췌장암 이종이식 모델에서 Doxorubicin을 탑재한 미세기포 집합체와 집속초음파 병행 치료의 상호증강 효과

학위논문 (박사) -- 서울대학교 대학원 : 의과대학 의학과, 2021. 2. 이재영.The synergistic effects of a doxorubicin (Dox)-loaded microparticle-microbubble complex (DMMC) and focused ultrasound (FUS) with a short duty cycle (5%) were evaluated in a pancreatic cancer xenograft model established by inoculating immunedeficient mice with CFPAC-1 cells. The efficacy of the DMMC with FUS (study 1), the effect of conjugating the particles as opposed to mixing them (study 2), and the levels of tumor apoptosis and intracellular Dox (study 3) were evaluated. The DMMC with FUS showed the lowest tumor growth rate (30.8 mm3/week) and the highest intracellular Dox uptake (8.8%) and tumor cell apoptosis rate (58.7%) among all treatments. The DMMC presented a significantly lower growth rate than the mixture of Dox-loaded microparticles and microbubbles (44.2 mm3/week, P<0.01) when they were combined with FUS. In conclusion, DMMC with short-duty-cycle FUS has promise for tumor growth suppression, which may be attributed to high intracellular Dox uptake.목적: 췌장암 이종이식 모델에서 Doxorubicin을 탑재한 미세기포 집합체 (DMMC)와 집속초음파 평행 치료의 상호 증강 효과를 평가하고자 한다. 방법: 면역결핍 마우스에 CFPAC-1을 접종하여 췌장암 이종이식 모델을 만들었다. DMMC는 Doxorubicin을 탑재한 알부민 미세입자와 미세기포와의 결합을 통해 생성하였다. 집속초음파 치료를 위해 음향파워 80.5W, 반복 주기 (duty cycle) 5%를 적용하였다. 마우스는 총 5 군 (집단 별 개체 수=5) 으로 나누어 4mg/Kg Doxorubicin로 치료를 시행하였다. 5군은 1) 대조군, 2) Doxorubicin 단독, 3) Doxorubicin와 미세기포 혼합물에 집속초음파 치료, 4) Doxorubicin 탑재 알부민 미세입자와 미세기포 혼합물에 집속초음파 치료, 5) Doxorubicin 탑재 알부민 미세입자와 미세기포 집합체 (DMMC)에 집속초음파 치료로 이루어져 있다. 제 1단계에서는 DMMC와 집속초음파 치료의 효과를 확인하고자 하였다. 제 2단계에서는 혼합물과 집합체의 치료효과를 비교하고자 하였다. 병태생리학적 분석을 위해, 동일한 조건으로 반복 실험 하였고, 종양 apoptosis와 세포 내 Doxorubicin 흡수 양 을 형광분석을 통해 분석하였다. 통계분석에는 Bonferroni correction을 동반한 Kruskal-Wallis 검정과 Mann- Whitney 검정을 이용하였다. 결과: 제 1단계 실험에서 DMMC와 집속초음파 병행치료를 시행한 군에서 유의하게 작은 종양크기 및 가장 느린 종양 성장속도를 보여주었다. 제 2단계 실험에서는, 유일하게 DMMC와 집속초음파 병행치료를 시행한 군에서 대조군과 비교시 유의하게 낮은 성장속도를 보여주었다 (P=0.01). 병태생리학적 분석에서, DMMC와 집속초음파 병행치료를 시행한 군이 Doxorubicin 단독치료 혹은 Doxorubicin과 FUS 병행 치료군보다 높은 세포 내 Doxorubicin 흡수를 보였다 (Ps<.001). DMMC와 집속초음파 병행 치료 군에서 종양세포 apoptosis 비율이 다른 실험군과 비교시 가장 높았다. 결론: DMMC와 집속초음파 병행치료는 췌장암 세포의 종양의 성장을 억제할 수 있는 것으로 사료되며, 이는 세포내의 높은 Doxorubicin 흡수에 기인한 것으로 보인다.Chapter 1. Introduction 1 Chapter 2. Materials and Methods 4 Chapter 3. Results 14 Chapter 4. Discussion 34 Chapter 5. Conclusion 41 References 42 Abstract in Korean 51Docto

췌장 IPMN의 악성도 평가: Multidetector CT와 MR/MRCP의 비교

학위논문 (석사)-- 서울대학교 대학원 : 임상의과학과, 2015. 2. 이정민.Introduction: To compare the diagnostic performances of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) with MR cholangiopancreatography (MRCP) in predicting the malignant potential of pancreatic intraductal papillary neoplasms (IPMN) and to evaluate their inter-modality agreement. Material and Methods: Institutional review board approval was obtained and the requirement for informed consent was waived for this retrospective study. In 129 patients with pathologically-proven pancreas IPMNs, three reviewers independently evaluated their preoperative MDCT and MRI with MRCP findings. Inter-modality agreement between MDCT and MRI with MRCP as well as interobserver agreement of each imaging modality in detecting high-risk stigmata and worrisome features were assessed. Diagnostic values of other signs of overt malignancy including the presence of parenchymal mass and locoregional extension were analyzed. Diagnostic performances and inter-modality consistency were assessed using receiver operating curve (ROC) analysis and weighted κ statistics. Results: Overall predictability of MDCT and MRI with MRCP for the malignancy potential of pancreatic IPMNs was similar (AUC: 0.82 and 0.82, respectively) with good inter-modality agreement (κ=0.75) and moderate interobserver agreement (κ=0.47~0.59) when we set high-grade dysplasia as the cutoff for malignancy. When parenchymal masses and locoregional extensions were considered as overt malignant signs, invasive IPMN predictability was significantly increased (AUC: 0.87 for CT and 0.88 for MRI) with high sensitivity (94.3%) and equivocal specificity (69.1%). Conclusion: Diagnostic performances in predicting the malignant potential of pancreatic IPMNs using MDCT and MRI with MRCP were similar while showing good inter-modality agreement, suggesting that interchangeable follow-up may be possibleAbstract i Contents iii List of tables and figures iv Introduction 1 Material and Methods 5 Results 16 Discussion 34 Appendix 40 References 42 Abstract in Korean 50Maste

Therapeutic effects of a mesenchymal stem cell‑based insulin‑like growth factor‑1/enhanced green fluorescent protein dual gene sorting system in a myocardial infarction rat model

The present study was conducted in order to improve gene expression efficiency of insulin‑like growth factor‑1 (IGF‑1)‑transfected mesenchymal stem cells (MSCs) using a non‑viral carrier and a simplified method of dual gene selection. The therapeutic efficacy of this MSC‑based IGF‑1/enhanced green fluorescent protein (EGFP) dual gene sorting system was evaluated in a rat myocardial infarction (MI) model. IGF‑1 and EGFP genes were expressed in MSCs in vitro. The purity of dual gene‑expressing MSCs was 95.1% by fluorescence‑activated cell sorting. Transfected MSCs injected into rats were identified based on green fluorescence, with an increased signal intensity observed in rats injected with sorted cells, compared with unsorted cells. IGF‑1 expression levels were additionally increased in the sorted group, and decreases in infarct size, fibrotic area and fraction of apoptotic cells were observed. These results demonstrated that IGF‑1 overexpression protects against fibrosis and apoptosis in the myocardium and reduces infarct size following MI. Additionally, the present vector sorting system may potentially be applied to other types of stem cell‑based gene therapy.ope

Comparing Properties of Variable Pore-Sized 3D-Printed PLA Membrane with Conventional PLA Membrane for Guided Bone/Tissue Regeneration

The aim of this study was to fabricate bioresorbable polylactide (PLA) membranes by 3D printing and compare their properties to those of the membranes fabricated by the conventional method and compare the effect of different pore sizes on the properties of the 3D-printed membranes. PLA membranes with three different pore sizes (large pore-479 μm, small pore-273 μm, and no pore) were 3D printed, and membranes fabricated using the conventional solvent casting method were used as the control group. Scanning electron microscopy (SEM) and micro-computed tomography (µ-CT) were taken to observe the morphology and obtain the porosity of the four groups. A tensile test was performed to compare the tensile strength, elastic modulus, and elongation at break of the membranes. Preosteoblast cells were cultured on the membranes for 1, 3 and 7 days, followed by a WST assay and SEM, to examine the cell proliferation on different groups. As a result, the 3D-printed membranes showed superior mechanical properties to those of the solvent cast membranes, and the 3D-printed membranes exhibited different advantageous mechanical properties depending on the different pore sizes. The various fabrication methods and pore sizes did not have significantly different effects on cell growth. It is proven that 3D printing is a promising method for the fabrication of customized barrier membranes used in GBR/GTR.ope

Effects of 1% Lidocaine Instillation on Overactive Bladder Induced by Bladder Outlet Obstruction in Rats

Purpose: Lidocaine is a common local anesthetic and antiarrhythmic drug that acts via the local anesthetic effect of blocking voltage-gated sodium channels in peripheral neurons. To evaluate lidocaine as a therapeutic agent, we investigated optimal concentrations and effects of intravesical lidocaine instillation in a bladder outlet obstruction (BOO)-induced rat model of overactive bladder (OAB). Materials and methods: To determine the therapeutic dosage of lidocaine, 16 female Sprague-Dawley (SD) rats (mean weight = 200 ± 20 g) were divided into four treatment groups: those receiving saline, 0.5% lidocaine, 1% lidocaine, and 2% lidocaine (n = 4 per group). Twenty-four additional SD rats were divided into two groups to investigate the effect of 1% lidocaine treatment in rats with BOO and normal rats (n = 12 per group). Cystometry was performed by infusing physiological saline and lidocaine into the bladder at a slow infusion rate (0.04 mL/min). Cystometric parameters were analyzed using PowerLab®. The expression of c-Fos, a protein expressed by C-fibers in the spinal cord (L6), was investigated via western blotting. Results: Among the test lidocaine doses, only 1% lidocaine increased the intercontraction interval (ICI) (control mean = 500.56 ± 24.4 s; treatment mean = 641.0 ± 49.3 s; p < .01) without changes in threshold pressure and basal pressure. In the BOO-induced OAB group, the ICI increased significantly after instillation of 1% lidocaine (control mean = 135.8 ± 12.87 s; OAB-group mean = 274.2 ± 33.21 s; p < .01). Detrusor overactivity and non-voiding contraction were observed in the control group but not in rats with BOO after lidocaine instillation. The expression of c-Fos in C-fibers in the spinal cord (L6) decreased significantly after 1% lidocaine treatment in rats with BOO. Conclusion: Intravesical instillation of 1% lidocaine improves cystometric parameters without deterioration of contractility by blocking excessive C-fiber activity in the rat model of BOO-induced OAB. Therefore, instillation of 1% lidocaine has minimal effects on normal nerves while blocking nerves that contribute to OAB. Our findings suggest that intravesical instillation of 1% lidocaine is a useful treatment for OAB.ope

Function of the Cold Receptor (TRPM8) Associated with Voiding Dysfunction in Bladder Outlet Obstruction in Rats.

PURPOSE: Bladder outlet obstruction (BOO) causes storage and voiding dysfunction in the lower urinary tract. We investigated the expression of transient receptor potential cation channel subfamily M member 8 (TRPM8) to evaluate the relationship between TRPM8 expression and overactive bladder (OAB) in a rat model of BOO. METHODS: Fifty female Sprague-Dawley rats were divided into 4 groups; normal (n=10), normal-menthol (n=10), BOO (n=15), BOO-menthol (n=15). After 3 weeks, cystometry was performed by infusing physiological saline and menthol (3 mM) into the bladder at a slow infusion rate. The histological changes and expression of TRPM8 in the bladder were investigated by Masson's trichrome staining, immunofluorescence and reverse transcription-polymerase chain reaction. RESULTS: Cystometry showed that the intercontraction interval (ICI; 428.2±23.4 vs. 880.4±51.2, P<0.001), micturition pressure (MP; 25.7±1.01 vs. 71.80±3.01, P<0.001), and threshold pressure (2.9±0.25 vs. 9.2±1.58, P<0.01) were significantly increased in BOO rats. The bladder wall was significantly dilated compared with the control. Detrusor muscle hypertrophy and a thick mucosa layer were observed in BOO bladder. After menthol treatment, ICIs were decreased and MPs were increased in the menthol treatment groups. TRPM8-positive cells and mRNA were predominantly increased in the bladder and dorsal root ganglia of all groups compared with the normal group. CONCLUSIONS: Increased bladder wall thickness and proportion of collagen probably affect voiding dysfunction. Furthermore, an increase of TRPM8 expression in BOO may induce entry of Ca(2+) from the extracellular space or stores. The increase of Ca(2+) probably causes contraction of smooth muscle in BOO. However, OAB symptoms were not observed after menthol treatment although the expression of TRPM8 was abundant in the bladder epithelium after menthol treatment. Although OAB in BOO models may be caused by complex pathways, regulation of TRPM8 presents possibilities for OAB treatment.ope

User Experience Design for Smoother Communications and Gaining Information in Easy-sharing between the Parents and the Grandparents : Smart phone Application for parents and the grandparents

최근 여성 경제활동 참가율의 지속적인 증가로 육아에 대한 어려움이 커지고 있으며, 젊은 맞벌이 부부 510만 가구 중 250만 가구가 육아를 조부모에게 맡기는 것으로 조사됐다. 이렇게 손자녀를 양육하는 조부모를 ‘황혼 육아족’이라 부르고 있으며, 평균 62.4세, 일반적인 노인층보다 높은 학력수준, 비교적 안정된 소득수준을 보이며 불황과 출산율 감소에도 육아용품 시장 성장의 큰 손으로 자리 잡고 있어 관심이 날로 더해지고 있는 추세이다. 이렇게 급속도로 늘어나는 손자녀 양육 조부모들을 위해 상품, 서비스 및 교육 등은 맞춤으로 제공되고 있으며 ‘조부모의 편의성’이 중요한 요소로 작용하고 있다. 하지만, 조부모의 편의성 충족만으로 신체적, 정신적으로 외부의 돌봄이 필요한 시기에 오히려 손자녀를 돌보고 있는 조부모의 실질적 어려움을 경감시킬 수 있을지 불확실하다. 많은 선행 연구에서 손자녀 돌봄 조부모의 신체적·심리 정서적 어려움에 대해 밝히고 있으나 실태파악에 그치는 경우가 많았다. 본 연구는 조부모 부모간 원활한 양육정보 공유 및 소통을 목표로 하였다. 손자녀를 돌보며 가장 원하는 것이 ‘가족들이 내 마음을 알아주고 위로해준다’이며, 자녀와의 육아방식 차이에서 오는 갈등이 우울감에 가장 큰 영향을 끼친다는 조사에 주목했다. 이에 본 연구에서는 조부모 부모간 원활한 양육정보의 공유 및 소통의 수단으로 스마트폰용 어플리케이션을 제안하였다. 수많은 육아관련 어플리케이션 중 조부모와 부모간 정보의 공유와 소통을 위한 서비스는 없었으며, 본 연구를 통해 성인자녀와의 상호작용과 정서적인 지지를 촉진하여 스트레스 경감에 긍정적 영향을 끼칠 수 있다는 것이 이 연구의 시사점이라고 할 수 있다. 본 연구를 진행하기에 앞서 문헌 연구와 현황조사를 통해 손자녀 양육 조부모에 대한 이해를 높였으며, 사전 인터뷰와 심층인터뷰 2번에 걸쳐 정성적 리서치를 진행하였고 어피니티 다이어그램(Affinity Diagram)을 활용한 인터뷰내용 구조화 작업을 통해, 간편 정보 획득, 개인/맞춤화, 편한 소통이라는 요구사항을 추출 및 압축할 수 있었다. 또한 이를 바탕으로 퍼소나와 시나리오를 작성하였다. 추가로 퍼소나의 고객 여정 맵(Customer Journey Map)을 작성하여 경험을 시각화함으로써 잠재된 니즈(Needs)를 찾을 수 있었고 간편메모, 아기식단, 아기하루, 육아정보, 정보함의 기능을 도출할 수 있었다. 각 기능의 상세화면과, 유즈 플로우(Use Flow)를 설계하여 스마트폰 어플리케이션으로 제안하였고, 프로토타입으로 사용성 평가를 진행하였다. 평가는 기능의 수행, 실용성에 집중하였으며, 그 결과 사용성에 전반적으로 만족하였으며 추후 사용 의사 여부에 대해 긍정적인 답변을 들었다. 따라서 본 스마트폰 어플리케이션 제안 연구는 양육을 중심으로 일어나는 조부모와 부모간 상이한 양육방식에 대한 갈등을 해소하고, 편안한 소통을 통해 정서적 지지를 주고받는 등 심리적·정서적 어려움에 도움을 줄 것으로 예상된다. 또한 학문적으로는 손자녀 돌봄 어려움에 대한 실태파악에 그치지 않고 실질적 해소를 다룬 연구의 활성화에 기여할 것이라 생각한다.;In recent research our society is becoming more difficult to raise a child due to continuous increase of Female-economic activity, and this results in 2.5 million of 5.1 million parents to work together for a living. This leads to a social phenomena that our grandparents to take responsibility of raising a child. These grandparents who raise their grandchildren are called ‘Twilight Infant-car Group’ these days and their average ages are 62.4. They are more educated than other grandparents are, relatively with stable salary and stable economic status. Despite the economic depression and low-birth-rate, their interests of nursery-products are increasing constantly as these nursery-product market keeps on growing bigger. As for this rapid growth in ‘Twilight Infant-car Group’, more services and educational programs are provided for their convenience. However, it is problematic that these programs and services would actually lighten their difficulties they are having in their everyday-life because they are also people who need more and constant care. According to many other previous researches and studies, they are having mental difficulties in fact but sadly these researches could not give any solutions to their problems. This study ultimately focuses on how to reduce these grandparents’ stresses and their mental difficulties. This study also tries to show that those grandparents want their family and children to know and become more aware of their condition and want to be comforted, and also emphases on several ways to solve the conflicts comes from the different methods of raising their children. So as one of the ways, this study suggests a smart-phone application which eventually will make and give an opportunity of smoother communications in easy-sharing between the parents and the grandparents. There were not this kind of application until now, through this study we want to support our parents and grandparents to interact and communicate more easily and so it would bring positive results in reducing of their mental difficulties. In prior to this study, through our and survey we could enhance the understandings of our grandparents, and we had qualitative survey and proceed with two different interviews; pre-interview and in-depth interview with the grandparents. Also, we were able to meet their needs of smoother communication and gaining information more easily for raising a child by using and utilizing the ‘Affinity Diagram’. From these researches we also were able to prepare a persona and a scenario. We also could visualize their experiences as the ‘Customer Journey Map’ which helped to find their potential needs additionally, and discover and create the following; simple-memo, meal-plans of babies, day-plans of babies, information on infant care, information box. We suggest screen-details of each functions and the creation of ‘Use Flow’ as an application that can be used in smart phones. Plus, they were created and tested for an easy usability as examples. The testing were proceeded mainly for the practical use of each functions and the results were satisfactory with positive feedbacks. Therefore this ‘Smart phone-application Suggestion Study’ is primarily concentrated on the method to resolve the conflicts between the parents and the grandparents followed by raising a child. Hopefully, this study would not only help them to communicate more easily, to exchange information, and to understand and support each other, but also help other researches and studies furthermore.I. 서론 1 A. 연구의 배경 및 목적 1 B. 연구의 내용 및 방법 3 C. 연구의 체계 4 II. 이론적 배경 5 A. 손자녀 양육 조부모의 특성 및 현황 5 B. 조부모 세대의 스마트폰 사용 행태와 UI에 대한 고찰 10 C. 사용자 경험 디자인의 개념 16 III. 육아관련 어플리케이션 사례조사 18 A. 육아관련 어플리케이션 사례조사 18 Ⅳ. 사용자 조사 23 A. 사용자 조사 목적 및 범위 23 B. 심층 인터뷰 26 1. 심층 인터뷰 설계 및 수행 26 2. 심층 인터뷰 수집 항목 27 3. 심층 인터뷰 내용 분석 28 C. 어피니티 다이어그램을 통한 결과 분석 34 Ⅴ. 퍼소나 분석과 요구사항 정의 37 A. 목표 지향 디자인 37 B. 퍼소나를 통한 사용자 모델링 38 1. 퍼소나1(primary persona) 39 2. 퍼소나2(secondary persona) 40 C. 고객 여정 맵을 통한 요구사항 규명 41 D. 컨셉 매트릭스를 통한 요구사항 정의 45 Ⅵ. UI설계 및 평가 48 A. UI디자인 전략 및 UX디자인 컨셉 도출 48 1. UI디자인 전략 48 2. UX디자인 컨셉 도출 48 B. 프로토타입 제안 50 1. Information Architecture 설계 50 2. Use Flow 구성 52 3. 프로토타입 53 4. 주요 동작 시나리오 59 5. 고객 여정 맵을 통한 요구만족 체크 61 C. 프로토타입 사용성 평가 65 1. 사용성 평가 설계 및 수행 65 2. 사용성 평가 결과 및 분석 66 3. 평가 결과를 반영한 프로토타입 수정 68 Ⅶ. 결론 및 제언 71 참고문헌 73 부록1. 77 부록2. 77 ABSTRACT 7

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