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Generalized pustular psoriasis (GPP) is a rare form of psoriasis, which is characterized by sudden onset of repeated erythema and pustule formation with generalized inflammation. Recent advances in molecular genetics have led to the identification of several genes associated with GPP, including IL36RN, CARD14, AP1S3, SERPINA3, and MPO. Of these, only limited cases of GPP have been reported to carry mutations in the AP1S3, SERPINA3, or MPO to date. In the present study, we investigated a Japanese patient with GPP and found a bi-allelic missense mutation c.1769G>T (p.Arg590Leu) in the MPO gene. Structural analysis predicted that the mutant MPO protein would abolish its ability to bind with heme protein. In vitro studies using cultured cells revealed that the mutant MPO was stably expressed, but completely lost its myeloperoxidase activity. Immunohistochemistry (IHC) using an anti-MPO antibody showed markedly-reduced expression of MPO protein in the patient’s skin, suggesting that the mutation would lead to an instability of the MPO protein in vivo. Finally, IHC with an anti-citrullinated Histone H3 antibody demonstrated a sparse formation of neutrophil extracellular traps within a Kogoj's spongiform pustule of the patient’s skin. Collectively, we conclude that the c.1769G>T (p.Arg590Leu) in the MPO is a complete loss-of-function mutation associated with GPP in the patient. Our data further underscore critical roles of the MPO gene in the pathogenesis of GPP.

Objective: Anastomotic leakage is a common and severe complication of esophageal reconstruction. Accordingly, there is a clinical need for novel methods to prevent it. We developed multilayered, growth factor-secreting fibroblast sheets that promote wound healing and angiogenesis. The present study aimed to assess the utility of allogenic multilayered fibroblast sheets in preventing esophageal anastomotic leakage in a rat model of esophageal reconstruction. Methods: Allogenic multilayered fibroblast sheets prepared from oral mucosal tissues were implanted at esophageal anastomotic sites. Results: The allogenic multilayered fibroblast sheet group had significantly higher burst pressure and collagen deposition compared to a control group five days postoperatively. The expression levels of collagen type I and III mRNAs around esophageal suture sites were higher in the allogenic multilayered fibroblast sheet group compared to the control group on postoperative days 0, 3, and 5. There was a trend toward lower anastomotic leakage and lower abscess scores in the allogenic multilayered fibroblast sheet group compared to the control group; however, these differences did not reach statistical significance. Allogenic multilayered fibroblast sheets completely disappeared at ten days after implantation. Further, no inflammation was observed at suture sites with implanted allogenic multilayered fibroblast sheets at five days after surgery. Conclusion: Allogenic multilayered fibroblast sheets may represent a promising method of preventing esophageal anastomotic leakage.

Many mail filtering methods have been proposed, but they have not yet achieved perfect filtering. One of the reasons for this is the influence of modified words created by spammers to slip through the mail filtering, in which words are modified by insert symbols, spaces, HTML tags, etc. For example,“ price$ for be$t drug$! ”，“ priceC I A L I S ”， “ <font>se</font>xu<font>al</font> ”, etc. These are frequently replaced with new strings by changing the combination of symbols ,HTML tags etc. Mail filtering is a technique that captures trends in words in training mails (mails received in the past) and applies these trends to words in test mails (newly received emails). Some of the above modified words appear in both training and test mails, i.e., words that could be used as features of spam mail by using them unprocessed, while others appear only in test mails, i.e., words that have not been learned and require special processing (e.g., removal of symbols, search for similar words, etc.) for their use. However, existing methods do not make these distinctions and treat them in the same way. Therefore, in order to bring the filtering performance of the existing methods closer to perfect filtering, we developed a method in which the above modified words are separated into words that appear in both training and test mails and words that appear only in test mails, and each of these words is used for mail filtering. In this study, we treat the above modified words as ”strange words”. Typical examples of such strange words include, in addition to the above, new words included in ham mails, proper nouns used in close relationships, and abbreviations. The results of this study are as follows (1) In order to compare the filtering performance between strange words and other words, filtering experiments were conducted using existing methods with strange words, nouns, verbs, and adjectives. The results showed that the filtering performance of the strange words was the best. This means that strange words have a significant impact on the filtering performance, and we expect to improve the filtering performance of existing methods by developing a new method to utilize strange words. (2) In order to examine the breakdown of strange words, we counted the number of words that appeared in both training and test mails, and the number of words that appeared only in test mails. The results were compared with those obtained for nouns, verbs and adjectives. We found that there are a significant number of strange words that appear in both training and test mails, but only in one of the groups, i.e., ham or spam mail. Words with this appearance pattern are most useful for mail filtering. On the other hand, we found that there are many strange words that appear only in test mails, i.e., words that cannot be learned. We expect to improve the filtering performance by separating these strange words and developing a new method to use each of them. (3) For the use of strange words, we developed (A) a method for using words that appear in both training and test mails, and (B) a method for using words that appear only in test mails, respectively. (A) To examine the breakdown of strange words that appear in both training and test mails, we divided them into two categories: words that appear only in ham and spam mails, i.e., words with patterns that improve filtering performance, and words that do not, and examined their frequency of occurrence. The results showed that the words with appearance patterns that improve filtering performance tend to appear more frequently than those without such patterns. This means that by using words with a certain number of occurrences in filtering, it is possible to use more words that improve filtering performance. We developed a method to do this and conducted experiments with different threshold values to find the optimal value, and confirmed that setting the threshold around 7 improves filtering performance. (B) We compared the number of strange words that appear only in the test mails between ham and spam mails, and found that the number tends to be higher in spam mail than in ham mail. In order to utilize this difference for filtering, we proposed a method to set a uniform spam probability for strange words that appear only in the test mails, and attempted to find the optimal spam probability. As a result, setting the spam probability to 0.7 improved the filtering accuracy from 98.2% to 98.9%. By using (A) and (B) above together, both words that appear in both training and test mails and words that appear only in test mails can be used for mail filtering to increase accuracy. Mail filtering has been improved and its performance has reached its limit. In order to further improve accuracy, i.e., to approach perfect filtering, a new perspective is needed, and this paper provides one such perspective: the use of strange words. This paper is organized as follows. In Chapter 1, we review the background of mail filtering methods, discuss how spammers use strange words to slip through such filters. The purpose and structure of this paper are then presented. In Chapter 2, we will discuss related research on examples of filtering methods that have been proposed so far are given. In Chapter 3, we describe the mail datasets, word handling, and strange words used in the this paper. This is followed by an explanation of the ROC curve, which is the measure used to evaluate the filtering performance, and explanation of scatter plots and box-and-whisker plots. In Chapter 4, we compare the filtering performance between strange words and other words, and show that strange words have a significant impact on the filtering performance. Furthermore, based on the results of a breakdown of the number of strange words, we discuss the possibility of improving filtering performance by separating words that appear in both training and test mails from those that appear only in the test mails. We will work on this in the next chapters and report the results. In Chapter 5, we develop a method to use (A) above, i.e., strange words that appear in both training and test mails. From the results of counting the number of words used in the subject and body of each email, we show that the number tends to be smaller for words that degrade the filtering performance. Based on these results, we propose a method that sets a threshold for the number of words used in the subject and body of mails, and uses only those words that exceed the threshold for classification. Experiments are conducted to find the optimal value by varying the threshold, and the effect of this method on performance is reported. In Chapter 6, we develop a method to use (B) above, i.e., strange words that appear only in the test mails. We compare the number of types of these words in ham and spam mails, and show that the number tends to be larger in spam mails, and that this feature can be used as a bias for detecting spam mails. In this paper, we deal with experiments using bsfilter and develop a method to set spam probabilities uniformly for strange words that appear only in the test mails. After searching for the optimal spam probability, we report that a spam probability of 0.7 greatly improves the filtering performance. In Chapter 7, we describes the processing flow combining the methods developed in Chapter 5 and Chapter 6. The paper is then summarized, including future prospects.

Steel truss bridges, which are one of the bridge structures applicable to long spans, are widely used as marine bridges connecting mainland and remote island. Since such steel truss bridges are built on the sea, they are exposed to severe corrosive environment due to the influence of airborne salt. In addition, there are many parts where it is not easy to inspect to detect abnormalities, so it is more difficult to eliminate the risk of member damage in such steel truss bridges than in general bridges. On the other hand, once the marine bridges are built, they become an indispensable facility for the life of the island. Therefore, if there are no other traffic routes to access an island, the sustainability of the marine bridge is an important issue that is directly linked to the sustainability of the remote island life. When member damage occurs in a steel truss bridge, it depends on redundancy, which means the margin for the load-bearing capacity and load-bearing function, whether the damage develops into chain damage or remains limited damage. Bridges with redundancy could be restored by repairing even if the member damages occurred, because they did not develop into chain damages. In some cases, vehicles could pass through with traffic restrictions. Although redundancy is an important performance for maintaining life on remote islands that have no alternative traffic routes, there are few studies on evaluation and improvement methods of redundancy for long steel truss bridges used for marine bridges. The purpose of this study is to propose a method for improving the redundancy of long steel truss bridges, and three research subjects are set to achieve this purpose. The first study subject is the investigation of the effect of truss joint modeling on redundancy evaluation, and is the subject to appropriately evaluate the redundancy of steel truss bridges. The second is also the subject related to the redundancy evaluation of steel truss bridges, and is the development of dynamic response calculation method that considers the vibration characteristics of steel truss bridges, which are vibration systems with multiple degrees of freedom. The third study subject is a proposal for methods to improve the redundancy of long steel truss bridges. This paper consists of five chapters. Chapter 1 is an introduction, and describes the background of the research, the setting of the purpose and research subjects, and the previous studies. Chapter 2 describes the study on the modeling of the truss joint. In the analysis of healthy steel truss bridges with no member damage, the sectional forces can be calculated appropriately even with analysis modeling in which frame elements of truss members are rigidly connected at the truss joints, simply. On the other hand, in the redundancy analysis of steel truss bridges with member damages, it is shown that it is necessary to consider the shape of the gusset plates at the truss joints in analysis modeling. Chapter 3 describes the study on the calculation method of dynamic response caused by damage of truss members. There are cases where the dynamic response due to member damage is calculated in the same way as a single-degree-of-freedom vibration system. However, this study develops a dynamic response calculation method considering the vibration characteristics of long steel truss bridges by using the eigenvector of steel truss bridges with member damage. A method is proposed to set the magnitude of the eigenvector using balance equation of the work given to the steel truss bridge by the sectional force unloaded from damaged member and the strain energy stored in the steel truss bridge. In addition, a method is proposed to calculate the dynamic response by setting the range of vibration modes using the sum of effective mass ratio, and selecting the eigenvector that has the greatest effect on the dynamic response for each member. It is shown that the proposed calculation method gives redundancy evaluation closer to time-history-response analysis than the method that calculates the dynamic response in the same way as a single-degree-offreedom vibration system. Chapter 4 describes the study on redundancy improvement for a long steel truss bridge. A combination of the countermeasure against members that trigger chain damage and the countermeasure against members with insufficient load-bearing capacity is planned. Analysis clarifies that the X bracing, which is a reinforcing structure in X shape, is an efficient reinforcement that works against multiple member damage cases as the countermeasure against the trigger member of member chain damage. Also, the load-bearing capacity is verified by a loading test of specimens with reinforced structures. Since the subject bridge has 18 truss panels where X bracing can be installed, the placement patterns were examined by the optimization method. It is clarified that the weight of reinforcing material can be reduced by installing X-braces only at four truss panels in the alternating areas, rather than installing at all 18 truss panels. Chapter 5 describes the summary of this study and future developments.

キメラ抗原受容体(CAR)-T細胞療法は造血器腫瘍において優れた抗腫瘍効果を示している一方、固形がんにおいては臨床応用がまだなされていない。臨床応用におけるハードルとなっている理由の一つとして、固形がんでは適切なCAR ターゲットが欠如しているということにある。GM2 は糖鎖にシアル酸を有するスフィンゴ糖脂質の一群であるガングリオシドの一つであり、様々なタイプの固形がんにおいて過剰発現している。本研究では、我々が以前に開発したインターロイキン7(IL-7)/ケモカインリガンド19(CCL19)産生型ヒトCAR-T細胞システムを用いて、GM2が固形腫瘍に対するCART細胞療法のターゲットとなりうるかという点についてヒト肺小細胞がん異種移植マウスモデルを用いて探究した。IL-7/CCL19 産生型抗GM2 CAR-T細胞治療を行ったところ、GM2 陽性腫瘍の完全な退縮が観察され、腫瘍内部への豊富なT 細胞浸潤や長期のメモリー応答形成も観察されたが、有害事象は認めなかった。加えて、臨床においてCAR-T 細胞使用時に問題となるサイトカイン放出症候群や神経毒性をコントロールする方法として、ガンシクロビル(GCV)投与によりアポトーシスが誘導される自殺システムである単純ヘルペスウイルス-チミジンキナーゼ(HSV-TK)をCAR-T細胞に遺伝子導入した。HSV-TK発現IL-7/CCL19産生型抗GM2 CAR-T細胞は、in vivoにおいてGCV投与により効果的に除去された。以上より、我々の研究はIL-7/CCL19産生型ヒト抗GM2CAR-T細胞のGM2陽性固形がん治療への臨床応用における安全性を実証し、その有望な治療効果を明らかにした。