Yong Gyu Park

Diffusion-weighted imaging of breast cancer: correlation of the apparent diffusion coefficient value with prognostic factors.

To evaluate the role of diffusion‐weighted imaging (DWI) in the detection of breast cancers, and to correlate the apparent diffusion coefficient (ADC) value with prognostic factors.

Nuclear localization of β-catenin is an important prognostic factor in hepatoblastoma

In this study, mutational and immunohistochemical analyses of β‐catenin were performed in 30 hepatoblastomas, to assess the prevalence of alterations of the Wnt pathway with respect to clinicopathological parameters and survival. Four missense mutations of β‐catenin (13.3%) were detected and there was strong immunoreactivity for β‐catenin in the cytoplasm and/or the nucleus in 97% of hepatoblastomas. Nuclear and cytoplasmic staining was demonstrated in 19 of 30 tumours (63%), while ten revealed only cytoplasmic staining. Statistically, this nuclear β‐catenin staining was significantly higher in the embryonal (Fisher exact test; p=0.00393) or undifferentiated type (p=0.00156) of hepatoblastoma than in the fetal type, but there was no difference between clinical stages I and II and clinical stages III and IV (p=0.175). Cumulative survival curves showed that nuclear β‐catenin staining (generalized Wilcoxon test; p=0.0088), undifferentiated histological type (p=0.0305), and clinical stages III and IV (p=0.0107) were significantly correlated with shorter survival time in these patients. Moreover, Cox multivariate analysis provides evidence that nuclear β‐catenin staining is the most important prognostic factor for survival (p=0.0090). It is therefore concluded that immunohistochemical analysis of β‐catenin might be a useful clinical tool for estimating the prognosis for patients with hepatoblastoma. Copyright

Inactivating mutations of CASPASE-7 gene in human cancers.

Caspase-7 is a caspase involved in the execution phase of apoptosis. To explore the possibility that the genetic alterations of CASPASE-7 might be involved in the development of human cancers, we analysed the entire coding region and all splice sites of human CASPASE-7 gene for the detection of somatic mutations in a series of human solid cancers, including carcinomas from stomach, colon, head/neck, esophagus, urinary bladder and lung. Overall, we detected CASPASE-7 mutations in two of 98 colon carcinomas (2.0%), one of 50 esophageal carcinomas (2.0%) and one of 33 head/neck carcinomas (3.0%). We expressed the tumor-derived caspase-7 mutants in 293 T cells and found that the apoptosis was reduced compared to the wild-type caspase-7. This is the first report on the CASPASE-7 gene mutations in human malignancies, and our data suggest that the inactivating mutations of the CASPASE-7 gene might lead to the loss of its apoptotic function and contribute to the pathogenesis of some human solid cancers.

Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer.

Many types of cancer cells are resistant to Fas-mediated apoptosis by several mechanisms, including the mutations of the genes involved in Fas-mediated apoptosis. In this study, to explore the possibility that the mutations of the genes involved in the proximal pathway of Fas-mediated apoptosis (Fas, FADD, caspase 8 and caspase 10) are involved in cancer metastasis, we have analysed somatic mutation and deletion of these genes in 80 non-small cell lung cancers (NSCLCs) with (n=43) and without (n=37) metastasis to the regional lymph nodes. We found 12 mutations (four Fas, four FADD, and four caspase 10 mutations) in 11 of 80 NSCLCs (13.8%). Interestingly, of these mutations, most mutations (10 out of 12) were detected in the NSCLCs with metastasis, and the frequency in the metastasis lesions (23%) was higher than that in the primary lesions of the NSCLCs without metastasis (5.4%). Furthermore, transfection study revealed that the tumor-derived mutants have decreased apoptosis inductions compared to the wild types. These data suggest that the inactivating mutations of the genes in the proximal pathway of Fas-mediated apoptosis may lead to a decreased cancer cell death and play a role in the metastasis of NSCLC.

The Human Cervical Cancer Oncogene Protein Is a Biomarker for Human Hepatocellular Carcinoma

Human cervical cancer oncogene (HCCR) was identified and appeared to function as a negative regulator of p53 gene. The objective of this study was to validate HCCR expression as a candidate marker for human hepatocellular carcinoma. HCCR epitope was identified as Y355LGTRR360. According to immunofluorescence study, HCCR was predominantly localized in the plasma membrane and cytoplasm of hepatocellular carcinoma. HCCR proteins were overexpressed in the tumorous compared with the nontumorous cirrhosis tissues. However, HCCR was not detected in normal liver tissue. Concentration of HCCR protein in the serum was measured in a total of 570 subjects, and comparisons were made to α-fetoprotein. Serological studies revealed 78.2% sensitivity of HCCR (cutoff value, 15 μg/ml), which was significantly higher than 64.6% of α-fetoprotein (P = 0.0098) and 95.7% specificity for hepatocellular carcinoma. Forty of 52 (76.9%) patients with carcinoma negative for α-fetoprotein showed positive values for HCCR. A positive rate of 69.2% in carcinoma patients with tumor sizes <2 cm was found to be a higher rate than measurement of α-fetoprotein. Furthermore, HCCR expression was also detected in liver cirrhosis at an intermediate level between carcinoma and normal groups, which gave 88.1% sensitivity and 79.0% specificity using 8 μg/ml as a cutoff value. In summary, the HCCR assay may have an advantage over the α-fetoprotein assay in that it is elevated according to disease progression from liver cirrhosis to carcinoma, and it is more frequently positive in patients with early, small hepatocellular carcinoma.

Methyl gallate and chemicals structurally related to methyl gallate protect human umbilical vein endothelial cells from oxidative stress.

Methyl gallate (meGAL) is known as one of major antioxidants. To investigate whether meGAL protects human cells from oxidative stress, meGAL extracted from Korean medicinal plant, Cercis chinensis leaves, was primarily screened using cell viability assay against oxidative stress. Human umbilical vein endothelial cells (HUVECs) were treated with three different concentrations of meGAL for indicated time. After or during meGAL treatment, H2O2 was added and incubated. meGAL showed free radical scavenging effect at low concentration (0.02 mM) and cell protective effect against H2O2-mediated oxidative stress. meGAL recovered viability of HUVECs damaged by H2O2-treatment, reduced the lipid peroxidation (LPO) and decreased the internal reactive oxygen species (ROS) level elevated by H2O2-treatment. Free radical scavenging effect of meGAL was proven to be very high. Differential display reverse transcription-PCR analysis showed that meGAL upregulated the levels of regulator of chromatin condensation 1, type 1 sigma receptor and phosphate carrier protein expressions, respectively. Based on structural similarity compared with meGAL, 14 chemicals were chosen and viability assay was performed. Four chemicals, haematommic acid (56.2% enhancement of viability), gallic acid (35.0%), methylorsellinic acid (23.7%), and syringic acid (20.8%), enhanced more potent cell viability than meGAL, which showed only 18.1% enhancement of cell viability. These results suggest that meGAL and four meGAL-related chemicals protect HUVECs from oxidative stress.

High-density lipoprotein cholesterol as a predictor of clinical outcomes in patients achieving low-density lipoprotein cholesterol targets with statins after percutaneous coronary intervention

Background A low level of high-density lipoprotein cholesterol (HDL-C) is strongly associated with cardiovascular events. However, the significance of HDL-C after statin therapy on the outcome of patients who have undergone percutaneous coronary intervention (PCI) with drug eluting stents (DES) is unclear. Objectives To investigate the significance of HDL-C after statin therapy on cardiovascular events in patients with coronary artery disease after DES implantation. Methods Patients who underwent PCI with DES from January 2004 to December 2009 were prospectively enrolled. The follow-up lipid panel of 2693 patients (median lab follow-up duration 225 days) who had continued using statins after PCI and who attained low-density lipoprotein cholesterol (LDL-C) <100 mg/dl was analysed. Major adverse cardiac events (MACE), including all-cause death, non-fatal myocardial infarction, and target vessel revascularisation according to follow-up HDL-C level (40 mg/dl for men or 50 mg/dl for women) were compared with the use of propensity scores matching. Results Median follow-up duration was 832 days. 1585 (58.9%) patients had low follow-up HDL-C and 1108 had high follow-up HDL-C. The low follow-up HDL-C group had significantly higher rates of MACE. Low follow-up HDL-C was a significant independent predictor of MACE (adjusted HR 1.404, 95% CI 1.111 to 1.774, p=0.004). In further analysis with propensity scores matching, overall findings were consistent. Conclusions Raising HDL-C levels may be a subsequent goal after achieving target LDL-C levels in patients with DES implantation.

Sarcopenia as a Determinant of Blood Pressure in Older Koreans: Findings from the Korea National Health and Nutrition Examination Surveys (KNHANES) 2008–2010

Background Blood pressure (BP) is directly and causally associated with body size in the general population. Whether muscle mass is an important factor that determines BP remains unclear. Objective To investigate whether sarcopenia is associated with hypertension in older Koreans. Participants We surveyed 2,099 males and 2,747 females aged 60 years or older. Measurements Sarcopenia was defined as an appendicular skeletal muscle mass divided by body weight (ASM/Wt) that was <1 SD below the gender-specific mean for young adults. Obesity was defined as a body mass index (BMI) ≥25 kg/m2. Subjects were divided into four groups based on presence or absence of obesity or sarcopenia. Hypertension was defined as a systolic BP (SBP) ≥140 mmHg, a diastolic BP (DBP) ≥90 mmHg, or a self-reported current use of antihypertensive medications. Results The overall prevalence of hypertension in the four groups was as follows 49.7% for non-obese non-sarcopenia, 60.9% for non-obese sarcopenia, 66.2% for obese non-sarcopenia and 74.7% for obese sarcopenia. After adjustment for age, gender, regular activity, current smoking and alcohol use, the odds ratio (OR) for having hypertension was 1.5 (95% confidence interval (CI) = 1.23–1.84) in subjects in the non-obese sarcopenia group, 2.08 (95% CI = 1.68–2.57) in the obese non-sarcopenia group and 3.0 (95% CI = 2.48–3.63) in the obese sarcopenia group, compared with the non-obese non-sarcopenia group (p for trend <0.001). Controlling further for body weight and waist circumference did not change the association between hypertension and sarcopenia. The association between sarcopenia and hypertension was more robust in the subjects with diabetes mellitus. Conclusion Body composition beyond BMI has a considerable impact on hypertension in elderly Koreans. Subjects with sarcopenic obesity appear to have a greater risk of hypertension than simply obese or sarcopenia subjects.

Consolidation hyperthermic intraperitoneal chemotherapy using paclitaxel in patients with epithelial ovarian cancer

We evaluated the efficacy and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) using paclitaxel as consolidation therapy in patients with epithelial ovarian cancer.

Efficient nonadhesive ex vivo expansion of early endothelial progenitor cells derived from CD34+ human cord blood fraction for effective therapeutic vascularization

Endothelial progenitor cells (EPCs) have been shown to have therapeutic potential in ischemic disease. However, the number of EPCs for cell therapy is limited. In this study, instead of the typical adherent culture method, we investigated a more efficient, clinically applicable nonadhesive expansion method for early EPCs using cord blood‐derived cells to overcome rapid cellular senescence. After a suspension culture of isolated CD34+ cells in serum‐free medium containing each cytokine combination was maintained for 9 d, the number of expanded functional EPCs was assessed by an adherent culture assay. Compared to mononuclear cells, the CD34+ fraction was superior in its expansion of functional EPCs that could differentiate into acLDL/UEA‐1+ cells without significant cellular senescence, whereas the CD34‐ fraction showed no EPC expansion. Among the cytokine combinations tested for the CD34+ fraction, a combination (SFIb) consisting of stem cell factor (SCF), FMS‐like tyrosine kinase 3 ligand, interleukin‐3, and basic fibroblast growth factor resulted in a reproducible 64‐ to 1468‐fold EPC expansion from various cord blood origins. Interestingly, the SFIb combination displayed markedly increased EPC expansion (2.43‐fold), with a higher percentage of CD34+ cells (2.17‐fold), undifferentiated blasts (2.38‐fold) and CXCR4+ cells (1.68‐fold) compared to another cytokine combination (SCF, thrombopoietin, and granulocyte colony‐stimulating factor), although the two cytokine combinations had a similar level of total mononucleated cell expansion (~10% difference). Accordingly, the cells expanded in the SFIb combination were more effective in recovery of blood flow and neovascularization in hind‐limb ischemia in vivo. Taken together, these results suggest that the nonadhesive serum‐free culture conditions of the CD34+ fraction provide an effective EPC expansion method for cell therapy, and an expansion condition leading to high percentages of CD34+ cells and blasts is likely important in EPC expansion.—O, E., Lee, B. H., Ahn, H.‐Y., Shin, J.‐C., Kim, H.‐Y., Kim, M., Park, I. Y., Park, Y.‐G., Joe, Y. A. Efficient nonadhesive ex vivo expansion of early endothelial progenitor cells derived from CD34+ human cord blood fraction for effective therapeutic vascularization. FASEB J. 25, 159–169 (2011). www.fasebj.org