의료 영상에서 특징점 추출 및 비강체 정합을 위한 어텐션 기반 특징 추출 방법론

학위논문(박사) -- 서울대학교대학원 : 공과대학 컴퓨터공학부, 2024. 2. 신영길.In the field of medical image analysis, attention mechanisms have enhanced deep learning models by concentrating on salient features and suppressing irrelevant ones. This dissertation aims to improve two medical imaging tasks through attention mechanisms: (1) landmark detection and (2) deformable image registration. For each task, a task-specific attention method is introduced, demonstrating its effective utilization. In landmark detection, aggregating global context with local features is required for obtaining accurate results. This dissertation introduces a novel patch-wise attention module designed to encode and weigh the relative importance of global and local features. The attention module employs a multi-layer perceptron to calculate attention weights. Experimental results on cephalometric landmark detection demonstrate that the proposed local patch-wise attention mechanism plays a significant role in enhancing accuracy. The structured attention, developed in a patch-wise fashion, significantly enhances local feature encoders, further improving the final accuracy. In addition to landmark detection, attention mechanisms are pivotal for deformable image registration tasks. A precise understanding of the spatial correspondence between floating and reference images is necessary for successful registration. This dissertation proposes a robust backbone registration network that incorporates the Transformer's self-attention and cross-attention mechanisms, along with a coarse-to-fine displacement vector field estimation scheme. Moreover, the introduction of a feature-based loss function guides the registration network for more precise alignment measurement. Experimental results demonstrate the crucial role of the proposed method in achieving an accurate registration. The integration of attention mechanisms and the coarse-to-fine estimation approach proves to be effective in handling deformations. Furthermore, the proposed feature-based alignment measure successfully complements existing similarity metrics, contributing to the overall success of the registration method. It is essential to explore and develop appropriate attention mechanisms for medical imaging applications. This dissertation introduces task-specific attention mechanisms for landmark detection and deformable registration. Improvements in accuracy can be achieved by extracting and aggregating the information related to each task. Keywords: attention mechanism, self-attention, cross-attention, global-local attention, landmark detection, deformable image registration, feature-based similarity, correlation Student Number: 2018-34367의료 영상 분석에서 주목받고 있는 어텐션 메커니즘은 핵심적인 특징에 집중하고 관련 없는 특징을 억제함으로써 심층 학습 모델을 향상시킨다. 본 논문에서는 어텐션 메커니즘을 활용하여 특징점 검출 및 변형 영상 정합 (비강체 영상 정합) 각 주제에 대해 특화된 방법론을 제안한다. 특징점 검출에서 정확한 결과를 위해서는 전역적 특징과 지역적 특징을 통합하는 것이 중요하다. 본 논문은 전역 및 지역적 특징의 상대적 중요도를 부여하는 패치 단위의 어텐션 메커니즘을 제안한다. 어텐션 메커니즘은 다층 퍼셉트론을 활용하여 어텐션 가중치를 계산한다. 세팔로 특징점 검출에 대한 실험 결과는 제안된 지역 패치 단위의 어텐션 메커니즘이 정확도 향상에 중요한 역할을 한다는 것을 보여준다. 패치 단위로 제안된 구조적 어텐션은 지역 특징 인코더를 향상시켜 최종 정확도를 높이는 데 기여한다. 특징점 검출 뿐만 아니라, 어텐션 메커니즘은 변형 영상 정합에서도 중요하다. 부동 및 기준 영상 간의 공간적 일치 관계를 잘 이해하는 것이 정합의 성공에 필요하다. 본 논문은 트랜스포머의 셀프 어텐션과 크로스 어텐션을 활용한 정합 모델을 제안한다. 더불어, 특징 기반 손실 함수를 도입하여 정합 모델이 더 정확히 정합 정도를 알 수 있도록 안내한다. 실험 결과는 제안한 방법이 정확한 정합을 달성하는 데 중요한 역할을 한다는 것을 보여준다. 어텐션 메커니즘과 대략-세밀 추정 방법의 통합은 정합을 효과적으로 처리하는 데 기여한다. 더불어, 제안된 제안된 특징 기반 손실 함수는 기존 유사성 지표를 성공적으로 보완하여 정합의 전반적인 성공에 기여한다. 의료 영상 분석에서 각 주제에 적합한 어텐션 매커니즘을 제안하는 것은 매우 중요하다. 본 논문에서는 특징점 검출 및 변형 영상 정합에 특화된 어텐션 메커니즘을 제안한다. 각 주제에 관련된 정보를 효과적으로 추출하고 통합함으로써 정확도를 향상시킨다.Chapter 1 Introduction 1 1.1 Background and motivation 1 1.2 Problem statement 4 1.3 Main contributions 7 1.4 Content and organization 10 Chapter 2 Related Work 11 2.1 Attention mechanisms in computer vision 11 2.1.1 Spatial attention 11 2.1.2 Channel attention 12 2.1.3 Channel and spatial attention 12 2.1.4 Self-attention 13 2.2 Methods for cephalometric landmark detection 19 2.2.1 Classical methods 19 2.2.2 Deep learning-based methods 20 2.3 Methods for deformable image registration 21 2.3.1 Preliminaries 21 2.3.2 Classical methods 32 2.3.3 Deep learning-based methods 33 2.4 Feature correlation and its applications 41 2.4.1 Applications in computer vision 41 2.4.2 Applications in medical image registration 43 Chapter 3 Attention-based Cephalometric Landmark Detection 46 3.1 Overview 46 3.2 Overall architecture 47 3.3 Single-pass global and local feature fusion 48 3.4 Auxiliary local encoder loss 50 3.5 Local patch-wise attention 50 3.6 Implementation and training details 52 3.7 Experimental results 54 3.7.1 Datasets 54 3.7.2 Evaluation metrics 55 3.7.3 Comparison 57 3.7.4 Ablation study 60 3.8 Discussion 64 Chapter 4 Attention-based Deformable Registration 66 4.1 Overview 66 4.2 Overall architecture 67 4.3 Registration network 69 4.3.1 Feature extraction 69 4.3.2 Displacement vector fields estimation 71 4.4 Feature correlation-based distance loss 76 4.4.1 Motivation 77 4.4.2 Loss calculation 79 4.5 Implementation and training details 82 4.6 Experimental results 84 4.6.1 Datasets 85 4.6.2 Evaluation metrics 87 4.6.3 Baseline methods 89 4.6.4 Comparison 90 4.6.5 Ablation study 102 4.6.6 Parameter study 105 4.7 Discussion 106 Chapter 5 Conclusion 109 Bibliography 111 초록 128박

폐외결핵 진단 지연의 위험인자에 대한 연구

학위논문 (석사) -- 서울대학교 대학원 : 의과대학 의학과, 2021. 2. 박상원.Background: The proportion of extrapulmonary tuberculosis (EPTB) of overall tuberculosis (TB) cases is increasing. EPTB significantly contributes to increase of TB-related mortality, complications, sequelae, and disabilities. EPTB is more difficult to diagnose than pulmonary TB. The delayed diagnosis and treatment of EPTB can cause complications, lifelong sequelae, and increase in socioeconomic burden. This study aimed to understand the detailed epidemiologic data on EPTB in South Korea and identify risk factors associated with its delayed diagnosis and treatment. Methods: Patients newly diagnosed with EPTB were retrospectively enrolled from eleven general hospitals nationwide in South Korea from January 2017 to December 2018. Recent epidemiologic status and basic characteristics of patients with EPTB were described. The subjects were subdivided into early versus delayed diagnosis groups, depending on the duration from the first visit to TB medication: 7 or >7 days, respectively. Univariable and multivariable analysis of the early and delayed groups were performed to identify risk factors for delayed diagnosis and treatment in EPTB. Results: Final 594 patients were enrolled. Lymph node TB (28.3%) was predominant form followed by abdominal (18.4%) and disseminated TB (14.5%). Concurrent lung involvement was 17.8%. The rate of treatment success and failure were 86.2% and 0.5%, respectively. The all-cause mortality rate was 2.2%. The duration from the onset of illness to first visit, from the first visit to diagnostic testing and TB medication were median 22, 9 and 19 days, respectively. Diagnostic tests showed no significant difference in positivity between groups. Acute nature of clinical manifestation in immunosuppression (odd ratio [OR] 0.269, 95% confidence interval [95%CI] 0.077–0.943), disseminated TB (OR 0.306, 95%CI 0.131-0.714), pericardial TB (OR 0.135, 95%CI 0.042–0.438) and meningeal TB (OR 0.066, 95%CI 0.020–0.224) was associated with early diagnosis. Delayed diagnosis was associated with outpatient-clinic visits (OR 2.323, 95%CI 1.320–4.087), delayed sample acquisition, diagnostic departments other than infection or pulmonology (OR 3.360, 95%CI 1.070–10.553 for gastroenterology, OR 3.113, 95%CI 1.385–6.997 for surgical departments). Conclusion: The delay in diagnosis and treatment of EPTB was related not to differences in microbiologic characteristics of EPTB itself but to the acuteness of clinical manifestation, promptness of sample acquisition, route of patient visits and expertise in TB. Therefore, it is necessary to establish a clinical system that promptly acquires diagnostic samples, and reinforcing consultation and collaboration with TB specialists for earlier diagnosis of EPTB to reduction of complications and socioeconomic burden.배경 전체 결핵감염 중 폐외결핵이 차지하는 비율은 증가하고 있다. 폐외결핵은 결핵 관련 사망, 합병증, 후유증, 그리고 장애의 증가에 상당히 기여한다. 폐외결핵은 폐결핵보다 진단하기 어렵다. 폐외결핵 진단 및 치료의 지연은 합병증과 평생 지속될 후유증 및 사회경제적 부담의 증가를 야기할 수 있다. 교정 가능한 요인을 교정하여 진단 시기를 앞당기기 위해 폐외결핵의 진단을 지연시키는 위험인자를 밝히고자 한다. 방법 2017년 1월부터 2018년 12월 사이에 국내 11개 종합병원에서 새롭게 진단된 폐외결핵 환자들이 후향적으로 연구에 포함되었다. 폐외결핵의 최근 역학과 환자들의 기본적인 특성을 기술하였다. 연구대상자는 의료기관 첫 방문부터 항결핵제 투여까지의 기간을 기준으로 조기진단군 (7일 이하) 과 지연진단군 (7일 초과)으로 나뉘었다. 폐외결핵의 진단 및 치료 지연의 위험인자를 찾기 위해 그룹간 단변수, 다변수 분석을 시행하였다. 결과 최종적으로 594명의 환자가 연구에 포함되었다. 림프절 결핵 (28.3%) 이 가장 흔하였고, 복부 결핵 (18.4%), 파종성 결핵 (14.5%) 순으로 뒤를 이었다. 폐침범이 동반된 경우는 17.8% 였다. 치료의 성공과 실패는 각각 86.2%, 0.5% 였고, 사망률은 2.2% 였다. 의료기관 방문 전 증상의 지속기간은 중위수 22일이었다. 의료기관 첫 방문부터 진단적 검사의 시행까지는 중위수 9일이 걸렸고, 항결핵제의 투여까지는 중위수 19일이 소요되었다. 진단적 검사의 양성률은 두 그룹간 유의미한 차이를 보이지 않았다. 면역억제제를 복용중인 환자 (교차비: 0.269, 95% 신뢰구간: 0.077–0.943)에서 증상의 급성 발현, 파종성 결핵 (교차비: 0.306, 95% 신뢰구간: 0.131-0.714), 결핵심장막염 (교차비: 0.135, 95% 신뢰구간: 0.042–0.438), 결핵수막염 (교차비: 0.066, 95% 신뢰구간: 0.020–0.224)은 조기진단과 관련이 있었다. 지연진단은 첫 방문 시 외래로 방문한 경우 (교차비: 2.323, 95% 신뢰구간: 1.320–4.087), 검체 채취의 지연, 감염내과나 호흡기내과와 같은 결핵 전문 진료과에서 진단받지 않은 경우(위장관내과의 교차비: 3.360, 95% 신뢰구간: 1.070–10.553, 외과계 진료과의 교차비: 3.113, 95% 신뢰구간: 1.385–6.997)와 관련되어 있었다. 결론 폐외결핵의 진단 및 치료의 지연은 결핵균의 미생물학적 특성의 차이가 아닌, 임상 증상의 급성발현, 검체 채취의 신속성, 환자의 의료기관 방문 경로와 결핵에 대한 진료과의 전문성과 관련되어 있었다. 그러므로 폐외결핵을 더 신속하게 진단하여 합병증 및 사회경제적 부담을 줄이기 위해서는, 진단적 검체를 신속하게 얻을 수 있는 진료시스템 및 결핵 전문가와의 협진을 강화하는 것이 필요하다.Abstract i Contents iv List of figures and tables vi Introduction 1 Methods 4 1. Subjects and study design 4 2. Data collection 6 3. Definition of terms 6 4. Statistical analysis 8 Results 10 I General characteristics of EPTB 10 1. Baseline characteristics 10 2. Diagnostic tests 14 II Factors associated with delayed diagnosis and treatment 15 Discussion 24 References 28 Abstract in Korean 32Maste

이차원 니켈 기반 금속유기구조체 기반의 산소발생반응 촉매

학위논문 (석사) -- 서울대학교 대학원 : 공과대학 재료공학부(하이브리드 재료), 2021. 2. 장호원.Two-dimensional (2D) metal-organic framework (MOF) nanosheets Ni-NDC MOF (NDC= naphthalene-2,6-dicarboxylic acid) are prepared by a facile surfactant-assisted one-pot hydrothermal synthesis. The obtained ultrathin 2D Ni-MOF nanosheets are extremely thin, which contributes to their excellent electrical properties. These unique nanostructures make them good candidates as electrode materials for high-performance water splitting catalysts to enlarge the active sites and enhance stability. In a three-electrode system, 2D Ni-MOF@NF had an overpotential of 160 mV at 10 mA cm-2 and a Tafel slope of 19 mV dec-1. To utilize this outstanding characteristic, NiMo was deposited on MOF@NF to fabricate a bifunctional catalyst. NiMo proved not to disturb the OER performance of MOF and improve the HER catalytic performances, resulting in 1.56 V overpotential at 20 mA cm-2 at a two-electrode system. This remarkable value is comparable to conventional catalysts such as Pt/C and IrO2. More importantly, the NiMo/MOF@NF exhibits almost no degradation after 1000 cycles of linear sweep voltammetry and long term stability test under constant voltages. The 2D Ni-MOF nanosheets, combined with NiMo alloy, offers superior performance in alkaline condition with outstanding electrochemical activity and high durability.기존의 화석연료 기반 에너지원을 대체할 수 있는 지속가능한 친환경 에너지원에 대한 연구의 중요성이 커지고 있다. 태양, 풍력, 조력 등을 이용한 에너지원이 초기에 주목받았지만 에너지를 생산하는 조건이 한정적이며 저장할 수 없는 한계를 가지고 있다. 반면, 수소 에너지는 외부 환경과는 무관하게 물을 전기 분해하여 쉽게 생산할 수 있고, 수소를 다양한 형태로 저장함으로써 에너지를 비축할 수 있기 때문에 최근 연구가 활발히 이루어지고 있다. 물 분자는 전기 에너지를 가하여 수소와 산소로 분리되며 각각의 반은은 수소발생반은 (HER) 과 산소발생반응 (OER)로 나뉜다. 전체 반응은 열역학적으로 1.23 V 의 전위에서 발생해야한다. 하지만 실제 반응은 반응속도가 느리기 떄문에 1.23 V 이상의 과전압 (overpotential)이 필요하며, 과전압은 전극 재료와 특성에 따라서 달라진다. 전극 물질의 전기 전도도와 이온 이동성 등의 요소를 고려하여 반응 효율이 높은 전기화학촉매 연구가 요구되어 지고있다. 금속유기구조체 (MOF)는 기본적으로 부도체이기 때문에 촉매로서의 역할이 제한된다고 여겨졌지만, 특히, 금속유기구조체는 유기리간드의 구조에 따라서 다양한 형태를 만들 수 있으며 이차원 다공성 구조를 통해 표면적이 넓고 촉매 반응이 일어나는 금속 이온들이 표면에 많이 노출될 수 있어서 전도성 금속유기구조체의 발전으로 뛰어난 촉매효율을 드러내고 있다. 본 논문에서는 니켈과 2,6-나프탈렌다이카르복시산을 이용한 이차원 .금속유기구조체 나노시트를 니켈폼 위에 합성하여 산소발생반응 촉매로서 향상된 효과를 입증하였으며, 더 나아가 니켈몰리브데늄을 금속유기구조체 나노시트 사이에 박막을 형성함으로써 수소발생반응 촉매로서의 효과또한 보여주었다.Abstract ....................................................................................................... 1 Table of Contents ........................................................................................ 2 List of Tables ............................................................................................... 3 List of Figures ............................................................................................. 4 Chapter 1 Electrochemical catalysts: Mechanisms and metal-organic frameworks ................................................................................................. 6 1.1 Background .......................................................... 7 1.2 Electrochemical catalysts .................................... 9 1.3 Metal-organic frameworks ................................. 10 1.3.1 Introduction .......................................... 10 1.3.2 Top-down and Bottom-up synthesis of 2D MOF nanosheets ...................................................... 12 1.3.3 Unique properties ................................. 15 1.4 References ............................................................ 16 Chapter 2 Direction-controlled growth of 2D Ni-MOF nanosheets on nickel foam ................................................................................................. 21 2.1 Introduction ......................................................... 22 2.2 Experimental Procedures ................................... 23 2.3 Results and Discussion ........................................ 26 2.3.1 The structure of Ni-NDC ..................... 26 2.3.2 Electrochemical performance of Ni-NDC@NF & NiMo/MOF@NF ........................................... 34 2.4 Conclusion ........................................................... 47 2.5 References ............................................................ 48 Abstract in Korean …………………………………………………….. 49Maste

Functional studies on the phosphorylation of Mis18α in the regulation of cell division

학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 생명과학부, 2018. 2. 백성희.Mis18α, a component of Mis18 complex comprising of Mis18α, Mis18β, and M18BP1, is known to localize at the centromere from late telophase to early G1 phase and plays a priming role in CENP-A deposition. Although its role in CENP-A deposition is well established, the other function of Mis18α remains unknown. Here, I elucidate a new function of Mis18α that is critical for the proper progression of cell cycle independent of its role in CENP-A deposition. I find that Aurora B kinase phosphorylates Mis18α during mitosis not affecting neither centromere localization of Mis18 complex nor centromere loading of CENP-A. However, the replacement of endogenous Mis18α by phosphorylation-defective mutant causes mitotic defects including micronuclei formation, chromosome misalignment, and the chromatin bridges or lagging chromatids. Interestingly, PLK1, another mitotic kinase, shows decreased recruitment in Mis18α phosphorylation-defective cell lines. PBD of PLK1 recognizes Mis18α phosphorylation so that its kinetochore recruitment can be enhanced. Together, my data demonstrate that Aurora B kinase-mediated mitotic phosphorylation of Mis18α is a crucial event for faithful cell cycle progression through the enhanced recruitment of PLK1 to the kinetochore.CHAPTER I. Introduction 1 I-1 Cell cycle 2 1.1 Introduction of cell cycle 2 1.2 Regulation of cell cycle 2 I-2 Aurora B kinase 6 2.1 Functions of Aurora B kinase in cell cycle 6 2.2 Substrates of Aurora B kinase 8 I-3 PLK1 10 3.1 Functions of PLK1 in cell cycle 10 3.2 Physical interaction with the substrates 13 I-4 Mis18α 16 4.1 Previous study on Mis18α 16 CHAPTER II. Mis18α is phosphorylated by Aurora B kinase during mitosis 19 II-1. Summary 20 II-2. Introduction 22 II-3. Results 24 II-4. Discussion 51 II-5. Materials and Methods 53 CHAPTER III. Phosphorylated Mis18αenhances PLK1 recruitment on kinetochore 58 III-1. Summary 59 III-2. Introduction 61 III-3. Results 62 III-4. Discussion 78 III-5. Mater Methods 81 CHAPTER IV. Conclusion 85 REFERENCES 91 국문초록 / ABSTRACT IN KOREAN 105Docto

설치류의 파킨슨병 모델에서 도파민계 및 세로토닌계 장애의 상호 연관성

Dept. of Medicine/박사Depression frequently accompanies Parkinson’s disease (PD) and has a great impact on patients’ quality of life and disease progression. Previous research suggested that dopamine and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonergic system in the same subject by using consecutive PET imaging. The interconnection between motor symptoms and depression was also examined. [18F]FP-CIT was applied to assess dopamine transporters and serotonin 1A (5-HT1A) receptors were evaluated by [18F]Mefway in unilateral 6-hydroxydopamine (6-OHDA) lesioned and sham operated rats. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region-of-interests (ROIs) were drawn in the striatum and cerebellum for the dopamine system and hippocampus and cerebellum for the 5-HT system. Non-displaceable binding potential in the striatum and hippocampus were compared between 6-OHDA and sham groups. As a result, unilateral 6-OHDA-lesioned rats exhibited significant bilateral reduction of hippocampal BPND for 5-HT1A receptors compared with the sham group and there was a positive correlation between striatal BPND for DAT. The severity of motor symptoms was also closely related to the depression. Taken together, the data demonstrate that destruction of the dopaminergic system causes the reduction of the serotonergic system and that the degrees of change in these neurotransmitter systems are also related with behavioral impairment in PD.ope

메틸셀룰로오스 유도체 기반 독소루비신-시스플라틴 동시전달체의 합성 및 특성분석

학위논문 (석사)-- 서울대학교 대학원 : 농업생명과학대학 바이오시스템.소재학부(바이오소재공학전공), 2019. 2. 김태일.본 연구에서는 메틸셀룰로오스 유도체를 주사슬로 사용하여 글루탐산이 접합 된 약물전달체를 합성하고 두 가지 약물을 함께 담지 함으로써 약물 동시전달시스템으로서의 가능성을 확인하였다. 메틸셀룰로오스를 산화시켜 폴리에틸렌이민 (분자량 2000 Da)으로 그라프팅하여 일차아민을 도입한 후 폴리글루탐산을 개환중합을 통해 합성함으로서 말단에 카르복시기를 갖는 새로운 약물전달체 MCPE를 합성하였다. 약물전달체의 화학적 구조는 1H NMR과 FT-IR을 통해 확인하였다. 폴리에틸렌이민은 메틸셀룰로오스의 단위 글루코오스 9.6개 당 하나가 도입되었으며 글루탐산은 MCPEI2k 단위체 당 각각 5.3, 13.2, 44개가 도입된 것을 확인하였다. 반응시킨 글루탐산 당량에 따라 각각의 고분자를 MCPE1, MCPE2.5, MCPE5로 명명하였다. SEC를 이용해 상대분자량을 측정하였고, 산-염기 적정실험을 통해 각각의 고분자가 19.43, 20.21, 20.47%의 완충용량을 가짐을 확인하였다. 이 중 약물이 담지 된 후에도 가장 안정적인 구조를 유지하는 MCPE2.5 고분자를 이용해서 독소루비신과 시스플라틴을 담지 하였다. 독소루비신만 담지 한 복합체의 DLC (Drug loading Content)와 DLE (Drug loading Efficiency)는 4.4%와 23%로 계산되었다. 두 약물이 모두 담지 된 복합체의 경우, 독소루비신 DLC, DLE는 각각 8.7, 47.6%와 11.6, 65.6%, 시스플라틴은 복합체 단위 질량 당 (g) 0.047, 0.025 mmol의 백금이 반응한 것으로 계산되었다. 시스플라틴이 추가로 담지 되었을 때, 가교 형성을 통해 독소루비신이 빠져나오는 것을 막아주어 독소루비신의 담지 효율을 높여준 것을 알 수 있었다. 약물-고분자 복합체의 전달 효율을 높이기 위해 히알루론산 (분자량 100 kDa)과 섞어 입자를 제조하였다. 입자의 형성은 DLS를 통해 확인하였으며, 두 약물이 모두 담지 된 복합체의 경우 약 200 nm 크기의 안정적인 입자를 형성하는 것을 확인하였다. 독소루비신 방출 거동 확인을 통해 시스플라틴의 가교가 독소루비신의 급속한 방출을 억제해줌을 확인하였다. 고분자의 세포독성을 확인하기 위해 MTT 실험을 진행하였고, MCPE 고분자와 히알루론산 모두 전체 농도 범위에서 독성이 거의 없는 것을 알 수 있었다. 최종적으로 히알루론산과 복합화를 통해 제조한 복합체의 암세포사멸효과를 확인함으로써 MCPE 고분자의 약물 동시전달체로서의 가능성을 확인하였으며, 두 약물이 모두 담지 된 경우에 두 약물이 각각 담지 되었을 경우의 효과의 합보다 높은 효과를 보이는 것을 통해 두 약물의 상승효과를 확인하였다.In this study, methyl cellulose derivatives, as a backbone polymer, was conjugated with glutamic acids for doxorubicin and cisplatin delivery. After polyethyleneimine (PEI, 2000 Da) conjugation with oxidized methyl cellulose, poly(glutamic acid) (E) was further introduced to primary amine groups in PEI by ring-opening polymerization. In this way, methyl cellulose-polyethyleneimine-poly(glutamic acid) copolymer (MCPE) was synthesized and its chemical structure was confirmed by 1H NMR, FT-IR and SEC. The calculated conjugation ratio of PEI was one per 9.6 of MC glucose unit, and E was 5.3, 13.2, 44 per 1 MCPEI2k unit, respectively. Hence, MCPE polymers were named as MCPE1, MCPE2.5 and MCPE5 based on the feeding ratio of E. The DLC and DLE of a complex containing only doxorubicin were calculated as 4.4% and 23% respectively. When the cisplatin was added, DLC and DLE of doxorubicin were 8.7%, 47.6% and 11.6%, 65.6% respectively. For the cisplatin, 0.047 and 0.025 mmol of platinum were contained per drug-polymer complex unit mass (g). After the chelation of cisplatin, it was confirmed that the formation of crosslink increased the efficiency of the doxorubicin encapsulation by preventing it from escaping. Nanoparticles were manufactured by mixing with hyaluronic acid (HA) to increase the uptake efficiency of the complex into cells. The nanoparticles could form about 200 nm sized stable structure. MTT results showed that MCPE polymers and HA have lower cytotoxicity than PEI25k in almost cell lines. Finally, anticancer activity of MCPE2.5/DOX/HA, MCPE2.5/DOX/CIS/HA were verified by MTT test with various doxorubicin concentration. It was found that MCPE2.5/DOX/CIS/HA has higher anticancer activity than MCPE2.5/DOX/HA due to synergistic effect of doxorubicin and cisplatin. These results show that MCPE2.5 has a potential for drug delivery systems which can be applied to combination cancer therapy.초록 i 목차 iii List of Tables vii List of Figures viii 제 1 장 서론 1 제 2 장 문헌연구 4 2.1 다당류를 이용한 약물 전달시스템 4 2.1.1 메틸셀룰로오스 기반의 약물 전달시스템 4 2.1.2 히알루론산 기반의 약물 전달시스템 6 2.1.3 기타 다당류의 약물 전달시스템으로서의 활용 7 2.2 폴리글루탐산을 이용한 약물 전달시스템 8 2.2.1 의료용 소재로서의 폴리글루탐산의 특징 8 2.2.2 약물 전달시스템에서의 폴리글루탐산의 활용 9 2.3 병합요법을 위한 약물 동시전달시스템 11 2.3.1 병합요법을 이용한 암 치료 11 2.3.2 독소루비신과 시스플라틴의 동시전달시스템 13 제 3 장 재료 및 방법……………………… 16 3.1 재 료 16 3.2 실험방법 17 3.2.1 메틸셀룰로오스 유도체 기반 고분자의 합성 17 3.2.1.1 개환 중합을 위한 단량체의 합성 17 3.2.1.2 개환 중합을 이용한 MCPE의 합성 17 3.2.2 MCPE의 특성 분석 19 3.2.2.1 1H NMR을 이용한 구조 분석 19 3.2.2.2 FT-IR을 이용한 구조 분석 19 3.2.2.3 SEC를 이용한 분자량 측정 19 3.2.2.4 MCPE의 산-염기 적정 20 3.2.3 약물을 담지한 MCPE2.5의 제조 21 3.2.3.1 독소루비신을 담지한 MCPE2.5의 제조 21 3.2.3.2 시스플라틴을 담지한 MCPE2.5의 제조 21 3.2.3.3 독소루비신과 시스플라틴을 담지한 MCPE2.5의 제조 21 3.2.4 MCPE2.5/DOX, MCPE2.5/CIS, MCPE2.5/DOX/CIS의 특성분석 22 3.2.4.1 MCPE2.5/DOX의 독소루비신 함량 확인 22 3.2.4.2 MCPE2.5/CIS의 시스플라틴 함량 확인 23 3.2.4.3 FT-IR을 이용한 MCPE2.5/CIS의 시스플라틴 킬레이트화 확인 23 3.2.4.4 MCPE2.5/DOX/CIS의 독소루비신과 시스플라틴 함량 확인 23 3.2.5 MCPE2.5/DOX/HA와 MCPE2.5/DOX/CIS/HA 입자의 제조 24 3.2.6 MCPE2.5/DOX/HA와 MCPE2.5/DOX/CIS/HA 입자의 특성분석 24 3.2.6.1 DLS를 이용한 MCPE2.5/DOX/HA와 MCPE2.5/ DOX/CIS/HA 입자의 평균 입자 크기 및 표면전하 확인 24 3.2.6.2 MCPE2.5/DOX/HA와 MCPE2.5/DOX/CIS/HA 입자 의 독소루비신 방출 평가 25 3.2.7 MCPE2.5/DOX, MCPE2.5/CIS, MCPE2.5/DOX/CIS의 세포실험 25 3.2.7.1 세포배양 25 3.2.7.2 MCPE의 세포 대사 활성 확인 26 3.2.7.3 MTT실험을 통한 MCPE2.5/DOX/HA, MCPE2.5/ DOX/CIS/HA의 암세포사멸능력 평가 27 제 4 장 결과 및 고찰 …………………… 28 4.1 MCPE의 합성 및 특성 분석 28 4.1.1 MCPE의 합성 28 4.1.2 1H NMR을 이용한 MCPE의 구조 분석 30 4.1.3 FT-IR을 이용한 MCPE의 구조 분석 37 4.1.4 SEC를 이용한 분자량 측정 37 4.1.5 MCPE의 산-염기 적정 42 4.2 MCPE2.5/DOX, MCPE2.5/CIS, MCPE2.5/ DOX/CIS의 특성 분석 44 4.2.1 MCPE2.5/DOX의 독소루비신 함량 확인 44 4.2.2 MCPE2.5/CIS의 시스플라틴 함량 확인 45 4.2.3 MCPE2.5/CIS의 시스플라틴 킬레이트화 확인 45 4.2.4 MCPE2.5/DOX/CIS의 독소루비신과 시스플라틴 함량 확인 48 4.3 MCPE2.5/DOX/HA, MCPE2.5/DOX/CIS/HA 의 특성 분석 51 4.3.1 MCPE2.5/DOX/HA와 MCPE2.5/DOX/CIS/HA 입자의 평균 입자 크기 및 표면전하 확인 51 4.3.2 MCPE2.5/DOX/HA와 MCPE2.5/DOX/CIS/HA의 독소루 비신 방출 평가 52 4.4 MCPE2.5/DOX, MCPE2.5/DOX/CIS의 생물학 적 평가 57 4.4.1 MCPE의 세포 대사 활성 확인 57 4.4.2 MCPE2.5/DOX/HA, MCPE2.5/DOX/CIS/HA의 암세포 사멸능력 평가 60 제 5 장 결론 …………………………… 67 참고문헌 ……………………………………… 69 Abstract ……………………………………… 83Maste

Allergen-specific Immunotherapy in Patients with Atopic Dermatitis

Allergy specific immunotherapy (SIT) has been established as an effective treatment in patients with allergic asthma and rhinitis. Although its efficacy has been relatively controversial in patients with atopic dermatitis, recent controlled trials and meta-analyses have reported significant improvement in subjective symptoms in some patients with moderate-to-severe atopic dermatitis. There are a few limitations with SIT safety and patient compliance. Efforts are being made to overcome these limitations, including using recombinant allergens and adjuvants, as well as different routes of administration, such as transdermal delivery. Herein, we review the mechanism of SIT in patients with atopic dermatitis, clinical trial results, its use in clinical practice, limitations, and future direction. (Korean J Dermatol 2018;56(2):91∼98)ope

Current Status of Patient Education in the Management of Atopic Dermatitis in Korea

Patient education is important for successful management of atopic dermatitis; however, due to limited time and resources, patient education remains insufficient. This study aimed to investigate the current state of education provided by Korean dermatologists, pediatric allergists, and allergists to patients with atopic dermatitis. A questionnaire survey consisting of items regarding educational programs for patients with atopic dermatitis was conducted via e-mail. In total, 153 participants responded to the questionnaires, and 26.8% indicated that they have had separate educational programs. The workforce involved in the educational program included nurses, residents or fellows, dieticians, pharmacists, and clinical psychologists. Most education protocols addressed the characteristics and natural course of atopic dermatitis and environmental management. Overall, 96.7% of the participants replied that an additional charge is needed for education; moreover, additional assistance from an academic society or association, in the form of medical staff, organized data, and advertisement, is required to develop and provide a well-structured educational program. A standardized education protocol will effectively provide appropriate education for patients with atopic dermatitis. Arrangement of education fees, covered by the National Health Insurance Service, will lead to the establishment of a structured educational program and participation of an additional medical workforce.restrictio

[18F]-Fluorodeoxyglucose Positron Emission Tomography Can Contribute to Discriminate Patients with Poor Prognosis in Hormone Receptor-Positive Breast Cancer.

BACKGROUND: Patients with hormone receptor-positive breast cancer typically show favorable survival. However, identifying individuals at high risk of recurrence among these patients is a crucial issue. We tested the hypothesis that [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans can help predict prognosis in patients with hormone receptor-positive breast cancer. METHODS: Between April 2004 and December 2008, 305 patients with hormone receptor-positive breast cancer who underwent FGD-PET were enrolled. Patients with luminal B subtype were identified by positivity for human epidermal growth factor receptor-2 (HER2) or high Ki67 (≥14%) according to criteria recently recommended by the St. Gallen panelists. The cut-off value of SUVmax was defined using the time-dependent receiver operator characteristic curve for recurrence-free survival (RFS). RESULTS: At a median follow up of 6.23 years, continuous SUVmax was a significant prognostic factor with a hazard ratio (HR) of 1.21 (p = 0.021). The cut-off value of SUVmax was defined as 4. Patients with luminal B subtype (n = 82) or high SUVmax (n = 107) showed a reduced RFS (p = 0.031 and 0.002, respectively). In multivariate analysis for RFS, SUVmax carried independent prognostic significance (p = 0.012) whereas classification with immunohistochemical markers did not (p = 0.274). The Harell c-index was 0.729. High SUVmax was significantly associated with larger tumor size, positive nodes, HER2 positivity, high Ki67 (≥14%), high tumor grade, and luminal B subtype. CONCLUSIONS: Among patients with hormone receptor-positive breast cancer, FDG-PET can help discriminate patients at high risk of tumor relapse.ope

Centennial History of Yonsei University Dermatology in Korea: 1917 to 2017

Yonsei Dermatology celebrated its centennial in 2017, marking 100 years since Kung Sun Oh established the first Department of Dermatology and Urology in Korea in 1917. Following the footsteps of Kung Sun Oh, a pioneer of Korean dermatology, its members united and worked to provide the best medical service and achieve academic milestones in dermatology. Over the past hundred years, Yonsei Dermatology has played a pivotal role in the advancement of medical science and academia in Korea. The main activities of the department include medical care, education, and dermatologic research. Its research activities have encompassed a wide spectrum of dermatologic manifestations from skin immunology and pathology to introduction of newly developed treatment technologies. As Kung Sun Oh was the first Korean professor of dermatology at Severance Medical School and a passionate educator, we continue to serve his will by nurturing medical students and dermatology specialists to serve as global medical leaders. The Kung Sun Oh Memorial Lecture, first hosted in 1977, was the beginning of mutual international academic exchange in the field of dermatology in Korea. The memorial lecture has played a major role in advancing the academic status of Korean dermatological science by inviting distinguished dermatologists from around the world as guest lecturers. Yonsei Dermatology has played a key role in the history of modern medicine and dermatology in Korea over the last 100 years and continues to make an impact. Copyright © The Korean Dermatological Association and The Korean Society for Investigative Dermatology.ope