Myung-Hwa Kim

Proto-oncogene FBI-1 (Pokemon) and SREBP-1 Synergistically Activate Transcription of Fatty-acid Synthase Gene (FASN)

FBI-1 (Pokemon/ZBTB7A) is a proto-oncogenic transcription factor of the BTB/POZ (bric-à-brac, tramtrack, and broad complex and pox virus zinc finger) domain family. Recent evidence suggested that FBI-1 might be involved in adipogenic gene expression. Coincidentally, expression of FBI-1 and fatty-acid synthase (FASN) genes are often increased in cancer and immortalized cells. Both FBI-1 and FASN are important in cancer cell proliferation. SREBP-1 is a major regulator of many adipogenic genes, and FBI-1 and SREBP-1 (sterol-responsive element (SRE)-binding protein 1) interact with each other directly via their DNA binding domains. FBI-1 enhanced the transcriptional activation of SREBP-1 on responsive promoters, pGL2-6x(SRE)-Luc and FASN gene. FBI-1 and SREBP-1 synergistically activate transcription of the FASN gene by acting on the proximal GC-box and SRE/E-box. FBI-1, Sp1, and SREBP-1 can bind to all three SRE, GC-box, and SRE/E-box. Binding competition among the three transcription factors on the GC-box and SRE/E-box appears important in the transcription regulation. FBI-1 is apparently changing the binding pattern of Sp1 and SREBP-1 on the two elements in the presence of induced SREBP-1 and drives more Sp1 binding to the proximal promoter with less of an effect on SREBP-1 binding. The changes induced by FBI-1 appear critical in the synergistic transcription activation. The molecular mechanism revealed provides insight into how proto-oncogene FBI-1 may attack the cellular regulatory mechanism of FASN gene expression to provide more phospholipid membrane components needed for rapid cancer cell proliferation.

ZBTB2, a Novel Master Regulator of the p53 Pathway

We found that ZBTB2, a POK family transcription factor, is a potent repressor of the ARF-HDM2-p53-p21 pathway important in cell cycle regulation. ZBTB2 repressed transcription of the ARF, p53, and p21 genes, but activated the HDM2 gene. In particular, ZBTB2 repressed transcription of the p21 gene by acting on the two distal p53 binding elements and the proximal Sp1 binding GC-box 5/6 elements. ZBTB2 directly interacted with Sp1 via its POZ domain and zinc fingers, which was important in the repression of transcription activation by Sp1. ZBTB2 and Sp1 competed with each other in binding to the GC-box 5/6 elements and the two p53 binding elements. ZBTB2 directly interacted with p53 via its zinc fingers, inhibiting p53 binding and repressing transcription activation by p53. The POZ domain, required for transcription repression, interacted with corepressors such as BCoR, NCoR, and SMRT. The interactions deacetylated histones Ac-H3 and -H4 at the proximal promoter. Although ectopic ZBTB2 stimulated cell proliferation, knock-down of ZBTB2 expression decreased cell proliferation and DNA synthesis. Overall, our data suggest that ZBTB2 is a potential proto-oncogenic master control gene of the p53 pathway and, in particular, is a potent transcription repressor of the cell cycle arrest gene p21 by inhibiting p53 and Sp1.

The proto-oncoprotein FBI-1 interacts with MBD3 to recruit the Mi-2/NuRD-HDAC complex and BCoR and to silence p21WAF/CDKN1A by DNA methylation

The tumour-suppressor gene CDKN1A (encoding p21Waf/Cip1) is thought to be epigenetically repressed in cancer cells. FBI-1 (ZBTB7A) is a proto-oncogenic transcription factor repressing the alternative reading frame and p21WAF/CDKN1A genes of the p53 pathway. FBI-1 interacts directly with MBD3 (methyl-CpG–binding domain protein 3) in the nucleus. We demonstrated that FBI-1 binds both non-methylated and methylated DNA and that MBD3 is recruited to the CDKN1A promoter through its interaction with FBI-1, where it enhances transcriptional repression by FBI-1. FBI-1 also interacts with the co-repressors nuclear receptor corepressor (NCoR), silencing mediator for retinoid and thyroid receptors (SMRT) and BCL-6 corepressor (BCoR) to repress transcription. MBD3 regulates a molecular interaction between the co-repressor and FBI-1. MBD3 decreases the interaction between FBI-1 and NCoR/SMRT but increases the interaction between FBI-1 and BCoR. Because MBD3 is a subunit of the Mi-2 autoantigen (Mi-2)/nucleosome remodelling and histone deacetylase (NuRD)-HDAC complex, FBI-1 recruits the Mi-2/NuRD-HDAC complex via MBD3. BCoR interacts with the Mi-2/NuRD-HDAC complex, DNMTs and HP1. MBD3 and BCoR play a significant role in the recruitment of the Mi-2/NuRD-HDAC complex– and the NuRD complex–associated proteins, DNMTs and HP. By recruiting DNMTs and HP1, Mi-2/NuRD-HDAC complex appears to play key roles in epigenetic repression of CDKN1A by DNA methylation.

The Effect of Outpatient Cost Sharing on Health Care Utilization of the Elderly

OBJECTIVESnThe purpose of this study was to analyze the effect of outpatient cost-sharing on health care utilization by the elderly.nnnMETHODSnThe data in this analysis was the health insurance claims data between July 1999 and December 2008 (114 months). The study group was divided into two age groups, namely 60-64 years old and 65-69 years old. This study evaluated the impact of policy change on office visits, the office visits per person, and the percentage of the copayment-paid visits in total visits. Interrupted time series and segmented regression model were used for statistical analysis.nnnRESULTSnThe results showed that outpatient cost-sharing decreased office visits, but it also decreased the percentage of copayment-paid visits, implying that the intensity of care increased. There was little difference in the results between the two age groups. But after the introduction of the coinsurance system for those patients under age 65, office visits and the percentage of copayment-paid visits decreased, and the 60-64 years old group had a larger decrease than the 65-69 years old group.nnnCONCLUSIONSnThis study evaluated the effects of outpatient cost-sharing on health care utilization by the aged. Cost sharing of the elderly had little effect on controlling health care utilization.

The effects of fermented soybean meal on immunophysiological and stress-related parameters in Holstein calves after weaning

The present experiment was conducted to investigate the effects of partial substitution of soybean meal (SBM) with fermented SBM (FSBM) on immunophysiological and stress-related parameters in Holstein calves after weaning. Eighteen Holstein calves were randomly assigned to receive either SBM or FSBM (5% of SBM was replaced with FSBM) calf starter and calves were weaned at 42 d of age. It was noted that FSBM contained a lower content of trypsin inhibitor but higher crude protein, amino acids, and small-sized peptides than those of SBM. The group fed FSBM calf starter significantly increased body weight gain and intakes of both feed and milk, when compared with those fed SBM calf starter at 4 wk of age. Calves fed the FSBM calf starter had significantly lower fecal scores than those fed the SBM calf starter during both pre- and postweaning periods. Calves also had better health scores when fed the FSBM calf starter than those fed SBM during the preweaning period. Weaning challenge significantly increased proinflammatory cytokines, tumor necrosis factor α, IL-1β, and IL-6 levels at 1d postweaning (DPW). The TNF-α and IL-6 levels of the SBM group were significantly higher compared with those of the FSBM group at 3 DPW. Acute phase proteins (serum amyloid A and haptoglobin) in the serum were increased after weaning. Concentrations of serum amyloid A and haptoglobin in calves fed FSBM calf starter were significantly lower than those fed the SBM calf starter at 3 and 5 DPW, respectively. The concentration of cortisol was significantly lower in the FSBM group than that of the SBM group at 3 DPW. Weaning stress did not cause drastic changes in the total serum immunoglobulin levels and composition of peripheral lymphocytes. Our results indicate that FSBM may not only improve growth performance, feed intake, and health conditions during the preweaning period, but also alleviate stress responses, which was indicated by reduced induction of stress hormone, proinflammatory cytokines, and acute phase proteins in Holstein calves after weaning.

Developing a Hospital-Wide All-Cause Risk-Standardized Readmission Measure Using Administrative Claims Data in Korea: Methodological Explorations and Implications

Background: The purpose of this study was to propose a method for developing a measure of hospital-wide all-cause risk-standard -ized readmissions using administrative claims data in Korea and to discuss further considerations in the refinement and implemen-tation of the readmission measure.Methods: By adapting the methodology of the United States Center for Medicare & Medicaid Services for creating a 30-day read-mission measure, we developed a 6-step approach for generating a comparable measure using Korean datasets. Using the 2010 Korean National Health Insurance (NHI) claims data as the development dataset, hierarchical regression models were fitted to calcu-late a hospital-wide all-cause risk-standardized readmission measure. Six regression models were fitted to calculate the readmission rates of six clinical condition groups, respectively and a single, weighted, overall readmission rate was calculated from the readmis-sion rates of these subgroups. Lastly, the case mix differences among hospitals were risk-adjusted using patient-level comorbidity variables. The model was validated using the 2009 NHI claims data as the validation dataset.Results: The unadjusted, hospital-wide all-cause readmission rate was 13.37%, and the adjusted risk-standardized rate was 10.90%, varying by hospital type. The highest risk-standardized readmission rate was in hospitals (11.43%), followed by general hospitals (9.40%) and tertiary hospitals (7.04%).Conclusion: The newly developed, hospital-wide all-cause readmission measure can be used in quality and performance evalua-tions of hospitals in Korea. Needed are further methodological refinements of the readmission measures and also strategies to im-plement the measure as a hospital performance indicator.Keywords: Patient readmission; Patient readmission; Quality indicators; Risk-adjustment; Hospital

The Association Between Treatment Frequency and Treatment Outcome for Cardiovascular Surgeries

Background This study analyzed the association between the volume of heart surgeries and treatment outcomes for hospitals in the last five years. Methods Hospitals that perform heart surgeries were chosen throughout Korea as subjects using from the Health Insurance Review and Assessment Service. The treatment outcome of the heart surgeries was defined as the mortality within 30 postoperative days, while the annual volume of the surgeries was categorized. Logistic regression was used as the statistical analysis method, and the impacts of the variables on the heart surgery treatment outcomes were then analyzed. Results The chance of death of patients who received surgery in a hospital that performed 50 or more surgeries annually was noticeably lower than patients receiving operations from hospitals that performed fewer than 50 surgeries annually, indicating that the chance of death decreases as the annual volume of heart surgeries in the hospital increases. In particular, the mortality rate in hospitals that performed more than 200 surgeries annually was less than half of that in hospitals that performed 49 or fewer surgeries annually. Conclusion These results indicate that accumulation of a certain level of heart surgery experience is critical in improving or maintaining the quality of heart surgeries. In order to improve the treatment outcomes of small hospitals, a support policy must be implemented that allows for cooperation with experienced professionals.

Patient safety practices in Korean hospitals

Purpose: The aims of this study were to assess the presence of core patient safety practices in Korean hospitals and assess the differences in reporting and learning systems of patient safety, infrastructure, and safe practices by hospital characteristics. Methods: The authors developed a questionna...