T1 MRI 조영제로서 마이셀 캡슐화 ESIONs의 개발 : 혈액 내 순환 연장 및 간 담즙 배설 향상

학위논문 (박사) -- 서울대학교 대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과, 2020. 8. 이동수.가돌리늄 조영제의 독성에 대한 임상적 우려로 인해, 자기 공명 영상 (MRI)을 위한 새로운 조영제의 개발에 대한 관심이 증가하고 있다. 최근, 초소형 산화철 나노 입자 (ESIONs)는 생체 적합성 T1 조영제로서 상당한 주목을 받고 있다. ESIONs는 철 산화물 나노 입자 (IONPs)를 바탕으로 한 기존의 T2 조영제의 고유한 한계를 극복할 수 있다. 하지만 현재까지 ESIONs의 생체내 동태에 대한 연구는 제한적인 상태다. 향후 ESIONs의 임상적용을 위해서는 관련 연구가 필요한 상황이다. 본 연구에서, ESIONs은 비교적 높은 r1 이완도와 낮은 r2/r1 비를 보여 효율적인 T1 조영제로서의 가능성을 확인하였다. 실험실적 안정성 시험과 생체 내 안전성 시험을 바탕으로 64Cu의 방사능은 ESIONs의 생체 내 역학을 잘 반영한다는 것이 밝혀졌다. 방사성 표지 된 ESIONs을 이용하여 생체 내 분포 및 약동학을 평가한 결과, ESIONs는 비교적 긴 시간 혈액 내 분포하였으며 간담도를 통해 빠르게 배설되는 것을 확인하였다. 또한, PET/MRI를 사용하여, PET 유래 방사능의 동적 변화 및 MRI 신호 강도를 동일한 시점에서 직접 비교 평가하였다. PET 및 MRI 신호의 불일치는 고농도 범위의 ESIONs가 투여되는 경우나 ESIONs가 세포 내로 함입되는 경우 발생함을 밝혔다. 비교적 긴 혈액 순환 시간과 간담도계를 통한 빠른 배설을 바탕으로 ESION은 혈액 풀 영상 조영제로서 높은 효율성과 안전성을 동시에 가질 것으로 기대된다. 또한, 방사능 표지 ESION은 서로의 강점과 약점을 보완함으로써 다양한 임상 상황에서 적용 가능할 것으로 기대된다.Due to clinical concerns about gadolinium toxicity, there is growing interest in the development of alternative contrast agents for magnetic resonance imaging (MRI). Recently, extremely small-sized iron oxide nanoparticles (ESIONs) are attracting considerable attention as a biocompatible T1 contrast agent, which can overcome inherent limitations of conventional T2 contrast agents based on iron oxide nanoparticles (IONPs). Still, there is a lack of studies regarding the actual fate of this novel ESIONs when administered in vivo, which is essential for further clinical translation. In this study, in vivo biodistribution and pharmacokinetics of micelle encapsulated ESIONs were demonstrated after radiolabeling. Furthermore, using simultaneous positron emission tomography (PET) /MRI, dynamic change of PET derived radioactivity and MRI signal intensity was directly compared at the same time point. Micelle encapsulated ESIONs can be an efficient T1 contrast agent with fair r1 relaxivity of 3.43 mM-1s-1 and a low r2/r1 ratio of 5.36. Radiolabeling process did not significantly affect the characteristics of the micelle encapsulated ESIONs. In vitro and in vivo stability test revealed that radioactivity of 64Cu well reflects the in vivo dynamics of micelle encapsulated ESIONs. Biphasic blood clearance was observed from the biodistribution study, showing relatively long blood circulation time of 62 min at the distribution phase and 12.8 hours at a elimination phase. As the radioactivity in the blood pool decreased, uptake in the liver increased, and after reaching a peak within 4 hours, it gradually decreased. Up to 40% of administered radiolabeled ESIONs were eliminated through the hepatobiliary system within 24 hours. Direct comparison of PET and MRI signal revealed that in vivo discordancy may occur at the high concentration range of ESIONs or when they are internalized into the intracellular space. Micelle encapsulated ESIONs, with relatively long blood circulation time and rapid excretion through the hepatobiliary system, are promising T1 contrast agent which can potentially offer both efficiency and safety. Furthermore, radiolabeled ESIONs, by complementing each others strengths and weaknesses, can be further applied to monitor the microscopic distribution in various clinical situations.Introduction 11 Purpose 17 Materials and Methods 18 Synthesis of ESIONs 18 Radiolabeling of micelle encapsulated ESIONs 18 Characterization of ESIONs 21 Stability Test 21 Animal study 22 Part 1. Biodistribution of 64Cu-ESIONs 22 Part 2. Direct comparison of PET and MRI signal in vivo 24 Part 3. Monitoring microscopic distribution of radiolabeled ESIONs in vivo 26 Transmission electron microscopy (TEM) 29 Concentration measurement 29 Results 30 pH-dependent characteristic change of ESIONs 30 Characteristics of radiolabeled ESIONs 33 Stability Test 37 Part 1. Biodistribution of 64Cu-ESIONs 39 Image-based in vivo biodistribution study 39 Ex vivo biodistribution study 42 In vivo stability 45 Part 2. Direct comparison of PET and MRI signal in vivo 49 Image-based comparison of blood pool signal 49 Phantom study of dose-dependent signal change 51 Dose-dependent difference in MRI signal in vivo 53 Image-based comparison of liver signal 55 Comparison between cell retention fraction and liver SIR 57 TEM study of cell internalization in liver 60 Part 3. Monitoring microscopic distribution of radiolabeled ESIONs in vivo. 63 Discussion 65 Conclusions 80 References 81 Abstract in Korean 99Docto

입자의 종류마다 다른 대칭성에 관한 연구

학위논문 (박사)-- 서울대학교 대학원 : 물리·천문학부(물리학전공), 2012. 8. 김형도.본 논문에서는, 표준모형으로 설명하지 못하는 입자 물리의 문제들을 다루기 위하여 다양한 대칭성, 주로 입자의 종류마다 다른 대칭성을 이용한 표준모형의 확장을 논의한다. 우선, 위계 문제에 대한 설명으로, 초대칭을 도입한다. 전약 상호작용이 깨지는 스케일의 근원을 페차이-퀸 대칭성에 의한 다음으로 최소인 표준모형의 초대칭 확장으로 이해한다. 위계 문제를 푸는 가장 간단한 경우로, 세번째 세대 짝쿼크들이 가벼운 유효초대칭을 다룬다. 유효초대칭에서의 짝쿼크 질량들은 입자의 종류다마 다른, 즉 세번째 세대에 작용하지 않는 U(1)$'$ 대칭성을 도입하여 설명한다. 이러한 입자마다 다른 대칭성은 입자들의 질량 위계와 섞임을 설명하는데 중요한 역할을 한다. 특히, 섞임 행렬은 최대 CP깨짐과 같은 고유한 특징을 반영한 기술로 이해할 수 있다. 섞임각들은 입자 종류마다 다른 대칭성으로 설명할 수 있다. $D_{12}$ 군을 이용하여 카비보각 $15^{\rm o}$, 태양섞임 $30^{\rm o}$, 대기 섞임 $45^{\rm o}$ 를 얻는다. 이들 값은 어느 정도 크기를 가지는 $\theta_{13}$ 등 최근 중성미자 실험 결과에 의하여 수정되어야 한다. 본 논문에서 다루었듯이, 입자 종류마다 다른 대칭성은 표준 모형 너머의 새로운 물리가 될 수 있다.In this thesis, we study extension of the Standard Model through various symmetries, mainly flavor dependent ones, motivated by problems in particle physics which cannot be resolved within the Standard Model framework. First, as a solution to the hierarchy problem, we observe supersymmetry. The origin of the electroweak symmetry breaking scale can be understood in the context of next-to-minimal supersymmetric Standard Model with the Peccei-Quinn symmetry. As a minimal setup for hierarchy problem, effective supersymmetry, a model with the light third generation squarks, can be considered. The spectrum in the effective supersymmetry can be realized by introducing flavor dependent U(1)$'$ gauge symmetry, under which the third generation quarks and squarks are uncharged. Such kind of flavor dependent symmetry plays a crucial role in investigating the origin of fermion mass hierarchies and mixing patterns. Moreover, mixing pattern can be understood from appropriate parameterization showing intrinsic properties, such as maximal CP violation. Mixing angles are predicted by flavor dependent discrete symmetry. Structure based on $D_{12}$ group gives Cabibbo angle $15^{\rm o}$, solar angle $30^{\rm o}$, and atmospheric angle $45^{\rm o}$. These values should be modified in accordance with the up-to-date neutrino observations, reporting sizable $\theta_{13}$. In this way, flavor dependent symmetries are expected to be good candidates for new physics beyond the Standard Model.I. Introduction 1.1 Electroweak symmetry breaking 1.2 Flavor structures of quarks and leptons II. The Standard Model of particle physics 2.1 Spontaneous breaking of electroweak gauge symmetry 2.2 Gauge anomaly and cancelation in the Standard Model 2.3 Three-flavor model with mixing III. Problems in the Standard Model 3.1 Massive Neutrinos 3.2 Gauge Hierarchy Problem 3.3 Flavor Problem 3.4 Strong CP Problem 3.5 Cosmological Problem IV. Supersymmetry as a solution of the gauge hierarchy problem 4.1 Current Status of the study on the EWSB 4.1.1 Higgs search at the LHC 4.1.2 Supersymmetry searches in the LHC 4.2 Minimal supersymmetric Standard Model 4.2.1 Model description 4.2.2 Higgs sector 4.2.3 sparticle masses 4.3 Higgs sector in the NMSSM and PQ symmetry 4.3.1 μ term from Peccei-Quinn symmetry 4.3.2 CP even Higgs mass 4.3.3 CP odd Higgs mass 4.4 Effective SUSY from flavor non-universal U(1)′ mediation 4.4.1 Supersymmetry breaking mediation mechanism 4.4.2 Effective Supersymmetry 4.4.3 Soft mass terms and sparticle spectrum 4.4.4 U(1)′ charge assignments reflecting flavor structure 4.4.5 Flavor problem in the supersymmetry V. Flavor Problem in a view of flavor dependent symmetry 5.1 Structure of the CKM matrix 5.1.1 Parameterizations of the CKM matrix 5.1.2 Jarlskog determinant 5.1.3 Interpretation of the Wolfenstein parametrization 5.2 Quark and Lepton Mixings from discrete D12 symmetry 5.2.1 Properties of dihedral group D12 and breaking pattern 5.2.2 Model for the CKM matrix 5.2.3 Double seesaw mechanism model for the PMNS matrix 5.2.4 Vacuum stability in D12 breaking 5.3 Realistic parameterizations for the PMNS matrix VI. ConclusionDocto

Tc-99m HDP 단일 광자 단층 촬영 / 컴퓨터 단층 촬영 정량화를 이용한 측두하악관절 질환 평가

학위논문 (석사)-- 서울대학교 대학원 : 의학과, 2016. 2. 이원우.Purpose: The purpose of this study was to evaluate the usefulness of a quantitative parameter (standardized uptake value [SUV]) from single-photon emission computed tomography/computed tomography (SPECT/CT) for the evaluation of temporomandibular joint disorder (TMD). Methods: Forty-four temporomandibular joints (TMJs) of 22 TMD patients (male:female, 5:17age, 30.0 ± 12.1 years) were evaluated in this study. The patients underwent conventional planar bone scintigraphy and subsequently SPECT/CT 3–4 h after injection of Tc-99m hydroxymethylene diphosphonate. Planar scintigraphy parameter (relative ratio [RR]) and SPECT/CT parameters (SUVmean and SUVmax) were compared for the visual assessment of TMD on the planar scintigraphy (normal=19, mild–moderately abnormal=18, and severely abnormal=7) and the presence of TMJ arthralgia (arthralgic=18, and non-arthralgic=26). Results: SUVmax gradually increased from normal (2.82 ± 0.73) to mild–moderately abnormal (3.56 ± 0.76, p 0.05). On the other hand, SUVmax was significantly greater in arthralgic TMJs (4.15 ± 1.11) than in non-arthralgic TMJs (2.97 ± 0.75, p = 0.0001), as was SUVmean (1.63 ± 0.42 versus 1.30 ± 0.31, respectively, p = 0.0045). However, there was no significant difference in RR (3.61 ± 0.57 versus 3.76 ± 0.68, p = 0.4497). In receiver-operating characteristic curve analyses for arthralgic TMJ, SUVmax had the greatest area-under-the-curve (0.815), followed by SUVmean (0.744), which were both significantly better than that of RR (0.514) (p = 0.0093 for SUVmax, and p = 0.0350 for SUVmean). Conclusions: SUVmax derived from bone SPECT/CT may be useful for the evaluation of TMD. Quantitative bone SPECT/CT is a promising imaging tool for the evaluation of TMD.Introduction 1 Materials and Methods 3 Patients 3 Planar bone scintigraphy 5 Quantitative bone SPECT/CT 8 Statistical analysis 9 Results 11 The quantitative parameters of RR, SUVmean, and SUVmax 11 Comparisons of the quantitative parameters according to visual grade 11 Comparisons of the quantitative parameters according to TMJ arthralgia 12 Visual assessment versus TMJ arthralgia 16 Comparisons of the quantitative parameters according to TMD subtype 18 Discussion 19 Conclusion 23 References 24 Abstract in Korean 28Maste

An Updated Meta-analysis on the Risk of Urologic Cancer in Patients with Systemic Lupus Erythematosus

Background: The risk of urologic cancers in patients with systemic lupus erythematosus (SLE) remains uncertain. We investigated the association between SLE and incident urologic cancers through a systematic review and meta-analysis. Methods: We searched the PubMed, EMBASE, and the Cochrane Library to identify articles that recorded prostate, bladder, or kidney cancers in SLE patients from inception to August 31, 2018. We included observational, case-control, or cohort studies with no language restriction. Two investigators screened and extracted the data independently. Results: Fourteen cohort studies with 83,860 SLE patients were finally analyzed. Overall, SLE patients were at increased risk of bladder cancer (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.15-3.21) but not of prostate or kidney cancer. However, subgroup analyses showed a reduced risk of prostate cancer in <10-year follow-up studies (HR, 0.68; 95% CI, 0.51-0.89) and an elevated risk of kidney cancer in patients with SLE in Western studies (HR, 2.00; 95% CI, 1.02-3.92), community-based studies (HR, 4.54; 95% CI, 2.17-9.52), prospective studies (HR, 6.84; 95% CI, 2.71-17.26), <10-year follow-up studies (HR, 1.88; 95% CI, 1.38-2.57), and low-quality studies (HR, 2.05; 95% CI, 1.50-2.80). Conclusion: This study indicates that SLE increases the risk of bladder cancer but not prostate or kidney cancer. Well-designed long-term studies are required to confirm these associations.ope

High-Dose Vitamin C Promotes Regression of Multiple Pulmonary Metastases Originating from Hepatocellular Carcinoma

We report a case of regression of multiple pulmonary metastases, which originated from hepatocellular carcinoma after treatment with intravenous administration of high-dose vitamin C. A 74-year-old woman presented to the clinic for her cancer-related symptoms such as general weakness and anorexia. After undergoing initial transarterial chemoembolization (TACE), local recurrence with multiple pulmonary metastases was found. She refused further conventional therapy, including sorafenib tosylate (Nexavar). She did receive high doses of vitamin C (70 g), which were administered into a peripheral vein twice a week for 10 months, and multiple pulmonary metastases were observed to have completely regressed. She then underwent subsequent TACE, resulting in remission of her primary hepatocellular carcinoma.ope

여러가지 post-and-core로 수복된 상악 중절치의 유한요소법적 분석

Thesis(masters) --서울대학교 대학원 :치의학과 (치과보존학전공),2009.2.Maste

Comparative study of Molybdenum Sulfide, Nitride, and Carbide supported on β-alumina for Hydrodesulfurization(HDS)

Maste

Inverse relationship between vitamin D levels and platelet indices in Korean adults

Background and aims: Vitamin D deficiency and increased platelet indices are associated with increased rate or risk of several diseases such as cardiovascular disease and metabolic syndrome, respectively. We investigated whether vitamin D deficiency is associated with increased platelet count (PC) and mean platelet volume (MPV). Methods and results: The study included 3190 subjects older than 20 years. Subjects were divided into three groups based on their vitamin D levels: vitamin D deficiency (20.0 ng/ml). The associations between platelet indices and various parameters were analyzed by Pearson's correlation analysis and t-tests. Then, multivariate linear regression analyses were done correcting for associated parameters. PC and MPV showed a negative correlation with vitamin D groups by ANOVA and multiple linear regression. PC was inversely related with vitamin D group after adjusting for sex, age, regular exercise, white blood cell count, total cholesterol, hemoglobin, and creatinine levels (β ± SE = -3.461 ± 1.512, P = 0.022). MPV was also inversely related with vitamin D group after adjusting for regular exercise, hemoglobin level, and total cholesterol level (β ± SE = -0.080 ± 0.026, P = 0.002), and this relationship remained statistically significant after adjusting for regular exercise, hemoglobin level, total cholesterol level, diabetes, hypertension, and body mass index (β ± SE=-0.082 ± 0.026, P = 0.002). Conclusion: PC and MPV are inversely associated with vitamin D levels in adults.restrictio

Stabilities and Electron Irradiation Effects on Glass Waste Forms for Immobilization of Cs+ and Sr2+ from Pyro-processing

MasterCs+ captured fly ash filter waste from pyro-processing was vitrified by glass waste form (hereinafter referred to as Cs+-glass). Carbonate Sr2+ waste including Ba2+ from pyro-processing was immobilized by glass waste form (hereinafter referred to as Sr2+-glass). 1.4MeV electrons were irradiated on the glass specimens in order to simulate the beta radiation of 137Cs and 90Sr on glass waste forms. Density, glass transition temperature (Tg), Vickers hardness and linear thermal expansion coefficient of pristine and irradiated glasses were measured. All of measured pristine and irradiated glass properties were similar to that of commercial nuclear waste glass waste forms. Chemical durability of pristine glass waste forms was estimated by product consistency test (PCT) and normalized release mass values were well below the U.S. criteria. Furthermore, electron paramagnetic resonance (EPR) and Magic angle spinning nuclear magnetic resonance (MAS NMR) were used to elucidate the existence of irradiation induced paramagnetic defect centers and structural modification of glass networks. In case of Cs+-glass, none of network formers were influenced by electron irradiation. For Sr2+-glass, only Si structure was polymerized due to electron irradiation except for B and Al structure. Work on thermal stability of a full-size canister for both glass waste forms was supported by computer simulation. As a result, the maximum temperature of glass waste forms will not go higher than glass transition temperature during an accident and preserve the glass performance

Risk of pancreatic cancer in patients with systemic lupus erythematosus: a meta-analysis

Object Accumulating evidences suggest that the incidence of several cancers is higher in systemic lupus erythematosus (SLE) than in general population. However, the finding on pancreatic cancer risk is inconsistent. This meta-analysis aimed to determine whether SLE patients are at risk for pancreatic cancer. Methods We searched PubMed, Embase, and the Cochrane database to screen the studies meeting our criteria. The hazard ratios (HRs) and its 95% confidence interval (CIs) were calculated from a meta-analysis. Results Eleven cohort studies were included in the final analysis. Overall, patients with SLE had an increased risk of pancreatic cancer (HR = 1.42, CI = 1.32-1.53). In subgroup analysis, hospital-based (HR = 1.43, CI = 1.32-1.54), retrospective (HR = 1.42, CI = 1.32-1.54), over 10 years followed (HR = 1.44, CI = 1.33-1.55), and low-quality studies (HR = 1.42, CI = 1.31-1.53) remained robust. Significant publication bias was not observed among the studies (p = 0.533). Conclusions The synthesized evidence from our meta-analysis demonstrated that SLE was associated with increased risk for pancreatic cancer. A well-designed, long-period followed study is needed to confirm this association.restrictio