다중 조파 신호 분석을 이용한 동역학 힘 현미경법

학위논문 (석사) -- 서울대학교 대학원 : 자연과학대학 물리·천문학부(물리학전공), 2021. 2. 제원호.동역학 힘 현미경은 물질 표면의 구조와 특성을 원자 및 분자 단위에서 측정하는 도구로써 응집물질 물리뿐 아니라 화학, 생물학, 재료공학 등 다양한 학문의 발전에 이바지하였다. 이러한 업적이 가능했던 이유는 동역학 힘 현미경이 마이크로미터부터 나노미터 이하의 분해능으로 국소적인 영역에서 탐침과 시료 사이에 상호작용하는 물리적인 힘을 측정할 수 있기 때문이다. 동역학 힘 현미경에서의 힘 측정은 시료와의 상호작용으로 인해 섭동된 탐침의 움직임으로부터 힘을 역산하는 힘 복원이라는 과정을 거쳐야 한다. 하지만 가장 상용되는 힘 복원 방법론은 탐침의 진동 진폭이 상호작용의 감쇠길이와 상응하게 되면 정확도가 떨어지고 복원식이 불안정해진다는 문제점이 제기되었다. 해당 진폭에서 이러한 문제점이 생기는 이유는 기존의 방법론들의 탐침의 움직임이 단순 조화 진동을 하고 있다는 가정이 힘이 급격하게 변하는 구간에서 고조파 진동이 상당해짐에 따라 깨지게 되기 때문이다. 결과적으로 모든 진폭과 탐침-시료 거리에서 유효한 일반적인 힘 복원 방법론의 필요성이 대두되었다. 이 논문에서는 다중 조파 신호 분석을 이용한 동역학 힘 현미경법을 이러한 문제점의 해결책으로 제시한다. 이 새로운 플랫폼은 보편적인 조건에서 동역학 힘 현미경의 탐침의 공명 진동수 신호뿐 아니라 고조파 진동수 신호를 고려하여 힘 복원을 한다. 이 논문은 다음 단계들을 겨쳐 다중 조파 신호 기반 현미경법을 구축한다. 우선, 동역학 힘 현미경에서 나타나는 고조파 신호를 이론적으로 탐구한다. 동역학 힘 현미경의 두 가지 작동방식인 진폭 변조와 주파수 변조에서 임의의 보존력과 비보존력을 가정할 때 생성되는 고조파 신호의 정확하고 해석적인 표현식을 구한다. 그다음으로 동역학 힘 현미경의 두 가지 작동방식을 위한 일반적인 힘 복원 방법론을 제시한다. 이 방법론은 모든 진동 진폭과 탐침-시료 거리에 대해 정확하게 힘을 복원한다. 이러한 접근 방식은 기존의 방법론에 비해 두 가지 측면에서 월등히 뛰어나다: (i) 복원식들의 근사식을 사용하더라도 더 높은 정확도와 계산속도로 힘을 복원하며 (ii) 진폭 오류에 대해 더 강인하여 기존 방법론의 힘 복원 불안정성을 극복한다. 이 연구가 향후 다방면의 동역학 힘 현미경 실험에 접목되어 단분자 검출, 원자 단위의 물리-화학적 힘 규명, 새로운 전자 전달 성질 발견 등에 응용될 것을 기대한다.The success of the dynamic force microscopy (DFM) in quantifying structures and features of material surfaces at the atomic and molecular level has led to numerous progress in condensed matter physics, chemistry, biology, and material science. Its success is based on the ability to measure the local physical forces between the DFM probe and sample with spatial resolution ranging from few micrometers to sub-nanometers. Measuring forces using DFM requires conversion of the perturbed motion of the probe due to tip-sample interactions to force-distance curves, which is called force reconstruction. However, the most widely used force reconstruction method has recently been reported to yield non-negligible error and exhibit reconstruction instabilities when the oscillation amplitude is comparable to the decay length of the interaction. The main reason for these failures at such amplitudes is that the probe oscillation is no longer simply harmonic, which conventional methods assume, as higher harmonic motions become considerable at the regime where force changes rapidly. Consequently, a novel, universal force reconstruction scheme that works in all amplitudes and the entire tip-sample distances has become crucial. This thesis resolves this issue by developing DFM based on multi-harmonic signal analysis. This platform enables versatile force reconstruction using signals not only at the resonance frequency of the DFM probe, but also at its higher harmonics. Here, the following studies are performed for formulation of this new approach. First, the higher harmonic signals in DFM are theoretically analyzed. Exact, analytic expressions for higher harmonics generated from arbitrary conservative and dissipative forces are derived for two operation modes of DFM, amplitude-modulation and frequency-modulation. Moreover, universal force reconstruction formulas, which completely recover both the conservative and dissipative forces for entire oscillation amplitudes and tip-sample distances, are derived for two operation modes of DFM. This approach provides force reconstruction scheme that outperforms the conventional methods in two ways: (i) the higher accuracy at faster computation speed even by employing an approximated form of the reconstruction formulas, and (ii) the greater robustness with respect to the oscillation-amplitude error, overcoming the reconstruction instability. This thesis is expected to be of great potential importance in the field of surface science, as it may lead to a significant improvement in DFM-based experiments, including single molecule detection, identification of physicochemical interactions, and discovery of novel electron transport properties.Abstract i List of Figures vi Chapter 1 Introduction 1 1.1 Dynamic Force Microscopy 1 1.2 Force Reconstruction in Dynamic Force Microscopy 3 1.3 Multi-harmonic Atomic Force Microscopy 4 1.4 Outline of the Thesis 5 Chapter 2 Generation of Higher Harmonics in Dynamic Force Microscopy 14 2.1 Introduction 14 2.2 Theoretical Formulation 15 2.2.1 Amplitude-Modulation MHAFM 17 2.2.2 Frequency-Modulation MHAFM 19 2.3 Simulation Results 21 2.4 Conclusion 26 Chapter 3 Force Reconstruction in Dynamic Force Microscopy using Multi-harmonic Signal Analysis 30 3.1 Introduction 30 3.2 Theoretical Formulation 31 3.2.1 Amplitude-Modulation MHAFM 31 3.2.2 Frequency-Modulation MHAFM 33 3.3 Reconstruction Results 35 3.4 Conclusion 45 Chapter 4 Conclusion 47 초록 49Maste

무질서한 비등방성계에서의 직류 전도도에 대한 다이어그램 접근법

학위논문 (석사) -- 서울대학교 대학원 : 자연과학대학 물리·천문학부(물리학전공), 2020. 8. 민홍기.Transport in disordered systems is one of central themes in condensed matter physics. For systems with an isotropic energy dispersion, various theoretical approaches, including the Boltzmann transport theory and the Kubo formula, have provided us with useful frameworks for studying transport in disordered systems. Notably, it turns out that the two approaches give the consistent correction to dc conductivity in isotropic systems. However, it has been elusive to correctly compute transport properties of systems with an arbitrarily anisotropic Fermi surface, especially by using a diagrammatic approach. Motivated by this point, this thesis is devoted to the development of a diagrammatic formalism for computing the dc conductivity of anisotropic systems. We start by developing a generalized theory of transport in the semiclassical regime (i.e. $k_{\rm F}\ell_{e}\gg 1$), in the presence of electron-impurity and electron-phonon scatterings, respectively. First, we brief on the semiclassical Boltzmann approach in anisotropic multiband systems. Next, using the Kubo formula, we study the ladder approximation in anisotropic multiband systems and derive a relation satisfied by the transport relaxation time. As a result, we verify that the two theories are generally equivalent. Then we turn to a unique transport feature in the quantum regime (i.e. $k_{\rm F}\ell_{e}\sim1$), so-called weak localization. We rewrite the Bethe-Salepter equation and derive a Cooperon ansatz, which captures the anisotropy and Berry phase of the system. Using this ansatz, we develop a systematic quantum interference theory and apply it to various phases of few-layer black phosphorus. As a result, we predict that the magnetoconductivity at the semi-Dirac transition point will exhibit a nontrivial power-law dependence on the magnetic field, while following the conventional logarithmic field dependence of two-dimensional systems in the insulator and Dirac semimetal phases. Notably, the ratio between the magnetoconductivity and Boltzmann conductivity turns out to be independent of the direction, even in strongly anisotropic systems.불순물이 있는 계에서의 전하 수송은 응집 물질 물리의 중요한 연구 주제 중 하나이다. 등방성 에너지 분산을 가지는 계에서는 볼츠만 수송 이론과 다이어그램 접근법 (diagrammatic approach) 등을 통해 전기 전도도를 계산하는 방법이 잘 구축되어 있다. 이와 달리 비등방성 에너지 분산을 가지는 계의 전기 전도도를 정확히 계산하는 것은 까다로운 문제이다. 이에 본 논문에서는 다이어그램 접근법을 이용해 비등방성계의 수송 성질을 연구하기 위한 엄밀한 계산 체계를 고안하였다. 첫째로 비등방성 다층띠를 가지는 계에서의 고전적인 수송 이론을 구축하였다. 먼저 볼츠만 수송 이론을 일반화하였고, 그 다음 사다리 다이어그램이 전기 전도도에 주는 보정을 계산하여 수송 풀림 시간 (transport relaxation time) 이 만족하는 관계식을 얻었다. 이를 통해 두 이론이 일반적으로 같은 결과를 준다는 것을 보였다. 또한 양자 영역에서의 독특한 수송 현상인 약한 국소화에 대해 연구하였다. 먼저 비등방성계에서 베테-샐피터 (Bethe-Salpeter) 방정식의 쿠페론 (Cooperon) 해를 유도하였고, 이를 이용해 다층 흑린의 여러 상 (phase) 에서 약한 국소화를 연구하였다. 그 결과, 다른 상들과 달리 반-디락 준금속 전이점 (semi-Dirac transition point) 에서 자기 전도도의 자기장 의존성이 독특한 멱법칙을 따름을 확인하였다. 또한 자기 전도도와 볼츠만 전도도의 비율이 방향 의존성을 가지지 않음을 증명하였다.1 Introduction 1 2 Semiclassical Boltzmann transport theory 5 2.1 Elastic scattering 5 2.2 Inelastic scattering 7 3 Ladder vertex corrections 9 3.1 Impurity scattering 10 3.2 Phonon scattering 14 3.3 Ward identities 19 3.4 Alternative derivations for the vertex corrections 20 3.5 Discussion 23 4 Quantum interference corrections 24 4.1 Bethe-Salpeter equation 24 4.2 Cooperon ansatz 26 5 Quantum interference effects in few-layer black phosphorus 28 5.1 Model 29 5.2 Weak localization and antilocalization 30 5.2.1 Insulator phase and SDTP 31 5.2.2 DSM phase with intranode scattering 32 5.2.3 DSM phase with internode scattering 34 5.3 Magnetoconductivity 35 5.3.1 Insulator phase 35 5.3.2 DSM phase 37 5.3.3 SDTP 38 5.4 Discussion 41 6 Conclusion 44Maste

임의의 초기 정책에 대한 선형 시스템의 데이터 기반 최적 제어 및 쿠프만 연산자를 활용한 비선형 시스템에 대한 응용

학위논문(박사) -- 서울대학교대학원 : 공과대학 기계항공공학부, 2023. 8. 김유단.A model-free off-policy reinforcement learning algorithm is proposed for solving optimal control problems for dynamic systems. The algorithm is designed to converge to not only the optimal but also stabilizing policy, which is one of the most critical concerns in designing the controller for safety-critical systems such as unmanned aerial vehicles. Unlike typical approximate dynamic programming methods, an initial stabilizing policy is not required by the proposed algorithm, which is a key advantage. In the first part of the dissertation, a data-driven surrogate Q-leaning algorithm is proposed for linear systems based on the extended Kleinman iteration that solves algebraic Riccati equation. To allow an initial unstable policy, the value function is redefined implicitly to evaluate the performance index of the unstable policy. Based on this implicit value function, an action-value function called the surrogate Q-function is proposed by augmenting virtual control dynamics in the state space to properly define values of state and control input pairs. An off-policy data-driven method called the surrogate Q-learning is then provided based on the surrogate Q-function, which enables the reuse of data obtained from an arbitrary control sources, e.g., trained human experts or fine-tuned PID controllers. The convergence of the extended Kleinman iteration to the unique positive definite solution, which yields the optimal stabilizing policy, is proven based on matrix inertia theory since the surrogate Q-learning is equivalent to the extended Kleinman iteration. The second part of the dissertation is devoted to an application of the proposed reinforcement learning algorithm to nonlinear systems. The Koopman operator theory is employed to linearize nonlinear systems in an infinite-dimensional space, called the Koopman lifting linearization. The controllability and observability of linearized systems are investigated by assuming that there exists a finite-dimensional invariant subspace of the Koopman operator spanned by a mapping called the lifting. The equivalence between two optimal control problems for the original nonlinear system and the linearized system is shown under several conditions on the lifting. To find the lifting satisfying all of the conditions, a diffeomorphic lifting approximation by coupling flow-based invertible deep neural network is employed. A meta-learning framework is proposed to train the network to approximate a common lifting for a group of systems, and therefore the mode-free surrogate Q-learning can be applied to uncertain systems. Numerical simulations using illustrative nonlinear systems with known optimal controllers are used to demonstrate the feasibility of the proposed framework, along with practical considerations and implementation details.본 논문에서는 최적제어 문제를 해결하기 위해 비모델(model-free) 강화학습 알고리듬을 제안하였다. 제어 시스템의 안정성은 제어기 설계 시 필수적으로 고려되어야 할 사항으로 본 논문에서 제안한 알고리듬은 학습되는 제어기가 최적일 뿐만 아니라 안정한 제어기로 수렴하도록 설계되었다. 기존의 근사 동적 프로그래밍 기법들과는 달리, 제안한 알고리듬은 안정한 초기 제어기를 필요로 하지 않는데, 이는 불안정한 평형점을 가지는 시스템의 비모델 학습 관점에서 주요한 장점이다. 논문의 전반부에서는 데이터만을 이용해 선형 시스템의 안정한 최적제어기를 학습할 수 있는 새로운 형태의 Q-학습 알고리듬을 제안한다. 초기 불안정한 제어 입력을 허용하기 위해 성능지수를 평가하기 위한 가치함수를 음함수 형태 재정의하고, 선형 시스템에 대해 존재성과 유일성을 보였다. 가상의 제어 동역학을 상태변수에 추가한 확장된 상태공간에서의 가치 음함수로 Q-함수를 정의하고, 이를 기반으로 하는 정책 반복법 기반의 Q-학습 알고리듬을 제안하였다. 이 알고리듬은 학습 중인 제어기로부터 데이터를 얻을 필요가 없는 off-policy 기법으로, 시스템의 숙련된 운영자나 실험적으로 설계된 PID 제어기를 통해 얻은 데이터를 사용할 수 있다는 장점이 있다. 제안한 Q-러닝 알고리듬을 이용하면 학습되는 제어기가 유한 단계 이내에 안정화 되며, 최종적으로 대수적 리카티(Riccati) 방정식의 안정한 선형 최적해로 수렴함을 행렬 관성 이론을 기반으로 증명하였다. 논문의 후반부는 제안된 강화학습 알고리즘을 비선형 시스템에 적용하는 문제를 다룬다. 이를 위해 비선형 시스템을 무한 차원 공간에서 선형화하는 쿠프만(Koopman) 연산자 이론을 활용한다. 리프팅(lifting)이라 불리는 매핑에 의해 생성되는 쿠프만 연산자의 유한 차원의 불변 부분공간이 존재한다고 가정할 때, 선형화된 시스템의 최적제어를 위해 가제어성과 가관측성을 가지기 위한 조건을 정립한다. 리프팅에 대한 여러 조건을 바탕으로 기존 비선형 시스템 최적제어 문제와 선형화된 시스템의 최적제어 문제 간의 동치성을 증명하고, 앞서 제안한 강화학습 알고리즘을 사용할 수 있는 이론적 근거를 마련한다. 모든 조건을 만족하는 리프팅을 찾기 위해 가역 심층신경망을 활용한 미분동형(diffeomorphic) 리프팅 근사법을 제안한다. 특정 시스템 그룹에 대해 공통된 리프팅이 존재한다면 그룹 내의 불확실한 시스템에 대해 제안한 비모델 강화학습을 활용할 수 있다는 점에 착안하여, 공통 리프팅을 학습하는 메타 러닝(meta learning) 프레임워크를 개발하였다. 마지막으로 이미 알려진 최적 제어기와 비선형 동역학을 갖는 비선형 시스템을 사용하여 수치 시뮬레이션을 수행하고, 제안된 프레임워크의 타당성과 구현 세부사항을 살펴보았다.1 Introduction 1 1.1 Problem Statement 1 1.2 Background, Motivation, and Necessities 3 1.3 Literature Review 6 1.3.1 Iterative Methods for Solving AREs 6 1.3.2 Model-Free Policy Iteration Methods 7 1.3.3 ADP Methods Without Initial Admissible Policies 8 1.3.4 The Koopman Operator for Control 8 1.3.5 Learning-Based Koopman Operator Applications 10 1.4 Objectives and Contributions 11 1.4.1 Objectives 11 1.4.2 Contributions 11 1.5 Dissertation Outline 15 2 Theoretical Backgrounds 17 2.1 Notation 17 2.2 Mathematical Preliminaries 18 2.2.1 The Matrix Inertia Theorem 18 2.2.2 Fréchet Derivatives 18 2.2.3 The Koopman Operator 19 2.3 Linear System Theory 22 2.3.1 Controllability and Observability 22 2.3.2 Algebraic Riccati Equations 23 2.3.3 Lyapunov Equations 25 2.4 The Kleinman Iteration 27 2.5 Meta-Learning 30 2.5.1 Optimization Problem Formulations 30 2.5.2 Closed-Form Base Learners 31 3 Data-Driven Optimal Control for Unknown Linear Systems 33 3.1 Implicit Value Functions 33 3.2 The Surrogate Q-Learning 38 3.2.1 Surrogate Q-Functions for Continuous-Time Systems 38 3.2.2 The Surrogate Q-Learning Algorithm 42 3.2.3 The Data-Driven Surrogate Q-Learning 46 3.3 The Extended Kleinman Iteration 49 3.3.1 Existence of Solutions 50 3.3.2 Selection of Design Parameters 52 3.4 Convergence Analysis 54 3.4.1 Monotonic Stabilization 54 3.4.2 Local Convergence 56 3.4.3 Global Convergence 59 3.5 Illustrative Numerical Examples 65 3.5.1 Validation of the Extended Kleinman Iteration 65 3.5.2 Validation of the Data-Driven Surrogate Q-Learning 66 4 Application to Nonlinear Optimal Control Problems 73 4.1 NonlinearOptimalControlProblems 74 4.2 Koopman Operators for Optimal Control Problems 76 4.2.1 Koopman Lifting Linearization 76 4.2.2 Equilibrium Points 78 4.2.3 Lifted Optimal Control Problems 79 4.3 The Meta-Learning Framework 85 4.3.1 Koopman Groups and Common Liftings 85 4.3.2 Diffeomorphic Lifting Approximation 86 4.3.3 Base Learner Formulation 89 4.3.4 Meta-Learner Formulation 91 4.3.5 Offline and Online Learning Synthesis 93 5 Numerical Simulation 95 5.1 Koopman Group of Nonlinear Systems 95 5.2 The Meta-Learning Stage 98 5.2.1 Meta-Learning Setups 98 5.2.2 Meta-Learning Results 99 5.3 The Surrogate Q-Learning Stage 105 5.3.1 Surrogate Q-Learning Setups 105 5.3.2 Surrogate Q-Learning Results 106 6 Conclusion 113 6.1 Concluding Remarks 113 6.2 Direction for Further Research 115 Bibliography 117 Appendix A The Glow Implementation 131 A.1 Flows 131 A.1.1 ActivationLayers 131 A.1.2 1×1 Convolution Layers 133 A.1.3 Affine Coupling Layers 134 국문초록 135박

고양이 동맥혈전색전증에 적용한 Tissue Plasminogen Activator와 Rivaroxaban의 효과와 치료결과

학위논문(석사) -- 서울대학교대학원 : 수의과대학 수의학과, 2023. 2. Inhyung Lee.Thrombolytic therapy is beneficial for reestablishing arterial blood flow, but its use is restricted because of its side effects, including hemorrhagic complications and reperfusion injuries. This study aimed to report the outcomes of acute feline arterial thromboembolism (ATE) treated with tissue plasminogen activator (tPA) and the factor Xa inhibitor, rivaroxaban (RVX). This retrospective observational study recruited 16 cats with feline ATE treated between July 2017 and July 2021 from a referral animal hospital in South Korea. Seven and nine cats were treated with dual (tPA + RVX) therapy and only RVX therapy, respectively. Medical records were reviewed for evidence of adverse events—hemorrhagic complications, hyperkalemia, and reperfusion injury—and clinical conditions at admission. The primary outcome was survival to discharge, and the principal safety outcome was major bleeding. The day to complete ATE resolution, which was confirmed via vascular ultrasound, was 7.3 ± 4.5 days in the dual therapy group. In all 16 cats, three cats and four cats in the dual therapy group and RVX group, respectively, experienced bleeding complications. The median survival time for all cats was 29 days (range 1–1574 days), 386 days (range 42–1574 days) in dual therapy group, and 5 days (range 1–344 days) in RVX group. The recurrence rate of ATE while on therapy was 6.2%, in which this cat did not receive consistent medication, and the time to recurrence was 379 days. In conclusion, dual therapy with tPA and rivaroxaban resulted in increased survival rates than conservative therapy for acute feline ATE.고양이 동맥혈전색전증에서 혈전용해치료법은 동맥 혈류의 재관류에 도움을 주어 임상증상을 개선시킨다. 하지만 혈전용해치료법에 따르는 출혈 및 재관류 손상의 생명을 위협하는 부작용으로 인해 사용이 제한되고 있다. 본 연구는 고양이 동맥혈전색전증에서 tissue plasminogen activator (tPA)와 rivaroxaban을 적용하여 치료한 결과를 보고하고자 실시하였다. 본 연구는 2017년 7월부터 2021년 7월까지 이차진료 동물병원에서 고양이 동맥혈전색전증 치료를 받은 16마리의 고양이를 대상으로 실시하였다. 16마리의 고양이 중에서 7마리는 dual 요법(tPA + rivaroxaban)으로 치료하였으며, 9마리는 rivaroxaban 단독요법으로 치료하였다. 진료 기록은 응급 내원 당시의 임상 증상과 치료 중에 발생하는 출혈성 합병증, 고칼륨혈증, 재관류 손상과 같은 부작용을 확인하기 위해 검토되었다. 치료의 주요한 목표는 생존하여 퇴원하는 것이었다. Dual 요법군에서 혈전용해제 (tPA) 투여 후 혈관 초음파를 통해 확인된 동맥혈전색전의 완전 소실 확인기간(일)은 7.3 ± 4.5 로 확인됐다. Dual 요법군과 rivaroxaban 단독요법군에 속한 고양이 3마리 (42%)와 4마리 (44%)에서 출혈성 합병증이 나타났다. 모든 고양이의 평균 생존 기간의 중앙값은 29일이었으며, Dual 요법군과 rivaroxaban 단독요법군에서 평균 생존 기간의 중앙값은 각각 386일과 5일이었다. 치료 중 동맥혈전색전증의 재발률은 6.2% 이었다. 해당 고양이는 경구약물치료를 중단한 이후 동맥혈전색전증이 재발한 것이었으며, 중단일로부터 재발까지의 기간은 379일이었다. 본 연구 결과를 통해 고양이 동맥혈전색전증에 tPA와 rivaroxaban을 함께 적용한 dual 요법의 치료가 혈전용해제를 사용하지 않는 기존의 치료 요법보다 생존율을 증가시키는 것을 확인했다.Introduction 1 Materials and Methods 4 Statistical Methods 7 Results 9 1. Study population and characteristics 9 2. Adverse events 11 3. Clinical outcomes 11 4. Table 1 13 5. Table 2 14 6. Table 3 15 7. Figure 1 16 8. Figure 2 17 Discussion 18 Conclusions 24 References 25 Abstract in Korean 31석

실험적으로 유도된 염증 및 암화 모델에서 17-oxo-docosahexaenoic acid 및 taurine chloramine의 보호 효과 및 기전 연구

학위논문(박사) -- 서울대학교대학원 : 약학대학 약학과, 2023. 2. 서영준.Taurine chloramine (TauCl)은 육류, 생선, 계란 및 우유를 포함한 일부 식품에서 발견되는, 준필수 황 함유 β-아미노산인 Taurine에서 대사된 내인성 항염증 물질이다. 일반적으로 TauCl과 Taurine은 다양한 유형의 세포에서 조직 손상에 의해 유발되는 염증 매개체의 생성을 감소시킨다. 본 논문연구에서 실험적으로 유도된 대장염에 대한 TauCl의 보호 효과를 확인하였다. 2,4,6-Trinitrobenzene sulfonic acid (TNBS)에 의해 유도된 대장염증은 TauCl의 경구 투여에 의해 경감되었다. 또한 TauCl의 투여는 TNBS로 유도된 마우스의 대장 점막에서 세포자멸사를 감소시켰다. 이는 necrosis factor-α, interleukin-6 와 cyclooxygenase-2 (COX-2)를 포함하는 염증성 인자와 4-hydroxy-2-nonenal (4-HNE)을 포함하는 산화적 스트레스 인자의 억제를 통해 확인되었다. TauCl은 또한 염증 신호전달을 매개하는 두 가지 주요 전사 인자인 nuclear factor kappa light chain enhancer of activated B cells (NFκB) 및 signal transducer and activator of transcription 3 (STAT3)의 활성화를 억제하였다. 특히, TNBS로 유도된 마우스의 대장에서 산화적 스트레스 및 염증에 대한 TauCl의 보호 효과는 nuclear factor erythroid 2-related factor 2 (Nrf2)의 높은 활성화 및 heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase (NQO1)과 같은 표적 유전자의 발현 량 증가와 관련이 있음을 관찰할 수 있었다. 이러한 결과는 TauCl이 Nrf2에 의해 유도되는 항산화 유전자 발현의 상향조절을 통해 대장염에 대한 보호효과를 보임과 동시에, NFκB와 STAT3에 의해 매개되는 염증성 신호를 억제함을 나타낸다. 태양광, 특히 자외선에 대한 과도한 노출은 광노화를 일으키며 피부염 및 피부암 발생의 주요 원인이다. 본 연구는 광손상으로부터 피부를 효과적으로 보호할 수 있는 후보 물질을 찾기 위해 염증 조직으로 집중된 대식세포의 Taurine으로부터 생성되는 TauCl을 사용하여 수행되었다. 180 mJ/cm2 강도의 Ultraviolet B (UVB) 조사는 마우스 표피에서 산화적 손상과 세포 사멸을 유발하였다. TUNEL-양성 표피 세포의 감소 및 세포사멸 억제 단백질인 Bcl-xL의 발현량 증가, cleaved caspase-3의 감소 및 4-HNE의 억제에 의해 입증된 바와 같이 이러한 피부염증은 국소 도포 처리된 TauCl에 의해 경감됨을 확인하였다. 또한 두 가지 주요 염증 효소인 COX-2와 inducible nitric oxide synthase (iNOS)의 발현은 TauCl 처리된 마우스에서 유의하게 낮음을 확인하였고, 염증성 사이토카인 (Tnf, Il6, Il1b, Il10)의 전사 또한 유사한 경향성을 나타내는 것을 확인하였다. 또한 TauCl의 항염증 효과는 STAT3의 활성화 억제 및 Nrf2의 활성화를 통한 HO-1, NQO1과 같은 항산화 효소의 유도 와도 관련 있음을 확인하였다. 이러한 연구 결과들을 통해 대장염 및 피부염에 대한 TauCl의 화학적 암예방효과는 염증을 매개하는 표적 단백질들의 활성화를 경감시킴과 동시에 활성산소종의 제거와 관련된 항산화 단백질들의 증가된 발현을 통해 매개된다고 할 수 있다. 급성 염증은 조직 복구와 항상성 회복을 위한 자기 한정적 과정이다. 급성 염증이 적절하게 해소되지 않으면 염증 반응이 지속되어 천식, 관절염, 동맥경화증, 심지어 암 과도 같은 여러 만성 질환을 유발할 수 있다. 세포자연사는 조직의 염증 해소 단계에서 관찰되는 세포예정사의 가장 중요한 과정이다. 죽거나 죽어가는 세포의 축적은 지속적인 염증 반응을 일으키거나 악화시키기 때문에 세포 사멸 세포의 제거는 염증 조절에 필수적인 역할을 한다. 포식작용은 대식세포의 식세포 작용에 의해 죽거나 죽어가는 세포가 제거되는 과정이다. CD36을 포함한 다양한 식세포 수용체는 식균 작용을 하는 것으로 여겨지는 세포를 인식함으로써 이 과정에 관여한다. 포식작용은 염증의 해소에 기여함으로써 2차 괴사, 염증의 심화, 그리고 만성 염증을 예방하는데 필수적인 역할을 한다. 외부 및 내부 염증 자극에 반응하여 항상성을 유지하는 가장 중요한 관문이자 기관으로서 피부의 중요성은 아무리 강조해도 지나치지 않는다. 표피에서 급성 염증의 해소가 제대로 이루어지지 않으면 염증의 중증도를 악화시킬 수 있다. Docosahexaenoic acid (DHA)는 오메가3 불포화지방산 중 하나로, 대사과정을 거쳐 생물학적으로 활성화된 친전자성 대사체를 생성한다. 그 대사체중 하나인, 17-oxo-DHA는 활성화된 대식세포에서 COX-2와 탈수소효소에 의해 DHA로부터 생성된다. STAT3는 UVB로 유도된 피부염증 및 피부암 발생에서 중요한 역할을 한다. STAT3의 활성화에 필수적인 Tyr705의 인산화는 17-oxo-DHA로 처리된 무모 마우스에서 유의하게 감소하였다. 또한 UVB 조사로 인해 유도된 세포 사멸의 발생은 17-oxo-DHA의 국소 도포로 인해 경감되었으며 이는 TUNEL-양성 세포의 비율 감소로 입증하였다. 17-oxo-DHA의 처리는 또한 산화적 스트레스의 지표 단백질 발현을 감소시켰고, Nrf2의 발현과 관련 항염증 및 항산화 단백질 발현을 증가시켜 염증성 사이토카인 생성을 약화시키고, 염증의 해소를 가속화하였다. 포식작용은 대식세포의 식균활동에 의해 수행되는 염증의 해소에 중추적인 역할을 한다. 이 실험에서 17-oxo-DHA에 의한 골수 유래 대식세포의 포식작용 능력의 변화를 관찰하였고, 그 결과 17-oxo-DHA의 처리에 의해 골수 유래 대식세포의 포식작용이 증가함을 확인하였다. 또한 이 결과는 스캐빈저 수용체인 CD36 및 Nrf2의 발현량의 증가와 관련 있음을 Nrf2 knockout 마우스들을 통해 확인할 수 있었다. 결론적으로, 17-oxo-DHA의 도포는 산화적 스트레스를 억제하고 대식세포의 포식작용 능력을 강화하여 염증의 해소 단계를 활성화시켜 UVB에 의해 유도된 피부염 및 피부암으로부터 보호효과를 나타내었고, 이러한 효과는 Nrf2의 활성화와 그에 따른 항산화 단백질 발현의 증가를 통해 확인되었다. 따라서 17-oxo-DHA는 UVB로 인한 피부 손상을 해결할 수 있는 치료제로서의 가능성이 있음을 시사한다.Taurine protects tissues from oxidative damage and inflammation through up-regulation of anti-oxidant and anti-inflammatory gene expression and accelerates the biological and structural repair of damaged tissues. During the oxidative burst, hydrogen peroxide (H2O2) is produced, which is converted to highly reactive hypochlorous acid (HOCl) by the myeloperoxidase activity of the activated neutrophils in the presence of chloride ion. HOCl has bactericidal activity, but at the site of acute inflammation, but it can also be detrimental to host. At the inflamed site, taurine reacts with residual HOCl, resulting in the formation of taurine chloramine (TauCl). From previous studies, TauCl is known to inhibit the production of pro-inflammatory mediators of tissue damage, such as chemokines and cytokines in various cells and tissues. In this study, I investigated the protective effect of TauCl against colitis caused by 2,4,6-trinitrobenzene sulfonic acid (TNBS). TauCl administration attenuated oxidative stress as assessed by 4-hydroxy-2-nonenal (4-HNE) production and expression/production of pro-inflammatory factors such as tumor necrosis factor-α, interleukin- 6, and cyclooxygenase-2 (COX-2). TauCl also inhibited the activation of two key transcription factors, NFB and STAT3 mediating pro-inflammatory signaling. Specifically, the protective effects of TauCl against oxidative stress and inflammation in the colon of TNBS-treated mice were associated with increased activation of Nrf2 and upregulation of its target genes and proteins. To further elucidate the protective role of TauCl under inflammatory conditions, an experimentally induced murine dermatitis model was employed. Excessive exposure to solar radiation, especially ultraviolet rays, causes extensive photodamage, a major cause of dermatitis and skin cancer. Upon irradiation of ultraviolet B (UVB) at an intensity of 180 mJ/cm2 induced oxidative damage and cell death in the epidermis of mice. These symptoms were alleviated through the topical application of TauCl. In addition, the UVB-induced expression of pro-inflammatory cytokines was lower in the skin of TauCl treated mice than that of the vehicle-treated control group. The anti-inflammatory effects of TauCl are related to the inhibition of STAT3 signaling with concomitant activation of Nrf2 and induction of antioxidant enzymes such as heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Taken together, these results suggest that TauCl exerts protective effects against colitis and dermatitis through the upregulation of Nrf2-dependent cytoprotective gene expression while downregulation of proinflammatory signaling mediated by NFκB and STAT3. Docosahexaenoic acid (DHA) is one of the prototype omega-3 (ω-3) polyunsaturated fatty acids and has been reported to inhibit inflammatory and carcinogenic processes. 17-Oxo-DHA is an electrophilic fatty acid metabolite, produced from DHA via a series of steps involving COX-2 and dehydrogenase in activated macrophages. 17-Oxo-DHA was found to play an important role in UVB-induced dermatitis and photocarcinogenesis. In the present study, it was confirmed that UVB-induced phosphorylation of Tyr705, which is essential for the activation of STAT3, was inhibited by topically applied 17-oxo-DHA in mouse skin in vivo. Topical application of 17-oxo-DHA reduced the expression of oxidative stress markers in UVB-irradiated mouse skin. These protective effects were associated with the inhibition of inflammatory cytokines and acceleration of the resolution of inflammation through activation of Nrf2 and concurrent upregulation of anti-inflammatory and antioxidant proteins. Macrophages play an essential role in the resolution of inflammation by exerting the phagocytic activity. Treatment with 17-oxo-DHA enhanced the engulfment of dead epidermal cells by macrophages. These effects were attributable to increased expression of the scavenger receptor, CD36 induced by Nrf2. In conclusion, 17-oxo-DHA inhibits oxidative stress and inflammation as well as enhances the efferocytosis activity of macrophages to accelerate the resolution phase. These effects were associated with elevated expression of antioxidant and anti-inflammatory/proresolving proteins via the activation of the Nrf2 signal pathway. Thus, 17-oxo-DHA is an endogenous molecule with the potential as a therapeutic agent to alleviate inflammatory symptoms.Chapter I. Taurine Chlroramine and 17-Oxo-Docosahexaenoic Acid as Novel Endogenous Proresolving and Anti-inflammatory Substances with Chemopreventive Potential 1 1. Introduction 2 2. NF-κB and STAT3 as two representative proinflammatory signaling molecules 4 3. Taurine chloramine 6 4. 17-Oxo-docosahexaenoic acid (17-Oxo-DHA) 8 5. Regulation of the Nrf2 signaling pathway by taurine chloramine and 17-oxo-DHA 9 6. References 14 Statement of Purpose 21 Chapter Ⅱ. Protective Effects of Taurine Chloramine on Experimentally Induced Colitis: NFκB, STAT3, and Nrf2 as Potential Targets 22 1. Abstract 23 2. Introduction 25 3. Materials and Methods 28 4. Results 36 5. Discussion 52 6. References 56 Chapter Ⅲ. Topically Applied Taurine Chloramine Protects Against UVB-induced Oxidative Stress and Inflammation in Mouse Skin 60 1. Abstract 61 2. Introduction 63 3. Materials and Methods 65 4. Results 73 5. Discussion 86 6. References 90 Chapter Ⅳ. Protective Effects of an Electrophilic Metabolite of Docosahexaenoic Acid on UVB-induced Oxidative Cell Death, Dermatitis, and Carcinogenesis 99 1. Abstract 100 2. Introduction 102 3. Materials and Methods 105 4. Results 117 5. Discussion 152 6. References 157 Conclusion 166 Abstract in Korean 167박

The institutional learning curve is associated with survival outcomes of robotic radical hysterectomy for early-stage cervical cancer-a retrospective study

BACKGROUND: Despite recent advances in diagnosis and treatment, cervical cancer continues to be a significant health problem worldwide. Whereas robot-assisted surgery has advantages over the abdominal approach, and minimally invasive techniques are being used increasingly, these may be associated with a higher recurrence rate and lower overall survival than the abdominal approach. The objective of this study was to compare the surgical and survival outcomes between abdominal radical hysterectomy (ARH) and robotic radical hysterectomy (RRH). METHODS: A retrospective cohort of patients undergoing radical hysterectomy for cervical cancer from 2006 to 2018 was identified. Patients with stage IA to IB cervical cancer were included and grouped: ARH vs. RRH. The RRH group was further divided into two groups based on the year of enrollment: RRH1 (2006-2012) and RRH2 (2013-2018). Tumor characteristics, recurrence rate, progression-free survival (PFS), and overall survival (OS) were compared between the groups. P-values < 0.05 (two-sided) were considered statistically significant. RESULTS: A total of 310 patients were identified: 142 and 168 underwent ARH and RRH, respectively. RRH1 and RRH2 had 77 and 91 patients, respectively. Interestingly, RRH2 was more likely to have a larger tumor size (1.7 ± 1.4 vs. 2.0 ± 1.1 vs. 2.4 ± 1.7 cm, P = 0.014) and higher stage (P < 0.001) than RRH1. However, RRH2 showed significantly favorable PFS in contrast to RRH1. There was no difference between ARH and RRH2 in PFS (P = 0.629), whereas overall, the RRH group showed significantly shorter PFS than the ARH group. In the multivariate analysis, the institutional learning curve represented by the operation year was one of the significant predictors for PFS (hazard ratio [HR] 0.065, P = 0.0162), along with tumor size (HR 5.651, P = 0.0241). CONCLUSIONS: The institutional learning curve, represented by the operation year, is one of the most significant factors associated with outcomes of RRH for early-stage cervical cancer.ope

Mutation landscape of germline and somatic BRCA1/2 in patients with high-grade serous ovarian cancer

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors targeting BRCA1/2 mutations are available for treating patients with high-grade serous ovarian cancer. These treatments may be more appropriately directed to patients who might respond if the tumor tissue is additionally tested by next-generation sequencing with a multi-gene panel and Sanger sequencing of a blood sample. In this study, we compared the results obtained using the next-generation sequencing multi-gene panel to a known germline BRCA1/2 mutational state determined by conventional Sanger sequencing to evaluate the landscape of somatic mutations in high-grade serous ovarian cancer tumors. METHODS: Cancer tissue from 98 patients with high-grade serous ovarian cancer who underwent Sanger sequencing for germline BRCA1/2 analysis were consecutively analyzed for somatic mutations using a next-generation sequencing 170-gene panel. RESULTS: Twenty-four patients (24.5%) showed overall BRCA1/2 mutations. Seven patients (7.1%) contained only somatic BRCA1/2 mutations with wild-type germline BRCA1/2, indicating acquired mutation of BRCA1/2. Three patients (3.1%) showed reversion of germline BRCA1 mutations. Among the 14 patients (14.3%) with both germline and somatic mutations in BRCA1/2, two patients showed different variations of BRCA1/2 mutations. The next-generation sequencing panel test for somatic mutation detected other pathogenic variations including RAD51D and ARID1A, which are possible targets of poly (ADP-ribose) polymerase inhibitors. Compared to conventional Sanger sequencing alone, next-generation sequencing-based tissue analysis increased the number of candidates for poly (ADP-ribose) polymerase inhibitor treatment from 17.3% (17/98) to 26.5% (26/98). CONCLUSIONS: Somatic mutation analysis by next-generation sequencing, in addition to germline BRCA1/2 mutation analysis, should become the standard of care for managing women with high-grade serous ovarian cancer to widen the indication of poly (ADP-ribose) polymerase inhibitors.ope

Establishment of a novel malignant Brenner tumer cell Line

Objective: Ovarian cancer is the most lethal disease among gynecologic malignancies. Although many efforts have been made to explore the mechanisms involved in its development, the genetic events in the pathogenesis of ovarian cancer are still unclear. We characterized a cell line (designated OHK) established from a malignant Brenner tumor cell. Methods: The cells were obtained during the operation of a 43-year-old Korean woman with ovarian cancer. The OHK cells continuously propagated in vitro over a period of about 36 months and, to date, have undergone over 200 passages, without being infected by either Mycoplasma or any bacteria. We measured the doubling time of OHK cells. To investigate the tumorigenecity of OHK, cells were inoculated subcutaneously into the back of nude mice. Several tumor markers were analyzed using culture media and lysates of cytosol. Morphology and ultrastructure were analyzed by phase-contrast microscopy and electron microscopy. OHK was also analyzed for gene mutation, the typing of human leukocyte antigen and Flow cytometric cell cycle analysis and DNA index. Results: They proliferated in a monolayered sheet showing a pavement-like arrangement without suppression by intercellular contacts. They also formed epithelial cell lining in shapes of polymorphism and polygons. Doubling time was 38.4 hour which was relatively slow compared to other cancer cells. Microscopic view revealed intranuclear infoldings which are typical in malignant Brenner tumors. The OHK cells secreted significantly high level of CA 125 into the culture medium. A 215th codon at exon 4 of p53 was mutated to C/C in OHK. BRCA 1 was a wild type and polymorphisms were detected in exons 2, 10, 11, 14 and 17 of BRCA 2. The cells showed aneuploidy with DNA index of 1.589 measured by flow cytometry. When transplanted into nude mice, OHK cells successfully induced tumor which was histopathologically resembled malignant Brenner tumor. Conclusion: These results strongly suggest that OHK is a typical cell line of malignant Brenner tumor. This may provide a useful cellular resource for studying the pathogenesis of malignant Brenner tumor.ope

Six months response rate of combined oral medroxyprogesterone/levonorgestrel-intrauterine system for early-stage endometrial cancer in young women: a Korean Gynecologic-Oncology Group Study

OBJECTIVE: To evaluate the efficacy of combined oral medroxyprogesterone acetate (MPA)/levonorgestrel-intrauterine system (LNG-IUS) treatment and to compare the diagnostic accuracy of endometrial aspiration biopsy with dilatation & curettage (D&C) in young women with early-stage endometrial cancer (EC) who wished to preserve their fertility. METHODS: A prospective phase II multicenter study was conducted from January 2012 to January 2017. Patients with grade 1 endometrioid adenocarcinoma confined to the endometrium were treated with combined oral MPA (500 mg/day)/LNG-IUS. At 3 and 6 months of treatment, the histologic change of the endometrial tissue was assessed. The regression rate at 6 months treatment and the consistency of the histologic results between the aspiration biopsy and the D&C were evaluated. RESULTS: Forty-four patients were enrolled. Nine voluntarily withdrew and 35 patients completed the protocol treatment. The complete regression (CR) rate at 6 months was 37.1% (13/35). Partial response was shown in 25.7% of cases (9/35). There were no cases of progressive disease and no treatment-related complications. A comparison of the pathologic results from aspiration biopsy and D&C was carried out for 33 cases. Fifteen cases were diagnosed as "EC" by D&C. Among these, only 8 were diagnosed with EC from aspiration biopsy, yielding a diagnostic concordance of 53.3% (κ=0.55). CONCLUSION: Combined oral MPA/LNG-IUS treatment for EC showed 37.1% of CR rate at 6 months. Considering the short treatment periods, CR rate may be much higher if the treatment continued to 9 or 12 months. So, this treatment is still a viable treatment option for young women of early-stage EC. Endometrial aspiration biopsy with the LNG-IUS in place is less accurate than D&C for follow-up evaluation of patients undergoing this treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01594879.ope

Risk prediction for late-stage ovarian cancer by meta-analysis of 1525 patient samples.

BACKGROUND: Ovarian cancer causes more than 15000 deaths per year in the United States. The survival of patients is quite heterogeneous, and accurate prognostic tools would help with the clinical management of these patients. METHODS: We developed and validated two gene expression signatures, the first for predicting survival in advanced-stage, serous ovarian cancer and the second for predicting debulking status. We integrated 13 publicly available datasets totaling 1525 subjects. We trained prediction models using a meta-analysis variation on the compound covariable method, tested models by a "leave-one-dataset-out" procedure, and validated models in additional independent datasets. Selected genes from the debulking signature were validated by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in two further independent cohorts of 179 and 78 patients, respectively. All statistical tests were two-sided. RESULTS: The survival signature stratified patients into high- and low-risk groups (hazard ratio = 2.19; 95% confidence interval [CI] = 1.84 to 2.61) statistically significantly better than the TCGA signature (P = .04). POSTN, CXCL14, FAP, NUAK1, PTCH1, and TGFBR2 were validated by qRT-PCR (P < .05) and POSTN, CXCL14, and phosphorylated Smad2/3 were validated by immunohistochemistry (P < .001) as independent predictors of debulking status. The sum of immunohistochemistry intensities for these three proteins provided a tool that classified 92.8% of samples correctly in high- and low-risk groups for suboptimal debulking (area under the curve = 0.89; 95% CI = 0.84 to 0.93). CONCLUSIONS: Our survival signature provides the most accurate and validated prognostic model for early- and advanced-stage high-grade, serous ovarian cancer. The debulking signature accurately predicts the outcome of cytoreductive surgery, potentially allowing for stratification of patients for primary vs secondary cytoreduction.ope