메타 분석을 이용한 유방암과 그에 따른 생식요인들의 연관성 연구

학위논문 (석사) -- 서울대학교 대학원 : 의과대학 의학과, 2020. 8. 박수경.서론: 유방암은 여성에게 가장 큰 위험을 주는 암이며 이에 따른 위험도는 생식 요인들과 외인성 호르몬에 기인한다는 것은 잘 알려져 있는 사실이다. 또한 유방암과 reproductive factors 간의 연관성에 대한 메타 분석 연구들은 많이 진행되어 있으나 아직까지 전체 reproductive factors 간의 최신 동향을 연구한 연구는 한국인을 포함하여 부족한 현실이다. 따라서 본 연구에서는 체계적 문헌 고찰 및 meta-analysis를 통하여 부족한 한국인의 메타 결과를 재 수립하고 한국인의 결과와 비교를 하기 위하여 전세계인의 결과를 비교 분석을 한 뒤 각 요인들에 걸맞는 범주를 수립하는 것이다. 방법: 연구를 수행하기 위하여 우선 체계적 문헌 고찰을 수행한 뒤, 통계적인 기법을 이용하여 메타 분석을 진행한다. PICO 기법을 이용하여 검색어 전략을 수행하며 검색원으로는 PubMed와 KoreaMed를 이용하였다. 연구논문 중 유방암과 그에 따른 위험 요인들의 위험도 산출 및 신뢰구간 산출에 관한 논문들을 선택하여 random effect model (변량효과 모형)을 이용하여 전체 summary RR을 산출한다. 또한 연구 디자인, 나라별 그리고 출판 연도로 subgroup analysis (하위 그룹 분석)을 수행한다. 결과: 한국 인구집단의 경우 각 요인들에 따른 유방암 한국인들의 메타 결과를 이용하여 각 요인들의 인구집단 기여율 (PAF)를 계산할 예정이기 때문에 모든 결과(RRs)들은 1보다 큰 방향으로 산출되었다. 결론적으로 대부분의 생식요인들이 유의함을 보였으나 임신 여부, 모유 수유 여부, 경구피임약 복용 여부에 대해서 유의하지 않음을 보였다. 또한 이 인구집단을 세계로 확장하였을 때, 경구피임약을 복용한 여성이 그렇지 않은 여성에 비해 약 10%정도의 유방암 위험도를 보이는 반면 호르몬치료제를 시행한 여성은 그렇지 않은 여성에 비해 약 30%정도 높은 유방암 위험도를 보인다. 더 나아가, 나라별 하위 그룹 분석을 시행하였을 경우 유럽과 미국 대륙을 서양이라고 하였을 때, 각 요인들에 따른 위험도가 증가한 경우 나라별로 위험도가 산발적 이었으며 각 요인들이 보호 요인인 경우 아시아가 서양보다는 더 보호 요인을 보인다. 추가적인 출판 연도를 이용한 하위 그룹 분석 결과의 경우 출판 연도를 기준으로 한 생식요인들의 차이점을 발견하긴 하였지만 1990년도 이전의 논문들의 부족으로 인하여 유의한 근거를 수립하지는 못하였다. 고찰 및 결론: 본 연구는 modifiable과 unmodifiable 한 생식요인들의 변수를 모아 유방암과 그에 따른 생식요인들의 결과를 확인하며 더 나아가 한국형 PAF 값을 산출하기 위하여 한국인 메타 값을 재정립함이다. 또한 세계 인구로 확장하였을 때에도 각 생식 요인들의 위험도를 재 확인함에 있다.Introduction: It is well known that breast cancer (BC) is a main risk for women and its association between reproductive and exogenous hormone factors have already undergone many progressions. Also, there have been many meta-analysis studies of breast cancer and each risk factor. However, contemporary research for each factors is needed, especially for the South Korean (hereafter, Korean) population. The purposes of this study are to systematically review the literature of corresponding studies to define a new estimation of a Korean meta-analysis, and to confirm continuous variables into a categorical status. Methods: Firsts, systematic and comprehensive research of a systematic review was conducted. Second, statistical analysis of the meta-analysis was sequentially conducted. Third, PICO (Population, Intervention, Comparison, and Outcome) statements were used for search strategies and update searching was performed in the journal PubMed until the publication of April 30, 2020. The literature representing the relative risk ratio (RR), odds ratio (OR) or hazard ratio (HR) of the association between breast cancer and reproductive factors and 95% confidential intervals (CIs) were selected. Pooling the effect size was estimated by using the random effect model. A subgroup analysis was performed according to the study design, country and publication date. Results: For the results of the Korean population, we set the reference in the direction of larger than 1 to calculate the population attributable risk (PAF) later. As a result, most of the reproductive variables were significant except for parity, duration of breastfeeding and oral contraceptive use. However, the trend of breast cancer and reproductive factors was the same as the global trend. For the Global population, the risk of medication of an oral contraceptive was approximately 10% higher than the general healthy women. On the other hand, the use of the combination of hormone replacement therapy (HRT) had approximately 30% higher risk than the general healthy women. Furthermore, in the subgroup analysis by country of the Global population, if the reproductive factors were at the risk point, the risk was sporadic by the various reproductive factors. Also if the reproductive factors were at the protective point, then Asian countries were more protective to breast cancer then Western countries (age at menarche, parity, number of childbirths, and duration of breastfeeding). In subgroup analysis by publication date, the relation of publication date has revealed in some reproductive factors, but it was difficult to calculate the rationale due to the lack of 1990s publication study. Conclusions: This study summarized the modifiable factors and unmodifiable factors of breast cancer and confirmed the trend of the risk of breast cancer. Also, in order to calculate the Korean PAF model, we conducted a Korean meta-analysis to produce the latest indicators. Furthermore, we categorized and identified appropriate categories of continuous reproductive variables.Ⅰ. Introduction 1 1. Epidemiology of breast cancer 1 2. The relationship between reproductive factors and exogenous hormone factors 1 3. Breast cancer of Korean population attributable risk (PAF) 2 4. Objectives 3 Ⅱ. Materials and Methods 5 1. Search and selection of literature for systematic review and meta-analysis 5 2. Study group for raw data analysis 6 3. Data Extraction 7 4. Statistical analysis 7 A. Systematic review and meta-analysis 7 B. Raw data analysis 8 Ⅲ. Results 10 1. Results of Korean meta-analysis to estimate the summary RR of each reproductive factors 10 A. Incidence of breast cancer 10 B. Mortality of breast cancer 14 2. Meta-analysis of the Global population 19 3. Subgroup analysis of Global population 23 A. Study design 23 B. Country (Continent) 26 C. Publication date 35 Ⅳ. Discussion 39 1. Summary of the results 39 A. Korean meta-analysis: 1st objective 39 B. Global population meta-analysis: 2nd & 3rd objective 40 2. Biological plausible mechanism 42 3. Limitations and strengths of our study 44 Ⅴ. Conclusion 45 Ⅵ. Reference 97 초 록 111Maste

인간거대세포바이러스 감염과정에서 STING의 친바이러스성 기능연구

학위논문 (박사) -- 서울대학교 대학원 : 자연과학대학 생명과학부, 2021. 2. 안광석.Once inside the host cell, DNA viruses must overcome the physical barrier posed by the nuclear envelope to establish a successful infection. The mechanism underlying this process remains unclear. Here I show that the herpesvirus exploits the immune adaptor STING to facilitate nuclear import of the viral genome. Following the entry of the viral capsid into the cell, STING binds to the viral capsid and mediates capsid docking to the nuclear pore complex and subsequent accumulation of the viral genome in the nucleus. Depleting STING in cells permissive to HCMV inhibits viral gene expression, and overexpressing STING renders nonpermissive cells susceptible to HCMV and HSV-1 viral gene expression, suggesting that this proviral activity of STING is conserved throughout the herpesvirus family. Intriguingly, in monocytes as HCMV latent reservoirs, STING deficiency delays the establishment of HCMV latency and leads to a defective viral reactivation. My findings identify STING as a pro-viral host factor crucial in herpesvirus infection.허피스바이러스 중 하나인 인간거대세포바이러스(HCMV)의 성공적인 감염을 위해서는 세포막 통과와 핵막 통과 후 핵 안으로의 바이러스 게놈 전달이 필수적이다. 지금까지 인간거대세포바이러스의 세포투과성을 결정짓는 다양한 세포막 수용체 단백질들이 발견되었던 반면, 핵막 통과 과정에서 기능적으로 중요한 숙주 단백질에 대한 연구는 미비하다. 본 연구는 핵막 통과 과정에 있어 중요한 양성적 매개자로서 STING의 새로운 기능을 규명하였다. 이전까지의 연구에 따르면, STING은 인터페론 반응을 매개하는 항바이러스적 신호전달 단백질로 알려져 있었다. 하지만 본 연구에서는 숙주세포 내에서 STING의 발현이 적으면 극초기 감염 과정에서 핵 안으로의 바이러스 게놈 전달 효율이 감소하고 유전자 발현이 지연 및 감소되는 것을 발견하였다. 또한, STING이 바이러스 캡시드 구조물과 핵공복합체가 효율적으로 결합할 수 있도록 도와주는 물리적 매개 단백질임을 생화학적 방법으로 확인하였다. 이러한 STING의 새로운 역할은 바이러스 용균 감염 세포뿐만 아니라 잠복-재생산 감염 세포 모두에서 통용되는 세포 비특이적 현상이며, 다른 허피스바이러스에서도 관찰되는 것으로 미루어 보아 진화적으로 잘 보존된 중요한 기능이라는 점을 검증하였다. 본 연구 결과가 선천성 면역 반응과 바이러스 초기 감염 과정 간의 상호작용에 대한 깊은 이해의 시발점을 마련하고, 나아가 백신 개발에 있어 중요한 단초를 제공할 것이라 기대한다.Ⅰ. ABSTRACT 1 Ⅱ. INTRODUCTION 3 1.Human Cytomegalovirus (HCMV). 3 2.Entry and post-entry of HCMV. 5 3.Misdelivery of the viral genome at Nuclear Pore Complex (NPC) and innate immunity. 12 4.Cytosolic DNA sensing pathway. 15 Ⅲ. RESULTS 18 1.STING is critical for HCMV gene expression during immediate-early phase infection. 18 2.The proviral role of STING does not involve its canonical innate immune function. 28 3.STING plays a role in nuclear import of the HCMV genome. 36 4.STING-facilitated binding of the viral capsid to Nup358 of the NPC is crucial for HCMV infection. 48 5.Ectopic expression of STING converts otherwise non-permissive cells to a susceptible state for herpesvirus infection. 82 6.Establishment of latency and reactivation of HCMV in monocytes is STING-dependent. 98 Ⅳ. DISCUSSION 111 Ⅴ. EXPERIMENTAL PROCEDURES 116 Ⅵ. REFERENCES 127 Ⅶ. ABSTRACT IN KOREAN 135 Ⅷ. APPENDIX 137Docto

Guideline for Appropriate Use of Cardiac CT in Heart Disease1

Heart disease is one of the leading causes of deaths in Korea, along with malignant neoplasms and cerebrovascular diseases. The proper diagnosis and management for patients with suspected heart diseases should be warranted for the public health care. Advances in CT technology have allowed detailed images of the heart to be obtained, which enable evaluations not only of the coronary arteries but also of other cardiac structures. Currently, the latest multi-detector CT machines are widespread around Korea. The appropriate use of cardiac CT may lead to improvements of the physicians' medical performances and to reduce medical costs which eventually contribute to promotions of public health. However, until now, there has been no guidelines regarding the appropriate use of cardiac CT in Korea. We intend to provide guidelines for the appropriate use of cardiac CT in heart diseases based on scientific data. The purpose of this guideline is to assist the clinicians and other health professionals when using cardiac CT for diagnosis and treatments of heart diseases.ope

Assessment of extracellular volume fraction using dual-energy CT in doxorubicin-induced dilated cardiomyopathy in a rabbit model : comparison with contrast-enhanced magnetic resonance imaging and histology

Dept. of Medicine/박사Purpose: To assess the feasibility of extracellular volume (ECV) fraction using dual-energy computed tomography (CT) and to compare it with magnetic resonance imaging (MRI) T1 mapping and histologic findings. Materials and methods: A dilated cardiomyopathy rabbit (DCR) model was made by injecting doxorubicin into the rabbits (adult male New Zealand white rabbits, 3-4 kg) at doses of 1.0 mg/kg twice a week. Every rabbit underwent both dual-energy CT and magnetic resonance imaging (MRI) within two hours with pre-/post-contrast T1 mapping using modified Look-Locker inversion recovery (MOLLI) sequence, late gadolinium enhancement (LGE), and cine MR on a clinical 3-T system. The rabbits underwent CT and MR examination before drug administration (control group) and DCR model at various post-modeling intervals (6 weeks, 12 weeks or 16 weeks after DCR modeling). CT ECV was quantitatively assessed by measuring Hounsfield units (HUs) in the septum in a cardiac short-axis view on iodine maps. MR ECV was assessed in the same area with CT. The left ventricle ejection fraction (LVEF) was obtained from the cine MR images using Simpson''s method. Results: Fifteen rabbits were scanned prior to modeling, and then four controls were sacrificed for histology. The remaining eleven underwent DCR modeling and were scanned at various post-modeling intervals (Group I; 6-week modeling, n = 11: group II; 12-week modeling, n = 8: and group III; 16-week modeling, n = 5). The mean CT ECV values (%) of group I-III were significantly higher than control group (Control vs. group I vs. group II vs. group III; 28.5 (range, 25.9-31.3) vs. 35.3 (range, 30.2-40.1) vs. 41.9 (range, 35.6-44.1), vs. 42.1 (range, 39.2-46.4), p < 0.001) and there was a good correlation between CT ECV and MR ECV (r = 0.888, p < 0.001) and between CT ECV and degree of fibrosis (r = 0.811 p < 0.001) Conclusion: ECV using dual-energy CT shows good correlation with MRI and histology. Noninvasive measurement of ECV in animals with doxorubicin-induced diffuse myocardial fibrosis is feasible with dual-energy CT without misregistration errors.ope

저용량 베타차단제가 낮은 심박수 무증상 환자의 심박수, 심박변화, 그리고 전향적 동조화 심장 CT에 미치는 영향1

Purpose : We assessed the effect of a low-dose β-blocker on heart rate (HR), HR variability (HRV) and image quality of prospective electrocardiography-gated coronary CT angiography (CCTA) in healthy subjects with low HR. Materials and Methods : CCTA was performed with a 64-slice CT in 75 subjects with a HR of less than 65 beats per minute (bpm). Subjects were divided into 2 groups: Group 1 (G1), 35 with a low dose β-blocker; and Group 2 (G2), 40 without pre-medication. The image quality (IQ) of the CCTA was assessed on a 4-point grading scale (1, poor; 4, excellent). Results : Initial HR (bpm) was not different between the 2 groups. HR during CCTA was lower in G1 than G2 (50.3 ± 5.6 vs. 53.3 ± 4.8, p = 0.016). HRV was not different between the 2 groups. Per-segment analysis showed better IQ at the mid-segment of the right coronary artery (3.0 ± 0.9 vs. 2.5 ± 1.1, p = 0.039) and the first diagonal branch (3.4 ± 0.6 vs. 3.1 ± 0.7, p = 0.024), in the G1 than the G2 group, respectively. The IQ was negatively correlated with HR, but no correlation was found between HRV and IQ. The IQs in the per-vessel analysis were not different between the 2 groups. Conclusion : Low-dose β-blocker reduced HR and improved the IQ of CCTA in a few segments, even at a HR of less than 65 bpm. However the effect was limited.ope

Dual-Energy CT for Pulmonary Embolism: Current and Evolving Clinical Applications

Pulmonary embolism (PE) is a potentially fatal disease if the diagnosis or treatment is delayed. Currently, multidetector computed tomography (MDCT) is considered the standard imaging method for diagnosing PE. Dual-energy CT (DECT) has the advantages of MDCT and can provide functional information for patients with PE. The aim of this review is to present the potential clinical applications of DECT in PE, focusing on the diagnosis and risk stratification of PE.ope

Regional Amyloid Burden Differences Evaluated Using Quantitative Cardiac MRI in Patients with Cardiac Amyloidosis

Objective: This study aimed to investigate the regional amyloid burden and myocardial deformation using T1 mapping and strain values in patients with cardiac amyloidosis (CA) according to late gadolinium enhancement (LGE) patterns. Materials and methods: Forty patients with CA were divided into 2 groups per LGE pattern, and 15 healthy subjects were enrolled. Global and regional native T1 and T2 mapping, extracellular volume (ECV), and cardiac magnetic resonance (CMR)-feature tracking strain values were compared in an intergroup and interregional manner. Results: Of the patients with CA, 32 had diffuse global LGE (group 2), and 8 had focal patchy or no LGE (group 1). Global native T1, T2, and ECV were significantly higher in groups 1 and 2 than in the control group (native T1: 1384.4 ms vs. 1466.8 ms vs. 1230.5 ms; T2: 53.8 ms vs. 54.2 ms vs. 48.9 ms; and ECV: 36.9% vs. 51.4% vs. 26.0%, respectively; all, p < 0.001). Basal ECV (53.7%) was significantly higher than the mid and apical ECVs (50.1% and 50.0%, respectively; p < 0.001) in group 2. Basal and mid peak radial strains (PRSs) and peak circumferential strains (PCSs) were significantly lower than the apical PRS and PCS, respectively (PRS, 15.6% vs. 16.7% vs. 26.9%; and PCS, -9.7% vs. -10.9% vs. -15.0%; all, p < 0.001). Basal ECV and basal strain (2-dimensional PRS) in group 2 showed a significant negative correlation (r = -0.623, p < 0.001). Group 1 showed no regional ECV differences (basal, 37.0%; mid, 35.9%; and apical, 38.3%; p = 0.184). Conclusion: Quantitative T1 mapping parameters such as native T1 and ECV may help diagnose early CA. ECV, in particular, can reflect regional differences in the amyloid deposition in patients with advanced CA, and increased basal ECV is related to decreased basal strain. Therefore, quantitative CMR parameters may help diagnose CA and determine its severity in patients with or without LGE.ope

파브리병에서의 심장 자기공명영상의 역할

Fabry disease is a rare X-linked metabolic disorder that is characterized by the accumulation of glycosphingolipids in various organs, resulting from the deficiency of alpha-galactosidase A. Cardiac involvement is relatively common; myocardial inflammation, left ventricular hypertrophy, and myocardial fibrosis secondary to abnormal lipid deposition in myocytes are often observed. Hence, the diagnosis of cardiac involvement is crucial for evaluating patient prognosis. Cardiac MRI is the standard technique for measuring the function, volume, and mass of the ventricles. It is also useful for myocardial tissue characterizations. The evaluation of native myocardial T1 values can facilitate early diagnosis of cardiac involvement, while measurements of left ventricular myocardial mass can be used to monitor treatment outcomes, in patients with Fabry disease. Consequently, cardiac MRI can provide useful information for diagnosing, monitoring, and treating patients with Fabry disease.ope

Korean guidelines for the appropriate use of cardiac CT

The development of cardiac CT has provided a non-invasive alternative to echocardiography, exercise electrocardiogram, and invasive angiography and cardiac CT continues to develop at an exponential speed even now. The appropriate use of cardiac CT may lead to improvements in the medical performances of physicians and can reduce medical costs which eventually contribute to better public health. However, until now, there has been no guideline regarding the appropriate use of cardiac CT in Korea. We intend to provide guidelines for the appropriate use of cardiac CT in heart diseases based on scientific data. The purpose of this guideline is to assist clinicians and other health professionals in the use of cardiac CT for diagnosis and treatment of heart diseases, especially in patients at high risk or suspected of heart disease.ope

2014 Korean guidelines for appropriate utilization of cardiovascular magnetic resonance imaging: a joint report of the Korean Society of Cardiology and the Korean Society of Radiology.

Cardiac magnetic resonance (CMR) imaging is now widely used in several fields of cardiovascular disease assessment due to recent technical developments. CMR can give physicians information that cannot be found with other imaging modalities. However, there is no guideline which is suitable for Korean people for the use of CMR. Therefore, we have prepared a Korean guideline for the appropriate utilization of CMR to guide Korean physicians, imaging specialists, medical associates and patients to improve the overall medical system performances. By addressing CMR usage and creating these guidelines we hope to contribute towards the promotion of public health. This guideline is a joint report of the Korean Society of Cardiology and the Korean Society of Radiology.ope