[Show abstract][Hide abstract] ABSTRACT: Polymorphisms in angiogenesis-related genes and metabolic syndrome (MetS) risk factors play important roles in cancer development. Moreover, recent studies have reported associations between a number of 3[prime]-UTR polymorphisms and a variety of cancers. The aim of this study was to investigate the associations of three VEGF 3[prime]-UTR polymorphisms (1451C > T [rs3025040], 1612G > A [rs10434], and 1725G > A [rs3025053]) and MS with colorectal cancer (CRC) susceptibility in Koreans.
A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of VEGF polymorphisms was performed by TaqMan allelic discrimination assays. Cancer risks of genetic variations and gene-environment interactions were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of multivariate logistic regression analyses.
VEGF 1451C > T was significantly associated with rectal cancer risk (Dominant model; AOR =1.58; 95% CI =1.09 - 2.28; p =0.015) whereas VEGF 1725G > A correlated with MetS risk (Dominant model; AOR =1.61; 95% CI =1.06 - 2.46; p =0.026). Of the gene-environment combined effects, the interaction of VEGF 1451C > T and MetS contributed to increased RC risk (AOR =3.15; 95% CI =1.74 - 5.70; p < .001) whereas the combination of VEGF 1725G > A and MetS was involved with elevated CC risk (AOR =2.68; 95% CI =1.30 - 1.55; p =0.008).
Our results implicate that VEGF 1451C > T and 1725G > A may predispose to CRC susceptibility and the genetic contributions may be varied with the presence of MetS.
BMC Cancer 11/2014; 14(1):881. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To gain insight into the natural history of cytomegalovirus (CMV) infection following unrelated cord blood transplantation (UCBT) in seropositive patients, we analyzed the data of 349 seropositive patients who received UCBT in Korea between 2000 and 2011. CMV reactivation occurred in 49 % (171/349) of the CMV-seropositive transplant recipients at a median of 31 days post UCBT. One hundred sixty-four out of 171 patients (96 %) received preemptive therapy. The median duration of CMV reactivation was 29 days. In multivariate analysis, weight >22 kg, use of total body irradiation, use of pre-transplant antithymocyte globulin, graft-versus-host disease (GVHD) prophylaxis with mycophenolate mofetil, and presence of grade II-IV acute GVHD were independent predictors of CMV reactivation. CMV reactivation did not impact transplantation-related mortality (TRM), leukemia relapse, or survival. CMV disease was diagnosed in 62 patients (17.8 %) at a median 55 days after UCBT. Longer duration of CMV reactivation was the only risk factor for progression to CMV disease (p = 0.01). CMV disease resulted in higher TRM (56.0 vs. 31.4 %, p < 0.01) and lower survival (36.1 vs. 55.1 %, p = 0.02).
Annals of Hematology 11/2014; · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hereditary protein S deficiency from a mutation in the PROS1 gene causes a genetic predisposition to develop venous thromboembolic disorders in humans. Recently, the acknowledgment of the clinical significance of large copy number mutations in protein S deficiency has increased. In this study, the authors investigated the genomic architecture of PROS1 in order to understand the microscopic sequence environment leading to large intragenic copy number mutations in the gene. The study subjects were 3 unrelated male patients with hereditary protein S deficiency from a tandem duplication mutation involving exons 5-10 of PROS1. Breakpoint analyses revealed 10-bp microhomology sequences in the intervening sequence (IVS)-4 and IVS-10 at the duplication junction without additional sequence changes, suggesting a single replication-based event as the potential molecular mechanism of rearrangement and founder effect in the mutant alleles. Further analyses on nucleotide sequences flanking the microhomology sequence revealed the presence of a repeat element (LTR-ERV1) and quadruplex-forming G-rich sequences in IVS-4. The results from genotyping multi-allelic short tandem repeats supported founder effect in the identical mutations in the 3 unrelated patients. In conclusion, we identified unique genomic architectures in the intervening sequences of PROS1 that underlie a large intragenic tandem duplication mutation leading to inherited thrombophilia.
[Show abstract][Hide abstract] ABSTRACT: Background
Data on the incidence of venous thromboembolism (VTE) following major surgery in Asian populations are limited.Methods
Using the Korean Health Insurance Review and Assessment Service database, we performed a nationwide population-based epidemiologic study to estimate the incidence of VTE after major orthopaedic, cancer, and benign surgeries. VTE cases were identified from all patients undergoing major surgery between 2007 and 2011 using both diagnostic and drug codes as treatment evidence of VTE within 5 weeks of surgery. We also calculated the relative risk of VTE in major orthopaedic and cancer surgery compared to benign surgery.ResultsThe overall rates of postoperative VTE were 1.24%, 0.67%, and 0.05% for major orthopaedic, cancer, and benign surgeries, respectively. Hip fracture (1.60%) and colorectal cancer surgeries (1.67%) were associated with the highest rates of VTE, and the rates steadily increased during the study period. Advanced age, female sex, and general anaesthesia were independent risk factors for VTE. Patients undergoing surgery for colorectal, pancreatic, ovarian, and oesophageal cancer, and major orthopaedic surgery had more than a 20-fold higher risk of VTE than those undergoing benign surgery.Conclusions
This is the largest epidemiologic study to investigate the incidence of VTE after major surgery in Asia, demonstrating that the rates of postoperative VTE are lower than in Caucasian populations. This study contributes to a better understanding of the differences in postoperative VTE development between Korean and Caucasian populations; the data also suggest that perioperative prophylactic strategies in Asians should be based on studies of such populations.This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 05/2014; · 6.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Silent brain infarction (SBI) is an asymptomatic cerebrovascular disorder. The aim of the present study was to investigate the association between adrenoceptor‑α2 (ADRA2) gene polymorphisms and SBI. A total of 361 patients with SBI and 467 healthy control subjects were examined. The polymerase chain reaction was performed to genotype the ADRA2A 1780G>A, ADRA2B 301‑303 insertion/deletion (I/D) and ADRA2C 322‑325I/D polymorphisms. The frequency of the ADRA2C 322‑325I/D polymorphism was significantly different between patients with SBI and control subjects. When interaction analyses were performed for vascular risk factors, the ADRA2C 322‑325ID genotype increased the risk for SBI in the presence of hypertension and elevated plasma homocysteine levels. The ADRA2C 322‑325ID genotype and plasma homocysteine levels showed a significant synergistic effect for SBI. In addition, the ADRA2A 1780AA genotype was associated with elevated plasma homocysteine levels. Although further analysis of the association between ADRA2 polymorphisms and clinical risk factors of SBI is required, the present study of a limited set of SBI risk factors with ADRA2 polymorphisms provides the first evidence of the involvement of ADRA2 gene family members in the development of SBI. Further studies using larger and more heterogeneous populations are required to validate the association of ADRA2 polymorphisms with SBI.
Molecular Medicine Reports 03/2014; · 1.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxaliplatin is a platinum compound used in patients with gastrointestinal malignancies. It is known to evoke a drug-induced immune-mediated thrombocytopenia, which has not been reported in Korea. We describe a 53-year-old man who developed oxaliplatin-induced immune-mediated thrombocytopenia during chemotherapy for colon cancer. Oxaliplatin-dependent IgG platelet antibodies were detected in his serum on flow cytometry. He was treated with immunoglobulin and corticosteroids without any complications. Physicians should consider oxaliplatin-induced immune-mediated thrombocytopenia, when a sudden, isolated thrombocytopenia develops during chemotherapy with oxaliplatin.
[Show abstract][Hide abstract] ABSTRACT: In 2010, we proposed the first Korean Guidelines for the Prevention of Venous Thromboembolism (VTE). It was applicable to Korean patients, by modifying the contents of the second edition of the Japanese guidelines for the prevention of VTE and the 8th edition of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines. From 2007 to 2011, we conducted a nationwide study regarding the incidence of VTE after major surgery using the Health Insurance Review and Assessment Service (HIRA) database. In addition, we have considered the 9th edition of the ACCP Evidenced-Based Clinical Practice Guidelines, published in 2012. It emphasized the importance of clinically relevant events as opposed to asymptomatic outcomes with preferences for both thrombotic and bleeding outcomes. Thus, in the development of the new Korean guidelines, three major points were addressed: 1) the new guidelines stratify patients into 4 risk groups (very low, low, moderate, and high) according to the actual incidence of symptomatic VTE from the HIRA databases; 2) the recommended optimal VTE prophylaxis for each group was modified according to condition-specific thrombotic and bleeding risks; 3) guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and/or physician advice.
Journal of Korean medical science 02/2014; 29(2):164-171. · 0.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the association between potentially functional plasminogen activator inhibitor-1 (PAI-1) genetic polymorphisms and primary ovarian insufficiency (POI).
Urban university-based hospital.
A cohort of 137 POI patients and 227 controls.
Genotyping of five PAI-1 polymorphisms (-844G>A [rs2227631], -675 4G/5G [rs1799889], 43G>A (Ala>Thr) [rs6092], 9785G>A [rs2227694], and 11053T>G [rs7242]) was assessed by polymerase chain reaction-restriction fragment length polymorphism assay.
PAI-1 polymorphisms 9785GA+AA, -844A/9785A, 4G/9785A, and 9785A/11053G were associated with POI occurrence. Moreover, -844GA+AA and 11053TG+GG were associated with lower serum E2 levels in controls.
We have identified an association between five PAI-1 polymorphisms and POI occurrence. However, the mechanism underlying the function of these polymorphisms in POI remains to be determined. Further studies are needed to improve understanding of the roles of PAI-1 polymorphisms and genes in related pathways, using a larger and more heterogeneous cohort.
Fertility and sterility 12/2013; · 4.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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).
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.
Our data suggest that TS and RFC1 polymorphisms are associated with CRC prognosis in Korean patients. Further studies are needed to verify these findings.
[Show abstract][Hide abstract] ABSTRACT: Acquired hemophilia A (AHA) is a bleeding disorder caused by the development of an auto-antibody against endogenous factor VIII (FVIII). In this study, the epitope of the autoantibody was identified in a 67-year-old female patient with AHA. A prolonged activated partial thromboplastin time (77.4 s) that failed to correct in an incubation mixing test (68.2 s), a decreased FVIII activity, and a high FVIII inhibitor (14.6 Bethesda units/mL) were observed. Enzyme-linked immunosorbent assay demonstrated that the antibody belonged to the immunoglobulin G4 subclass. An immunoblotting assay revealed the light chain (A3/C1/C2 domain) of FVIII as the binding region of the antibody. The bleeding experienced by our patient resulted from the interference of FVIII binding to both FIX by anti-A3 antibodies and phospholipids and von Willebrand factor by anti-C2 antibodies. To the best of our knowledge, this is the first study in Korea characterizing an autoantibody in the context of AHA.
[Show abstract][Hide abstract] ABSTRACT: Patients with cancer have been associated with increased risk of recurrent venous thromboembolism (VTE). However, data on recurrent VTE in Asian patients with advanced solid cancers are limited. METHODS: This study was conducted using data from the Korean VTE registry, which is an ongoing, prospective database. Patients were eligible if they had diagnosed with recurrent/metastatic solid cancers and initiated anticoagulation therapy following index VTE diagnosis. A total of 449 patients were included in this analysis. The 6-month and 12-month cumulative incidences of recurrent VTE were 20.6% and 27.0%, respectively. Isolated pulmonary embolism (PE) (51%) was the most predominant recurrence type. Pancreas as the primary tumor site, poor Eastern Cooperative Oncology Group performance status at the time of index VTE diagnosis, and initial presentation with PE were independent risk factors for developing recurrent VTE. With a median follow-up of 29.1months (range, 1.0-91.2), the median overall survival (OS) was 11.9months. Patients with recurrent VTE had a significantly worse OS than those without recurrent VTE (median, 8.4 vs. 13.0months, respectively; P=0.001). In conclusion, the incidence of recurrent VTE in Korean patients with advanced solid cancers is comparable with Caucasian patients. Pancreas as the primary tumor site, poor performance status, and initial presentation with PE are independent recurrent VTE risk factors in advanced cancer VTE patients. Additionally, OS is adversely affected by recurrent VTE.
[Show abstract][Hide abstract] ABSTRACT: 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 analyzed retrospectively 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 1mg/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-IV acute GVHD by 100 days after CBT was higher in patients with PES than in those without PES (56.0% vs. 34.4%, P<0.01). 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.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2013; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children with CP, were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy. The main outcomes were changes in scores on the following measures during the six months treatment period: the Gross Motor Performance Measure (GMPM), Gross Motor Function Measure, and Bayley Scales of Infant Development-II (BSID-II) Mental and Motor scales. (18) F-fluorodeoxyglucose positron emission tomography ((18) F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at six months. DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group. (18) F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. The incidence of serious adverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain.
[Show abstract][Hide abstract] ABSTRACT: 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 × 10(5) or 1 × 10(6) 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 × 10(6) 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.