Meta-Analysis of Tumor Stem-Like Breast Cancer Cells Using Gene Set Analysis

학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2016. 8. 박정일.일반적으로 종양개시세포는 epithelial-to-mesenchymal-transition 성질을 가지며 증식속도가 빨라 암의 전이를 일으키는데 중요한 역할을 한다. 그러나 아직까지 종양개시세포에 관하여 확실한 마커는 알려지지 않았으며 종양개시세포 관련기전과 마커의 연구를 위해 가장 많이 사용되는 방법은 종양개시세포의 성질을 나타낸다고 알려진 sphere cells과 그 대조군인 adherent cells의 비교방법이다. 본 연구는 서로 다른 유방암 종양개시세포 연구에서 얻은 sphere cells과 adherent cells의 유전자 발현 데이터를 이용하여 메타분석을 수행함으로써 유방암 종양개시세포의 기전을 밝히고 새로운 마커를 검색하였다. 이를 위해 Gene Expression Omnibus에서 출처가 다른 유방암 종양개시세포 연구에서 3개의 유전자 발현 데이터를 얻고 이를 ComBat 알고리즘을 이용하여 하나의 데이터로 통합하였으며, 여기에 본 연구진과 공동으로 연구를 수행한 아주대학교에서 유전자 발현 데이터를 제공하여 본 연구에 추가하였다. 메타분석을 진행하기 위해 위의 결과로 얻은 두 개의 데이터에 각각 gene set analysis를 적용하여 유의성 있는 gene set을 얻은 후 두 데이터 모두에서 공통적으로 유의성을 보인 4개의 gene set을 얻었다. 유방암 종양개시세포에 관여하는 유전자 마커는 유의성을 보인 4개의 gene set이 포함하는 유전자 중에서, 두 데이터 모두에서 p-value < 0.05를 만족하고 발현이 증가했던 CXCR4와 CXCL1을 포함하는 6개의 유전자로 선택하였다. 실험적 검증을 위하여 아주대학교에서 최종적으로 얻어진 6개의 유전자에 대해 quantitative reverse transcription-polymerase chain reaction을 수행하였고 6개의 유전자 중에서 CXCR4, CXCL1, HMGCS1이 MCF-7의 sphere cells에서 adherent cells과 비교했을 때 발현이 증가하였다. 본 연구는 gene set analysis를 이용하여 메타분석을 수행하였으며 이를 통해 유방암 종양개시세포 기전에 관여하는 4개의 gene set과 유전자 마커인 CXCR4, CXCL1, HMGCS1을 제시하였다. 최종적으로 메타분석에 gene set analysis를 도입함으로써 통계적인 유의성을 가질 뿐만 아니라 gene set 개념을 바탕으로 생물학적 기전 정보를 고려한 유전자 마커를 제시하였다.Ⅰ. 서론 1 Ⅱ. 재료 및 방법 4 1. 데이터 수집 4 2. 세포배양 및 유전자 발현 profiling 5 3. 데이터 전처리 6 4. Gene set analysis 7 5. 통계적 검증과 개별 유전자 마커 선택 7 6. Reverse transcription-PCR 9 Ⅲ. 결과 9 1. 수집된 데이터의 성격 9 2. Gene set analysis와 통계적 검증 11 3. 개별 유전자 마커 선택 13 4. Reverse transcription-PCR 18 Ⅳ. 결론 19 Ⅴ. 참고 문헌 21 Ⅵ. 부록 26 1. The Gene Expression Omnibus (GEO) 26 2. 메타분석 (Meta-analysis) 28 3. Affymetrix 31 4. ComBat method (R 설치 및 R package 설치) 32 5. Illumina 38 6. Gene set analysis 42 7. Prediction analysis for microarrays (PAM) 44 8. Globaltest 46 9. ArrayExpress 47 10. affy 48 11. DAVID 49 12. Entrez ID 51 13. Leave-one-out cross validation 51 14. C-X-C chemokine receptor type 4 (CXCR4) 53 15. C-X-C motif chemokine 12 (CXCL12) 56 16. chemokine (C-X-C motif) ligand 1 (CXCL1) 56 17. Hydroxymethylglutaryl-CoA synthase (HMGCS1) 57 Abstract 58Docto

李萬敷의 道東編 과 李瀷의 道東錄 을 통해본 근기남인의 ‘道東’ 의식

본 연구는 息山 李萬敷(1664~1732)의 道東編 과 星湖 李瀷(1681~1763)의 道東錄 의 저술배경, 내용 및 구조, 특징 등을 살펴봄으로써 근기남인계의 ‘道東’ 의식의 실체를 시론한 것 이다. 도동편 은 退溪 李滉(1501~1570)과 栗谷 李珥(1536~1584) 등 한국 성리학자들만의 언설을 性理大全 의 체제로 망라한 것으로, 식산은 도통의 적전을 퇴계로 상정하면서도 율곡의 설까지 아울러 수록함으로써 학파와 정파에 관계없이 한국 유학의 발전상을 보여주고자 하였다. 도동록 은 퇴계의 언설을 近思錄 체제에 준하여 정리한 것으로, 성호는 사서의 입문서인 근사록 을 의식한 채 퇴계설을 정리함으로써 한국적 도학 전통의 기원을 밝히고 이를 한국적 도학 입문서 로 삼고자 하였다. 두 저서는 모본의 차이로 인해 편차 구성, 인용 문헌의 범위, 분량 등이 일치 하지는 못하다. 그러나 각 저서의 저자들은 한국 유학자의 언설만을 대상으로 삼아 수집 및 편집 하고 이를 동일한 표제로 명명함으로써 ‘道學’ 또는 ‘道統’의 東傳을 형용하고자 하였으며, 이 과 정에서 공통적으로 퇴계를 도학의 정점이자 도통의 적전으로 설정하는 모습을 보인다. 식산과 성호는 당쟁의 소용돌이 속에서 출사를 포기하고 학문에 매진하여 후일 근기남인을 대 표하는 석학으로 인정받았다. 두 저서가 저술된 시기는 남인이 정계에서 축출되고 서인 노론 정 권이 들어서고, 尤庵 宋時烈(1607∼1689)의 유지를 이은 노론의 존명의리사상이 萬東廟와 大報壇 이라는 중화계승 상징물로 가시화되던 때였다. 근기남인계인 두 학자로서는 노론이 선점한 중화 계승 의식에 상응하면서도 저들이 구축한 주자학 절대주의 및 춘추의리와는 구별되는 사유를 제 시할 필요가 있었다. 두 학자의 ‘도동’ 서적 저술은 근기남인계 지식인으로써의 책임의식과 위기 의식의 발로로, 퇴계가 도학의 정점이자 도통의 적전으로 설정되었다는 점은 이러한 사정과 무관 하지 않다. 한국 유학의 발전상을 드러내고 그 중심을 퇴계로 설정함으로써 식산과 성호가 제시 하고자 한 ‘도동’ 의식은 주자학 그 자체에 대한 정치한 분석에 기반하고 일련의 상징물로 가시 화된 노론식의 ‘중화계승’ 의식과는 분명히 구분되는 지점이 있다.이 논문은 2020년도 서울대학교 규장각한국학연구원 국내 신진학자 초청 연구교류 사업의 지원을 받아 수행된 연구임

Gender differences in hypertension control among older korean adults: Korean social life, health, and aging project

OBJECTIVES: Controlling blood pressure is a key step in reducing cardiovascular mortality in older adults. Gender differences in patients' attitudes after disease diagnosis and their management of the disease have been identified. However, it is unclear whether gender differences exist in hypertension management among older adults. We hypothesized that gender differences would exist among factors associated with hypertension diagnosis and control among community-dwelling, older adults. METHODS: This cross-sectional study analyzed data from 653 Koreans aged ≥60 years who participated in the Korean Social Life, Health, and Aging Project. Multiple logistic regression was used to compare several variables between undiagnosed and diagnosed hypertension, and between uncontrolled and controlled hypertension. RESULTS: Diabetes was more prevalent in men and women who had uncontrolled hypertension than those with controlled hypertension or undiagnosed hypertension. High body mass index was significantly associated with uncontrolled hypertension only in men. Multiple logistic regression analysis indicated that in women, awareness of one's blood pressure level (odds ratio [OR], 2.86; p=0.003) and the number of blood pressure checkups over the previous year (OR, 1.06; p=0.011) might influence the likelihood of being diagnosed with hypertension. More highly educated women were more likely to have controlled hypertension than non-educated women (OR, 5.23; p=0.013). CONCLUSIONS: This study suggests that gender differences exist among factors associated with hypertension diagnosis and control in the study population of community-dwelling, older adults. Education-based health promotion strategies for hypertension control might be more effective in elderly women than in elderly men. Gender-specific approaches may be required to effectively control hypertension among older adults.ope

Social Network Characteristics and Body Mass Index in an Elderly Korean Population

OBJECTIVES: Research has shown that obesity appears to spread through social ties. However, the association between other characteristics of social networks and obesity is unclear. This study aimed to identify the association between social network characteristics and body mass index (BMI, kg/m(2)) in an elderly Korean population. METHODS: This cross-sectional study analyzed data from 657 Koreans (273 men, 384 women) aged 60 years or older who participated in the Korean Social Life, Health, and Aging Project. Network size is a count of the number of friends. Density of communication network is the number of connections in the social network reported as a fraction of the total links possible in the personal (ego-centric) network. Average frequency of communication (or meeting) measures how often network members communicate (or meet) each other. The association of each social network measure with BMI was investigated by multiple linear regression analysis. RESULTS: After adjusting for potential confounders, the men with lower density (0.83) and lower size (1-2), but not in the women (p=0.393). The lowest tertile of communication frequency was associated with higher BMI in the women (β=0.885, p=0.049), but not in the men (p=0.140). CONCLUSIONS: Our study suggests that social network structure (network size and density) and activation (communication frequency and meeting frequency) are associated with obesity among the elderly. There may also be gender differences in this associationope

Appendicular skeletal muscle mass and insulin resistance in an elderly korean population: the korean social life, health and aging project-health examination cohort

BACKGROUND: Increasing evidence supports an association between age-related loss of muscle mass and insulin resistance. However, the association has not been fully investigated in the general population. Thus, we investigated the association between appendicular skeletal muscle mass (ASM) and insulin resistance in an elderly Korean population. METHODS: This cross-sectional study included 158 men (mean age, 71.8) and 241 women (mean age, 70.6) from the Korean Social Life, Health and Aging Project, which started in 2011. In this study, ASM was measured by bioelectrical impedance analysis and was analyzed in three forms: ASM (kg), ASM/height(2) (kg/m(2)), and ASM/weight (%). The homeostasis model assessment of insulin resistance (HOMA-IR) was used as a measure of insulin resistance. The relationships between the ASM values and the HOMA-IR were investigated by multiple linear regression models. RESULTS: The HOMA-IR was positively associated with ASM (β=0.43, P<0.0001) and ASM/height(2) (β=0.36, P<0.0001) when adjusted for sex and age. However, after additional adjustment for body weight, HOMA-IR was inversely associated with ASM (β=-0.43, P<0.001) and ASM/height(2) (β=-0.30, P=0.001). Adjustment for other potential confounders did not change these associations. Conversely, HOMA-IR was consistently and inversely associated with ASM/weight before and after adjustment for other potential confounders. CONCLUSION: Our results support the idea that lower skeletal muscle mass is independently associated with insulin resistance in older adults. When evaluating sarcopenia or muscle-related conditions in older adults, their whole body sizes also need to be considered.ope

Medical Care Utilization During 1 Year Prior to Death in Suicides Motivated by Physical Illnesses

OBJECTIVES: Many epidemiological studies have suggested that a variety of medical illnesses are associated with suicide. Investigating the time-varying pattern of medical care utilization prior to death in suicides motivated by physical illnesses would be helpful for developing suicide prevention programs for patients with physical illnesses. METHODS: Suicides motivated by physical illnesses were identified by the investigator's note from the National Police Agency, which was linked to the data from the Health Insurance Review and Assessment. We investigated the time-varying patterns of medical care utilization during 1 year prior to suicide using repeated-measures data analysis after adjustment for age, gender, area of residence, and socioeconomic status. RESULTS: Among 1994 suicides for physical illness, 1893 (94.9%) suicides contacted any medical care services and 445 (22.3%) suicides contacted mental health care during 1 year prior to suicide. The number of medical care visits and individual medical expenditures increased as the date of suicide approached (p<0.001). The number of medical care visits for psychiatric disorders prior to suicide significantly increased only in 40- to 64-year-old men (p=0.002), women <40 years old (p=0.011) and women 40 to 64 years old (p=0.021) after adjustment for residence, socioeconomic status, and morbidity. CONCLUSIONS: Most of the suicides motivated by physical illnesses contacted medical care during 1 year prior to suicide, but many of them did not undergo psychiatric evaluation. This underscores the need for programs to provide psychosocial support to patients with physical illnesses.ope

The Korean Social Life, Health and Aging Project-Health Examination Cohort

The Korean Social Life, Health, and Aging Project (KSHAP) is a population-based longitudinal study of health determinants among elderly Koreans. The target population of the KSHAP are people aged 60 years or older and their spouses living in a rural community of Korea. A complete enumeration survey was conducted in the first wave of the KSHAP on 94.7% (814 of 860) of the target population between December 2011 and July 2012. The KSHAP-Health Examination (KSHAP-HE) cohort consists of 698 people who completed additional health examinations at a public health center (n=533) or at their home (n=165). Face-to-face questionnaires were used to interview participants on their demographics, social network characteristics, medical history, health behaviors, cognitive function, and depression symptoms. Health center examinations included anthropometric measures, body impedance analysis, resting blood pressure measurement, radial artery tonometry, bone densitometry, the timed up-and-go test, and fasting blood analysis. However, only anthropometric measures, blood pressure measurement, and non-fasting blood analysis were available for home health examinations. Collaboration is encouraged and access to the KSHAP baseline data will be available via the website of the Korean Social Science Data Archive (http://www.kossda.or.kr).ope

Serum 25-Hydroxyvitamin D and Insulin Resistance in Apparently Healthy Adolescents

PURPOSE: Vitamin D deficiency is a common condition that is associated with diabetes and insulin resistance. However, the association between vitamin D and insulin resistance has not been fully studied, especially in the general adolescent population. Therefore, we assessed the association between serum 25-hydroxyvitamin D [25(OH)D] level and insulin resistance among apparently healthy Korean adolescents. METHODS: A total of 260 (135 male and 125 female) adolescents in a rural high school were assessed for serum 25(OH)D, fasting plasma glucose, and insulin. All of the participants were aged 15 to 16 years old, and without known hypertension or diabetes. Serum 25(OH)D was analyzed both as a continuous and categorical variable in association with insulin resistance. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). Increased insulin resistance was operationally defined as a HOMA-IR value higher than the sex-specific 75th percentile. RESULTS: In male adolescents, every 10 ng/ml decrease in 25(OH)D level was associated with a 0.25 unit increase in HOMA-IR (p = 0.003) after adjusting for age and BMI. Compared to those in the highest quartile, male adolescents in the lowest 25(OH)D quartile were at significantly higher risk for insulin resistance: unadjusted odds ratio 4.06 (95% CI, 1.26 to 13.07); age and BMI adjusted odds ratio 3.59 (95% CI, 1.03 to 12.57). However, 25(OH)D level, either in continuous or categorical measure, was not significantly associated with insulin resistance among female adolescents. CONCLUSIONS: This study suggests that serum 25(OH)D level may be inversely associated with insulin resistance in healthy male adolescents.ope

Factors Associated with a Low-sodium Diet: The Fourth Korean National Health and Nutrition Examination Survey

OBJECTIVES: The low-sodium diet is a known preventive factor for hypertension and cardiovascular disease. Factors associated with low-sodium diets should be identified to reduce sodium intake effectively. This study was conducted to identify factors correlated with a low-sodium diet. METHODS: This cross-sectional study analyzed data from a total of 14,539 Koreans aged 20 years or older, who participated in the Fourth (2007-2009) Korean National Health and Nutrition Examination Survey. A low-sodium diet was defined as having ≤2,000 mg/day based on 24-hour recalls. Multiple logistic regression models were used to assess sex, age, education, number of family members, household income, occupation, alcohol drinking, total energy intake, frequency of eating out, and hypertension management status for their associations with low-sodium diets. RESULTS: Among all participants, only 13.9% (n=2,016) had low-sodium diets. In the multivariate analysis, 40-49 years of age, clerical work jobs, higher total energy intake, and frequent eating out were inversely associated with low-sodium diets. And female sex and living-alone were associated with low-sodium diets. Lower frequency of eating out was significantly associated with low-sodium diets, even after adjusting for total energy intake and other potential confounders. Adjusted odds ratios (95% confidence interval) for a low-sodium diet were 1.97 (1.49-2.61), 1.47 (1.13-1.91), 1.24 (0.96-1.61), and 1.00 (reference) in people who eat out <1 time/month, 1-3 times/month, 1-6 times/week, and ≥1 time/day, respectively. CONCLUSIONS: Our study suggests that sex, age, number of family members, occupation, total energy intake, and lower frequency of eating out were associated with a low-sodium diet in Korean adults.ope

(The)Effects of Ubiquitous interactivity characteristic of new product on adoption and diffusion

학위논문(박사)--서울대학교 대학원 :경영학과 경영학전공,2005.Docto