標的抗原ヒトP-cadherinの機能解析と抗体医薬設計

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 津本 浩平, 東京大学教授 浜窪 隆雄, 東京大学教授 長棟 輝行, 東京大学教授 山東 信介, 東京大学講師 鈴木 健夫University of Tokyo(東京大学

The Effectiveness of Semi-Supervised Learning Techniques in Identifying Calcifications in X-ray Mammography and the Impact of Different Classification Probabilities

Identifying calcifications in mammograms is crucial for early breast cancer detection, and semi-supervised learning, which utilizes a small dataset for supervised learning combined with deep learning, is anticipated to be an effective approach for automating this identification process. This study explored the impact of semi-supervised learning on identifying mammographic calcifications by including 712 mammographic images from 252 patients in public datasets. Initially, 212 mammogram images were segmented into patches and classified visually for calcification presence. A subset of these patches, derived from 169 mammogram images, was used to train a ResNet50-based classifier. The classifier was evaluated using patches generated from 43 mammograms as a test data set. Additionally, 500 more mammogram images were processed into patches and analyzed using the trained ResNet50 model, with semi-supervised learning applied to patches exceeding certain classification probabilities. This process aimed to enhance the classifier’s accuracy and achieve improvements over the initial model. The findings indicated that semi-supervised learning significantly benefits the accuracy of calcification detection in mammography, underscoring its utility in enhancing diagnostic methodologies

Peptide-Catalyzed Diastereo- and Enantioselective Cyclopropanation of Aromatic α,β-Unsaturated Aldehydes

Highly diastereo- and enantioselective cyclopropanation of aromatic α,β-unsaturated aldehydes was achieved using a resin-supported peptide catalyst under aqueous conditions. In the peptide sequence, the residue possessing an oxygen atom with the appropriate length of the side chain was essential for attaining good diastereoselectivity

Characterization of a Radical <i>S</i>‑Adenosyl‑l‑methionine Epimerase, NeoN, in the Last Step of Neomycin B Biosynthesis

The last step of neo­mycin biosynthesis is the epimer­ization at C-5‴ of neo­mycin C to give neo­mycin B. A candidate enzyme responsible for the epimer­ization was a putative radical <i>S</i>-adenosyl-l-methionine (SAM) enzyme, NeoN, which is uniquely encoded in the neo­mycin biosynthetic gene cluster and remained an unassigned protein in the neo­mycin biosynthesis. The reconstituted and reduced NeoN showed the expected epimer­ization activity in the presence of SAM. In the epimer­ization, 1 equiv of SAM was consumed to convert neo­mycin C into neo­mycin B. The site of neo­mycin C reactive toward epimer­ization was clearly confirmed to be C-5‴ by detecting the incorporation of a deuterium atom from the deuterium oxide-based buffer solution. Further, alanine scanning of the NeoN cysteine residues revealed that C249 is a critical amino acid residue that provides a hydrogen atom to complete the epimer­ization. Furthermore, electron paramagnetic resonance analysis of the C249A variant in the presence of SAM and neo­mycin C revealed that a radical intermediate is generated at the C-5‴ of neo­mycin C. Therefore, the present study clearly illustrates that the epimer­ization of neo­mycin C to neo­mycin B is catalyzed by a unique radical SAM epimerase NeoN with a radical reaction mechanism

Relationship between sacral‐abdominal wall distance and grip strength in postmenopausal osteoporotic patients

Abstract Background An increase in waist circumference (WC) is a factor in lifestyle‐related diseases. The rectus abdominis muscle is a skeletal muscle that attaches to the pelvis from the xiphoid process and is thought to be affected by kyphosis deformity and posterior pelvic tilt. The purpose of this study is to examine differences between sacral‐abdominal wall distance (SAD) and WC and to determine whether they are associated with fall risk, frailty, markers of sarcopenia (grip strength and lean body mass), and spinal alignment. A secondary objective is to examine these differences by stratification by grip strength. Methods This retrospective study included 239 women aged 65 years or older (mean age 76.5 ± 6.7 years) attending an outpatient osteoporosis clinic. Bone mineral density and skeletal body composition (muscle mass index and trunk lean mass) were measured using dual‐energy X‐ray absorptiometry. SAD, pelvic tilt, and sagittal longitudinal axis were measured from simple X‐ray images of the spine sides. WC, grip strength, frailty, and fall risk score were investigated. Statistics were performed using Stat Flex, with two‐sided P < 0.05 being significantly different. Results WC was correlated with SAD (R = 0.68, P < 0.001). The SAD cut‐off value for a WC of 90 cm was 167 mm. The relationship between grip strength, SAD, and WC, weaker grip strength was associated with greater SAD; however, no significant difference was noted in WC. WC was not correlated with pelvic alignment but was correlated with body mass index (P < 0.01). Meanwhile, SAD was correlated with body mass index, pelvic tilt, sagittal longitudinal axis (P < 0.01), spinal alignment, and WC. Logistic regression analysis was performed with a grip strength of less than 18 kg as the objective variable. We found that the conditions for a grip strength of less than 18 kg were older age (P < 0.001), increased SAD (P = 0.02), and decreased trunk lean body mass. There was a decrease in grip strength (P < 0.05) and an increase in frailty (P < 0.05) and falls (P < 0.01) score in patients with SAD of 167 mm or greater. Conclusions SAD and WC were found to be correlated; SAD was associated with body weight, posterior pelvic tilt, and anterior spinal tilt deformity, while WC was related to body weight. Increased SAD was found to be linked with decreased grip strength and increased risk of falls. This study was the first to examine a new measurement, SAD, for its utility in assessing grip strength, spinal alignment, frailty, and fall risk

Longitudinal Verification of Post-Nuclear Accident Food Regulations in Japan Focusing on Wild Vegetables

Focusing on the importance of wild vegetables for local residents, this study aims to validate the effects of food regulations under the current criteria (e.g., 100 Bq/kg for general foods) established approximately a year after the Fukushima Dai-ichi Nuclear Power Plant accident. Over 2,500,000 monitoring tests were performed under the criteria until fiscal year (FY) 2020. We estimated changes in internal exposure dose using test results. The effective dose was estimated using the radioactive concentration randomly sampled from the results, food intake, and dose conversion factor. As a new attempt, dose estimation reflecting the intake of wild vegetables that may have irreplaceable value for local residents was conducted. The median, 95th, and 99th percentile of the estimated dose without reflecting the wild vegetables&rsquo; intake were 0.0485, 0.183, and 10.6 mSv/year, respectively, in the estimation with all test results (no regulation) and 0.0431, 0.0786, and 0.236 mSv/year, respectively, in the estimation with results within the standard limits (regulated) in FY2012. These doses decreased with time. Although estimated doses with or without the reflection of wild vegetables&rsquo; intake were similar, estimation that is more plausible is possible, particularly for a high percentile, by reflecting the wild vegetables&rsquo; intake. Radiation doses (regulated) were significantly less than 1 mSv/year in different FYs. In Japan, food regulation measures benefit food safety

Abstract Number ‐ 59: Study on Rupture Prediction Model for Small Unruptured Cerebral Aneurysms Using Random Forest

Introduction Hemodynamic, morphological, and clinical factors have been reported to be involved in aneurysm rupture. Hemodynamic factors could be calculated by computational fluid dynamics (CFD) analysis. In addition, machine learning has been used in various medical fields in recent years, and it is expected to be applicable to the prediction of aneurysm rupture. In this study, we built a rupture prediction model for the small aneurysms (3∼10 mm) using Random Forest, which is one of the machine learning algorithms. This model included hemodynamic parameters from CFD simulations, morphological parameters of each aneurysm, and clinical information. The model was applied to the other patient dataset, and we verified the model’s prediction accuracy. Methods In this study, the ruptured case was defined as an aneurysm that ruptured during the follow‐up term. On the other hand, the unruptured case was defined as an aneurysm that remained stable during the follow‐up for more than two years (average follow‐up term is about nine years), and registered in the database of Jikei Hospital between January 1, 2003 and April 30, 2020. Only small aneurysms (3∼10 mm) were considered in the present study. Based on the criteria, we identified 507 aneurysms (ruptured: 41, unruptured: 466), in which CFD analysis has been completed. Among these aneurysms, 405 aneurysms (ruptured: 32, unruptured: 373) were used to build the rupture prediction model as Training data, and 102 aneurysms (ruptured: 9, unruptured: 93) were used to verify the prediction accuracy as Test data. We used 3‐dimensional arterial geometries that were reconstructed from computed tomography angiography images for conducting CFD simulations and morphological measurements. For the ruptured aneurysms, the image acquired before the rupture was used. We obtained 138 hemodynamic parameters, 7 morphological parameters, and 6 clinical information in each case. From the Training data, we proposed the rupture prediction model with these parameters using Random Forest. Then, we introduced the test data into the model, and its sensitivity and specificity were estimated. Results The sensitivity and specificity of this model for the Test data were 88.9% and 83.9%, respectively. In addition, aspect ratio (AR), the maximum height of the cerebral aneurysm (Hmax), and the spatially maximum values of the oscillatory shear index on the aneurysm wall (OSImax) were obtained as the top three of the important features to predict aneurysm rupture. Furthermore, the values of these parameters of ruptured aneurysms are higher than those of unruptured aneurysms. For unruptured and ruptured cases, average AR were 0.770±0.260 [‐] and 1.02±0.382 [‐], average Hmax were 3.39±1.22 [mm] and 4.96±1.96 [mm], and average OSImax were 0.399±0.105 [‐] and 0.460±0.0328 [‐], respectively. These results imply that cerebral aneurysms with high Hmax, high AR, and high OSImax are more likely to rupture. Conclusions Ruptured aneurysms tend to have high AR, high Hmax, and high OSImax. The sensitivity and specificity of our prediction model were 88.9% and 83.9%, respectively. The rupture prediction model obtained from this study may predict the aneurysm rupture in advance

Estimation of Effect of Radiation Dose Reduction for Internal Exposure by Food Regulations under the Current Criteria for Radionuclides in Foodstuff in Japan Using Monitoring Results

This study examined the effect of food regulations under the current criteria (e.g., 100 Bq/kg for general foods) established approximately a year after the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. Foods are monitored to ensure that foods exceeding the standard limit are not distributed; ~300,000 examinations per year have been performed especially since FY2014. This study comprehensively estimated the internal exposure dose resulting from the ingestion of foods containing radioactive cesium using the accumulated monitoring results. Committed effective dose was conservatively calculated as the product of the radioactive concentration randomly sampled from test results, food intake, and dose coefficient. The median, 95th, and 99th percentile of the dose were 0.0479, 0.207, and 10.6 mSv/y, respectively, in the estimation with all test results (without regulation), and 0.0430, 0.0790, and 0.233 mSv/y, respectively, in the estimation with results within the standard limits (with regulation) in FY2012. In FY2016, the dose with and without regulation were similar, except for high percentile, and those doses were significantly smaller than 1 mSv/y, which was adopted as the basis for the current criteria. The food regulation measures implemented in Japan after the FDNPP accident have been beneficial, and food safety against radionuclides has been ensured

Estimation of Effect of Radiation Dose Reduction for Internal Exposure by Food Regulations under the Current Criteria for Radionuclides in Foodstuff in Japan Using Monitoring Results

This study examined the effect of food regulations under the current criteria (e.g., 100 Bq/kg for general foods) established approximately a year after the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. Foods are monitored to ensure that foods exceeding the standard limit are not distributed; ~300,000 examinations per year have been performed especially since FY2014. This study comprehensively estimated the internal exposure dose resulting from the ingestion of foods containing radioactive cesium using the accumulated monitoring results. Committed effective dose was conservatively calculated as the product of the radioactive concentration randomly sampled from test results, food intake, and dose coefficient. The median, 95th, and 99th percentile of the dose were 0.0479, 0.207, and 10.6 mSv/y, respectively, in the estimation with all test results (without regulation), and 0.0430, 0.0790, and 0.233 mSv/y, respectively, in the estimation with results within the standard limits (with regulation) in FY2012. In FY2016, the dose with and without regulation were similar, except for high percentile, and those doses were significantly smaller than 1 mSv/y, which was adopted as the basis for the current criteria. The food regulation measures implemented in Japan after the FDNPP accident have been beneficial, and food safety against radionuclides has been ensured