京都大学 / 新制・課程博士 / 博士(医学) / 甲第24487号 / 医博第4929号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 上野 英樹, 教授 髙折 晃史 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

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Partial discharge measurement is a common method for monitoring and diagnostics of power transformers, and can detect insulation malfunctions before they lead to failure. Different parameters extracted from the measured PD activity can be correlated to the PD source, and as a result it is possible to identify the PD source by analyzing the PD activity. In this thesis, possible defects that could cause harmful PDs in transformers were investigated. These defects include corona in oil, a void in pressboard, a metal object at floating potential, surface discharge in oil, a free bubble in oil and small free metallic particles in oil. The characteristics of disturbing discharge sources were analyzed, like corona in air, surface discharge in air, and discharge from an unearthed object near to the test setup. The PD activity was recorded both in the time domain and phase domain, and possible characteristics for each PD pattern and waveform were extracted in order to find the best characteristic for the purpose of classification. The results show that in the phase domain parameters such as phase of occurrence, repetition rate and shape of PD Pattern are most suitable for classification while magnitude of discharge can only be useful in specific cases. The results show that the PD waveforms correlated to different defects are similar; however the time domain data include all the information from the phase domain, and also has the power to identify the number of PD sources.  The PD dependency on temperature was investigated on the four test objects including surface discharges in oil, corona in oil, bubble discharges in oil, and metal object at floating potential. The effect of humidity was investigated for corona in oil. The results show that at higher temperature the corona activity in oil and PD activity due to a metal object at floating potential in oil decrease. However, for a bubble in oil and for surface discharge in oil the PD activity increases with the increase of the oil temperature. It was shown that the amount of moisture in oil has a strong impact on number of corona pulses in oil. The last part focused on ageing of oil-impregnated paper due to PD activity. Investigation was made of the behavior of PD activity and its corresponding parameters such as PD repetition rate and magnitude, from inception until complete puncture breakdown. The results show that both the number and magnitude of PD increase over time until they reach to a peak value. After this point over time both curves decrease slowly, and eventually full breakdown occurs. The effect of thermal ageing of oil impregnated paper on time to breakdown and PD parameters was investigated. The results show that thermal aging of oil-impregnated paper increases the number and magnitude of PD. Dielectric spectroscopy was performed on the samples before and after PD ageing and the result was used in order to explain the behavior of PD over time. / <p>QC 20121129</p>

Participatory design approach emphasizes user involvement to contribute to interactive systems throughout the design process. The potential user participates in many activities in different physical meetings and workshops. This approach helps the designers to develop better tools to support users work but it is difficult to get them to co-design at the same place and time for many reasons. I have also experienced this kind of difficulty in the school projects involving users in the design process. Many new technologies nowadays have been introduced and used for different purposes so I have asked myself how I can use this to get control over this kind of difficulty. And how to bring people together online to co- design instead of having any physical workshops. Today, many online technologies are used to facilitate PD activities and bring the potential users together regardless of time and space. Some researchers have investigated online media platforms that people are familiar with, for example Facebook to reach their users. Some of them use online tools developed for conducting participatory design online.This study investigates how to design remote/online meeting formats to engage people with different media habits in the early stages of participatory design to get inspiration for redesigning a website. It is very important for a participatory design at a distance to understand and adapt to individual media habits and technological skills because this aspect is crucial for the success of bringing the participants together online and persuade them to contribute including making them willing to involve and perform their online work tasks. The project facilitator should get to know already in the beginning of the project about different communication ways that each participant prefers and usually uses in their daily life. To make sure that the facilitator can reach the potential users and bring them to collaborate online and give their contribution to a design in time. This study shows also that the relation between the participants and the temple or the facilitator is crucial for the success of getting them to contribute. Another aspect that the facilitator needs to take into account is to know about the users’ technological background. This can be used as basic information to choose online tools or media platforms to design online meeting formats to engage people in the design process. The tools that match the participants’ skills make them focus more on their work tasks rather than technical issues. But even if someone has high computer skills, it does not mean that he wants to work with whatever tools in some online activities, the facilitator has to adapt according to what they prefer or give them choices and flexibility. In addition, it is not enough only to observe and provide different channels for the participants to get feedback. It is hard to observe people working online and not everyone says what they think to the facilitator. To know how the users interact with and think about different online meeting formats during the design project by doing feedback interview after each PD stage helps the facilitator to improve online meeting formats for the next steps. The facilitator gets possibilities to repeat and clarify some issues during the project, encourages the participant to continue or contribute more, and prepares them for the next steps. The participants get better understanding of the project and motivation to move on.

A partial discharge (PD) is the dissipation of energy caused by the buildup of localized electric field intensity. In high voltage devices such as transformers, this buildup of charge and its release can be symptomatic of problems associated with aging, such as floating components and insulation breakdown. This is why PD detection is used in power systems to monitor the state of health of high voltage transformers. If such problems are not detected and repaired, the strength and frequency of PDs increases and eventually leads to the catastrophic failure of the transformer, which can cause external equipment damage, fires and loss of revenue due to an unscheduled outage. Reliable online PD detection is a critical need for power companies to improve personnel safety and decrease the potential for loss of service. The PD phenomenon is manifested in a variety of physically observable signals including electric and acoustic pulses and is currently detected using a host of exterior measurement techniques. These techniques include electrical lead tapping and piezoelectric transducer (PZT) based acoustic detection. Many modern systems use a combination of these techniques because electrical detection is an older and proven technology and acoustic detection allows for the source to be located when several sensors are mounted to the exterior of the tank. However, if an acoustic sensor could be placed inside the tank, not only would acoustic detection be easier due to the increased signal amplitude and elimination of multipath interference, but positioning could also be performed with more accuracy in a shorter time. This thesis presents a fiber optic acoustic sensing system design that can be used to detect and locate PD sources within a high voltage transformer. The system is based on an optical acoustic (OA) sensor that is capable of surviving the harsh environment of the transformer interior while not compromising the transformer's functionality, which allows for online detection and positioning. This thesis presents the theoretical functionality and experimental validation of a band-limited OA sensor with a usable range of 100-300 kHz, which is consistent with the frequency content of an acoustic pulse caused by a PD event. It also presents a positioning system using the time difference of arrival (TDOA) of the acoustic pulse with respect to four sensors that is capable of reporting the three-dimensional position of a PD to within ±5cm on any axis. / Master of Science

Power transformers are one of the most important components in the electrical energy network. Extending transformer life is very economically valuable due to power outage. Therefore the development of instruments to monitor the transformer condition is of great interest. Detection of partial discharges (PDs) in power transformers is an effective diagnostic because it may reveal and quantify an important aging factor and provide information on the condition of the transformer. However, partial discharge diagnostics are still not effectively used for online monitoring of transformers because of the complexity of PD measurements and difficulties of discriminating of PDs and other noise sources. This thesis presents a further study of detection and location of partial discharges in power transformers based on previous work conducted at the Center for Photonics Technology (CPT) at Virginia Tech. The detection and positioning system consists of multiple extrinsic Fabry-Parot interferometric (EFPI) fiber acoustic sensors which can survive the harsh environment of oil-filled transformers. This thesis work is focused on optimal arrangement of multiple sensors to monitor and locate PD activities in a power transformer. This includes the following aspects. First, the sensor design requirements are discussed in order to successfully detect and accurately position the PD sources. In the following sections, Finite Element Method (FEM) is used to model the EFPI sensor fabricated at CPT. Experiments were conducted to measure the angular dependence of the frequency response of the sensor. It is shown that within the range of ±45º incident angles, the sensitivity varies by 3-5dB. Finally, the thesis demonstrates a PD positioning experiment in a 500 gallon water tank (R à H = 74" à 30" cylinder) using a hyperbolic positioning algorithm and time difference of arrival (TDOA). Finally we demonstrated that 100% of the positioning data is bounded by a 22.7à 4.1à 5.3 mm₃ cube, with a sensing range of 810 mm using the leading edge method with FIR filtering. / Master of Science

<p dir="ltr">Immunotherapy has revolutionized the field of oncology. While a lot of antibodies and small molecule inhibitors have been developed for this, a lot of targets remain undruggable in humans.</p><p dir="ltr">Targeted protein degradation has opened a new horizon in drug discovery where we can target these undruggable proteins. Proteolysis targeting chimeras using the ubiquitin-proteasomal system is one of the most popular TPD strategies that complement lysosomal degradation strategies to degrade intracellular proteins, typically using bifunctional small molecule degraders. Recently, large biomolecular and antibody conjugates have been developed for degrading membrane and extracellular proteins in cells, such as lysosomal targeting chimeras (LYTACs) and genetically encoded LYTACS, among several others. However, larger molecules have limitations in penetrating solid tumors. This dissertation work focused on the development of bifunctional small molecule degraders for programmed death-ligand 1 (PD-L1), a transmembrane protein ligand for the immune checkpoint programmed cell death 1 (PD-1). PD-L1 is highly expressed on several tumors, such as triple-negative breast cancer (TNBC), non-small cell lung carcinoma, and renal cancer, and is known to suppress cancer-killing immune cells via interaction with PD-1 on T-cells. In addition, PD-L1 is also present on macrophages in the tumor microenvironments leading to further immune suppression and acquired resistance to anti-PD-1 therapy is associated with the upregulation of alternative immune checkpoints, thereby reducing anti-tumor efficacy. We have designed and synthesized bifunctional small molecules as PD-L1 degraders with different recruiters and linkers guided by computational studies with known PD-1/PD-L1 structures to show both cell surface and total protein degradation in human TNBC cells. In a separate project, we also developed small molecule conjugates to degrade an intracellular integral membrane protein of the endoplasmic reticulum with an unknown 3D structure, namely Diglyceride acyltransferase 2 (DGAT2). Recently, our lab identified DGAT2 as a new target for combating Alzheimer’s disease. Specifically, DGAT2 catalyzes triacylglycerol (TAG) synthesis using diacylglycerol and fatty acyl CoA as substrates. The accumulation of TAGs, mechanistically linked to DGAT2, results in “fat” or lipid droplets (LDs) inside the cells. Our lab showed that microglial cells (resident immune cells in the brain) accumulate LDs in the postmortem brains of human patients and mouse models (5xFAD) of Alzheimer’s disease and that the LD accumulation is driven by amyloid-beta (Ab) – a hallmark of Alzheimer’s disease – via DGAT2 pathway. Further, these LD-laden microglia have phagocytic defects and are spared Aβ thereby affecting plaque accumulation and clearance. Inhibiting DGAT2 reduces the amount of TAG in the brain, which in turn reduces LDs and restores microglial ability to phagocytose Ab. However, commercially available DGAT2 inhibitors were unable to reduce LD load in older 5xFAD mice. Using AlphaFold’s models of DGAT2, we designed and identified sites to synthesize bifunctional DGAT2 degraders that resulted in reduced LDs in mouse primary microglial cells and enhanced phagocytosis of Aβ plaques in vivo in aged 5xFAD mice. Our approach shows a framework to develop bifunctional small molecule degraders for membrane proteins to potentially combat immune dysregulation in chronic diseases.</p>