associated with a worse 3-yr relapsefree survival rate (52.7±20.9% vs. 85.9±14.8%, P=0.014). Multivariate analyses revealed that XIAP overexpression was an independent unfavorable prognostic factor for relapse-free survival (hazard ratio, 6.16; 95% confidence interval, 1.48-25.74; P=0.013). Collectively, XIAP overexpression may be used as an unfavorable prognostic marker in childhood AML.
doi:10.3346/jkms.2009.24.4.605
PMCID: PMC2719207  PMID: 19654940
X-Linked Inhibitor of Apoptosis Protein; Apoptosis; Inhibitor of Apoptosis Protein; Leukemia, Myeloid, Acute

Results 1-4 (4)