Doctor of Philosophy

dissertationVisualization and exploration of volumetric datasets has been an active area of research for over two decades. During this period, volumetric datasets used by domain users have evolved from univariate to multivariate. The volume datasets are typically explored and classified via transfer function design and visualized using direct volume rendering. To improve classification results and to enable the exploration of multivariate volume datasets, multivariate transfer functions emerge. In this dissertation, we describe our research on multivariate transfer function design. To improve the classification of univariate volumes, various one-dimensional (1D) or two-dimensional (2D) transfer function spaces have been proposed; however, these methods work on only some datasets. We propose a novel transfer function method that provides better classifications by combining different transfer function spaces. Methods have been proposed for exploring multivariate simulations; however, these approaches are not suitable for complex real-world datasets and may be unintuitive for domain users. To this end, we propose a method based on user-selected samples in the spatial domain to make complex multivariate volume data visualization more accessible for domain users. However, this method still requires users to fine-tune transfer functions in parameter space transfer function widgets, which may not be familiar to them. We therefore propose GuideME, a novel slice-guided semiautomatic multivariate volume exploration approach. GuideME provides the user, an easy-to-use, slice-based user interface that suggests the feature boundaries and allows the user to select features via click and drag, and then an optimal transfer function is automatically generated by optimizing a response function. Throughout the exploration process, the user does not need to interact with the parameter views at all. Finally, real-world multivariate volume datasets are also usually of large size, which is larger than the GPU memory and even the main memory of standard work stations. We propose a ray-guided out-of-core, interactive volume rendering and efficient query method to support large and complex multivariate volumes on standard work stations

99mTc-MSA와 염료 접합체를 사용한 감시림프절 맵핑용 다중모드영상제의 개발

학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2019. 2. 정재민.Purpose: Sentinel lymph node (SLN) is the first regional lymph node (LN) existing nearest to the primary tumor. The detection of SLN in breast cancer and melanoma patients is important to evaluate tumor staging or to establish therapeutic decision-making. Blue dyes, radiotracers, combination of a radiotracer and blue dye method and radiolabeled blue dyes have been clinically used for SLN detection. However, these methods still have some limitations. Here, the aim for this study was to develop a SLN mapping agent using 99mTc-labeled mannosylated human serum albumin (MSA) and dyes. Various dyes were tested by in vitro experiments such as binding efficiency with MSA, size exclusion liquid chromatography with HPLC and fluorescent screening. The selected dye, naphthol blue black (NBB) which showed the highest binding efficiency with MSA, was tested regarding its ability for SLN mapping by visual investigation, fluorescence imaging, and single photon emission computed tomography (SPECT)/computed tomography (CT). Methods: Visible screening was performed using 8 different dyes. Each 1 mM dye solution was prepared by dissolving 1 μmol of dye in 1 mL of distilled water (DW) and the solution was serially diluted from 0.25 to 0.001 mM with DW. The color of the prepared solutions was compared by visual inspection. To determine values of MSA-dye conjugates, UV-VIS-NIR spectrum assay was conducted and optical density (OD) was measured by Varioskan Flash screening mode at 350-850 nm. Binding efficiencies between MSA and various dyes were measured by thin-layer chromatography at 10, 30 min, 1, 2, 6, and 24 h after incubation. TLC plates were scanned by Fujifilm LAS 3000 and the spots were quantified by multi-gauge 3.0. HPLC was used to distinguish the size between before and after dye and MSA conjugation. Fluorescence imaging was performed at 420-780 nm excitation and 520-845 nm emission to find out the wavelength band which exhibits strong fluorescence for MSA-dye conjugates. To evaluate the ability of MSA-NBB conjugate for SLN mapping, MSA-NBB conjugate or only NBB was injected to a same male BALB/c mice and visible and fluorescence images were obtained at 10, 30 min, 1, and 2 h post-injection. For SPECT/CT imaging, MSA-NBB conjugate was labeled with 99mTc and the conjugate complex was subcutaneously injected into the left footpad of the mouse. SPECT/CT images were obtained at 10, 30 min, 1, and 2 h after injection. Results: All dyes that were used in visible screening showed a clear color at 0.25 mM. As dilution, some dyes were difficult to identify color of the solution and NBB, PBVF, NY, BR and EB showed most visible at low concentration at 0.004 mM. In order to compare each of MSA-dye conjugates by a quantified value, values were calculated by Beer-Lambert Law using OD values at peak wavelength. MSA-PBVF conjugate demonstrated the highest value of 141,481 M−1·cm−1, followed by MSA-EB conjugate (99259.3), MSA-ICG conjugate (87037.0) and MSA-NBB conjugate (62222.2). Size exclusion HPLC confirmed that MSA-dye conjugates was formed as a monomer. All the prepared MSA-dye conjugates was stable for 24 h and no other aggregates were found in the chromatogram. TLC results showed that binding efficiencies of all dyes were increased depending on the concentration of MSA and the reaction time. Especially, NBB had the highest binding affinity with MSA among all the tested dyes requiring the least amount of MSA (2.5 mg) and the short reaction time (10 min). Binding ratio was calculated that 0.7 of NBB was bound with 1.0 of MSA. Based on these results, NBB was selected for the in vivo application. Fluorescence of MSA-NBB conjugate was detected at excitation 600 nm, emission 670 nm and fluorescence of unbound dyes or MSA was not detected at the same range. In visible image, MSA-NBB conjugate accumulated more in the popliteal lymph node that NBB alone at all the investigational time. The fluorescence of MSA-NBB conjugate and NBB alone were accumulated in the popliteal LN at 10 min at 4.48±0.34 and 4.24±0.18 flux (108 p/s), respectively. While the fluorescence of MSA-NBB conjugate in the popliteal LN was maintained for 2 h (4.81±1.24 flux (108 p/s)), the fluorescence of NBB alone rapidly decreased (2.61±0.46 flux (108 p/s)). MSA-NBB conjugate showed about two-fold higher popliteal LN uptake as compared with NBB alone from 30 min to 2 h after footpad injection. In SPECT/CT images, 99mTc-MSA-NBB conjugate was highly accumulated in the popliteal and inguinal LN. The SUVmean value of 99mTc-MSA-NBB conjugate in the popliteal and inguinal LN was 13.08±2.33 and 3.00±1.64 at 10 min and 17.83±5.85 and 4.99±3.44 at 2 h, respectively. SPECT/CT results showed that the popliteal LN uptake of 99mTc-MSA-NBB conjugate was about 3.5-fold higher than inguinal LN uptake at all time points. Conclusion: In this study, 99mTc-MSA-NBB conjugate was developed as a multimodal SLN mapping agent for direct visualization, fluorescence and SPECT/CT. The ability of 99mTc-MSA-NBB conjugate for accumulation in SLN was assessed by evaluating the popliteal LN uptake which is closest to the foot pad by visual monitoring, fluorescence imaging, and SPECT/CT. The results demonstrated that 99mTc-MSA-NBB conjugate binds quickly to SLN and accumulates in SLN until 2 h after footpad injection. Based on these results, 99mTc-MSA-NBB conjugate has a great potential as an SLN mapping agent for clinical use.목적: 감시림프절은 원발성 종양으로부터 가장 가까이에 위치한 림프절이다. 유방암환자, 흑색종 암환자에서 감시림프절을 검출하는 것은 종양 병기를 평가하고, 수술 중 치료 결정을 하는데 중요한 역할을 한다. 현재 임상에서 청색 염료, 방사성 추적자, 방사성 추적자와 청색 염료 방법의 조합 그리고 방사성 동위원소가 표지된 청색 염료가 감시림프절 검출에 이용되고 있다. 그러나 이러한 방법에는 각각 한계가 있었다. 본 연구의 목표는 99mTc이 표지된 MSA와 염료를 사용한 감시림프절 맵핑 영상제를 개발하는 것이었다. MSA와의 결합효율, 사이즈 배제 크로마토그래피를 이용한 고성능액체크로마토그래피 실험, 형광 모니터링과 같은 시험관 실험을 통해 다양한 염료를 테스트하였다. 그 중 MSA와 가장 높은 결합 효율을 보인 NBB가 선택되었고, 육안 검사, 형광 이미징 그리고 단일 광자 방출 컴퓨터 단층 촬영/컴퓨터 단층 촬영 (SPECT/CT)을 통해 감시림프절 맵핑 성능을 평가하였다. 방법: 육안검사는 8개의 염료를 사용하여 수행되었다. 1 mM의 염료 용액은 1 µmol의 염료를 1 mL의 증류수에 녹여 준비하였고, 증류수를 이용하여 0.25 mM에서 0.001 mM까지 연속 희석하였다. 준비된 염료 용액의 색상은 육안검사를 통해 비교되었다. MSA-염료 접합체의 분자흡광계수 (ε)를 구하기 위해, UV-VIS-NIR 스펙트럼 분석을 수행하였고 흡광도 (OD)는 350-850 nm의 Varioskan flash screening mode에서 측정되었다. MSA와 다양한 염료간의 결합 효율은 반응 10분, 30분, 1시간, 2시간, 6시간 그리고 24시간 후 박층크로마토그래피를 통해 측정되었다. 박층크로마토그래피 플레이트는 Fujifilm LAS 3000를 이용하여 스캔하였고, multi-gauge 3.0를 이용하여 정량평가 하였다. 염료와 MSA 접합 전후의 크기를 확인하기 위하여 고성능액체크로마토그래피를 실행하였다. MSA-염료 접합체가 강한 형광 신호를 나타내는 파장대를 찾기 위해, 여기 420-780 nm, 방출 520-845 nm에서 형광 이미징 실험을 수행하였다. 감시림프절 맵핑을 위한 MSA-NBB 접합체의 성능을 평가하기 위해, MSA-NBB 접합체 혹은 NBB를 수컷 BALB/c 마우스 (총 12마리)에 투여 후 10분, 30분, 1시간 그리고 2시간에 육안 사진과 형광 이미지를 얻었다. SPECT/CT를 얻기 위해, MSA-NBB 접합체를 99mTc으로 표지 하였고, 마우스(총 3마리) 좌측 발바닥에 피하 주사하였다. 약품 투여 10분, 30분, 1시간, 2시간 후 SPECT/CT를 얻었다. 결과: 육안 검사에서 모든 염료가 0.25 mM에서 명확한 색을 나타냈다. 희석된 일부 염료는 용액의 색을 확인하기 어려웠고, NBB, PBVF, NY, BR 그리고 EB는 0.004 mM의 낮은 농도에서도 잘 보였다. MSA-염료 접합체 각각을 정량화된 값으로 비교하기 위해, 흡광도 (OD)와 Beer-Lambert Law를 이용하여 분자흡광계수 ()를 계산하였다. MSA-PBVF 접합체는 141,481 M−1·cm−1로 가장 높은 분자흡광계수를 나타내었으며, MSA-EB 접합체 (99259.3), MSA-ICG 접합체 (87037.0) 그리고 MSA-NBB 접합체 (62222.2)가 뒤를 이었다. 사이즈 배제 고성능액체크로마토그래피를 통해 MSA-염료 접합체가 단량체로 존재한다는 것을 확인하였다. 크로마토그램에서 준비된 모든 MSA-염료 접합체는 24시간 동안 안정하였고, 다른 응집체는 발견되지 않았다. 박층크로마토그래피결과는 MSA 농도와 결합 반응 시간이 증가됨에 따라 모든 염료와 MSA간의 결합 효율이 증가함을 보여주었다. 특히, 테스트된 모든 염료 중 NBB가 가장 적은 양의 MSA (2.5 mg)와 짧은 시간 (10분)내에 가장 높은 결합 친화력을 보였다. 결합 비율(mol/mol)은 NBB 0.7이 MSA 1과 결합된 것으로 계산되었다. 이러한 결과를 바탕으로, 생체 내 적용 실험을 위해 NBB가 선택되었다. MSA-NBB 접합체의 형광 신호는 여기 600 nm, 방출 670 nm에서 검출되었으며, 결합되지 않은 염료와 MSA의 형광 신호는 동일한 파장에서 검출되지 않았다. 육안검사에서, MSA-NBB 접합체가 NBB 단독으로 투여하였을 때 보다 모든 시간대에서 더 많은 슬와림프절 축적을 나타냈다. 약품 투여 10분 후 슬와림프절에 축적된 MSA-NBB 접합체와 NBB의 형광 세기는 각각 4.48±0.34 그리고 4.24±0.18 flux (108 p/s)이었다. 약품 투여 2시간 후 MSA-NBB 접합체의 슬와림프절 축적(4.81±1.24 flux (108 p/s))은 유지되었으나, NBB의 형광 세기는 빠르게 감소 (2.61±0.46 flux (108 p/s))하였다. 약품 투여 30분에서 2시간까지 MSA-NBB 접합체는 NBB 단독으로 투여하였을 때 보다 약 2배 높은 슬와림프절 축적을 보였다. SPECT/CT에서, 99mTc-MSA-NBB 접합체는 슬와림프절과 서혜부림프절에 높은 섭취를 보였다. 약품 투여 10분 후 슬와림프절과 서혜부림프절 각각에 섭취된 99mTc-MSA-NBB 접합체의 SUVmean은 13.08±2.33, 3.00±1.64이었고, 약품 투여 2시간 후에는 17.83±5.85, 4.99±3.44이었다. SPECT/CT 결과를 통해, 모든 시간대에서 99mTc-MSA-NBB 접합체의 슬와림프절 축적이 서혜부림프절 축적보다 약 3.5배 높음을 확인하였다. 결론: 본 연구에서, 99mTc-MSA-NBB 접합체는 육안 검사, 형광 이미지 및 SPECT/CT를 위한 다중모드 감시림프절 맵핑 영상제로 개발되었다. 우리는 육안검사, 형광 이미지 그리고 SPECT/CT를 통해, 발바닥으로부터 가장 가까이에 위치한 슬와림프절 축적을 평가함으로써 99mTc-MSA-NBB 접합체의 감시림프절 축적 능력을 평가하였다. 결과는 99mTc-MSA-NBB 접합체가 감시림프절에 빠르게 결합하고, 약품투여 2시간 후까지 감시림프절에 축적됨을 보여 주었다. 이러한 결과를 바탕으로, 99mTc-MSA-NBB 접합체가 임상에서 감시림프절 맵핑을 위해 사용될 가능성이 있음을 확인하였다.ABSTRACT ----------------------------------------------------------------------------------2 LIST OF FIGURES AND TABLES ----------------------------------------------------9 LIST OF ABBREVIATIONS -----------------------------------------------------------11 INTRODUCTION ------------------------------------------------------------------------14 MATERIALS AND METHODS -------------------------------------------------------19 Preparation of MSA and kits for 99mTc labeling ----------------------------------20 In vitro visibility test of dyes ----------------------------------------------------------21 Absorption spectra and molar absorption coefficient () of MSA-dye conjugates ---------------------------------------------------------------------------------------------22 In vitro measurements for the binding efficiencies of dyes with MSA ----------22 Size exclusion HPLC before and after MSA and dye conjugation --------------25 Electrophoresis for the binding mechanism study of MSA and dyes ------------25 In vitro fluorescence monitoring of MSA-dye conjugates-------------------------26 In vivo visible and fluorescence experiments of MSA-NBB conjugate for the detection of SLN ------------------------------------------------------------------------29 Preparation for 99mTc-MSA-NBB conjugate ----------------------------------------29 Analysis of SPECT/CT ----------------------------------------------------------------30 Stability test of 99mTc-MSA-NBB conjugate in in vivo ---------------------------31 RESULTS -----------------------------------------------------------------------------------33 In vitro visibility test of dyes ----------------------------------------------------------33 Absorption spectra and molar absorption coefficient () of MSA-dye conjugates ---------------------------------------------------------------------------------------------35 In vitro measurements for the binding efficiencies of dyes with MSA ----------39 Size exclusion HPLC before and after MSA and dye conjugation----------------44 Electrophoresis for the binding mechanism study of MSA and dyes ------------48 In vitro fluorescence monitoring of MSA-dye conjugates ------------------------50 In vivo visible and fluorescence experiments of MSA-NBB conjugate for the detection of SLN------------------------------------------------------------------------52 Preparation for 99mTc-MSA-NBB conjugate ----------------------------------------56 Analysis of SPECT/CT ----------------------------------------------------------------61 Stability test of 99mTc-MSA-NBB conjugate in in vivo ---------------------------63 DISCUSSION ------------------------------------------------------------------------------65 CONCLUSION ----------------------------------------------------------------------------73 REFERENCES ----------------------------------------------------------------------------74 국문초록 ------------------------------------------------------------------------------------82Docto

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