Effective L2 cache organizations for shared memory multiprocessor systems

학위논문(박사)--서울대학교 대학원 :전기·컴퓨터공학부,2003.Docto

Development of Yb-doped on-chip microlaser based on sol-gel process

학위논문(석사) - 한국과학기술원 : 나노과학기술대학원, 2017.2,[iii , 33 p. :]기존의 높은 Q 인자를 가진 광공진기는 실리콘을 열처리로 산화반응 시킨 실리카 박막으로 제작되었지만 이터븀이나 어븀을 도핑하는데 한계가 있기 때문에 졸-겔 공정을 이용한 실리카 박막을 만드는 방법이 연구되었다. 하지만 졸-겔 공정으로 제작한 마이크로 디스크는 표면 거칠기가 높다는 단점을 가지고 있어 $CO_2$ 레이저로 리플로우 공정을 시켜 마이크로토로이드 형태로 만드는 방법만을 사용하였다. 이 때 문제점은 리플로우 공정 과정에서 주변 소자들을 손상 시킬 수 있고 마이크로 디스크의 구조나 크기를 제어하기 힘들다는 점이다. 따라서 본 연구의 목표는 졸-겔 공정으로 제작한 마이크로 디스크의 표면 거칠기를 낮추어 향후 리플로우 공정 없이 디스크 레조네이터 형태로 제작 가능하게 하고 졸-겔 공정에서 실리카 박막 표면에 자주 발생하는 크랙이 생기지 않고 두께가 균일한 박막을 제작하는 것이다. 이를 위해 졸-겔 공정 과정인 졸-겔 합성 조건, 스핀코팅 조건, 어닐링 조건, 고밀도화 조건을 마이크로 디스크 제작에 최적화시켜 크랙이 발생하지 않고 두께가 균일한 실리카 박막을 제작하였고, 이 박막으로 제작한 마이크로 디스크의 거칠기가 낮은 표면을 얻었다. 표면 거칠기가 낮은 마이크로 디스크 제작이 가능해졌기 때문에 향후 $XeF_2$ 식각을 통해 디스크 레조네이터 형태로 연구가 가능하고 크랙이 생기지 않기 때문에 대면적을 이용한 다양한 형태의 소자로 응용이 가능할 것으로 보인다.한국과학기술원 :나노과학기술대학원

혈관신생억제 및 종양선택적 전달을 위한 다중표적형 항암제의 설계와 개발

학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2015. 2. 변영로.Despite the rapid advances of cancer research, cancer is still one of the leading causes of mortality worldwide. During the past decades, research of anticancer agents mostly focused on selective targeting of tumor-specific antigens in the context of molecular targeted therapy as well as targeted drug delivery to improve the therapeutic index of the traditional chemotherapy. However, due to the intrinsic genetic diversity and complexity of tumors, the targeted therapeutics showed only limited improvements. Therefore, a breakthrough of the fundamental concept in cancer treatment has been deemed necessary. In this dissertation, novel therapeutic alternatives are proposed and evaluated that could contribute to the further advance in the cancer therapeutics. Part one concerns development of a heparin-based anti-angiogenic agent LHT7 ? a sodium taurocholate conjugated LMWH ? that inhibits multiple stages of angiogenesis, and investigation of its mode of action. This study showed that the conjugation of sodium taurocholates abolished the intrinsic capability of LMWH to interact with ATIII while enhancing the binding property on VEGF, resulting in decreased anticoagulant activity and enhanced anti-angiogenic activity. The differential effects of sodium taurocholate conjugation to LMWH on its interaction between ATIII and VEGF were attributable to the unique structure of sodium taurocholate: the bulky and rigid sterane core of taurocholate sterically concealed the ATIII-binding pentasaccharide unit of LMWH, while the terminal sulfate group generated additional interactions with VEGF leading to a stronger binding. The major advantage of exploiting heparin as a lead compound for the development of novel anti-angiogenic agents comes from the intrinsic capability of interacting and regulating wide array of pro-angiogenic factors. LHT7 was speculated to block FGF2 and PDGF-B in addition to VEGF. Since these three pro-angiogenic factors play key roles in multiple stages of angiogenesis, simultaneous blockade of these factors resulted in potent suppression of tumor angiogenesis as well as tumor growth. The results of this study suggested that LHT7 would potentially overcome the resistance issue shown in the conventional anti-angiogenic agents. Part two discusses development of doxorubicin prodrugs that target induced-apoptosis for effective delivery of chemotherapeutics to the tumor regardless of its genomic property. The first doxorubicin prodrug involves two distinct features for an effective tumor targeting: EPR effect-mediated tumor accumulation with extended plasma half-life, and radiation-induced apoptosis targeting. This prodrug ? EMC-DEVD-S-DOX ? comprises a maleimide group, which binds to the circulating albumin after intravenous administration, and a DEVD motif, which is cleaved by caspase-3 upregulated in the tumor cells that are exposed to radiation. The EMC-DEVD-S-DOX showed a prolonged plasma half-life with selective accumulation within tumor tissue, and released free doxorubicin only when combined with radiotherapy. The second doxorubicin prodrug ? RGDEVD-DOX ? comprises an integrin αvβ3 recognizing RGD sequence and a DEVD sequence. The RGD moiety selectively delivers the prodrug to the tumor during the initial phase of administration and induces apoptosis in certain subclone of tumor cells as well as tumor endothelial cells that overexpress integrin αvβ3. The caspase-3 from the apoptotic cells further activates other molecules of the prodrug, forcing those to release hydrophobic active compound with facilitated cell penetration regardless of integrin αvβ3 expression. Therefore, it could affect broader range of tumor cells within the tumor tissue, thereby providing more effective therapeutic outcomes. Since the upregulation of the caspase-3, which is the key event of the proposed drug delivery strategy, is common during the apoptosis, the genomic diversity of tumor cells hardly influences the efficacy of the currently developed prodrugs.ABSTRACT i Table of Contents iii List of Tables ix List of Figures ix Abbreviations xvi Introduction 1 References 3 Part I.Study of mode of action and multiple pathway inhibitory capability in tumor angiogenesis of heparin-based agent LHT7 5 1. General Introduction 7 1.1. Tumor angiogenesis 7 1.1.1. Physiology of tumor angiogenesis 7 1.1.2. Angiogenesis inhibition 10 1.1.3. Resistance to angiogenesis inhibitors 13 1.2. Heparin 17 1.2.1. Structural Characteristics of Heparin 18 1.2.2. Anticoagulant Activity of Heparin 19 1.2.2. Heparin in Cancer 20 1.3. Rationale of the research 22 References 23 2. Potentiation of anti-angiogenic activity of heparin by blocking the ATIII-interacting pentasaccharide unit and increasing net anionic charge 35 2.1. Introduction 36 2.2. Materials and Methods 38 2.2.1. Cell lines 38 2.2.2. Synthesis 38 2.2.3. Characterization of the synthesized LMWH-derivatives 41 2.2.4. Surface plasmon resonance (SPR) analysis 43 2.2.5. Molecular dynamics 43 2.2.6. Computer simulated molecular docking 44 2.2.7. X-ray μCT angiography 45 2.2.8. Tumor growth suppression 46 2.2.9. Histological analysis 46 2.2.10. Ex vivo imaging of whole-body distribution 46 2.2.11. Immunofluorescence 47 2.2.12. Platelet uptake study of fluorescent-labeled LHT7 47 2.2.13. Statistical analysis 48 2.3. Results 48 2.3.1. Effects of the conjugated sodium taurocholate between the interaction of LMWH and ATIII determined by computerized docking simulation 48 2.3.2. Anticoagulant activities of LHT7 and its structural analogs 49 2.3.3. Effects of the conjugated sodium taurocholate between the interaction of LMWH and VEGF determined by computerized molecular dynamics 50 2.3.4. VEGF binding affinities of LHT7 and its structural analogs 51 2.3.5. Effect of LHT7 on tumor angiogenesis in vivo 52 2.3.6. Anticancer effects of LHT7 on distinct types of carcinoma xenografts 53 2.3.7. Intratumor localization of LHT7 54 2.3.8. LHT7 uptake by platelets 54 2.4. Discussion 70 2.5. Conclusion 76 References 76 3. Multiple-stage angiogenesis inhibition of LHT7 by blocking VEGF, FGF2, and PDGF-B 81 3.1. Introduction 82 3.2. Materials and Methods 84 3.2.1. Cell lines 84 3.2.2. Transwell chemotactic migration assay 84 3.2.3. MTT cytotoxicity assay 85 3.2.4. HUVEC spheroid sprouting assay 85 3.5.5. Endothelial tube formation assay 86 3.2.6. Matrigel plug angiogenesis assay 87 3.2.7. Receptor tyrosine kinase phosphorylation studies 87 3.2.8. In vitro pericyte migration to endothelial tube 88 3.2.9. In vitro pericyte-endothelium adhesion assay 88 3.2.10. Surface plasmon resonance (SPR) analysis 89 3.2.11. Dynamic contrast enhanced magnetic resonance imaging 89 3.2.12. Statistical analysis 90 3.3. Results 90 3.3.1. HUVEC migration inhibitory effect and cytotoxicity evaluation of LHT7 90 3.3.2. Inhibitory effect of LHT7 in endothelial sproutings 91 3.3.3. Inhibitory effect of LHT7 in endothelial tubular differentiation 92 3.3.4. Inhibitory effect of LHT7 in the angiogenesis induced by VEGF and FGF2 in matrigel plugs 92 3.3.5. VEGF-VEGFR2 and FGF2-FGFR1 signaling pathway blockade by LHT7 93 3.3.6. Inhibitory effect of LHT7 on pericyte recruitment to endothelium linings 94 3.3.7. Determination of cytotoxicity on pericytes and possible effects in the endothelial cell and pericyte adhesion of LHT7 95 3.3.8. Inhibitory effect of LHT7 on PDGF-B-induced angiogenesis in matrigel plugs 95 3.3.9. PDGFB-PDGFRβ signaling pathway blockade by LHT7 96 3.3.10. Characterization of tumor vasculatures in LHT7-treated tumor-bearing animals using DCE-MRI 97 3.4. Discussion 112 3.5. Conclusion 115 References 115 Part II. Novel strategy for site-specific delivery system and development of doxorubicin prodrugs 119 4. General Introduction 121 4.1. Tumor heterogeneity 121 4.1.1. Intertumor heterogeneity 121 4.1.2. Intratumor heterogeneity 122 4.2. Apoptosis targeted prodrug system 124 4.2.1. Caspase in apoptosis 125 4.2.2. Substrate recognition by caspases 127 4.3. Tumor targeting strategies 131 4.3.1. Passive tumor targeting 131 4.3.1.1. Albumin as a carrier for tumor targeting 134 4.3.1.2. Exploiting endogenous albumin for albumin-bound agents 137 4.3.2. Active tumor targeting strategy 140 4.3.2.1. Integrins 144 4.3.2.2. RGD peptide sequence for targeting integrin αvβ3 146 4.4. Rationale of the research 148 References 149 5. Albumin-binding radiation-induced apoptosis targeted doxorubicin prodrug 165 5.1. Introduction 166 5.2. Materials and methods 169 5.2.1. Cell lines 169 5.2.2. Synthesis 169 5.2.3. EMC-DEVD-S-DOX binding study with HSA 171 5.2.4. HSA-DEVD-S-DOX analysis by SDS-PAGE 171 5.2.5. Determination of thiol concentration of HSA using Ellmans test 172 5.2.6. Preparation and characterization of HSA-DEVD-S-DOX 172 5.2.7. EMC-DEVD-S-DOX incubation study in plasma 173 5.2.8. Western blot 173 5.2.9. MTT cytotoxicity assay 174 5.2.10. Cellular uptake imaging 174 5.2.11. HPLC determination of caspase-mediated activation 175 5.2.12. Pharmacokinetic study 175 5.2.13. Ex vivo biodistribution imaging 176 5.2.14. Tumor growth suppression 176 5.3. Results 177 5.3.1. Synthesis of EMC-DEVD-S-DOX 177 5.3.2. Albumin-binding of EMC-DEVD-S-DOX 177 5.3.3. Caspase-3-mediated cleavage of HSA-DEVD-S-DOX 179 5.3.4. In vitro efficacy of HSA-DEVD-S-DOX 180 5.3.5. Caspase-3 upregulation induced by activated HSA-DEVD-S-DOX 180 5.3.6. Pharmacokinetic study 181 5.3.7. Tumor accumulation of EMC-DEVD-Cy5.5 181 5.3.8. Tumor growth suppression of EMC-DEVD-S-DOX 182 5.4. Discussion 198 5.5. Conclusion 200 References 201 6. Integrin αvβ3 targeted caspase-3-dependently activated doxorubicin prodrug 203 6.1. Introduction 204 6.2. Materials and Methods 206 6.2.1. Cell lines 206 6.2.2. Synthesis 206 6.2.2. Integrin αvβ3 dependent cellular uptake imaging 208 6.2.3. siRNA transfection. 209 6.2.4. Flow cytometry 210 6.2.5. HPLC determination of caspase-mediated activation 210 6.2.6. MTT cytotoxicity assay 211 6.2.7. Western blots 211 6.2.8. Caspase-3 cellular activity assay 212 6.2.9. Cellular caspase-3 stain 213 6.2.10. Animal study 213 6.2.11. Statistical analysis 214 6.3. Results 214 6.3.1. Synthesis of RGDEVD-DOX 214 6.3.2. Integrin αvβ3 dependent cellular uptake of RGDEVD peptide 214 6.3.2. Caspase-3-mediated cleavage of RGDEVD-DOX 216 6.3.3. In vitro efficacy of RGDEVD-DOX 216 6.3.4. Caspase-3 upregulation induced by RGDEVD-DOX 217 6.3.5. Tumor growth suppression of RGDEVD-DOX 219 6.4. Discussion 238 6.5. Conclusion 240 References 240 Concluding remarks 243Docto

헤파린 타우로콜릭산의 신생혈관형성 억제 메커니즘의 규명

Thesis(masters) --서울대학교 대학원 :제약학과(물리약학전공),2010.2.Maste

Study on charge detection in GaAs quantum dot

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Optimal algorithms for finding the α-kernel and the minimum α for the existence of the α-kernel in a simple polygon

학위논문(석사) - 한국과학기술원 : 전산학과, 1993.2, [ [ii], 29, [4] p. ]한국과학기술원 : 전산학과

A Novel Series-resistance Extraction Method for Nano-scaled nMOSFETs Considering Mobility Degradation due to Vbs

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