So Young Chong

Association of the miR-146aC>G, 149C>T, 196a2C>T, and 499A>G polymorphisms with colorectal cancer in the Korean population.

MicroRNAs (miRNAs) are small, 18‐ to 22‐nucleotide non‐coding RNAs that regulate target gene expression. Although recent studies focused on various diseases that harbor the miR‐146aC>G (rs2910164), 149C>T (rs2292832), 196a2C>T (rs11614913), and 499A>G (rs3746444) polymorphisms, the role of miRNA genetic variants in colorectal cancer is still unknown. The present study aimed to evaluate the role of four miRNA polymorphisms in patients with colorectal cancer. We enrolled 446 colorectal cancer patients and 502 control subjects from the Korean population. We found a significantly increased colorectal cancer risk with the miR‐196a2CC genotype compared with the TT/CT genotype (AOR = 1.50; 95% CI = 1.11–2.04; P = 0.01; FDR‐P = 0.04). In the stratified analyses, we observed both weak and strong association data. We found stronger associations of the miR‐196a2 variants in the non‐diabetic and rectal cancer groups than other stratified groups. Our data suggest that the miRNA variants could affect the development of colorectal cancer in the Korean population.

Placenta-derived mesenchymal stem cells have an immunomodulatory effect that can control acute graft-versus-host disease in mice.

Background and Aims: Immunomodulatory properties of mesenchymal stem cells (MSCs) have been applied to reduce the incidence of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Among the various sources of MSCs that have immunomodulatory effects in vitro, only placenta-derived MSCs (PD-MSCs) have not been evaluated in an in vivo model of GVHD. In this study, we investigated the immunomodulatory properties of PD-MSCs in vitro and evaluated their clinical potential for controlling GVHD in an animal model. Methods: A GVHD animal model was established by transplanting C57BL/6 donor bone marrow cells and spleen cells into lethally irradiated BALB/c recipient mice. To control GVHD, human PD-MSCs were transplanted into recipient mice (5 × 105 or 1 × 106 cells). Results: PD-MSCs suppressed mitogen-stimulated T cell proliferation in vitro in a dose-dependent manner. Moreover, PD-MSCs inhibited cytokine secretion (interleukin-12, tumor necrosis factor-α and interferon-γ) of activated T cells. In vivo, the survival rate in the PD-MSC group (transplanted with 1 × 106 cells) was higher than that in the control group and histological scores were low in the PD-MSC group. Conclusion: We present the first evidence that human PD-MSCs can efficiently control GVHD in an HSCT in vivo model.

Polymorphisms of the pri-miR-34b/c promoter and TP53 codon 72 are associated with risk of colorectal cancer

The microRNA (miR)-34 family is a direct transcriptional target of tumor-suppressor TP53 and loss of miR-34 function may impair TP53-mediated cell cycle arrest and apoptosis. In the present study, we investigated whether the single nucleotide polymorphisms (SNPs) rs4938723 (T>C) in the promoter region of miR-34b/c and Arg72Pro (G>C) in codon 72 of TP53 are independently or complementarily associated with the risks and clinical outcomes of colorectal cancer (CRC) and whether the combined effect of these SNPs and metabolic risk factors are related to CRC. We evaluated the SNPs in 545 CRC patients and 428 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequence analysis. We found that the GC and GC/CC genotypes of TP53 Arg72Pro were associated with decreased risk of CRC (adjusted OR = 0.727 for GC; OR = 0.735 for GC/CC). The combined genotypes of TT-GC and CC-GG were significantly associated with reduced CRC risk (adjusted OR = 0.628 for TT-GC; OR = 0.381 for CC-GG, respectively). The SNP rs4938723 and diabetes mellitus (DM) together were associated with an increased CRC risk, but the SNP TP53 Arg72Pro CC with DM showed a protective effect against CRC. These findings indicate that rs4938723 in the promoter region of pri-miR-34b/c and the SNP in TP53 codon 72 were related to decreased risk of CRC in the population studied and those metabolic diseases and genetic variants influence each other with regard to CRC susceptibility.

Evaluation of modified non-overt DIC criteria on the prediction of poor outcome in patients with sepsis

BACKGROUND The diagnostic performance of modified criteria for non-overt disseminated intravascular coagulation (DIC) with the addition of antithrombin (AT) levels, protein C (PC) levels, and organ system failure scoring (OSF) to the International Society on Thrombosis and Hemostasis (ISTH) criteria for non-overt DIC was studied to determine the effect on predicting poor outcome in patients with sepsis. METHODS In total, 135 consecutive patients were studied. Hemostatic markers (platelet count, prothrombin time, D-dimer, AT, PC) were examined on days 0, 1, 2, 3, 4, and 7. ISTH overt and non-overt DIC scoring, OSF, and 28-day mortality were analyzed. RESULTS The numbers of patients with overt DIC, non-overt DIC and non-DIC were 42, 17 and 76 respectively. The 28-day mortality rates for ISTH overt DIC, ISTH non-overt DIC, and non-DIC were 47.6, 47.1, and 9.2%, respectively. By adding AT and PC to the ISTH non-overt DIC criteria, the 28-day mortality rate of overt DIC, non-overt DIC, and non-DIC changed to 47.6, 25.0, and 6.7%, respectively. By adding OSF to the ISTH non-overt DIC criteria to predict 28-day mortality in septic patients, receiver operating characteristic (ROC) curve analysis demonstrated that the area under the curve (AUC) of ISTH non-overt DIC (0.777) was significantly increased to 0.878 (P=0.018). However, neither AT nor PC increased the AUC. CONCLUSIONS Addition of OSF to the ISTH criteria for non-overt DIC gives a better prediction of poor outcome in patients with sepsis.

Association of eNOS polymorphisms (-786T>C, 4a4b, 894G>T) with colorectal cancer susceptibility in the Korean population.

BACKGROUND Polymorphisms of endothelial nitric oxide synthases (eNOS) have been shown to be associated with cancer susceptibility. However, the results of such studies are conflicting to date. We investigated whether polymorphisms of the eNOS gene correlated with patients with colorectal cancer (CRC), relative to healthy individuals. PATIENTS AND METHODS In the present study, we analyzed three polymorphisms of eNOS (-786T>C, 4a4b, and 894G>T) in 509 healthy controls and 528 patients with CRC. The genotyping of eNOS polymorphisms was performed using polymerase chain reaction or polymerase chain reaction-restriction fragment length polymorphism assays. RESULTS We found that the TC+CC genotype of the -786T>C polymorphism was significantly associated with an increased risk of CRC compared with the TT genotype. Similarly, the GT+TT genotype of the 894G>T polymorphism was associated with an increased susceptibility to CRC. However, no evidence was found for any association between the 4a4b polymorphism and CRC risk. In addition, the C/4b/G (-786T>C/4a4b/894G>T) haplotype was significantly associated with increased risk of CRC and C/4b/T (-786T>C/4a4b/894G>T) haplotype was only detected in CRC patients. CONCLUSIONS Our study suggests that the eNOS -786T>C and 894G>T polymorphisms may be associated with the development of CRC in the Korean population.

Frequency of Pro475Ser polymorphism of ADAMTS13 gene and its association with ADAMTS-13 activity in the Korean population.

Purpose The in vitro study suggested that proline to serine polymorphism in codon 475 (C1423T) of the A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats-13 (ADAMTS-13) gene is related to reduced activity of ADAMTS-13. In this study, the frequency of the Pro475Ser polymorphism in Koreans was studied and plasma ADAMTS-13 activity was measured to find out whether this polymorphism contributes to decreased ADAMTS-13 activity in Koreans. Patients and Methods The frequency of the C1423T allele of the ADAMTS13 gene was studied along with measuring plasma ADAMTS-13 activity in 250 healthy Korean individuals. Results The allele frequency of C1423T polymorphism was 4%, and the median activity of CT type was 107 (69 - 143)%, which was lower than in controls with the CC genotype [118 (48 - 197)%, (p = 0.021)]. Conclusion Therefore, the Pro475Ser polymorphism seems to be popular in the Korean population, and attenuates ADAMTS-13 plasma activity.

Pre-Engraftment Syndrome after Unrelated Cord Blood Transplantation: A Predictor of Engraftment and Acute Graft-versus-Host Disease

Pre-engraftment syndrome (PES) is poorly characterized, and its clinical significance and the prognostic impact after unrelated cord blood transplantation (CBT) are unclear. To address these issues, we retrospectively analyzed the incidence, risk factors, and clinical outcomes of PES in unrelated CBT recipients. Data of 381 patients who received unrelated CBT from 18 medical centers in Korea were reviewed. PES was defined as unexplained fever >38.3°C not associated with infection, and/or unexplained skin rash with or without evidence of fluid retention before neutrophil recovery. PES developed in 102 patients (26.8%) at a median of 7 days after CBT. Of these patients, 74 patients (72.5%) received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 95% showed clinical improvement. Risk factors for developing PES included low risk disease, myeloablative conditioning, graft-versus-host disease (GVHD) prophylaxis without methotrexate or corticosteroid, and >5.43 x 10(7)/kg infused nucleated cells. Absence of PES was one of the risk factors for graft failure in multivariate analysis. The cumulative incidence of grade II to grade IV acute GVHD by 100 days after CBT was higher in patients with PES than in those without PES (56.0% versus 34.4%, P < .01). PES was not associated with chronic GVHD, treatment-related mortality, relapse, or overall survival. PES seems to be common after CBT and may be associated with enhanced engraftment without significant morbidity.

Polymorphisms of folate metabolism-related genes and survival of patients with colorectal cancer in the Korean population.

BACKGROUND 5-Fluorouracil (5-FU) is a cornerstone of chemotherapy for colorectal cancer (CRC), and the major targets of 5-FU are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and reduced folate carrier 1 (RFC1). We hypothesized that polymorphisms in the genes encoding these proteins would be associated with CRC patient survival. PATIENTS AND METHODS We genotyped the following polymorphisms in 372 CRC patients: TS enhancer region (TSER), TS 1494del6, MTHFR 677C>T and 1298A>C, and RFC1 -43T>C, 80G>A, and 696C>T. Using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models, we evaluated associations between these polymorphisms and overall survival (OS). RESULTS The combined TS 1494 0bp6bp+6bp6bp genotype was associated with reduced OS compared to the TS 1494 0bp0bp genotype. Among rectal cancer patients, the RFC1 -43CC and 80AA genotypes were associated with favorable OS. CONCLUSIONS Our data suggest that TS and RFC1 polymorphisms are associated with CRC prognosis in Korean patients. Further studies are needed to verify these findings.

The 677C>T Mutation of the MTHFR Gene Increases the Risk of Venous Thromboembolism in Koreans and a Meta-Analysis From Asian Population

The frequency of methylenetetrahydrofolate reductase (MTHFR) mutations varies between racial and ethnic groups, and there are also conflicting data regarding MTHFR gene mutations in Asian patients with venous thromboembolism (VTE). The aim of this study was to examine the association between common MTHFR gene mutations (677C>T and 1298A>C) and risk of VTE in Koreans. This study was a retrospective case–control study. We enrolled 203 patients with VTE and 403 controls. For the 677C>T polymorphism, there was no difference in the frequency of the CT genotype and TT genotype between the patients with VTE and the controls. However, in the recessive analysis (CC + CT vs TT), the frequency of the TT genotype was significantly higher in VTE than in controls (odds ratio = 1.700; 95% confidence interval = 1.108-2.607, P = .015). In conclusion, the TT genotype of MTHFR 677C>T increases the risk of VTE in Koreans. This finding was supported by meta-analysis of previous Asian studies.

A Trp33Arg Mutation at Exon 1 of the MYH9 Gene in a Korean Patient with May-Hegglin Anomaly

In this report, we describe a Korean patient with May-Hegglin anomaly from a mutation of the MYH9 gene. The proband was a 21-year-old man with thrombocytopenia. He did not have a bleeding tendency. His neutrophil count was normal at 7490/mm3; however, the neutrophils contained abnormal basophilic inclusions in their cytoplasm. The platelet count was decreased at 15000/mm3 with giant platelets. Coagulation test results were not remarkable. Direct sequencing of MYH9 revealed that he was heterozygous for a mutation in exon 1, which was a 97T>A substitution mutation affecting codon 33, substituting tryptophan with arginine (Trp33Arg). Family study showed that both of his parents had normal phenotype and genotypes, indicating a de novo occurrence of the mutation in the proband.